SIG1

SIG1
Query
Query
O H N
Results
Date
1. Query
HO
ALK
97 reactions
2012-01-31 07h:06m:04s (EST)
Search as: Product, As drawn, No salts, No mixtures, No isotopes, No radicals
Copyright 2012 Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys is a trademark owned and protected by Elsevier Properties SA and used under license.
1/47
2012-01-31 07:06:55
SIG1
H N
HO
OH O
H N
O O Cl H
HO
HO
Rx-ID: 3821891 View in Reaxys 1/97 Yield 100 % Conditions & References Example Name 90.1 Example Title Preparation of 1-(3,4-dimethoxy-5-trifluoromethylthiobenzoyl)-4S-fluoropyrrolidine-2R-carboxylic acid hydroxyamide; Step 1 To a stirred solution [OF 4R-HYDROXYPYRROLIDINE-2R-CARBOXYLIC] acid (10.0 g, 76.3 mmol, [1] eq. ) in [MEOH] (300 mL) at [0 .deg.C] was added SOC12 (10.0 mL, excess) over the course of 1.5 min. The reaction was allowed to warm to [23 .deg.C.] After 16 h the reaction mixture was concentrated in vacuo to give 4R-hydroxypyrrolidine-2Rcarboxylic acid methyl ester hydrochloride salt as a white solid (15.9 g, 100percent yield) With thionyl chloride in methanol, Time= 16.025h, T= 0 - 23 C Patent; VICURON PHARMACEUTICALS, INC.; WO2004/7444; (2004); (A2) English View in Reaxys 99 % With thionyl chloride, 1.) RT, 1 h, 2.) reflux, 22 h Lin, Chun-Cheng; Shimazaki, Makoto; Heck, Marie-Pierre; Aoki, Shin; Wang, Ruo; et al.; Journal of the American Chemical Society; vol. 118; nb. 29; (1996); p. 6826 - 6840 View in Reaxys 90 % Example Name 31 To a solution of (2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid 31.1 (1.0 eq) in MeOH (31 eq) at 0 .deg.C was added S0C12 (1.2 eq) dropwise. The reaction solution was stirred at rt for 72 h. The resulting mixture was concentrated in vacuo to afford the compound 31.2 (90percent yield) as a white solid. LCMS (m/z): 146.0 [M+H] +. 1H NMR (400 MHz, DMSO-i/6) 3: 4.44 (d, J = 6.8 Hz, 1H), 4.33 (s, 1H), 3.70 (s, 3H), 3.03-3.00 (m, 1H), 2.30-2.23 (m, 1H), 2.14-2.09 (m, 1H), 1.17 (t, J = 7.2 Hz, 1H). With thionyl chloride, Time= 72h, T= 0 - 20 C Patent; BIOGEN IDEC MA INC.; ERLANSON, Daniel, A.; MARCOTTE, Doug; KUMARAVEL, Gnanasambandam; FAN, Junfa; WANG, Deping; CUERVO, Julio, H.; SILVIAN, Laura; POWELL, Noel; BUI, Minna; HOPKINS, Brian, T.; TAVERAS, Art; GUAN, Bing; CONLON, Patrick; ZHONG, Min; JENKINS, Tracy, J.; SCOTT, Daniel; SUNESIS PHARMACEUTICALS, INC.; LUGOVSKOY, Alexey, A.; WO2011/29046; (2011); (A1) English View in Reaxys With acetyl chloride, Time= 8h, Heating, Yield given Rosen, Terry; Chu, Daniel T. W.; Lico, Isabella M.; Fernandes, Prabhavathi B.; Marsh, Kennan; et al.; Journal of Medicinal Chemistry; vol. 31; nb. 8; (1988); p. 1598 - 1611 View in Reaxys With hydrogenchloride, Esterification Cheng, Menyan; De, Biswanath; Almstead, Neil G.; Pikul, Stanislaw; Dowty, Martin E.; Dietsch, Charles R.; Dunaway, C. Michelle; Gu, Fei; Hsieh, Lily C.; Janusz, Michael J.; Taiwo, Yetunde O.; et al.; Journal of Medicinal Chemistry; vol. 42; nb. 26; (1999); p. 5426 - 5436 View in Reaxys With thionyl chloride, Time= 6h, Heating Marusawa, Hiroshi; Setoi, Hiroyuki; Sawada, Akihiko; Kuroda, Akio; Seki, Jiro; Motoyama, Yukio; Tanaka, Hirokazu; Bioorganic & Medicinal Chemistry; vol. 10; nb. 5; (2002); p. 1399 - 1416 View in Reaxys With thionyl chloride, Time= 6h, T= 20 C , Methylation Merino, Pedro; Anoro, Sonia; Franco, Santiago; Merchan, Francisco L.; Tejero, Tomas; Tunon, Victoria; Journal of Organic Chemistry; vol. 65; nb. 5; (2000); p. 1590 - 1596 View in Reaxys
2/47
2012-01-31 07:06:55
SIG1
With thionyl chloride D'Costa, Moneesha; Kumar, Vaijayanti A.; Ganesh, Krishna N.; Organic Letters; vol. 1; nb. 10; (1999); p. 1513 1516 View in Reaxys With thionyl chloride, T= 0 - 20 C Garrabou, Xavier; Gomez, Livia; Joglar, Jesus; Bujons, Jordi; Clapes, Pere; Gil, Sergi; Parella, Teodor; Chemistry--A European Journal; vol. 16; nb. 35; (2010); p. 10691 - 10706 View in Reaxys With thionyl chloride in methanol, Time= 23h, T= 0 C , Reflux Example Name 1.4.2 [0346] Acetyl chloride (2.45 mL, 34.53mmoles) was slowly added to MeOH (25mL) in a reaction flask under inert atmosphere. To this was added a solution of Cis-4-Hydroxy-D- proline (3.235g, 24.67 mmol) and refluxed for 8h. The reaction mixture was cooled to room temperature, and poured into ether (200mL). The precipitated solid was suction filtered and dried to yield (2R,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride in quantitative yield. This was taken forward without purification. With acetyl chloride, Time= 8h, Inert atmosphere, Reflux Patent; COMENTIS, INC.; BILCER, Geoffrey, M.; LILLY, John, C.; SWANSON, Lisa, M.; WO2011/130383; (2011); (A1) English View in Reaxys
H N
HO
OH O
H N
O O
HO
HO
Rx-ID: 807156 View in Reaxys 2/97 Yield 100 % Conditions & References With thionyl chloride Barrett, Anthony G. M.; Pilipauskas, Daniel; Journal of Organic Chemistry; vol. 55; nb. 18; (1990); p. 5194 - 5196 View in Reaxys 100 % With hydrogenchloride, Heating Zhang, Xiaojun; Schmitt, Aaron C.; Jiang, Wen; Tetrahedron Letters; vol. 42; nb. 32; (2001); p. 5335 - 5338 View in Reaxys 100 % With sulfuric acid, Time= 0.2h, T= 145 C , Flow reactor process, Fischer esterification Tamborini, Lucia; Conti, Paola; Pinto, Andrea; Micheli, Carlo De; Tetrahedron: Asymmetry; vol. 21; nb. 2; (2010); p. 222 - 225 View in Reaxys 100 % Example Name 1.1 Example Title (2S,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)-pyrrolidine-1-carboxylate (8) EXAMPLE 1 (2S,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)-pyrrolidine-1-carboxylate (8) Compound 8 was synthesised from trans-4-hydroxy-L-proline by the reported procedures [Rosen et al., J. Med. Chem. 1988, 31, 1598]. 1H NMR (400 MHz, CDCl ): 0.08 (s, 6H), 0.87 (s, 9H), 1.47 (s, 9H), 1.96 (m, 1H), 1.98 (s, 1H), 3.34 (dd, J=4.0, 14.6 3 Hz, 1H), 3.42 (d, J=12.0 Hz, 1H), 3.55 (m, 1H), 3.71 (m, 1H), 4.11 (m, 1H), 4.27 (m, 1H), 4.91 (dd, J=0.8 Hz, 12.0 Hz, 1H). With thionyl chloride in methanol Patent; Tanaka, Fujie; Barbas, Carlos F.; Zhang, Haile; US2007/117986; (2007); (A1) English View in Reaxys
3/47
2012-01-31 07:06:55
SIG1
99 %
With thionyl chloride, 1.) r.t., 1 h, 2.) reflux, 22 h Mayer, Scott C.; Ramanjulu, Joshi; Vera, Matthew D.; Pfizenmayer, Amy J.; Joullie, Madeleine M.; Journal of Organic Chemistry; vol. 59; nb. 18; (1994); p. 5192 - 5205 View in Reaxys
99 %
With thionyl chloride, Fisher esterification Trabocchi, Andrea; Rolla, Massimo; Menchi, Gloria; Guarna, Antonio; Tetrahedron Letters; vol. 46; nb. 45; (2005); p. 7813 - 7816 View in Reaxys
95 %
With acetyl chloride Rawson, David J.; Brugier, Delphine; Harrison, Anthony; Hough, Jo; Newman, Julie; Otterburn, Joe; Maw, Graham N.; Price, Jenny; Thompson, Lisa R.; Turnpenny, Paul; Warren, Andrew N.; Bioorganic and Medicinal Chemistry Letters; vol. 21; nb. 12; (2011); p. 3771 - 3773 View in Reaxys
93 %
With thionyl chloride Emery, Fabienne; Bisang, Christian; Favre, Michel; Jiang, Luyong; Robinson, John A.; Journal of the Chemical Society, Chemical Communications; nb. 18; (1996); p. 2155 - 2156 View in Reaxys
88 %
With thionyl chloride, acetyl chloride, Time= 4h, T= 40 C Iso, Yasuyoshi; Iroe, Tadashi; Iwaki, Tsutomu; Kii, Makoto; Sando, Yuji; et al.; Journal of Antibiotics; vol. 49; nb. 5; (1996); p. 478 - 484 View in Reaxys
80 %
With hydrogenchloride, Time= 2h, Heating Aldridge, W. Steven; Hornstein, Brooks J.; Serron, Scafford; Dattelbaum, Dana M.; Schoonover, Jon R.; Meyer, Thomas J.; Journal of Organic Chemistry; vol. 71; nb. 14; (2006); p. 5186 - 5190 View in Reaxys
75 %
in thionyl chloride Kemp, D. S.; Curran, Timothy P.; Tetrahedron Letters; vol. 29; nb. 39; (1988); p. 4931 - 4934 View in Reaxys With hydrogenchloride Poroschin et al.; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; (1959); p. 1851; engl. Ausg. S. 1768, 1769 View in Reaxys Smith; Bergmann; Journal of Biological Chemistry; vol. 153; (1944); p. 627,649 View in Reaxys With thionyl chloride Kaname, Mamoru; Yoshifuji, Shigeyuki; Tetrahedron Letters; vol. 33; nb. 52; (1992); p. 8103 - 8104 View in Reaxys Curran, Timothy P.; Chandler, Nicole M.; Kennedy, Robert J.; Keaney, Meghan T.; Tetrahedron Letters; vol. 37; nb. 12; (1996); p. 1933 - 1936 View in Reaxys Qiu, Xiao-Long; Qing, Feng-Ling; Synthesis; nb. 3; (2004); p. 334 - 340 View in Reaxys With thionyl chloride, Yield given Blanco, M. Jesus; Sardina, F. Javier; Tetrahedron Letters; vol. 35; nb. 45; (1994); p. 8493 - 8496 View in Reaxys With hydrogenchloride, Time= 1h, Ambient temperature
4/47
2012-01-31 07:06:55
SIG1
Iso, Yasuyoshi; Irie, Tadashi; Nishino, Yutaka; Motokawa, Kiyoshi; Nishitani, Yasuhiro; Journal of Antibiotics; vol. 49; nb. 2; (1996); p. 199 - 209 View in Reaxys With thionyl chloride, Time= 6h, Heating Sudau, Alexander; Nubbemeyer, Udo; Angewandte Chemie, International Edition in English; vol. 37; nb. 8; (1998); p. 1140 - 1143; Angewandte Chemie; vol. 110; (1998); p. 1178 - 1181 View in Reaxys With thionyl chloride, Time= 3h, T= 0 - 40 C Seno, Kaoru; Okuno, Takayuki; Nishi, Koichi; Murakami, Yasushi; Yamada, Katsutoshi; Nakamato, Shozo; Ono, Takashi; Bioorganic & Medicinal Chemistry Letters; vol. 11; nb. 4; (2001); p. 587 - 590 View in Reaxys With thionyl chloride, Time= 24h, T= 0 - 20 C Cossy, Janine; Mirguet, Olivier; Pardo, Domingo Gomez; Synlett; nb. 10; (2001); p. 1575 - 1577 View in Reaxys Stage 1: With thionyl chloride, Time= 0.5h, T= -10 C Stage 2:T= 20 C Arakawa, Yasushi; Ohnishi, Masafumi; Yoshimura, Norikazu; Yoshifuji, Shigeyuki; Chemical & Pharmaceutical Bulletin; vol. 51; nb. 8; (2003); p. 1015 - 1020 View in Reaxys 14 g With thionyl chloride, Time= 2h, Heating Qiu, Xiao-Long; Qing, Feng-Ling; Journal of Organic Chemistry; vol. 70; nb. 10; (2005); p. 3826 - 3837 View in Reaxys With thionyl chloride, Time= 72h, T= 20 C Roudeau, Remi; Pardo, Domingo Gomez; Cossy, Janine; Tetrahedron; vol. 62; nb. 10; (2006); p. 2388 - 2394 View in Reaxys With thionyl chloride, Time= 6h, T= 0 - 20 C Kamal, Ahmed; Shankaraiah, N.; Devaiah, V.; Reddy, K. Laxma; Tetrahedron Letters; vol. 47; nb. 37; (2006); p. 6553 - 6556 View in Reaxys With thionyl chloride Ishino, Takeru; Oriyama, Takeshi; Chemistry Letters; vol. 36; nb. 4; (2007); p. 550 - 551 View in Reaxys Metro, Thomas-Xavier; Pardo, Domingo Gomez; Cossy, Janine; Journal of Organic Chemistry; vol. 72; nb. 17; (2007); p. 6556 - 6561 View in Reaxys Example Name 13 Example 13 Bis-{2-[(S)-2-methylene-7-methoxy-5-oxo-1,3,,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-8yloxy]-ethyl}-carbamic acid tert-butyl ester Compound 1. Thionyl chloride (5.6 mL, 76.3 mmol) was added dropwise to dry methanol (76 mL) at -20 .deg.C, following by addition of trans-4-hydroxy-L-proline (5.0 g, 38.1 mmol). The resulting mixture was allowed to warm to rt and stirred for 20 h. The solvent was removed under reduced pressure, and the residue was further dried under high vacuum to provide trans-4-hydroxy-L-proline methyl ester 1 as a white solid: 1H-NMR (300 MHz, DMSO-d6) 2.18 - 2.23 (m, 2H), 3.06 (m, 1 H), 3.32 - 3.36 (m, 2H), 3.76 (s, 3H), 4.42 (br. s, 1 H), 4.48 (dd, J = 5.4, 8.1 Hz, 1H), 5.56 (br. s, 1 H); EIMS m/z 146 ([M]++1). With thionyl chloride, Time= 20h, T= -20 - 20 C Patent; Sanofi-Aventis; EP1813614; (2007); (A1) English
5/47
2012-01-31 07:06:55
SIG1
View in Reaxys With thionyl chloride, T= 20 C Kamal, Ahmed; Rajender; Reddy, D. Rajasekhar; Reddy, M. Kashi; Balakishan, G.; Shaik, T. Basha; Chourasia, Mukesh; Sastry, G. Narahari; Bioorganic and Medicinal Chemistry; vol. 17; nb. 4; (2009); p. 1557 - 1572 View in Reaxys With thionyl chloride, T= 0 - 40 C Wang, Chao; Yu, Chun; Liu, Changlu; Peng, Yungui; Tetrahedron Letters; vol. 50; nb. 20; (2009); p. 2363 - 2366 View in Reaxys With thionyl chloride Chiacchio, Ugo; Borrello, Luisa; Crispino, Lia; Rescifina, Antonio; Merino, Pedro; Macchi, Beatrice; Balestrieri, Emanuela; Mastino, Antonio; Piperno, Anna; Romeo, Giovanni; Journal of Medicinal Chemistry; vol. 52; nb. 13; (2009); p. 4054 - 4057 View in Reaxys Intermediate 7: (2S.4R)-l-tert-butyl 2-methyl 4-hydroxypyrrolidine- 1.2-dicarboxylate; H Thionyl chloride (47 g, 0.393 mol) was added drowise at 0 0C to a stirred solution of (2S,4R)-4- hydroxypyrrolidine-2-carboxylic acid (40 g, 0.31 mol) in methanol (200 mL). The reaction was allowed to proceed overnight, methanol removed, the residue redisolved in DCM (200 mL) and the organic phase was washed with 10percent NaHCO3(aq) (50 mL) and brine. Next, i-tert- butyldicarbonate (86.6g, 0.393 mol) and triethylamine (46.3g, 0.46 mol) were added at 00C to the organic phase and stirred overnight at room temperature. The mixture was washed with IN HCl (50 mL) and brine, dried over Na2SO4, concentrated to give (2S,4R)-l-tert-butyl 2-methyl 4- hydroxypyrrolidine- 1 , 2-dicarboxylate (intermediate 7) (46 g, yield: 62percent) as a white solid. 1H NMR (300 MHz, CDCl3) ppm 4.50 (br, IH), 4.39-4.45 (m, IH), 3.74 (s, 3H), 3.65 (m, IH), 2.05-2.32 (m, 3H), 1.43-1.47 (m, 9H) Stage 1: With thionyl chloride, T= 0 C Stage 2: With sodium hydrogencarbonate in dichloromethane, water Patent; GLAXOSMITHKLINE LLC; SCHMITZ, Frank Ulrich; RAI, Roopa; ROBERTS, Christopher Don; KAZMIERSKI, Wieslaw; GRIMES, Richard; WO2010/62821; (2010); (A1) English View in Reaxys
OH
H N
OH O
H N
O O
HO
HO
Rx-ID: 807158 View in Reaxys 3/97 Yield 99 % Conditions & References With hydrogenchloride in water, Time= 16h, Inert atmosphere, Reflux Jarvis, Scott B. D.; Charette, Andre B.; Organic Letters; vol. 13; nb. 15; (2011); p. 3830 - 3833 View in Reaxys 98 % With thionyl chloride, Time= 5h, Heating Curtis, Kim L.; Fawcett, John; Handa, Sandeep; Tetrahedron Letters; vol. 46; nb. 32; (2005); p. 5297 - 5300 View in Reaxys 98 % Example Name 1 Step 1: (2S, 4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid ethyl ester (2); Thionyl chloride (22.2 mL, 0.304 mol) was added dropwise to ethanol (92 mL) at 0.deg.C. 4-Hydroxy-proline 1 or (10 g, 0.076 mol) was added portionwise to that solution at 0.deg.C. The mixture was stirred at 0.deg.C for 5 min and then refluxed for 16 hrs. After completion of the reaction, the solvent was evaporated. The obtained white solid was washed with ether and filtered to yield the titled compound as a white solid (14.70 g, 98 percent). Used in the next step without further purification. With thionyl chloride, Time= 16.0833h, T= 0 C , Heating / reflux Patent; FAUST PHARMACEUTICALS; WO2005/118533; (2005); (A1) English
6/47
2012-01-31 07:06:55
SIG1
View in Reaxys 98 % With thionyl chloride Imaoka, Takuya; Akimoto, Takafumi; Iwamoto, Osamu; Nagasawa, Kazuo; Chemistry - An Asian Journal; vol. 5; nb. 8; (2010); p. 1810 - 1816 View in Reaxys With hydrogenchloride Kapfhammer; Matthes; Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie; vol. 223; (1934); p. 43,51 View in Reaxys With hydrogenchloride, Time= 8h, Ambient temperature, Yield given Ojima, Iwao; Kogure, Tetsuo; Yoda, Noriko; Journal of Organic Chemistry; vol. 45; nb. 23; (1980); p. 4728 - 4739 View in Reaxys With hydrogenchloride, ammonia, 1) reflux, 2 h, 2) 1 h, Multistep reaction Maksakov, V. A.; Kirin, V. P.; Golovin, A. V.; Russian Chemical Bulletin; vol. 44; nb. 10; (1995); p. 1941 - 1945; Izvestiya Akademi Nauk, Seriya Khimicheskaya; nb. 10; (1995); p. 2021 - 2025 View in Reaxys With hydrogenchloride, Heating Merino, Pedro; Revuelta, Julia; Tejero, Tomas; Chiacchio, Ugo; Rescifina, Antonio; Piperno, Anna; Romeo, Giovanni; Tetrahedron: Asymmetry; vol. 13; nb. 2; (2002); p. 167 - 172 View in Reaxys With thionyl chloride, Heating Schann, Stephan; Menet, Christel; Arvault, Paul; Mercier, Geraldine; Frauli, Melanie; Mayer, Stanislas; Hubert, Nadia; Triballeau, Nicolas; Bertrand, Hugues-Olivier; Acher, Francine; Neuville, Pascal; Bioorganic & Medicinal Chemistry Letters; vol. 16; nb. 18; (2006); p. 4856 - 4860 View in Reaxys With thionyl chloride, Time= 12h, T= 80 C Shiigi, Hirofumi; Mori, Hiroyuki; Tanaka, Tomoaki; Demizu, Yosuke; Onomura, Osamu; Tetrahedron Letters; vol. 49; nb. 36; (2008); p. 5247 - 5251 View in Reaxys With thionyl chloride, Time= 16h, Reflux Loenarz, Christoph; Mecinovic, Jasmin; Chowdhury, Rasheduzzaman; McNeill, Luke A.; Flashman, Emily; Schofield, Christopher J.; Angewandte Chemie, International Edition; vol. 48; nb. 10; (2009); p. 1784 - 1787 View in Reaxys
OH
H N
OH O
H N
O Cl O H
HO
HO
Rx-ID: 3821929 View in Reaxys 4/97 Yield 98 % Conditions & References With hydrogenchloride, Time= 3h Tanaka, Naoki; Goto, Riki; Ito, Rie; Hayakawa, Miho; Sugidachi, Atsuhiro; Ogawa, Taketoshi; Asai, Fumitoshi; Fujimoto, Koichi; Chemical & Pharmaceutical Bulletin; vol. 48; nb. 11; (2000); p. 1729 - 1739 View in Reaxys 98 % With thionyl chloride, Time= 5h, Heating Curtis, Kim L.; Evinson, Emma L.; Handa, Sandeep; Singh, Kuldip; Organic and Biomolecular Chemistry; vol. 5; nb. 21; (2007); p. 3544 - 3553
7/47
2012-01-31 07:06:55
SIG1
View in Reaxys 98 % With thionyl chloride, T= 0 C , Reflux Imaoka, Takuya; Iwamoto, Osamu; Noguchi, Kei-Ichi; Nagasawa, Kazuo; Angewandte Chemie, International Edition; vol. 48; nb. 21; (2009); p. 3799 - 3801 View in Reaxys 97 % Example Name 1.1 Example 1; Step 1 :To a mechanically stirred suspension of compound 1 (100.6 g, 0.767 mol) in EtOH (1000 ml) and cooled to O 0C was added SOCI2 (136.9 g, 1.15 mol, 84.0 ml) dropwise via addition funnel such that the internal temperature was < 15 0C. The reaction mixture was heated at reflux for 2.5 h, then cooled to O 0C. Ether (1000 ml) was added, and a white solid precipitated. The solid was isolated by vacuum filtration and washed with ether. The product 2 (HCI salt) was dried in a vacuum oven to give 146.3 g (97percent) of a white solid. MS (M+1): m/e 160. 1HNMR (DMSO) 1.25 (t, 3H), <n="19"/>2.05 (m, 1 H), 2.20 (m, 1 H)1 3.05 (d, 1 H), 3.40 (dd, 1 H), 4.20 (q5 2H), 4.45 (m, 2H)1 5.65 (broad s, 1 H). With thionyl chloride, Time= 2.5h, T= 0 - 15 C , Heating / reflux Patent; SCHERING CORPORATION; WO2008/8327; (2008); (A2) English View in Reaxys 97 % Example Name 1.1 Step 1:To a mechanically stirred suspension of compound 1 (100.6 g, 0.767 mol) in EtOH (1000 ml) and cooled to 0.deg. C. was added SOCl2 (136.9 g, 1.15 mol, 84.0 ml) dropwise via addition funnel such that the internal temperature was <15.deg. C. The reaction mixture was heated at reflux for 2.5 h, then cooled to 0.deg. C. Ether (1000 ml) was added, and a white solid precipitated. The solid was isolated by vacuum filtration and washed with ether. The product 2 (HCl salt) was dried in a vacuum oven to give 146.3 g (97percent) of a white solid. MS (M+1): m/e 160. 1H-NMR (DMSO) 1.25 (t, 3H), 2.05 (m, 1H), 2.20 (m, 1H), 3.05 (d, 1H), 3.40 (dd, 1H), 4.20 (q, 2H), 4.45 (m, 2H), 5.65 (broad s, 1H). With thionyl chloride, T= 0 C , Reflux Patent; SCHERING CORPORATION; US2011/3780; (2011); (A1) English View in Reaxys 96 % With thionyl chloride, Time= 4h, Reflux Murphy, Annabel C.; Mitova, Maya I.; Blunt, John W.; Munro, Murray H. G.; Journal of Natural Products; vol. 71; nb. 5; (2008); p. 806 - 809 View in Reaxys 95 % With hydrogenchloride, Time= 2h, Heating Baker, Gregory L.; Fritschel, Scott J.; Stille, John R.; Stille, John K.; Journal of Organic Chemistry; vol. 46; nb. 14; (1981); p. 2954 - 2960 View in Reaxys 94 % With thionyl chloride, Esterification Yanagi, Toshiharu; Kitajima, Akihiko; Anzai, Kinsei; Kodama, Kazuya; Mizoguchi, Jun-ichi; Fujiwara, Hiromichi; Sakiyama, Hideyo; Kamoda, Osamu; Kamei, Chiaki; Chemical & Pharmaceutical Bulletin; vol. 47; nb. 11; (1999); p. 1650 - 1654 View in Reaxys 88 % With thionyl chloride, Cooling with ice, Reflux Kristensen, Tor E.; Vestli, Kristian; Jakobsen, Martin G.; Hansen, Finn K.; Hansen, Tore; Journal of Organic Chemistry; vol. 75; nb. 5; (2010); p. 1620 - 1629 View in Reaxys 86 % With thionyl chloride, Time= 6h, Heating Tanaka, Ken-ichi; Sawanishi, Hiroyuki; Tetrahedron: Asymmetry; vol. 6; nb. 7; (1995); p. 1641 - 1656 View in Reaxys
8/47
2012-01-31 07:06:55
SIG1
80 %
With thionyl chloride, T= 20 C Watanabe, Akiko; Yamasaki, Tetsuo; Tanda, Kazuhiro; Miyagoe, Tatsunori; Sakamoto, Masanori; Kiyota, Naotoshi; Otsuka, Masami; Journal of Heterocyclic Chemistry; vol. 48; nb. 5; (2011); p. 1132 - 1139 View in Reaxys With hydrogenchloride Watanabe, Kiyoko; Fukumura, Toshimitsu; Sasaki, Shigeki; Maeda, Minoru; Takehara, Shuzo; Chemical & Pharmaceutical Bulletin; vol. 39; nb. 12; (1991); p. 3211 - 3214 View in Reaxys With thionyl chloride, Time= 6h, Heating Heindl, Cornelia; Huebner, Harald; Gmeiner, Peter; Tetrahedron: Asymmetry; vol. 14; (2003); p. 3141 - 3152 View in Reaxys Example Name 23.A Example 23; (S)- {4- [5- (5-tert-Butyl- (lS, 4S) -2,5-diaza-bicyclo [2.2. 1] hept-2-yl)-imidazo [ 1, 2- c] pyrimidin-7-yl]pyridin-2-yl}- (1-phcnyl-ethyl)-amine; Step A; To a 250 mL RBF, was added trans-4-hydroxy-L-proline, (2S, 4R)-4hydroxy-pyrrolidine-2-carboxylic acid) (13.1 g, 100 mmol), and 50 mL absolute ethanol. The above mixture was cooled down to 0 .deg.C and saturated with HC1 gas until all of the suspension was dissolved. The mixture was refluxed under nitrogen for 2 h. The mixture was cooled down to rt, and all solvent was removed by vacuum. The residue was kept in the refrigerator for 15 h, the white precipitate was filtered and washed with anhydrous ether 3 x 50 mL, to obtain the (2S, 4R)-4- hydroxy-pyrrolidine-2-carboxylic acid ethyl ester HC1 salt as a white solid. With hydrogenchloride, Time= 2h, T= 0 C , Heating / reflux Patent; AMGEN INC.; WO2005/70934; (2005); (A1) English View in Reaxys With hydrogenchloride Patent; Athena Neurosciences, Inc.; American Home Products; US6362341; (2002); (B1) English View in Reaxys With thionyl chloride, T= 0 C , Reflux Delunafreire, Kristerson R.; Tormena, Claudio F.; Coelho, Fernando; Synlett; nb. 14; (2011); p. 2059 - 2063; Art.No: S02011ST View in Reaxys
O N
O O O
H N
O O
HO
HO
Rx-ID: 24787773 View in Reaxys 5/97 Yield 100 % Conditions & References Example Name 1 A solution of 4.0 N HCl in dioxane (50 mL) was added to a solution of commercially available 4-hydroxy-pyrrolidine-1,2dicarboxylic acid 1-tert-butyl ester 2-methyl ester (30 g, 206 mmol) in dichloromethane (200 mL). After the reaction mixture was stirred at room temperature for 4 hours, it was concentrated to get a quantitative yield of crude intermediate XI, which was used in the next step without further purification. With hydrogenchloride in 1,4-dioxane, dichloromethane, Time= 4h, T= 20 C Patent; TaiGen Biotechnology Co., Ltd.; US2008/108632; (2008); (A1) English View in Reaxys Example Name B.85.1 Boc-aminoproline methyl ester (20g, 81.5 mmol) was dissolved inDCM (lOOmL) in a round bottomed flask. TFA (200mL) was added and thereaction was stirred at room temp for Ih. The mixture was then concentratedand azeotroped with
9/47
2012-01-31 07:06:55
SIG1
toluene (2xlOOmL). The crude mixture was then takenup in DCM (600mL). HATU (46.5g, 122 mmol), NMM (28.9g, 285 mmol), andacid (23.8g, 97.8 mmol) were added. The reaction mixture was stirred at roomtemperature for 15h. The reaction was then quenched with water, dilutedwith DCM, washed with sat. NaHCOs, and sat. NHO. The organic layer wasthen dried, concentrated, and purified via flash chromatography to providethe coupling product (21.6g, 73percent). This methyl ester (21.6g, 58.3 mmol) wasthen taken up in THF (lOOmL), MeOH (lOOmL), and water (lOOmL). LiOH(12.2g, 292 mmol) was added and the mixture was stirred at roomtemperature for Ih. The reaction was then diluted with water and the pH wasadjusted to 3 using IN HC1. The mixture was then extracted with EtOAc,dried, and concentrated to provide carboxylic acid (20.2g, 97percent). With trifluoroacetic acid in dichloromethane, Time= 1h, T= 20 C Patent; GILEAD SCIENCES, INC.; WO2006/20276; (2006); (A2) English View in Reaxys
H N
OH O
O
H N HCl OH
HO
Rx-ID: 22893546 View in Reaxys 6/97 Yield 87.6 % Conditions & References [TRANS-4-HYDROXY-L-PROLINE] (1; 10 g, 76.3 mmol) was dissolved in 200 ml of methanol, acetyl chloride (7.6 ml, 106.8 mmol) was added therein and the mixture was refluxed with stirring up for overnight. The mixture was cooled to RT (room temperature) and 500 ml of ether was added to form white crystal followed by filtration and drying under vacuum to yield the compound 2 (12.7 g, 87.6 percent): With acetyl chloride in methanol, diethyl ether, T= 20 C Patent; NEXGEN BIOTECHNOLOGIES, INC.; WO2003/104249; (2003); (A1) English View in Reaxys
H N
OH O
O HN
O H
Cl
HO
OH
Rx-ID: 24142442 View in Reaxys 7/97 Yield 98.0% Conditions & References Example Name R.5 Example Title Trans-4-Hydroxy-L-Proline Methyl Ester Hydrochloride REFERENCE EXAMPLE 5 Trans-4-Hydroxy-L-Proline Methyl Ester Hydrochloride A solution prepared by dissolving 13.9 g of trans-4-hydroxy-L-proline in 150 ml of methanol was cooled to -20.deg. C. and then 25 ml of thionyl chloride was dropwise added to the solution. After the completion of the dropwise addition, the resulting mixture was stirred at 40.deg. C. for 30 minutes. The reaction solution was concentrated, followed by addition of ether to the resulting residue, filtration of the crystals thus precipitated, washing the crystals with ether and drying them to give 18.86 g (yield 98.0percent) of the title compound. 1H-N.M.R. (DMSO-d ) : 2.03-2.26 (2 H, m), 3.03-3.12 (1 H, m), 3.37 (1 H, dd, J=12.1, 4.4 Hz), 3.76 (3H, s), 4.38-4.51 6 (2 H, m), 5.61 (1 H, brs), 8.75-9.25 (1 H, m), 10.25-10.75 (1 H, m); I.R. (KBr) cm-1: 3370, 2950, 1740, 1585, 1360, 1285, 1245. With thionyl chloride in methanol Patent; Wakamoto Pharmaceutical Co., Ltd.; US6225306; (2001); (B1) English View in Reaxys 92% Example Name 50 Example Title trans-4-Hydroxy-L-proline, Methyl Ester, Hydrochloride trans-4-Hydroxy-L-proline, Methyl Ester, Hydrochloride
10/47
2012-01-31 07:06:55
SIG1
To a freshly prepared sat. solution of hydrogen chloride in methanol (100 ml) was added trans-4-hydroxy-L-proline (10.0 g, 76.26 mmol). The resulting mixture was stirred at 22.deg. C. for 24 h, concentrated in vacuo and triturated with acetone at 0.deg. C. Filtration afforded the title compound (12.8 g, 92percent) as a white solid. With hydrogenchloride in methanol Patent; Bristol-Myers Squibb Company; US6350892; (2002); (B1) English View in Reaxys 92% Example Name 50 Example Title trans-4-Hydroxy-L-proline, methyl ester, hydrochloride trans-4-Hydroxy-L-proline, methyl ester, hydrochloride To a freshly prepared sat. solution of hydrogen chloride in methanol (100 ml) was added trans-4-hydroxy-L-proline (10.0 g, 76.26 mmol). The resulting mixture was stirred at 22.deg. C. for 24 h, concentrated in vacuo and triturated with acetone at 0.deg. C. Filtration afforded the title compound (12.8 g, 92percent) as a white solid. With hydrogenchloride in methanol Patent; Bristol-Myers Squibb Company; US6255496; (2001); (B1) English View in Reaxys
O
HO
O O N OH
HO
H N
O O Cl H
HO
Rx-ID: 24725501 View in Reaxys 8/97 Yield ~ 100 % Conditions & References Example Title Synthesis of cis-4-hydroxyproline methyl ester HCl salt (76) Synthesis of cis-4-hydroxyproline methyl ester HCl salt (76) Boc-cis-4-hydroxyproline (74) (450 mg, 1.95 mmol) was dissolved in methanol (10 mL) and cooled to 0.deg. C. To the above solution, 1.8 equivalents of thionyl chloride was added. The solution was heated to 45.deg. C. for 4 hours, and was then stirred overnight at room temperature. The reaction mixture was then concentrated under reduced pressure. cis-4-hydroxyproline methyl ester HCl salt started to crystallize out during the evaporation. The crystals were filtered off and washed several times with ether. The crystals were finally dried in a vacuum oven for 24 hours (40.deg. C.) to yield 76 (354 mg, ~100percent). With thionyl chloride, T= 0 - 45 C Patent; Mioskowski, Charles; Marin, Sandra De Lamo; Maruani, Martine; Gill, Manjinder; US2006/199853; (2006); (A1) English View in Reaxys ~ 100 % Boc-cis-4-hydroxyproline (74) (450 mg, 1.95 mmol) was dissolved in methanol (10 mL) and cooled to 0.deg. C. To the above solution, 1.8 equivalents of thionyl chloride was added. The solution was heated to 45.deg. C. for 4 hours, and was then stirred overnight at room temperature. The reaction mixture was then concentrated under reduced pressure. Cis-4-hydroxyproline methyl ester HCl salt started to crystallize out during the evaporation. The crystals were filtered off and washed several times with ether. The crystals were finally dried in a vacuum oven for 24 hours (40.deg. C.) to yield 76 (354 mg, 100percent). 76: MS: M+H+=146. 1H NMR (500 MHz, D2O): 4.47 (m, 2H), 3.91 (s, 3H, OMe), 3.52 (m, 2H), 2.57-2.47 (m, 2H). The ent-76 (compound 202) can be synthesized following the synthetic route (70-->74, 74->76) using DN-Boc-cis-4-hydroxyproline. With thionyl chloride, T= 0 - 45 C Patent; Chapal, Nicolas; McNicol, Patricia; Jette, Lucie; US2006/223884; (2006); (A1) English View in Reaxys
11/47
2012-01-31 07:06:55
SIG1
O N
O O
HO
O NH O
O HO
Rx-ID: 23331120 View in Reaxys 9/97 Yield Conditions & References Example Name 1 1-(2-{2-Cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]- acetylamino}-3, 3-dimethyl-butyryl)-4-hydroxy-pyrr olidine-2-carboxylic acid tert-butyl ester (6) [0156] Mixed (3) in EtOH, and added catalytic amount of 10percent Pd on carbon, then stirred under 1 atmosphere of hydrogen using a balloon. After 12 hours the reaction was shown to be complete by tlc, and the catalyst was filtered and washed with EtOH. The filtrate was concentrated and dried under high vacuum to give the amine as a yellow solid, which was carried on into the next step. Z-Tbg-OH (8.3g, 31. lmmols) was dissolved in NMP and to it was added EDC (6. 0g, 31. lmmols), HOBT (4.2g, 31. 1mmols), DMAP (340mgs, 2.8mmols), and cooled to 0.deg.C using and ice-water bath. To this mixture was added the amine as a solution in NMP, and the reaction was stirred for 2 days. The reaction was poured over ice and acidified with 0.5N hydrochloric acid to pH 5, and then extracted with EtOAc. The organic extracts were washed with saturated sodium bicarbonate, then water, and finally with brine. The organic layer was dried with sodium sulfate and concentrated in vacuo to give 14.8g of crude material. Purification was carried out using chromatography on Si02, eluting with 50percent EtOAc-Hexanes. Concentration of the homogeneous fractions yielded 10.5 grams of 4 as a colorless foam (85percent) and used as is in the next step. With hydrogen, palladium 10percent on activated carbon in ethanol, Time= 12h, p= 760.051Torr Patent; VERTEX PHARMACEUTICALS INCORPORATED; WO2005/35525; (2005); (A2) English View in Reaxys
H N
OH O
H N
O Cl O H
HO
HO
Rx-ID: 24437766 View in Reaxys 10/97 Yield 94.5% Conditions & References Example Name 22 Example Title Example 22 Example 22 3.27 g (27.5 mmol) of thionyl chloride was added dropwise to a suspension of cis-4-hydroxy-D-proline (3.00 g, 2.9 mmol) in ethanol (15 ml) and the mixture was refluxed for 2 hours. The mixture was concentrated, acetone was added to the residue and the solution was cooled on ice. The resultant precipitate was filtered and 4.23 g of (2R,4R)-(+)-2-(ethoxycarbonyl)-4-hydroxypyrrolidine hydrochloride was obtained as colorless needles (94.5percent). With thionyl chloride in ethanol, acetone Patent; Ajinomo Co., Inc.; US6127361; (2000); (A1) English View in Reaxys
H N
OH O
H N
O O Cl H
HO
HO
Rx-ID: 24515770 View in Reaxys 11/97 Yield 113% Conditions & References Example Name P.7.A.1 Example Title Step A-1. Step A-1.
12/47
2012-01-31 07:06:55
SIG1
Preparation of an ester compound To a suspension of cis-4-hydroxy-D-proline (16.46 g: 125.5 mmole) in methanol (66 ml), thionylchloride (9.16 ml: 125.5 mmole) is added in a nitrogen atmosphere under ice cooling, and the mixture is stirred at room temperature for 30 minutes. The mixture is further stirred to react at 40.deg. C. for 4 hours to give (2R,4R)-4-hydroxy-2-methoxycarbonylpyrrolidine hydrochloride as crude crystals (25.74 g). Yield: 113percent. Colorless crystals. NMR (D2 O) ppm: 2.3 to 2.6(m, 2H), 3.33(s, 1H), 3.4 to 3.5(m, 2H), 3.84(s, 3H), 4.6 to 4.7(m, 2H). IR (KBr) cm-1: 3320, 2980, 1728. With thionyl chloride in methanol Patent; Shionogi Seiyaku Kabushiki Kaisha; US5317016; (1994); (A1) English View in Reaxys
OH
H N
OH O
HO
O NH O HCl
HO
Rx-ID: 23137126 View in Reaxys 12/97 Yield 100 % Conditions & References Example Name 7 Example Title Intermediate 7.; ISO-PROPVL-4R)-4-HVDROXY-D-PROLINATE HVDROCHLORIDE To a suspension of cis-4-hydroxy-D-proline [(1.] [0G)] in dry iso-propanol (25ml) under nitrogen cooled to [0C] was added dropwise thionyl chloride (0. [8MI).] The reaction mixture was heated at [100C] for 6 hours. The mixture was concentrated in vacuo to afford the title compound as a white solid (1.6g, quantitative).'H NMR 400MHz (d4-MeOH) 5.17-5. 08 (1H, hep), 4.52-4. 47 (2H, m), 3.40-3. 32 (2H, m), 2.48-2. 41 (1H, m), 2.36-2. 32 (1H, m), 1.33-1. 30 (6H, d). With thionyl chloride, Time= 6h, T= 0 - 100 C Patent; CELLTECH R and D LIMITED; WO2004/22554; (2004); (A1) English View in Reaxys
H N
OH O
Cl
H N
O O Cl H
HO
HO
Rx-ID: 24504600 View in Reaxys 13/97 Yield 88% Conditions & References Example Name P.7.C.1 Example Title Step C-1. Step C-1. Preparation of an ester compound To a suspension of trans-4-hydroxy-L-proline (200 g: 1.525 mole) in methanol (800 ml), acetylchloride (163 ml: 2.288 mole) is added dropwise under ice cooling in a nitrogen atmosphere. The mixture is warmed to room temperature, mixed with thionyl chloride (55.7 ml: 0.763 mole), and stirred for 4 hours at 40.deg. C. to give (2S,4R)-4-hydroxy-2-methoxycarbonylpyrrolidine hydrochloride (244.27 g). Yield: 88percent. Colorless crystals. NMR (D2 O) ppm: 1.8 to 2.0(m, 1H), 2.0 to 2.2(m, 1H), 2.9 to 3.1(m, 1H), 3.17(dd, J=12.6 Hz, J=3.6 Hz, 1H), 3.49(s, 3H), 4.2 to 4.4(m, 2H). IR (KBr) cm-1: 3380, 3330, 2695, 2960, 1742. With thionyl chloride in methanol Patent; Shionogi Seiyaku Kabushiki Kaisha; US5317016; (1994); (A1) English View in Reaxys
O HO HN
OH Cl H
O O HN HCl OH
Rx-ID: 24887302 View in Reaxys 14/97
13/47
2012-01-31 07:06:55
SIG1
Yield 77.5%
Conditions & References Example Name 8.2 Example Title Preparation of (1R,4R)-2,5-diazabicyclo[ 2.2.1]heptane dihydrobromide (2) Allo-4-hydroxy-D-proline ethyl ester hydrochloride. A suspension of allo-4-hydroxy-D-proline hydrochloride (106.24 g, 0.63 mole) in absolute EtOH (550 mL) at 0.deg. C. was treated with dry HCl until the reaction became homogeneous. The solution was heated at reflux for 5 h. The reaction mixture was cooled to 23.deg. C. and allowed to stand 16 h. The reaction was cooled to 0.deg. C. the resulting precipitate was collected by suction filtration and washed with acetone to give allo-4-hydroxy-D-proline ethyl ester hydrochloride (95.53 g, 77.5percent, m.p. 145.deg.-147.deg. C.). With hydrogenchloride in ethanol Patent; Bristol-Myers Squibb Co.; US4994460; (1991); (A1) English View in Reaxys
H N
OH O
H N
O O
HO
HO
Rx-ID: 18133977 View in Reaxys 15/97 Yield 95% Conditions & References Example Name 110.1 Example Title (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dihydro-pyrrole-1-carbonyl)-phenyl]-amide} Step 1: (2R,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester (1) Cis-4-Hydroxy-D-proline (15 g, 115 mmol) was suspended in 150 mL anhydrous methanol under an argon atmosphere, then cooled to 0.deg. C. before bubbling in HCl gas for 15 minutes. The solution gradually became homogenous. The argon and HCl gas lines were removed and the solution was refluxed for 4 h. The solution was cooled and then concentrated under reduced pressure. The crude material was redissolved in 100 mL methanol and diethyl ether was added until a precipitate formed. The precipitate was filtered off, washed with diethyl ether, and dried in vacuo overnight to give 1 (20 g, 95percent) as a white solid. MS: APCI (AP+): 146 (M)+. in hydrogenchloride, methanol, diethyl ether Patent; Bigge, Christopher Franklin; Casimiro-Garcia, Agustin; Dudley, Danette Andrea; Edmunds, Jeremy John; Filipski, Kevin James; Kohrt, Jeffrey Thomas; Van Huis, Chad Alan; US2003/162787; (2003); (A1) English View in Reaxys Reaction Steps: 2 1: SOCl2 2: -5 C With thionyl chloride Kolodziej, Stephen A.; Nikiforovich, Gregory V.; Skeean, Richard; Lignon, Marie-Francoise; Martinez, Jean; Marshall, Garland R.; Journal of Medicinal Chemistry; vol. 38; nb. 1; (1995); p. 137 - 149 View in Reaxys Example Name 28.1 Example Title (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide} Step 1: (2R,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester. Cis-4-Hydroxy-D-proline (15 g, 115 mmol) was suspended in 150 mL anhydrous methanol under an argon atmosphere, then cooled to 0.deg. C. before bubbling in HCl gas for 15 minutes. The solution gradually became homogenous. The argon and HCl gas lines were removed and the solution was refluxed for 4 h.
14/47
2012-01-31 07:06:55
SIG1
The solution was cooled and then concentrated under reduced pressure. The crude material was redissolved in 100 mL methanol and diethyl ether was added until a precipitate formed. The precipitate was filtered off, washed with diethyl ether, and dried in vacuo overnight to reveal 1 (20 g, 95percent) as a white solid. MS: APCI (AP+): 146 (M)+. in hydrogenchloride, methanol, diethyl ether Patent; Bigge, Christopher Franklin; Casimiro-Garcia, Agustin; Dudley, Danette Andrea; Edmunds, Jeremy John; Filipski, Kevin James; Kohrt, Jeffrey Thomas; Van Huis, Chad Alan; US2003/162787; (2003); (A1) English View in Reaxys
H N
HO
OH O
H N
O O Cl H
HO
HO
Rx-ID: 3821922 View in Reaxys 16/97 Yield 100 % Conditions & References With thionyl chloride, Time= 4h, Ambient temperature Pickering, Lea; Malhi, Baljinder S.; Coe, Paul L.; Walker, Richard T.; Tetrahedron; vol. 51; nb. 9; (1995); p. 2719 - 2728 View in Reaxys 100 % With thionyl chloride, Time= 74h, Ambient temperature Blanco, Maria-Jesus; Sardina, F. Javier; Journal of Organic Chemistry; vol. 61; nb. 14; (1996); p. 4748 - 4755 View in Reaxys 100 % With thionyl chloride, Ambient temperature Westwood, Nigel B.; Walker, Richard T.; Tetrahedron; vol. 54; nb. 44; (1998); p. 13391 - 13404 View in Reaxys 100 % With thionyl chloride, Time= 4.16667h Chang, Meng-Yang; Chen, Hua-Ping; Heterocycles; vol. 65; nb. 7; (2005); p. 1705 - 1711 View in Reaxys 100 % With thionyl chloride, Time= 18h, T= 45 C Maison, Wolfgang; Arce, Eva; Renold, Peter; Kennedy, Robert J.; Kemp, Daniel S.; Journal of the American Chemical Society; vol. 123; nb. 42; (2001); p. 10245 - 10254 View in Reaxys 100 % With thionyl chloride, T= 0 - 20 C Enders, Dieter; Kirchhoff, Jan H.; Koebberling, Johannes; Peiffer, Thomas H.; Organic Letters; vol. 3; nb. 8; (2001); p. 1241 - 1244 View in Reaxys 100 % With hydrogenchloride Tamaki, Makoto; Han, Guoxia; Hruby, Victor J.; Journal of Organic Chemistry; vol. 66; nb. 10; (2001); p. 3593 3596 View in Reaxys 100 % With thionyl chloride, Time= 18h, T= 20 C Koch, David; Maechling, Simon; Blechert, Siegfried; Tetrahedron; vol. 63; nb. 30; (2007); p. 7112 - 7119 View in Reaxys 100 % With thionyl chloride, Time= 3h, Heating Chang, Meng-Yang; Chen, Shui-Tein; Chang, Nein-Chen; Heterocycles; vol. 60; nb. 5; (2003); p. 1203 - 1210 View in Reaxys
15/47
2012-01-31 07:06:55
SIG1
Chang, Meng-Yang; Kung, Yung-Hua; Wu, Tsun-Cheng; Journal of the Chinese Chemical Society (Taipei, Taiwan); vol. 54; nb. 3; (2007); p. 803 - 806 View in Reaxys 100 % Example Name 5.I To a stirred solution of (2S, 4i?)-4-hydroxypyrrolidine-2-carboxylic acid (13.1 g, 0.1 mol) in methanol (400 mL) cooled to 0.deg.C was added acetyl chloride (14.3 mL, 0.2 mol) over a period of 30 min. The reaction mixture was warmed to room temperature and stirred for 2 h. The volatiles were removed under reduced pressure and the residue was triturated with ether several times to get methyl (25',4/?)-4-hydroxypyrrolidine-2- carboxylate hydrochloride salt as a white powder (14.5 g) in 100percent yield, m/z (M+l) 145; 1H NMR (DMSOd6) 300 MHz 5.7-5.5 (s (br), IH), 4.55-4.35 (m, 2H), 3.76 (s, 3H), 3.35 (d, J= 12 Hz IH), 3.10 (d, J= 12 Hz IH), 2.25-2.0 (m, 2H). With acetyl chloride, Time= 2.5h, T= 0 - 20 C Patent; MATRIX LABORATORIES LTD.; WO2007/113634; (2007); (A1) English View in Reaxys 100 % With thionyl chloride Grygorenko, Oleksandr O.; Komarov, Igor V.; Cativiela, Carlos; Tetrahedron: Asymmetry; vol. 20; nb. 12; (2009); p. 1433 - 1436 View in Reaxys 99 % With thionyl chloride Haberhauer, Gebhard; Synlett; nb. 6; (2004); p. 1003 - 1006 View in Reaxys 99 % With acetyl chloride, Time= 8h, Heating Lee, K. S.; Lim, J. H.; Kang, Y. K.; Yoo, K. H.; Kim, D. C.; Shin, K. J.; Kim, D. J.; European Journal of Medicinal Chemistry; vol. 41; nb. 11; (2006); p. 1347 - 1351 View in Reaxys 99 % Example Name 1.a; 12 Acetyl chloride (4.14 g, 52.8 mmol) is dropped into a three neck round bottom flask containing anhydrous methanol (33 ml) in ice bath and under N2 flux. [(2S,4R)-(-)-4-Hydroxypyrrolidine-2-carboxylic acid (1) (5.0 g, 37.7 mmol) is added and the so obtained reaction mixture is firstly brought to room temperature (r.t.) then refluxed for 8 hours. Afterwards, the reaction is brought to room temperature and diethyl ether is added till complete precipitation of the reaction product, which, after Buchner filtration, is (2S,4R)-4-hydroxy-2-(methoxycarbonyl)pyrrolidine chloride (2). Yield 99percent; white solid m.p. 149-152 0C.1H NMR (DMSO, 500 MHz): 2.07 (ddd, IH, J = 4.5, 11.0, 13.0 Hz), 2.18 (m, IH), 3.05 (d, IH, J =12.0 Hz), 3.35 (m, IH), 3.74 (s, 3H, OMe), 4.40 (t, IH, J = 4,5 Hz), 4.44 (dd, IH, J = 6.5, 11.0 Hz), 4.68 (bs, OH), 9.32 (IH, NH), 10.44 (IH, NH).13C NMR (DMSO, 50 MHz): 37.0, 53.0, 57.4, 57.8, 68.4, 169.0.Elemental analysis. Calculated for C6Hi2ClNO3: C, 39.68; H, 6.66; Cl, 19.52; N, 7.71. Found: C, 39.66; H, 6.64; Cl, 19.50; N, 7.71. Theoretical mass for C6Hi2ClNO3: 181.05. Found: 181.00. With acetyl chloride, Time= 8h, T= 0 C , Heating / reflux, Product distribution / selectivity Patent; ISTITUTO DI RICERCHE DI BIOLOGIA MOLECOLARE P.ANGELETTI S.P.A.; WO2007/65883; (2007); (A1) English View in Reaxys 98 % With thionyl chloride, Time= 1.5h, Heating Lewis, Arwel; Wilkie, John; Rutherford, Trevor J.; Gani, David; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); nb. 22; (1998); p. 3777 - 3794 View in Reaxys 97 % With acetyl chloride, Time= 18h, T= 60 C , Esterification Shin, Kye Jung; Koo, Ki Dong; Yoo, Kyung Ho; Kim, Dong Chan; Kim, Dong Jin; Park, Sang Woo; Bioorganic & Medicinal Chemistry Letters; vol. 10; nb. 13; (2000); p. 1421 - 1425 View in Reaxys 96 % With thionyl chloride, Time= 4h, Ambient temperature
16/47
2012-01-31 07:06:55
SIG1
Issartel, V.; Spehner, V.; Bahaji, H.; Seilles, E.; Couquelet, J.; European Journal of Medicinal Chemistry; vol. 31; nb. 9; (1996); p. 717 - 724 View in Reaxys 96 % With acetyl chloride, Time= 8h, Heating Na, Ho Seong; Choi, Jaehyuck; Yu, Jaehoon; Shin, Kye Jung; Yoo, Kyung Ho; et al.; Heterocycles; vol. 48; nb. 11; (1998); p. 2365 - 2378 View in Reaxys 95 % With thionyl chloride, Time= 4h, Ambient temperature Diafi, Lahcen; Couquelet, Jacques; Tronche, Pierre; Gardette, Daniel; Gramain, Jean-Claude; Journal of Heterocyclic Chemistry; vol. 27; nb. 7; (1990); p. 2181 - 2187 View in Reaxys 95 % Example Name 1.1 Step 1 : (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (2). Thionyl chloride (11.6 ml, 160 mmol) was added to a stirred solution of (2S,4R)-4- hydroxypyrrolidine-2-carboxylic acid (10.0 g, 76.26 mmol) (1) in methanol (150 ml) at - 780C for 10 min. The mixture was then stirred in an ice bath for 30 minutes followed by stirring at RT for 30 min. Finally the mixture was refluxed for three hours and concentrated in vacuo to give (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (2) (17.90 g, 95percent) as a white solid. Used without further purification. MS m/z 146.2 (M+H)+; retention time = 0.19 min, method [I]. With thionyl chloride, Time= 4.16667h, T= -78 C , Heating / reflux Patent; ELAN PHARMACEUTICALS, INC.; WO2008/147800; (2008); (A1) English View in Reaxys 95 % With acetyl chloride Rawson, David J.; Brugier, Delphine; Harrison, Anthony; Hough, Jo; Newman, Julie; Otterburn, Joe; Maw, Graham N.; Price, Jenny; Thompson, Lisa R.; Turnpenny, Paul; Warren, Andrew N.; Bioorganic and Medicinal Chemistry Letters; vol. 21; nb. 12; (2011); p. 3767 - 3770 View in Reaxys 94 % With thionyl chloride Umashankara, M.; Babu, I. Ramesh; Ganesh, Krishna N.; Chemical Communications (Cambridge, United Kingdom); nb. 20; (2003); p. 2606 - 2607 View in Reaxys 93 % With thionyl chloride, Time= 16h, T= 45 C Kemp, D. S.; Curran, Timothy P.; Davis, William M.; Boyd, James G.; Muendel, Christopher; Journal of Organic Chemistry; vol. 56; nb. 23; (1991); p. 6672 - 6682 View in Reaxys 93 % With thionyl chloride, Time= 4.5h, Heating Bisang, Christian; Weber, Christoph; Robinson, John A.; Helvetica Chimica Acta; vol. 79; (1996); p. 1825 - 1842 View in Reaxys 93 % With thionyl chloride, Time= 4h, Heating Bisang, Christian; Jiang, Luyong; Freund, Ernst; Emery, Fabienne; Bauch, Christian; et al.; Journal of the American Chemical Society; vol. 120; nb. 30; (1998); p. 7439 - 7449 View in Reaxys 92 - 97 % Example Name 21.a Absolute methanol (8.0 equiv) was poured into a four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser and a drop funnel. L-hydroxyproline (1 equiv) was placed into the flask with stirring. To the suspension obtained was added dropwise at 10-15 0C distilled thionyl chloride (1.1 equiv). Then the mixture was stirred at 45 0C until TLC indicated completion (5 h) of the reaction. The suspension was cooled to 5-10 0C and then filtered and washed with dry diethyl ether. The mother liquor was evaporated in vacuo and the residue was recrystallized from dry methanol to give the title compound in 92-97percent yield.
17/47
2012-01-31 07:06:55
SIG1
With thionyl chloride, Time= 5h, T= 10 - 45 C Patent; PFIZER INC.; WO2006/27694; (2006); (A1) English View in Reaxys 87 % With hydrogenchloride Jordis, Ulrich; Sauter, Fritz; Siddiqi, Suhaib M.; Kueenburg, Bernhard; Bhattacharya, Kaberi; Synthesis; nb. 10; (1990); p. 925 - 930 View in Reaxys 87 % With hydrogenchloride, Time= 3h, Heating Jordis, Ulrich; Sauter, Fritz; Siddiqi, Suhaib M.; Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry; vol. 28; nb. 1-11; (1989); p. 294 - 296 View in Reaxys Cheng, Xian-Chao; Wang, Qiang; Fang, Hao; Tang, Wei; Xu, Wen-Fang; Bioorganic and Medicinal Chemistry; vol. 16; nb. 10; (2008); p. 5398 - 5404 View in Reaxys Cheng, Xian-Chao; Wang, Qiang; Fang, Hao; Tang, Wei; Xu, Wen-Fang; European Journal of Medicinal Chemistry; vol. 43; nb. 10; (2008); p. 2130 - 2139 View in Reaxys Cheng, Xian-Chao; Wang, Qiang; Fang, Hao; Tang, Wei; Xu, Wen-Fang; Bioorganic and Medicinal Chemistry; vol. 16; nb. 17; (2008); p. 7932 - 7938 View in Reaxys 79.5 % With acetyl chloride Gong, Jianzhi; Xu, Wenfang; Gong, Yanqing; Journal of Chemical Research, Synopses; nb. 11; (2009); p. 668 - 670 View in Reaxys 58 % With hydrogenchloride in various solvent(s), 1.) reflux, 2 h, 2.) 25 deg C, 24 h Eswarakrishnan, Venkatachalam; Field, Lamar; Journal of Organic Chemistry; vol. 46; nb. 21; (1981); p. 4182 4187 View in Reaxys With thionyl chloride, Time= 8h, Heating Schumacher, Kelly K.; Jiang, Jianjun; Joullie, Madeleine M.; Tetrahedron: Asymmetry; vol. 9; nb. 1; (1998); p. 47 - 54 View in Reaxys With thionyl chloride, Time= 6h, Heating Marusawa, Hiroshi; Setoi, Hiroyuki; Sawada, Akihiko; Kuroda, Akio; Seki, Jiro; Motoyama, Yukio; Tanaka, Hirokazu; Bioorganic & Medicinal Chemistry; vol. 10; nb. 5; (2002); p. 1399 - 1416 View in Reaxys With thionyl chloride, Time= 32h Greenwood, E. S.; Hitchcock, P. B.; Parsons, P. J.; Tetrahedron; vol. 1859; (2003); p. 3307 - 3314 View in Reaxys With thionyl chloride Kamal, Ahmed; Reddy, P. S. M. M.; Reddy, D. Rajasekhar; Laxman, E.; Murthy, Y. L. N.; Bioorganic & Medicinal Chemistry Letters; vol. 14; nb. 22; (2004); p. 5699 - 5702 View in Reaxys Evans, Paul; Journal of Organic Chemistry; vol. 72; nb. 5; (2007); p. 1830 - 1833 View in Reaxys 1.81 g With thionyl chloride, Time= 3h, Heating Chang, Meng-Yang; Pai, Chun-Li; Chen, Hua-Ping; Tetrahedron Letters; vol. 46; nb. 45; (2005); p. 7705 - 7709 View in Reaxys
18/47
2012-01-31 07:06:55
SIG1
With hydrogenchloride, Time= 2.5h, Heating Barkallah, Salim; Schneider, Stephen L.; McCafferty, Dewey G.; Tetrahedron Letters; vol. 46; nb. 30; (2005); p. 4985 - 4987 View in Reaxys With hydrogenchloride Li, Ya-Lin; XU, Wen-Fang; Bioorganic & Medicinal Chemistry; vol. 12; nb. 19; (2004); p. 5171 - 5180 View in Reaxys With thionyl chloride, Time= 6h, T= 20 - 45 C Mollica, Adriano; Paradisi, Mario Paglialunga; Varani, Katia; Spisani, Susanna; Lucente, Gino; Bioorganic & Medicinal Chemistry; vol. 14; nb. 7; (2006); p. 2253 - 2265 View in Reaxys With thionyl chloride, Time= 6h, T= 20 C , Methylation Merino, Pedro; Anoro, Sonia; Franco, Santiago; Merchan, Francisco L.; Tejero, Tomas; Tunon, Victoria; Journal of Organic Chemistry; vol. 65; nb. 5; (2000); p. 1590 - 1596 View in Reaxys With thionyl chloride, Time= 6.5h, T= 0 - 20 C Peng, Jianbiao; Clive, Derrick L. J.; Organic Letters; vol. 9; nb. 15; (2007); p. 2939 - 2941 View in Reaxys With thionyl chloride D'Costa, Moneesha; Kumar, Vaijayanti A.; Ganesh, Krishna N.; Organic Letters; vol. 1; nb. 10; (1999); p. 1513 1516 View in Reaxys With hydrogenchloride Liu, Feng-Zhi; Fang, Hao; Zhu, Hua-Wei; Wang, Qiang; Yang, Yue; Xu, Wen-Fang; Bioorganic and Medicinal Chemistry; vol. 16; nb. 1; (2008); p. 578 - 585 View in Reaxys Example Name 7.4 Example 7-4 Methyl (2S, 4R) -4-hydroxy-2-pyrrolidinecarboxylate hydrochloride Hydroxy proline (155g) was dissolved in"Hydrogen Chloride, MethanolReagentlO" (TokyoKaseiKogyoCo., Ltd. 900mL), and this mixture was heated at reflux for 2hrs. The resulting mixture was cooled to room temperature, and the solvent was removed in vacuo to give the target compound as white powder (215g). 1H-NMR (in DMSO-d6) : No. 2.30-1. 99 (2H, m), 3.14-2. 97 (1H, m), 3.45-3. 25 (1H, m), 3. 76 (3H, s), 4.57-4. 35 (2H, m), 9.23 (1H, br-s), 10. 32 (1H, br-s). With hydrogenchloride, Time= 2h, Heating / reflux Patent; FUJISAWA PHARMACEUTICAL CO., LTD.; WO2005/42533; (2005); (A2) English View in Reaxys Example Name 7 With thionyl chloride, Time= 4h Patent; Shionogi Co., Ltd.; EP1852436; (2007); (A1) English View in Reaxys With thionyl chloride, Time= 1h, Heating Palomo, Claudio; Landa, Aitor; Mielgo, Antonia; Oiarbide, Mikel; Puente, Angel; Vera, Silvia; Angewandte Chemie, International Edition; vol. 46; nb. 44; (2007); p. 8431 - 8435; Angewandte Chemie; vol. 119; nb. 44; (2007); p. 8583 - 8587 View in Reaxys With thionyl chloride, T= 0 - 20 C
19/47
2012-01-31 07:06:55
SIG1
Dhudshia, Bhartesh; Cooper, Benjamin F. T.; MacDonald, Charles L. B.; Thadani, Avinash N.; Chemical Communications (Cambridge, United Kingdom); nb. 4; (2009); p. 463 - 465 View in Reaxys Example Name 24 PREPARATION 24 (2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester Add thionyl chloride (1.07 mol, 128.2 g) drop wise to a solution of (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid (0.70 mol, 93.0 g) in dry methanol (2 L) at 0.deg. C. under a nitrogen atmosphere. Upon complete addition, warm the reaction mixture to room temperature and stir for 6 h. Concentrate the reaction mixture under reduced pressure to obtain the corresponding methyl ester hydrochloride. With thionyl chloride, Time= 6h, T= 20 C Patent; GAVARDINAS, Konstantinos; Jadhav, Prabhakar Kondaji; US2009/163472; (2009); (A1) English View in Reaxys Example Name 1-1 Example Title Preparation 1-1; Methyl (2S, 4R)-4-hydroxy-2-pyrrolidinecarboxylate hydrochloride Hydroxyproline (155g) was dissolved in Hydrogen Chlororide, Methanol Reagent 10 (TCI, 900mL), and this mixture was heated at reflux for 2hrs. The resulting mixture was cooled to room temperature, and the solvent was removed in vacuo to give the target compound as a white powder (215g). 1H-NMR (in DMSO-D6) : 6 2. 30-1. 99 (2H, m), 3.14-2. 97 (1H, m), 3.45-3. 25 (1H, m), 3.76 (3H, S), 4. 57-4.35 (2H, M), 9.23 (1H, br-s), 10.32 (1H, br-s). With hydrogenchloride in water, Time= 2h, Heating / reflux Patent; FUJISAWA PHARMACEUTICAL CO. LTD.; WO2004/99185; (2004); (A1) English View in Reaxys Example Name 244.1 To a stirred solution of 1' (2 g, 15.26 mmol) was added a solution prepared by adding thionyl choride (2 mL) to methanol (20 mL). The reaction mixture was heated at reflux <n="402"/>for 5 h. After completion of the reaction, methanol was removed under reduced pressure to give 2' as colorless salt (3.0 g) it was used as such in the next reaction With thionyl chloride, Time= 5h, Reflux Patent; AVILA THERAPEUTICS AND USES THEREOF; WO2009/158571; (2009); (A1) English View in Reaxys With thionyl chloride, Time= 4.58333h, T= 0 C , Reflux, Inert atmosphere Gomez-Bengoa, Enrique; Mielgo, Antonia; Otazo, Itziar; Palomo, Claudio; Velilla, Irene; Maestro, Miguel; Chemistry--A European Journal; vol. 16; nb. 18; (2010); p. 5333 - 5342 View in Reaxys With thionyl chloride, T= 0 - 20 C Garrabou, Xavier; Gomez, Livia; Joglar, Jesus; Bujons, Jordi; Clapes, Pere; Gil, Sergi; Parella, Teodor; Chemistry--A European Journal; vol. 16; nb. 35; (2010); p. 10691 - 10706 View in Reaxys With thionyl chloride, Time= 1.08333h, T= 0 - 65 C , Inert atmosphere Thai, Karen; Wang, Li; Gravel, Michel; Dudding, Travis; Bilodeau, Francois; Organic Letters; vol. 12; nb. 24; (2010); p. 5708 - 5711 View in Reaxys
OH
H N
OH O
H N
O O
HO
HO
Rx-ID: 4552785 View in Reaxys 17/97
20/47
2012-01-31 07:06:55
SIG1
Yield
Conditions & References With sulfuric acid, Time= 240h, Heating Monn, James A.; Valli, Matthew J.; Johnson, Bryan G.; Salhoff, Craig R.; Wright, Rebecca A.; et al.; Journal of Medicinal Chemistry; vol. 39; nb. 15; (1996); p. 2990 - 3000 View in Reaxys With hydrogenchloride, Heating Merino, Pedro; Revuelta, Julia; Tejero, Tomas; Chiacchio, Ugo; Rescifina, Antonio; Piperno, Anna; Romeo, Giovanni; Tetrahedron: Asymmetry; vol. 13; nb. 2; (2002); p. 167 - 172 View in Reaxys With hydrogenchloride Renau, Thomas E.; Leger, Roger; Filonova, Lubov; Flamme, Eric M.; Wang, Michael; Yen, Rose; Madsen, Deidre; Griffith, David; Chamberland, Suzanne; Dudley, Michael N.; Lee, Ving J.; et al.; Bioorganic & Medicinal Chemistry Letters; vol. 13; nb. 16; (2003); p. 2755 - 2758 View in Reaxys With thionyl chloride, Heating Schann, Stephan; Menet, Christel; Arvault, Paul; Mercier, Geraldine; Frauli, Melanie; Mayer, Stanislas; Hubert, Nadia; Triballeau, Nicolas; Bertrand, Hugues-Olivier; Acher, Francine; Neuville, Pascal; Bioorganic & Medicinal Chemistry Letters; vol. 16; nb. 18; (2006); p. 4856 - 4860 View in Reaxys Example Name 17.1 Step 1: (2R,4R)-4-Hydroxy-pyrrolidine-2-carboxylic Acid Ethyl Ester (1) To a stirred solution of cis-4-hydroxy-pyrrolidine-2-carboxylic acid (1 g, 7.6 mmol) in absolute ethanol (201 mL) is added dropwise thionyl chloride (0.67 mL, 9.15 mmol) at 0.deg. C. under nitrogen atmosphere. The reaction mixture is then refluxed under nitrogen for about 2 h. The mixture is cooled to room temperature, and all solvent is removed under reduced pressure. The white precipitate is filtered and washed with diethyl ether (1*25 mL), to obtain compound (1) as a white solid. 1H-NMR (400 MHz, DMSO-d ): 1.23 (t, 3H), 2.12 (d, 1H), 2.27 (t, 1H), 3.19 (q, 2H), 4.20 (m, 2H), 4.35 (s, 1H), 4.47 6 (d, 1H). Mass (M+1): m/z 160. With thionyl chloride, T= 0 C , Inert atmosphere, Reflux Patent; Andrews, Martin James Inglis; Chambers, Mark Stuart; Van De Poel, Herve; Bar, Gregory Louis Joseph; US2009/286798; (2009); (A1) English View in Reaxys
H N
HO
OH O
H N
O O
HO
HO
Rx-ID: 5290807 View in Reaxys 18/97 Yield 100 % Conditions & References With thionyl chloride Zhang, Haile; Mitsumori, Susumu; Utsumi, Naoto; Imai, Masanori; Garcia-Delgado, Noemi; Mifsud, Maria; Albertshofer, Klaus; Cheong, Paul Ha-Yeon; Houk, K. N.; Tanaka, Fujie; Barbas, Carlos F.; Journal of the American Chemical Society; vol. 130; nb. 3; (2008); p. 875 - 886 View in Reaxys With thionyl chloride, Time= 19h, T= -20 - 20 C , Esterification Russel, Michael G. N.; Beer, Margaret S.; Stanton, Josephine A.; Sohal, Bindi; Mortishire-Smith, Russell J.; Castro, Jose L.; Bioorganic & Medicinal Chemistry Letters; vol. 9; nb. 17; (1999); p. 2491 - 2496 View in Reaxys
21/47
2012-01-31 07:06:55
SIG1
With hydrogenchloride Dios, Alfonso de; Prieto, Lourdes; Martin, Jose Alfredo; Rubio, Almudena; Ezquerra, Jesus; Tebbe, Mark; Uralde, Beatriz Lopez de; Martin, Justina; Sanchez, Ana; LeTourneau, Deborah L.; McGee, James E.; et al.; Journal of Medicinal Chemistry; vol. 45; nb. 20; (2002); p. 4559 - 4570 View in Reaxys Stage 1: With thionyl chloride, Time= 0.5h, T= -10 C Stage 2:T= 20 C Arakawa, Yasushi; Ohnishi, Masafumi; Yoshimura, Norikazu; Yoshifuji, Shigeyuki; Chemical & Pharmaceutical Bulletin; vol. 51; nb. 8; (2003); p. 1015 - 1020 View in Reaxys Example Name 80.A EXAMPLE 80; Step A; A solution of cis-hydroxy-D-proline (2.98 g, 22.7 mmol) in methanol (20 mL) was treated with thionyl chloride (1.78 mL, 24.4 mmol) and stirred at room temperature for 1 h. The reaction mixture was then heated to 65.deg. C. overnight. Evaporation of the volatiles gave the crude methyl ester (4.0816 g), which was dissolved in dichloromethane (50 mL) and diisopropyl ethyl amine (9.59 mL, 55.1 mmol) was added. The reaction mixture was cooled to 0.deg. C. and neat benzyl chloroformate (3.71 mL, 26.0 mmol) was added via syringe. After stirring at 0.deg. C. for 30 minutes the cooling bath was removed. The reaction was quenched by pouring into an aqueous solution of citric acid (10percent, 50 mL) and the product was extracted into dichloromethane. The combined organic phases were back-washed with brine, dried with anhydrous sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by flash chromatography (silica gel, ethyl acetate:hexanes/4:6) to yield 4.0717 g (69percent) of the pure product. 1H NMR (500 MHz, CDCl3): 7.35 m (5H), 5.21 (d, J=12.6 Hz, 2H), 5.10 (d, J=13 Hz, 1H), 5.06 (d, J=12.35 Hz, 1H), 4.45 (m, 2H), 3.80 (s, 3H), 2.35 (m, 1H), 2.15 (m, 1H). With thionyl chloride, T= 20 - 65 C Patent; Butora, Gabor; Goble, Stephen D.; Pastemak, Alexander; Yang, Lihu; Zhou, Changyou; Moyes, Christopher R.; US2008/81803; (2008); (A1) English View in Reaxys Example Name 7.7.1 EXAMPLE 7Preparation of 6-[(2R,4S)-2-(2-chlorophenoxymethyl)-4-fluoropyrrolidin-1-yl]-9H-purine ("A7")7.1 30 g of (2R,4R)-4-hydroxy pyrrolidine-2-carboxylic acid are suspended in 200 ml of methanol and cooled to 0.deg. C. Thionyl chloride (18.1 ml) is subsequently added dropwise at the same temperature distributed over an hour. The reaction mixture (RM) is warmed to room temperature (RT) over 12 h, during which a clear solution forms. The solvent is removed in vacuo, and the residue obtained is recrystallised from ether, giving 50 g of methyl (2R,4R)-4-hydroxypyrrolidine-2carboxylate; Rt.: 0.386 min; [M+H]+146.2. With thionyl chloride, Time= 13h, T= 0 - 20 C Patent; Merck Patent GmbH; US2011/263561; (2011); (A1) English View in Reaxys
O
N
H N HCl OH
O
OH
Rx-ID: 23164726 View in Reaxys 19/97 Yield Conditions & References Example Name 93.4 Example Title Preparation of 1-(3,4-dimethoxy-5-trifluoromethylthiobenzoyl)-4S-hydroxypyrrolidine-2R-carboxylic acid hydroxyamide; Step 4 [4S-HYDROXYOXY-1-TRITYLPYRROLIDINE-2R-CARBOXYLIC] acid methyl ester (510 mg, 1.32 mmol, [1] eq. ) was treated with anhydrous 4.0 M [HC1] in dioxane (20 mL, excess). The resulting mixture was stirred vigorously at [23 JC] for 3 h, then concentrated to give 4S- hydroxyoxy-1-pyrrolidine-2R-carboxylic acid methyl ester hydrochloride salt. With hydrogenchloride in 1,4-dioxane, Time= 3h, T= 23 C
22/47
2012-01-31 07:06:55
SIG1
Patent; VICURON PHARMACEUTICALS, INC.; WO2004/7444; (2004); (A2) English View in Reaxys
O O
O
HCl OH HN
Rx-ID: 24963100 View in Reaxys 20/97 Yield 93% Conditions & References Example Name 8 Example Title Allo-4-cis-hydroxy-D-proline ethyl ester hydrochloride EXAMPLE 8 Allo-4-cis-hydroxy-D-proline ethyl ester hydrochloride 80 g of 4-cis-hydroxy-D-proline (0.61 mol) was suspended in 500 ml of anhydrous ethanol and anhydrous HC1 gas was allowed to bubble through the mixture until the reaction became homogeneous. The reaction was then heated to reflux for 5 hours and the volume of the solvent was reduced by one half. 100 ml of diethylether was added and the mixture was kept in a freezer overnight. The resulting precipitate was filtered and washed with diethylether and dried under reduced pressure to yield 111 g of product (93percent yield). M.P. 152.deg.-153.deg. C. in ethanol Patent; Braish; Tamim F.; Fox; Darrell E.; US5036153; (1991); (A1) English View in Reaxys
O N
O O O
H N
O Cl O H
HO
HO
Rx-ID: 25204981 View in Reaxys 21/97 Yield Conditions & References Example Name 1.A Example Title A. A. 4-Hydroxy-L-Proline Ethyl Ester Hydrochloride To a solution of N-Cbz-4-hydroxy-L-proline ethyl ester (3.29 g) in 40 ml ethanol was added 6 ml of ethanol saturated with gaseous HCl followed by 10percent palladium on carbon (0.50 g). The mixture was hydrogenated on a Parr Hydrogenator at 30-40 psi for 3 hours. The solution was filtered over celite and concentrated in vacuo to provide 2.09 g of the crystalline product. With hydrogenchloride, palladium in ethanol Patent; USV Pharmaceutical Corp.; US4555508; (1985); (A1) English View in Reaxys
O O O N OH H
H N O O HO
OH
Rx-ID: 22955275 View in Reaxys 22/97 Yield Conditions & References Example Name 11 Example Title EXAMPLE 11 [0057] The compound 4-OH-L-proline methyl ester, described supra, is believed to be a new compound, representative of a new group of compounds. The synthesis, of the compound and guidelines for synthesis of other members of this
23/47
2012-01-31 07:06:55
SIG1
family are now set forth. [0058] 4-hydroxy-L-proline was reacted with di-tert-butyl dicarbonate, in 1N NaOH at 5.deg. C. for 30 minutes, followed by stirring, at room temperature, for an additional 3.5 hours. [0059] The resulting protected 4-hydroxy proline was then reacted in dimethylformamide with potassium carbonate and methyl iodide, at 0.deg. C., for 30 minutes, followed by stirring for an hour, at room temperature, to produce the methyl ester. [0060] Deprotection of tert-butyl dicarbonate was then carried out using trifluoroacetic acid, and standard methods. [0061] The key component in this reaction is methyl iodide. By varying the alkyl halide, esters containing alkyl groups with from 1-30, preferably 1-26 carbon atoms, can be obtained. Stage 1: With potassium carbonate in DMF (N,N-dimethyl-formamide), Time= 1.5h, T= 0 - 20 C Stage 2: With trifluoroacetic acid in DMF (N,N-dimethyl-formamide) Patent; Wondrak, Georg T.; Roberts, Michael J.; Kim, Moonsun; Jacobson, Myron K.; Jacobson, Elaine L.; US2003/223941; (2003); (A1) English View in Reaxys
H N
HO
OH O
H N
O O
HO
HO
Rx-ID: 28356788 View in Reaxys 23/97 Yield Conditions & References Example Name 1 Intermediate 1 methyl (4S)-4-hydroxy-D-prolinateIn a three necked flask under argon atmosphere equipped with a magnetic stir bar and a reflux condenser was placed MeOH (7 ml_). To the system was added acetyl chloride (0.898 g, 11.4 mmol) in an ice bath followed by (4S)-4-hydroxy-D-proline (1 g, 7.6 mmol). The resultant mixture was heated at reflux for 12 hours and cooled down to room temperature. Ether was added to cause precipitation and the resulting brown powder was filtered off to afford the title compound. LC-MS: m/z, 146 (M+H). With acetyl chloride, Time= 12h, T= 0 C , Heating / reflux Patent; GLAXO GROUP LIMITED; WO2009/26197; (2009); (A1) English View in Reaxys With acetyl chloride Laine, Dramane; Palovich, Michael; McCleland, Brent; Petitjean, Emilie; Delhom, Isabelle; Xie, Haibo; Deng, Jianghe; Lin, Guoliang; Davis, Roderick; Jolit, Anais; Nevins, Neysa; Zhao, Baoguang; Villa, Jim; Schneck, Jessica; McDevitt, Patrick; Midgett, Robert; Kmett, Casey; Umbrecht, Sandra; Peck, Brian; Davis, Alicia Bacon; Bettoun, David; Medicinal Chemistry letters; vol. 2; nb. 2; (2011); p. 142 - 147 View in Reaxys With acetyl chloride Rawson, David J.; Brugier, Delphine; Harrison, Anthony; Hough, Jo; Newman, Julie; Otterburn, Joe; Maw, Graham N.; Price, Jenny; Thompson, Lisa R.; Turnpenny, Paul; Warren, Andrew N.; Bioorganic and Medicinal Chemistry Letters; vol. 21; nb. 12; (2011); p. 3771 - 3773 View in Reaxys
OH
H N
OH O
H N
O Cl O H
HO
HO
Rx-ID: 3821893 View in Reaxys 24/97 Yield 98 % Conditions & References With thionyl chloride, T= 0 C , Reflux Delunafreire, Kristerson R.; Tormena, Claudio F.; Coelho, Fernando; Synlett; nb. 14; (2011); p. 2059 - 2063; Art.No: S02011ST View in Reaxys
24/47
2012-01-31 07:06:55
SIG1
93 %
With hydrogenchloride, Time= 5h, Heating Braish, Tamim F.; Fox, Darell E.; Journal of Organic Chemistry; vol. 55; nb. l; (1990); p. 1684 - 1687 View in Reaxys
82 %
With thionyl chloride, Time= 6h, Heating Heindl, Cornelia; Huebner, Harald; Gmeiner, Peter; Tetrahedron: Asymmetry; vol. 14; (2003); p. 3141 - 3152 View in Reaxys
77 %
With thionyl chloride, Time= 4h, Reflux Murphy, Annabel C.; Mitova, Maya I.; Blunt, John W.; Munro, Murray H. G.; Journal of Natural Products; vol. 71; nb. 5; (2008); p. 806 - 809 View in Reaxys
H N
HO
OH O
H N
O O
HO
HO
Rx-ID: 30331853 View in Reaxys 25/97 Yield Conditions & References Example Title 5.1.33. (2S,4R)-1-N-Benzyl-4-hydroxy-2-methoxycarbonylpyrrolidine (36b) Thionyl chloride (20 ml, 0.275 mol) was added dropwise to a stirred suspension of (2R,4R)-4-hydroxyproline (35b) (30.00 g, 0.228 mol) in MeOH (900 ml) at 0 .deg.C. After the consumption of the starting material, methanol was evaporated under reduced pressure. The resulting solid was suspended in DCM (500 ml), and Et3N (127 ml, 0.915 mol) and BnBr (33 ml, 0.275 mol) were added. The mixture was refluxed for 10 h. The solvent was evaporated and the product purified by flash chromatography using a linear gradient of EtOH in CHCl3. The product was obtained as a light yellow oil in a 70percent yield (37.00 g, 0.160 mol). All spectral data recorded were in accordance with the literature data. With thionyl chloride, T= 0 C Kovackova, Sona; Dracinsky, Martin; Rejman, Dominik; Tetrahedron; vol. 67; nb. 7; (2011); p. 1485 - 1500 View in Reaxys
H N
HO
OH O Cl H
HO
H N
O O Cl H
HO
Rx-ID: 28400477 View in Reaxys 26/97 Yield 93 % Conditions & References With thionyl chloride, T= 0 C , Inert atmosphere Peng, Jianbiao; Clive, Derrick L. J.; Journal of Organic Chemistry; vol. 74; nb. 2; (2009); p. 513 - 519 View in Reaxys Example Name 26 PREPARATION 26 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester Add thionyl chloride (1.81 mol, 213.8 g, 1.5 eq) drop wise to a solution of (2R,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid hydrochloride (1.19 mol, 200 g) in dry methanol (2 L) at 0.deg. C. under a nitrogen atmosphere. Upon complete addition, warm the reaction mixture to room temperature and stir for 6 h. Concentrate the reaction mixture under reduced pressure to obtain the corresponding methyl ester hydrochloride. With thionyl chloride, Time= 6h, T= 0 - 20 C Patent; GAVARDINAS, Konstantinos; Jadhav, Prabhakar Kondaji; US2009/163472; (2009); (A1) English View in Reaxys
25/47
2012-01-31 07:06:55
SIG1
OH
H N
OH O Cl H
H N O Cl O H
HO
HO
Rx-ID: 1872963 View in Reaxys 27/97 Yield 77 % Conditions & References With hydrogenchloride, Time= 5h, Heating Baker, Gregory L.; Fritschel, Scott J.; Stille, John R.; Stille, John K.; Journal of Organic Chemistry; vol. 46; nb. 14; (1981); p. 2954 - 2960 View in Reaxys 69 % With thionyl chloride, Etherification Yanagi, Toshiharu; Kitajima, Akihiko; Anzai, Kinsei; Kodama, Kazuya; Mizoguchi, Jun-ichi; Fujiwara, Hiromichi; Sakiyama, Hideyo; Kamoda, Osamu; Kamei, Chiaki; Chemical & Pharmaceutical Bulletin; vol. 47; nb. 11; (1999); p. 1650 - 1654 View in Reaxys 67 % With hydrogenchloride in ethanol, Time= 5h, Heating Nishonov, Abdumalik A.; Ma, Xiaohui; Nair, Vasu; Bioorganic & Medicinal Chemistry Letters; vol. 16; nb. 15; (2006); p. 4099 - 4101 View in Reaxys With thionyl chloride, Time= 6h, Heating Tanaka, Ken-ichi; Sawanishi, Hiroyuki; Tetrahedron: Asymmetry; vol. 6; nb. 7; (1995); p. 1641 - 1656 View in Reaxys
O N
O O O
H N
O Cl O H
HO
HO
Rx-ID: 2663820 View in Reaxys 28/97 Yield 96 % Conditions & References With hydrogenchloride in ethyl acetate, Time= 3h Ng, Kam-mui Eva; Orgel, Leslie E.; Journal of Medicinal Chemistry; vol. 32; nb. 8; (1989); p. 1754 - 1757 View in Reaxys
O O N
O H
H N
O O
OH
HO
Rx-ID: 4522003 View in Reaxys 29/97 Yield Conditions & References With hydrogen, palladium on activated charcoal in ethanol, Time= 2.5h, p= 3102.9Torr , Ambient temperature Monn, James A.; Valli, Matthew J.; Johnson, Bryan G.; Salhoff, Craig R.; Wright, Rebecca A.; et al.; Journal of Medicinal Chemistry; vol. 39; nb. 15; (1996); p. 2990 - 3000 View in Reaxys
26/47
2012-01-31 07:06:55
SIG1
H N
OH O
HO
O O HCl NH
HO
Rx-ID: 24142128 View in Reaxys 30/97 Yield Conditions & References Example Name 11 Example Title Preparation of (2R-trans)-4-fluoro-2-pyrrolidinecarboxylic Acid EXAMPLE 11 Preparation of (2R-trans)-4-fluoro-2-pyrrolidinecarboxylic Acid A suspension of 65.0 g (0.50 mol) of cis-4-hydroxy-D-proline in 1500 mL of methanol was cooled to 0.deg. C. and 110 mL (179 g, 1.5 mol) of thionyl chloride was added dropwise at 0-5.deg. C. The mixture was then allowed to warm to room temperature overnight. The volatiles were removed under reduced pressure and the residue was triturated with diethyl ether to afford 98.73 g of crude cis-4-hydroxy-D-proline methyl ester hydrochloride as a white solid. With thionyl chloride in methanol Patent; Degussa AG; US6384234; (2002); (B1) English View in Reaxys
H N
OH O
H N
O O
HO
HO
Rx-ID: 28274971 View in Reaxys 31/97 Yield Conditions & References Example Name 3.1 Example Title Step 1. Step 1. Preparation of (2R,4S)-methyl 4-hydroxypyrrolidine-2-carboxylate (Compound 18) Thionyl chloride (0.83 ml, 11.4 mmol) is added dropwise into a suspension of H-D-Hyp-OH (1.0 g, 7.6 mmol) in methanol (25 ml) at 0.deg. C. The mix is stirred at room temperature for 1 hr, then 65.deg. C. for another 1 hr. Solvent is evaporated to dryness. Compound 18 is obtained as a white crystal and used for the next step. With thionyl chloride in methanol Patent; ACHILLION PHARMACEUTICALS, INC.; US2009/82261; (2009); (A1) English View in Reaxys
O O N
O O H
H N
O O Cl H
HO
OH
Rx-ID: 28518677 View in Reaxys 32/97 Yield Conditions & References Example Name 1 Scheme 1-83.7percent, 3 steps1-6 1-5All of the oximyl analogs were prepared from the common intermediate 1.-6. The synthesis of compound 1.-6 is outlined in Scheme 1. Deprotection of commercially available Boc-hydroxyproline 1.-1 with HCl in dioxane followed by coupling with acid 1.-2 using HATU, afforded intermediate 1.-3. Other amino acid derivatives containing a terminal alkene may be used in place of 1.-2 in order to generate varied macrocyclic structures (for further details see WO/0059929). Hydrolysis of 1-3 with LiOH followed by subsequent peptide coupling with cyclopropyl-containing amine 1.-4 yielded tri-peptide 1.-5. Finally, ring-closing metathesis with a ruthenium-based catalyst such as dichloro(o- isopropoxyphenylmethylene) (tricyclohexylphosphine)ruthenium(II) gave the desired key intermediate 1.-6 (for further details on ring closing metathesis see recent reviews: Grubbs et al, Ace. Chem. Res., 1995,
27/47
2012-01-31 07:06:55
SIG1
28, 446; Shrock et al, Tetrahedron 1999, 55, 8141; Furstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012; Trnka et al., Ace. Chem. Res. 2001, 34, 18; and Hoveyda et al., Chem. Eur. J. 2001, 7, 945). With hydrogenchloride in 1,4-dioxane Patent; ENANTA PHARMACEUTICALS, INC.; WO2009/73713; (2009); (A1) English View in Reaxys
O O
O N O HO O O
HN
OH
Rx-ID: 3718581 View in Reaxys 33/97 Yield Conditions & References With hydrogen, palladium on activated charcoal in methanol, Time= 2h Williams, Matthew A.; Rapoport, Henry; Journal of Organic Chemistry; vol. 59; nb. 13; (1994); p. 3616 - 3625 View in Reaxys 2.4 g With hydrogen, palladium on activated charcoal in methanol, Time= 10h, p= 760Torr , Ambient temperature Tanaka, Ken-ichi; Sawanishi, Hiroyuki; Tetrahedron: Asymmetry; vol. 6; nb. 7; (1995); p. 1641 - 1656 View in Reaxys
H N
HO
OH O
H N
O O
HO
HO
Rx-ID: 23840058 View in Reaxys 34/97 Yield Conditions & References Example Name 82 Thionyl chloride (612 ml) was added dropwise to a solution of L-hydroxyproline (1.0 g) in methanol (10 ml) at room temperature, and the resulting mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, followed by adding thereto chloroform (10 ml) and a saturated aqueous sodium hydrogencarbonate solution and then di-tert-butyl dicarbonate (2.5 g), and the resulting mixture was stirred at room temperature for 2 hours. The organic layer was concentrated under reduced pressure to obtain the title compound as a crude product (3.38 g). 1H NMR (400 MHz, CDCl3) ppm 5.58-5.48 (m, 2H), 5.06-5.03 (m, 1H), 4.87-4.86 (m, 1H), 4.25-4.23 (m, 2H), 3.82-3.74 (m, 2H), 3.68-3.60 (m, 2H), 3.56-3.53 (m, 4H), 3.45-3.33 (m, 2H), 3.38 (s, 3H), 3.15-3.12 (m, 4H), 1.78 (s, 3H), 1.48 (s, 9H), 1.27-1.16 (m, 9H). MS (ESI+) 580 (M++1, 100percent). With thionyl chloride, T= 20 C Patent; Dainippon Sumitomo Pharma Co., Ltd.; EP1659123; (2006); (A1) English View in Reaxys
O O Cl
H N
O Cl O
N
O O O
HO
HO
Rx-ID: 24965177 View in Reaxys 35/97 Yield Conditions & References Example Name R.3.1
28/47
2012-01-31 07:06:55
SIG1
Example Title REFERENCE EXAMPLE 3 (1) 76.0 g of (2R,4R)-2-ethoxycarbonyl-4-hydroxy pyrrolidine hydrochloride obtained by the method stated in J. Org. Chem. 46, 2954 (1981) were suspended in 380 ml of chloroform and to this, were added with 94.4 g of triethylamine and then dropwise with 79.6 g of benzyloxycarbonyl chloride. While cooling with water, the combined was stirred for 7 hours and then poured into ice-water and extracted with chloroform. The chloroform extract was after-treated to obtain (2R,4R)-N-benzyloxycarbonyl-2-ethoxycarbonyl-4-hydroxy pyrrolidine as an oily product. Yield 114.5 g. NMR (CDCl3)(TMS, ppm): 0.9-1.5 (3H), 2.0-2.5 (2H), 3.1-4.6 (7H), 5.13 (2H,s), 7.33 (5H, s). With triethylamine in chloroform Patent; Teikoku Chemical Industry Co., Ltd.; US5143935; (1992); (A1) English View in Reaxys
F
O N O HO O O
F F
O F HO F F HO
HO O
H N
O O
Rx-ID: 28095793 View in Reaxys 36/97 Yield Conditions & References Example Name 4.1 Step 4-1: Synthesis of methyl (4R)-4-hydroxy-L-prolinate trifluoroacetate To a solution of 2.00 g of 1-tert-butyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate in CHCl3 (20 ml) was added TFA (10 ml) under ice cooling, the reaction mixture was warmed to room temperature, then was stirred for 3 hours at the same temperature. Thereafter, the reaction solution was concentrated under reduced pressure to obtain 3.82 g of the title compound (crude form, colorless oil). The present compound was used in the next reaction without purification. MS (ESI pos.) m/z: 146 ([M+H]+) 1H-NMR (300 MHz, DMSO-d ) (ppm); 2.05-2.29 (m, 2H), 3.04-3.16 (m, 1H), 3.27-3.41 (m, 1H), 3.77 and 3.78 (each6 s, 3H), 4.40-4.67 (m, 2H), 9.06 (s, 1H), 9.98 (s, 1H) in chloroform, Time= 3h, T= 0 - 20 C Patent; TAISHO PHARMACEUTICAL CO., LTD.; US2008/318923; (2008); (A1) English View in Reaxys
H N
NH
O O
HO
I O O
Rx-ID: 4501735 View in Reaxys 37/97 Yield Conditions & References With hydrogen, palladium dihydroxide in ethanol, Time= 5h, p= 1861.7Torr , Ambient temperature Madau, Alessandra; Porzi, Gianni; Sandri, Sergio; Tetrahedron: Asymmetry; vol. 7; nb. 3; (1996); p. 825 - 830 View in Reaxys
29/47
2012-01-31 07:06:55
SIG1
H N
O N O HO
O O
HO
Rx-ID: 4501773 View in Reaxys 38/97 Yield Conditions & References With hydrogen, palladium dihydroxide in ethanol, Time= 5h, p= 1861.7Torr , Ambient temperature Madau, Alessandra; Porzi, Gianni; Sandri, Sergio; Tetrahedron: Asymmetry; vol. 7; nb. 3; (1996); p. 825 - 830 View in Reaxys
O N O O
H N
O O
HO
O
Rx-ID: 3139769 View in Reaxys 39/97 Yield Conditions & References With hydrogen, palladium dihydroxide in methanol, Time= 24h, p= 2280Torr Hara, Junko; Inouye, Yoshinobu; Kakisawa, Hiroshi; Bulletin of the Chemical Society of Japan; vol. 54; nb. 12; (1981); p. 3871 - 3872 View in Reaxys
O N O O
HO
H N
O O
O N O O
H N
O O
HO
O
30/47
2012-01-31 07:06:55
SIG1
O N
O O OH
H N
O O
HO
HO
Rx-ID: 17667006 View in Reaxys 42/97 Yield Conditions & References Reaction Steps: 2 1: 81 percent / Et3N / acetonitrile / 55 C 2: H2 / 5percent Pd/C / ethanol / 2.5 h / 3102.9 Torr / Ambient temperature With hydrogen, triethylamine, palladium on activated charcoal in ethanol, acetonitrile Monn, James A.; Valli, Matthew J.; Johnson, Bryan G.; Salhoff, Craig R.; Wright, Rebecca A.; et al.; Journal of Medicinal Chemistry; vol. 39; nb. 15; (1996); p. 2990 - 3000 View in Reaxys
H N
OH O
H N
O O
HO
HO
Rx-ID: 24717658 View in Reaxys 43/97 Yield Conditions & References Example Name 56.A Example Title Step A Step A 4(R)-Hydroxyproline methyl ester A suspension of 4(R)-hydroxyproline (35.12 g, 267.8 mmol) in methanol (500 ml) was saturated with gasseous hydrochloric acid. The resulting solution was allowed to stand for 16 hrs and the solvent evaporated in vacuo to afford the title compound as a white solid. 1 H NMR CD OD 4.60 (2H, m), 3.86(3H, s), 3.48(1H, dd, J=3.6 and 12.0 Hz), 3.23(1H, d, J=12.0 Hz), 2.43(1H, m) 3 and 2.21(1H, m) ppm. in methanol Patent; Merck and Co., Inc.; US5756528; (1998); (A1) English View in Reaxys
O O N
O O H
H N
O O
HO
OH
Rx-ID: 29326689 View in Reaxys 44/97 Yield Conditions & References With trifluoroacetic acid in dichloromethane, Time= 1.5h, T= 0 C Owens, Neil W.; Lee, Adrian; Marat, Kirk; Schweizer, Frank; Chemistry--A European Journal; vol. 15; nb. 40; (2009); p. 10649 - 10657 View in Reaxys
31/47
2012-01-31 07:06:55
SIG1
O
H N OH O HO
O HN H
OH
Rx-ID: 18379802 View in Reaxys 45/97 Yield Conditions & References Reaction Steps: 3 1: NaHCO3 / H2O / 2 h 2: tetrahydrofuran / 1.) r.t., 30 min, 2.) 55 deg C, 20.5 h 3: H2 / 10percent Pd/C / methanol / 2 h With hydrogen, sodium hydrogencarbonate, palladium on activated charcoal in tetrahydrofuran, methanol, water Williams, Matthew A.; Rapoport, Henry; Journal of Organic Chemistry; vol. 59; nb. 13; (1994); p. 3616 - 3625 View in Reaxys
O O
O N OH HO O O
HN
OH
Rx-ID: 18380335 View in Reaxys 46/97 Yield Conditions & References Reaction Steps: 2 1: tetrahydrofuran / 1.) r.t., 30 min, 2.) 55 deg C, 20.5 h 2: H2 / 10percent Pd/C / methanol / 2 h With hydrogen, palladium on activated charcoal in tetrahydrofuran, methanol Williams, Matthew A.; Rapoport, Henry; Journal of Organic Chemistry; vol. 59; nb. 13; (1994); p. 3616 - 3625 View in Reaxys
Cl
H N
OH O
H N
O O
HO
HO
Rx-ID: 24346022 View in Reaxys 47/97 Yield Conditions & References Example Name 30 Example Title (2R,4R)-2-Carbomethoxy-4-hydroxypyrrolidine (35) (2R,4R)-2-Carbomethoxy-4-hydroxypyrrolidine (35) In a 250 ml round bottom flask equipped with a magnetic stir bar and a reflex condenser were placed dry methanol (40 ml) and cooled in ice bath under argon atmosphere. To this stirred solution was added acetyl chloride (4.32 g, 55 mmol) followed by cis-4-hydroxy-D-proline 34 (5.00 g, 38.17 mmol). The resulting solution was heated at reflex for 7-8 h and cooled to room temperature. The solution was diluted with ether, and the resulting white solid was collected by suction, was with ether and dried under vacuum over solid NaOH. Yield; 6.9 g (100percent). 1 H-NMR (CDCl3): 2.09 (2 dd, 1H), 2.34 (m, 1H), 3.49-3.73 (m, 3H), 3.79 (s, 3H, CH3), 4.34 (m, 2H) in methanol Patent; ICN Pharmaceuticals, Inc.; US5969135; (1999); (A1) English View in Reaxys
32/47
2012-01-31 07:06:55
SIG1
H N
F HO
O
F F
O
F F
HO O N H O
O
HO
OH
Rx-ID: 24791539 View in Reaxys 48/97 Yield Conditions & References Example Name B.102.1 To a solution of ez's-hydroxyprolinemethyl ester (20 g, 81 mmol) inDCM (200 mL) was added TFA (40 mL). The reaction was stirred for 2 h withmonitoring by LC/MS. Strip solvent and coevaporate with toluene 2X thenchloroform 3X. Remove excess TFA by placing the reaction mixture underhigh vacuum for 5 h which afforded TFA salt (~ 21 g) as an orange viscous oil.LC/MS: 260 (M+ + l).To a solution of TFA salt (10.0 g, 40.7 mmol) in DMF (125 mL) was addedcyclopentyloxycarbonyl-fert-leucinecarboxylic acid (12g, 48 mmol), andHATU (23g, 61 mmol). The reaction mixture was cooled to 0 .deg.C and Hunig'sbase (28 mL, 163 mmol) was added slowly over 5 min. The reaction wasallowed to warm to room temperature and stirred for 1 h. Remove solventunder reduced pressure and dilute with ethyl acetate. Extract the organicswith sat sodium bicarb, water and brine. Purification of the product on silicagel (10-100percent ethyl acetate/ hexane) to afford dipeptide (14.2g, 94percent) as a whitesolid. aH NMR (300 MHz, CDCla): 8 5.51 (d, J= 8.7 Hz, 1H), 5.02 (m, 1H), 4.68(m, 1H), 4.56 (m, 1H), 4.44 (d, J= 9.1 Hz, 1H), 3.96-3.91 (bs, 4H), 3.83 (m, 1H),2.47 (m, 2H), 1.89-1.47 (bs, 10H), 1.09 (s, 9H). LC/MS: 371 (M+ +1). in dichloromethane, Time= 2h Patent; GILEAD SCIENCES, INC.; WO2006/20276; (2006); (A2) English View in Reaxys
OH Cl H
O O HN HCl OH
Cl
H
HO HN
Rx-ID: 24874692 View in Reaxys 49/97 Yield 212.1 g (75%) Conditions & References Example Title ALLO-4-HYDROXY-D-PROLINE ETHYL ESTER HYDROCHLORID (2) ALLO-4-HYDROXY-D-PROLINE ETHYL ESTER HYDROCHLORID (2) A slurry of 240 g (1.432 mole) mor Allo-4-hydroxy-D-Proline hydrochloride in 1.2 L of absolute ethanol was treated with dry hydrogene chloride until homogeneous. The solution was heated to the reflux temperature for 5 h. The mixture was kept at room temperature overnight, then cooled in an ice bath and the resulting precipitate was filtered, washed with acetone and dried under reduced pressure to yield 212.1 g (75percent) of (2) M.P. -148.deg. C. []D = +20.37.deg. (c=2, H2 O). in ethanol Patent; Bristol-Myers Company; US4954507; (1990); (A1) English View in Reaxys
OH
H N
OH O
H N
O O
HO
HO
Rx-ID: 28019207 View in Reaxys 50/97 Yield Conditions & References Example Name 132 Example 132. (4R)-4-Hydroxy-D-proline, Ethyl Ester (132); [0518] In accordance with the procedure of Shunji Sakuraba et al. (Chem. Pharm. Bull,1995, 43, 738), 4-hydroxy-L-proline (10 g, 76.3 mmol) was treated with Ac2O (72 mL, 0.763 mol, d 1.087) in AcOH followed by HCl in EtOH to afford the title compound as a white gum: 1H NMR H (250 MHz, CDCl3) 5.45 (IH, br s), 4.37 (2H, m), 4.18 (2H, q), 3.16 (2H, m), 2.28 (IH, ddd), 2.12 (IH, br d), 1.21 (3H, t). Stage 1: With acetic anhydride, acetic acid Stage 2: With hydrogenchloride
33/47
2012-01-31 07:06:55
SIG1
Patent; PANACOS PHARMACEUTICALS, INC.; NITZ, Theodore, J.; SALZWEDEL, Karl; FINNEGAN, Catherine; WILD, Carl; BRUNTON, Shirley; FLANAGAN, Stuart; MONTALBETTI, Christian; COULTER, Thomas, Stephen; KIMBER, Marc; MAGARACI, Filippo; JOHNSTON, David; WO2008/134035; (2008); (A1) English View in Reaxys
O
O
Cl
H N
OH O
H N
O O
HO
HO
Rx-ID: 24876282 View in Reaxys 51/97 Yield Conditions & References Example Name 41.A Example Title A. A. (2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid methyl ester Acetyl chloride (7.6 ml; 107 mmol) was added slowly to MeOH (70 ml). The reaction was exothermic. (2S,4R)-4-Hydroxy-2-pyrrolidinecarboxylic acid (10 g; 76.2 mmol) was added and the mixture was refluxed for 4 hours. At this time, another portion of 3 ml of acetyl chloride in 30 ml of MeOH was added. The mixture was refluxed an additional 3 hours. The reaction was cooled to room temperature and ~750 ml of Et2 O was added. The resulting colorless crystals were filtered and dried to afford 11.89 g of the title A compound. in methanol Patent; E. R. Squibb and Sons, Inc.; US4902684; (1990); (A1) English View in Reaxys
H N
O O
NH O NH 2
HO
Rx-ID: 17787738 View in Reaxys 52/97 Yield Conditions & References Reaction Steps: 2 1: iodine / tetrahydrofuran; H2O / 0.5 h / Ambient temperature 2: H2 / Pd(OH)2 / ethanol / 5 h / 1861.7 Torr / Ambient temperature With hydrogen, iodine, palladium dihydroxide in tetrahydrofuran, ethanol, water Madau, Alessandra; Porzi, Gianni; Sandri, Sergio; Tetrahedron: Asymmetry; vol. 7; nb. 3; (1996); p. 825 - 830 View in Reaxys
H N
NH
O O
HO
I O O
Rx-ID: 17787835 View in Reaxys 53/97 Yield Conditions & References Reaction Steps: 2 1: 90 percent / Na2CO3 / 24 h / Ambient temperature 2: H2 / Pd(OH)2 / ethanol / 5 h / 1861.7 Torr / Ambient temperature With hydrogen, sodium carbonate, palladium dihydroxide in ethanol Madau, Alessandra; Porzi, Gianni; Sandri, Sergio; Tetrahedron: Asymmetry; vol. 7; nb. 3; (1996); p. 825 - 830 View in Reaxys
34/47
2012-01-31 07:06:55
SIG1
O N O O
HO
H N
O O
Rx-ID: 17788060 View in Reaxys 54/97 Yield Conditions & References Reaction Steps: 3 1: NH3 / ethanol / 0.5 h / 0 C 2: iodine / tetrahydrofuran; H2O / 0.5 h / Ambient temperature 3: H2 / Pd(OH)2 / ethanol / 5 h / 1861.7 Torr / Ambient temperature With ammonia, hydrogen, iodine, palladium dihydroxide in tetrahydrofuran, ethanol, water Madau, Alessandra; Porzi, Gianni; Sandri, Sergio; Tetrahedron: Asymmetry; vol. 7; nb. 3; (1996); p. 825 - 830 View in Reaxys
OH
H N
OH O Cl H
H N
O O
HO
HO
Rx-ID: 31755363 View in Reaxys 55/97 Yield 73 % Conditions & References With thionyl chloride, T= 20 C Watanabe, Akiko; Yamasaki, Tetsuo; Tanda, Kazuhiro; Miyagoe, Tatsunori; Sakamoto, Masanori; Kiyota, Naotoshi; Otsuka, Masami; Journal of Heterocyclic Chemistry; vol. 48; nb. 5; (2011); p. 1132 - 1139 View in Reaxys
Cl
H N
OH O
H N
O O Cl H
HO
HO
Rx-ID: 3821896 View in Reaxys 56/97 Yield 100 % Conditions & References in methanol, Time= 8h, Heating Rosen, Terry; Fesik, Stephen W.; Chu, Daniel T. W.; Pernet, Andre G.; Synthesis; nb. 1; (1988); p. 40 - 44 View in Reaxys
OH
H N
OH O
H N
O Cl O H
HO
HO
Rx-ID: 3821916 View in Reaxys 57/97 Yield 94 % Conditions & References With hydrogenchloride, Time= 2h, Heating Karim, A.; Mortreux, A.; Petit, F.; Buono, G.; Pfeiffer, G.; Siv, C.; Journal of Organometallic Chemistry; vol. 317; (1986); p. 93 - 104 View in Reaxys
35/47
2012-01-31 07:06:55
SIG1
H N
OH O
H N
O Cl O H
HO
HO
Rx-ID: 11787701 View in Reaxys 58/97 Yield Conditions & References Reaction Steps: 2 1.1: Ac2O; AcOH / 5.5 h / Heating 1.2: 65 percent / aq. HCl / 3 h / Heating 2.1: 67 percent / HCl / ethanol / 5 h / Heating With hydrogenchloride, acetic anhydride, acetic acid in ethanol Nishonov, Abdumalik A.; Ma, Xiaohui; Nair, Vasu; Bioorganic & Medicinal Chemistry Letters; vol. 16; nb. 15; (2006); p. 4099 - 4101 View in Reaxys Reaction Steps: 2 1.1: Ac2O / acetic acid / 5.5 h / Heating 1.2: 96 percent / aq. HCl / 3 h / Heating 2.1: 82 percent / SOCl2 / 6 h / Heating With thionyl chloride, acetic anhydride in acetic acid Heindl, Cornelia; Huebner, Harald; Gmeiner, Peter; Tetrahedron: Asymmetry; vol. 14; (2003); p. 3141 - 3152 View in Reaxys Reaction Steps: 2 1: 1.) acetic anhydride, 2.) 2N HCl / 1.) glacial acetic acid, reflux, 5.5 h, 2.) reflux, 3 h 2: 77 percent / HCl (gas) / 5 h / Heating With hydrogenchloride, acetic anhydride Baker, Gregory L.; Fritschel, Scott J.; Stille, John R.; Stille, John K.; Journal of Organic Chemistry; vol. 46; nb. 14; (1981); p. 2954 - 2960 View in Reaxys
O
OH
O N OH HO
H N
O Cl O H
HO
Rx-ID: 1873983 View in Reaxys 59/97 Yield 57 % Conditions & References With hydrogenchloride, Heating Baker, Gregory L.; Fritschel, Scott J.; Stille, John R.; Stille, John K.; Journal of Organic Chemistry; vol. 46; nb. 14; (1981); p. 2954 - 2960 View in Reaxys
Cl
H N
OH O
H N
O O Cl H
HO
HO
Rx-ID: 9480534 View in Reaxys 60/97 Yield 92 % Conditions & References in methanol, Time= 8h, Heating Cho, Han-Won; Oh, Chang-Hyun; Lee, Ju-Shin; Lee, Soo-Chul; Choi, Jung-Hoon; Cho, Jung-Hyuck; Archiv der Pharmazie (Weinheim, Germany); vol. 336; nb. 11; (2003); p. 495 - 503 View in Reaxys
36/47
2012-01-31 07:06:55
SIG1
O O
N O O HO
H N
O O O
O S
HO
HO
HO
Rx-ID: 2740592 View in Reaxys 61/97 Yield 85 % Conditions & References in tetrahydrofuran, isopropyl alcohol, Time= 0.25h, Ambient temperature Papaioannou, Dionissios; Stavropoulos, George; Karagiannis, Kostas; Francis, George W.; Brekke, Trond; Aksnes, Dagfinn W.; Acta Chemica Scandinavica; vol. 44; nb. 3; (1990); p. 243 - 251 View in Reaxys
H N
HO
Cl O
H N
O O Cl H
HO
HO
Rx-ID: 23674389 View in Reaxys 62/97 Yield Conditions & References Example Name 4 4-(R)-Hydroxypyrrolidine-2-(R)-carboxylic acid methyl ester hydrochloride Add thionyl chloride (5.5 mL, 75.8 mmol) to an ice-cold suspension of 4-(R)- hydroxypyrrolidine-2- (R)-carboxylic acid (4.97 g, 31.9 mmol) in methanol (60 mL). Stir 10 min, then warm to room temperature and stir 3.5 h. Concentrate, add methanol, and concentrate again. Dissolve in absolute ethanol (25 mL) and precipitate with diethyl ether (50 mL) and filter. Dry cake under vacuum to give the title compound as a white solid (4.77 g, 82percent). MS (ES): m/z = 146.1 [M+H]. Patent; ELI LILLY AND COMPANY; WO2005/108358; (2005); (A2) English View in Reaxys
HO
HO
O NH Cl
HO
H N
O O
Rx-ID: 23674441 View in Reaxys 63/97 Yield Conditions & References Example Name 7 Add thionyl chloride (5.8 mL, 79.4 mmol) to an ice-cold suspension of 4- (S)- hydroxypyrrolidine-2- (R)-carboxylic acid (4.97 g, 31.9 mmol) in methanol (70 mL). Stir 10 min, then warm to room temperature and stir 3.5 h. Concentrate, add methanol and concentrate again to give the title compound as a white solid (7.18. g, 99percent). MS (ES): m/z = 146.1 [M+H]. Patent; ELI LILLY AND COMPANY; WO2005/108358; (2005); (A2) English View in Reaxys
H N
O O
OH O
H N
O O Cl H
HO
HO
Rx-ID: 3821951 View in Reaxys 64/97 Yield 83 % Conditions & References With hydrogenchloride, Ambient temperature Papaioannou, Dionissios; Stavropoulos, George; Karagiannis, Kostas; Francis, George W.; Brekke, Trond; Aksnes, Dagfinn W.; Acta Chemica Scandinavica; vol. 44; nb. 3; (1990); p. 243 - 251 View in Reaxys
37/47
2012-01-31 07:06:55
SIG1
H N
O O
O O
HO
HO
Rx-ID: 4876104 View in Reaxys 65/97 Yield Conditions & References With formic acid in 1,2-dichloro-ethane Demange, Luc; Menez, Andre; Dugave, Christophe; Tetrahedron Letters; vol. 39; nb. 10; (1998); p. 1169 - 1172 View in Reaxys
H N
O O Cl H
H N
O O
HO
HO
Rx-ID: 16958721 View in Reaxys 66/97 Yield Conditions & References Reaction Steps: 3 1: 76 percent / Et3N / CHCl3 / 0 C 2: 1.) PPh3, DEAD, PhCO2H; 2.) KOH / 1.) toluene; 2.) MeOH 3: HCO2H / 1,2-dichloro-ethane With potassium hydroxide, formic acid, triethylamine, triphenylphosphine, benzoic acid, diethylazodicarboxylate in chloroform, 1,2-dichloro-ethane Demange, Luc; Menez, Andre; Dugave, Christophe; Tetrahedron Letters; vol. 39; nb. 10; (1998); p. 1169 - 1172 View in Reaxys
H N
O O
O O
HO
HO
Rx-ID: 16958973 View in Reaxys 67/97 Yield Conditions & References Reaction Steps: 2 1: 1.) PPh3, DEAD, PhCO2H; 2.) KOH / 1.) toluene; 2.) MeOH 2: HCO2H / 1,2-dichloro-ethane With potassium hydroxide, formic acid, triphenylphosphine, benzoic acid, diethylazodicarboxylate in 1,2-dichloroethane Demange, Luc; Menez, Andre; Dugave, Christophe; Tetrahedron Letters; vol. 39; nb. 10; (1998); p. 1169 - 1172 View in Reaxys
O N O
HO
H N
O O O
O S
HO
Rx-ID: 21958919 View in Reaxys 68/97 Yield Conditions & References Reaction Steps: 2
38/47
2012-01-31 07:06:55
SIG1
1: 85 percent / triphenylphosphine (TPP), diethyl azodicarboxylate (DAED) / tetrahydrofuran / 48 h / Ambient temperature 2: 85 percent / tetrahydrofuran; propan-2-ol / 0.25 h / Ambient temperature With triphenylphosphine, diethylazodicarboxylate in tetrahydrofuran, isopropyl alcohol Papaioannou, Dionissios; Stavropoulos, George; Karagiannis, Kostas; Francis, George W.; Brekke, Trond; Aksnes, Dagfinn W.; Acta Chemica Scandinavica; vol. 44; nb. 3; (1990); p. 243 - 251 View in Reaxys
H N
N O OH HO
O O O
O S
HO HO
Rx-ID: 21971010 View in Reaxys 69/97 Yield Conditions & References Reaction Steps: 3 1: triphenylphosphine (TPP), diethyl azodicarboxylate (DAED) / tetrahydrofuran / 0.08 h / 0 C 2: 85 percent / triphenylphosphine (TPP), diethyl azodicarboxylate (DAED) / tetrahydrofuran / 48 h / Ambient temperature 3: 85 percent / tetrahydrofuran; propan-2-ol / 0.25 h / Ambient temperature With triphenylphosphine, diethylazodicarboxylate in tetrahydrofuran, isopropyl alcohol Papaioannou, Dionissios; Stavropoulos, George; Karagiannis, Kostas; Francis, George W.; Brekke, Trond; Aksnes, Dagfinn W.; Acta Chemica Scandinavica; vol. 44; nb. 3; (1990); p. 243 - 251 View in Reaxys
H N
O Cl O H
H N
O O
HO
HO
Rx-ID: 23591299 View in Reaxys 70/97 Yield Conditions & References Example Name 1 With ammonia in methanol, chloroform, Time= 0.0833333h Patent; SALAMA, Zoser, B.; WO2005/58816; (2005); (A1) German View in Reaxys
OH
H N
OH O
H N
O O
HO
HO
Rx-ID: 807151 View in Reaxys 71/97 Yield Conditions & References With hydrogenchloride Adams et al.; Journal of Biological Chemistry; vol. 208; (1954); p. 573,577 View in Reaxys
39/47
2012-01-31 07:06:55
SIG1
H N
HO
Cl O
H N
O O
HO
HO
Rx-ID: 4066277 View in Reaxys 72/97 Yield Conditions & References T= -5 C Kolodziej, Stephen A.; Nikiforovich, Gregory V.; Skeean, Richard; Lignon, Marie-Francoise; Martinez, Jean; Marshall, Garland R.; Journal of Medicinal Chemistry; vol. 38; nb. 1; (1995); p. 137 - 149 View in Reaxys
OH
trans-4-hydroxy-DL-proline-hydrochlor ide
HO
H N
O O
racemate
Rx-ID: 5706100 View in Reaxys 73/97 Yield Conditions & References Gaudry; Godin; Journal of the American Chemical Society; vol. 76; (1954); p. 139,141 View in Reaxys
OH
cis-4-hydroxy-DL-proline-hydrochlor ide
HO
H N
O O
racemate
Rx-ID: 5706101 View in Reaxys 74/97 Yield Conditions & References Gaudry; Godin; Journal of the American Chemical Society; vol. 76; (1954); p. 139,141 View in Reaxys
OH
H N
OH O
H N O Cl O H
HO
HO
Rx-ID: 4379748 View in Reaxys 75/97 Yield Conditions & References With thionyl chloride, Time= 6h, Heating Tanaka, Ken-ichi; Sawanishi, Hiroyuki; Tetrahedron: Asymmetry; vol. 6; nb. 7; (1995); p. 1641 - 1656 View in Reaxys
OH O
HO
H N
HO O N H O
HO racemate
racemate
Rx-ID: 10547666 View in Reaxys 76/97 Yield Conditions & References With acetyl chloride, Time= 24h Asari, Asnuzilawati; Angelov, Plamen; Auty, James M.; Hayes, Christopher J.; Tetrahedron Letters; vol. 48; nb. 14; (2007); p. 2631 - 2634 View in Reaxys
40/47
2012-01-31 07:06:55
SIG1
H N
HO
OH O Cl H
HO
H N
O O
HO
Rx-ID: 28219244 View in Reaxys 77/97 Yield Conditions & References With thionyl chloride Stevens, Kirk L.; Alberti, Jennifer G. Badiang; Caferro, Thomas R.; Chamberlain, Stanley D.; Dickson, Hamilton D.; Emerson, Holly K.; Hubbard, Robert D.; Petrov, Kimberly G.; Gerding, Roseanne M.; Reno, Michael J.; Rheault, Tara R.; Sammond, Douglas M.; Smith, Stephon C.; Uehling, David E.; Waterson, Alex G.; Alligood, Krystal J.; Keith, Barry R.; Mullin, Robert J.; Rusnak, David W.; Dickerson, Scott H.; Griffin, Robert J.; Wood, Edgar R.; Bioorganic and Medicinal Chemistry Letters; vol. 19; nb. 1; (2009); p. 21 - 26 View in Reaxys
OH
H N
OH O
H N
O O
HO
HO
Rx-ID: 4379747 View in Reaxys 78/97 Yield Conditions & References With hydrogenchloride, acetic anhydride, acetyl chloride, Multistep reaction Sakuraba, Shunji; Takahashi, Hisashi; Takeda, Hideo; Achiwa, Kazuo; Chemical & Pharmaceutical Bulletin; vol. 43; nb. 5; (1995); p. 738 - 747 View in Reaxys
H N
OH O
H N
O O
HO
HO
Rx-ID: 31755503 View in Reaxys 79/97 Yield Conditions & References Reaction Steps: 2 1.1: acetic anhydride; acetic acid / 5.5 h / 50 C / Reflux 1.2: 3 h / Reflux 2.1: thionyl chloride / 20 C With thionyl chloride, acetic anhydride, acetic acid Watanabe, Akiko; Yamasaki, Tetsuo; Tanda, Kazuhiro; Miyagoe, Tatsunori; Sakamoto, Masanori; Kiyota, Naotoshi; Otsuka, Masami; Journal of Heterocyclic Chemistry; vol. 48; nb. 5; (2011); p. 1132 - 1139 View in Reaxys
OH
H N
OH O
H N O O
HO
HO
Rx-ID: 4457892 View in Reaxys 80/97 Yield Conditions & References With hydrogenchloride, ammonia, 1) reflux, 2 h, 2) 1 h, Multistep reaction Maksakov, V. A.; Kirin, V. P.; Golovin, A. V.; Russian Chemical Bulletin; vol. 44; nb. 10; (1995); p. 1941 - 1945; Izvestiya Akademi Nauk, Seriya Khimicheskaya; nb. 10; (1995); p. 2021 - 2025 View in Reaxys
41/47
2012-01-31 07:06:55
SIG1
H N
HO
OH O
H N
O O Cl H
HO
HO
Rx-ID: 5042866 View in Reaxys 81/97 Yield Conditions & References With thionyl chloride, Time= 1.5h, Heating, Yield given Lewis, Arwel; Ryan, Martin D.; Gani, David; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); nb. 22; (1998); p. 3767 - 3776 View in Reaxys
H N
N N
OH O
H N
O O
(2S)-2r-carboxy-4t-hydroxy-1,1dimethyl-pyrrolidinium betaine Rx-ID: 5583438 View in Reaxys 82/97
HO
HO
Yield
Conditions & References With diethyl ether Kuhn; Brydowna; Chemische Berichte; vol. 70; (1937); p. 1333,1339 View in Reaxys
OH
H N
OH O
H N
O Cl O H
HO
HO
Rx-ID: 23573585 View in Reaxys 83/97 Yield Conditions & References Example Name 1 With hydrogenchloride, Time= 24h Patent; SALAMA, Zoser, B.; WO2005/58816; (2005); (A1) German View in Reaxys
H N
N N
OH O
H N
O O
O N+ O HO
HO
HO
Rx-ID: 807155 View in Reaxys 84/97 Yield Conditions & References With diethyl ether Kuhn; Brydowna; Chemische Berichte; vol. 70; (1937); p. 1333,1339 View in Reaxys
H N
N N
O
OH O
H N
O O
(2S)-2r-carboxy-4t-hydroxy-1,1dimethyl-pyrrolidinium betaine Rx-ID: 5583439 View in Reaxys 85/97
HO
HO
Yield
Conditions & References Kuhn; Brydowna; Chemische Berichte; vol. 70; (1937); p. 1333,1339 View in Reaxys
42/47
2012-01-31 07:06:55
SIG1
O O OH HN
Rx-ID: 24294217 View in Reaxys 86/97 Yield Conditions & References B. In a similar manner, the following esters are made: ... 3-ethoxycarbonylazetidine; 4-ethoxycarbonylthiazolidine; 2-ethoxycarbonylpyrroline; 2-ethoxycarbonylpyrrolidine; 2-ethoxycarbonyl-4-hydroxypyrrolidine; 4-ethoxycarbonyl-5,5-dimethylthiazolidine; 1-ethoxycarbonyl-1-aminocyclopropane; 2-ethoxycarbonyl-2-aminonorbornane; ... Patent; Berlex Laboratories, Inc.; US6008234; (1999); (A1) English View in Reaxys
H N
O O Cl H
HO
Rx-ID: 24519648 View in Reaxys 87/97 Yield Conditions & References Example Name 1 Example Title Preparation 1 Preparation 1 In an atmosphere of nitrogen, (2S,4R)-2-carboxy-4-hydroxypyrrolidine (100 g, 0.763 mol) was suspended in methanol (400 ml) and the suspension was cooled to 5.deg.-10.deg. C. Then, thionyl chloride (99.8 g, 0.839 mol) was added dropwise thereto under 20.deg. C. After completion of the dropwise addition, the reaction mixture was warmed to 60.deg.-62.deg. C. and stirred at this temperature for 1 hour. The reaction mixture was then cooled to 25.deg.-30.deg. C. for crystallization. To the mixture was added diisopropyl ether (180 ml) dropwise. After completion of the dropwise addition, the mixture was cooled to 0.deg.-5.deg. C. and stirred for 1 hour. The resulting crystal was collected by filtration and washed with diisopropyl ether (200 ml) twice. The washed crystal was dried in vacuo overnight to provide (2S,4R)-2-methoxycarbonyl-4-hydroxypyrrolidine hydrochloride (134.8 g). IR (Nujol): 3320, 1740, 1590, 1080, 1620, 900 cm-1 NMR (DMSO-d6, ): 5.64 (1H, s), 4.50-4.40 (1H, m), 4.42 (1H, s), 3.70 (1H, d, J=12 Hz), 3.60 (1H, d, J=12 Hz), 3.07 (1H, d, J=12 Hz), 2.22-2.20 (1H, m) Patent; Fujisawa Pharmaceutical Co., Ltd.; US5543525; (1996); (A1) English View in Reaxys
H N
O O
HO
Rx-ID: 24547041 View in Reaxys 88/97 Yield Conditions & References By following the procedures of Part B above and substituting for sarcosine amide the following compounds: L-proline-N,N-dimethylamide; L-proline methyl ester; and trans-4-hydroxy-L-proline methyl ester;
43/47
2012-01-31 07:06:55
SIG1
Patent; Arris Pharmaceutical Corporation; US5525623; (1996); (A1) English View in Reaxys
O HN
O H
Cl
OH
Rx-ID: 24842747 View in Reaxys 89/97 Yield 20.05 g (93.1%) Conditions & References Example Name 5.A Example Title A. A. (cis)-4-Hydroxy-L-proline, methyl ester hydrochloride Into a 1 liter Parr hydrogenation bottle was placed 29.90 g (107.12 mmol) of (cis)-1-benzyloxycarbonyl-4-hydroxy-Lproline, methyl ester (reference: J. Am. Chem. Soc., 79, 185, (1957)), 400 ml of methanol, 9.83 ml (117.90 mmol) of concentrated HCl, and 3.00 g of 10percent palladium on activated carbon. The mixture was shaken under a hydrogen atmosphere at 50 psi for 4 hours, then filtered through a Millipore filter; the palladium was washed with 100 ml of methanol. The filtrate was concentrated under vacuum to a minimal volume, then treated with 250 ml of ethyl acetate, which caused a white precipitate to form. The solids were filtered, washed twice with ethyl acetate and once with hexane, and dried under vacuum to yield 20.05 g (93.1percent) of the title compound. MS: m/e 146 (M+H, free amine). Anal. (corrected for 1.07 equivalent H2 O as determined by Karl Fischer analysis): Calcd: C, 35.88; H, 7.09; N, 6.98; Cl, 17.65. Found: C, 36.09, H, 7.47; N, 6.86; Cl, 17.17. Patent; E. R. Squibb and Sons, Inc.; US4912231; (1990); (A1) English View in Reaxys
OH O HO
H N
O O
Rx-ID: 24915049 View in Reaxys 90/97 Yield Conditions & References Example Name R.5.2 Example Title REFERENCE EXAMPLE 5-2 STR134 REFERENCE EXAMPLE 5-2 STR134 To a solution of (2S,4R)-1-benzyloxycarbonyl-2-methoxycarbonyl-4-hydroxypyrrolidine (4.34 g) in 95percent ethanol (44 ml), 10percent palladium-carbon (419 mg) and acetic acid (0.89 ml) were added. The mixture was vigorously stirred at room temperature for 1.5 hours under an atmospheric pressure of hydrogen. Removal of the catalyst gave (2S,4R)-2-methoxycarbonyl-4-hydroxypyrrolidine acetate. IRmax neat cm-1: 1745, 1585, 1420, 1240. Patent; Sumitomo Pharmaceuticals Company, Limited; US5093328; (1992); (A1) English View in Reaxys
H N
O Cl O H
HO
Rx-ID: 24923554 View in Reaxys 91/97 Yield Conditions & References Example Name R.2.1 Example Title REFERENCE EXAMPLE 2 (1)
44/47
2012-01-31 07:06:55
SIG1
To a mixture of 100 g of 4-hydroxy-L-proline[]D 20 =-76.5.deg. (c=2.5, H2 O) and 380 ml of ethanol, 109 g of thionyl chloride were dropwise added. Under heat-refluxing condition, the mixture was reacted for 4 hours and then cooled to precipitate the reaction product. 143.8 g of (2S,4R)-2-ethoxycarbonyl-4-hydroxy pyrrolidine hydrochloride were obtained as crystals. M.p. 153.5.deg. to 154.deg. C. []D 20 =-29.85.deg. (c=1.0, H2 O). NMR (DMSO-d6)(TMS ppm): 1.25 (3H, t), 1.9-2.4 (2H), 2.8-4.7 (4H), 4.23 (2H, q). Patent; Teikoku Chemical Industry Co., Ltd.; US5143935; (1992); (A1) English View in Reaxys
H N
O Cl O H
HO
Rx-ID: 24923926 View in Reaxys 92/97 Yield Conditions & References Example Name R.4.1 Example Title REFERENCE EXAMPLE 4 Into a solution of 5 g of thus obtained crystals in 25 ml of ethanol, 6.49 g of thionyl chloride were dropwise added and the combined was heat-refluxed for 4 hours. The rection mixture was concentrated, added with acetone and allowed to cool. The precipitates were filtered to obtain (2S,4S)-2-ethoxycarbonyl-4-hydroxy pyrrolidine hydrochloride. Yield 3.38 g M.p. 152.deg. to 154.5.deg. C. []D 20 =-20.34.deg. (c=1, H2 O). NMR (DMSO-d6)(ppm): 1.27 (3H,t), 2.0-2.7 (2H), 3.23 (2H, d), 4.22 (2H, q), 4.2-4.8 (2H), 5.50 (1H, broad), 9.77 (2H, broad). Patent; Teikoku Chemical Industry Co., Ltd.; US5143935; (1992); (A1) English View in Reaxys
O O O N O O S O
H N
O Cl O H
HO
O
Rx-ID: 24921338 View in Reaxys 93/97 Yield Conditions & References Example Name R.3.3 Example Title REFERENCE EXAMPLE 3 1.47 g of thus obtained crystalline material were suspended in 6 ml of ethanol and the suspension was added dropwise with 1.27 g of thionyl chloride and reacted with the same. The reaction mixture was concentrated under reduced pressure and to the residue, acetone was added to obtain crystals, which were recrystallized from ethanol to obtain (2R,4S)-2-ethoxycarbonyl-4-hydroxy pyrrolidine hydrochloride. Yield 1.08 g M.p. 153.deg. to 153.5.deg. C. []D 20 =+29.78 (c=1, H2 O). Patent; Teikoku Chemical Industry Co., Ltd.; US5143935; (1992); (A1) English View in Reaxys
45/47
2012-01-31 07:06:55
SIG1
OH
H N O Cl O HO H
O O
Rx-ID: 24937488 View in Reaxys 94/97 Yield Conditions & References Example Name R.3.4 Example Title REFERENCE EXAMPLE 3 (4) The similar experiments as stated in Reference Example (2) were repeated excepting using 8.99 g of (2R,4S)-2-ethoxycarbonyl-4-hydroxy pyrrolidine hydrochloride obtained in the preceeding para. (3), to obtain 7.54 g of (2R,4S)-2ethoxycarbonyl-N-ethyl-4-hydroxy pyrrolidine NMR datas were identical with those of the compound obtained in Reference Example 2 (2). Patent; Teikoku Chemical Industry Co., Ltd.; US5143935; (1992); (A1) English View in Reaxys
HO O N H O
Rx-ID: 23534057 View in Reaxys 95/97 Yield 78.6 % Conditions & References Example Name 1 Patent; SALAMA, Zoser, B.; WO2005/58816; (2005); (A1) German View in Reaxys
H N
O O
HO
Rx-ID: 5820866 View in Reaxys 96/97 Yield Conditions & References 4-Hydroxyprolin Grimm,L.; Grassmann,W.; Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie; vol. 337; (1964); p. 161 - 171 View in Reaxys Hydroxyprolin, Me., HCl Heyns,K.; Legler,G.; Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie; vol. 321; (1960); p. 161 - 183 View in Reaxys Hydroxyprolin, Me., SOCl2 Heyns,K.; Legler,G.; Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie; vol. 321; (1960); p. 161 - 183 View in Reaxys
H N
O O
HO
Rx-ID: 23599045 View in Reaxys 97/97 Yield Conditions & References Example Name 1 Patent; FAUST PHARMACEUTICALS; WO2005/118533; (2005); (A1) English
46/47
2012-01-31 07:06:55
SIG1
View in Reaxys
47/47
2012-01-31 07:06:55

SIG1

Caricato da

Informazioni sul documento

Descrizione originale:

Copyright

Formati disponibili

Condividi questo documento

Condividi o incorpora il documento

Opzioni di condivisione

Hai trovato utile questo documento?

Questo contenuto è inappropriato?

Copyright:

Formati disponibili

SIG1

Caricato da

Copyright:

Formati disponibili

SIG1

2012-01-31 07h:06m:04s (EST)

Search as: Product, As drawn, No salts, No mixtures, No isotopes, No radicals

Rx-ID: 24887302 View in Reaxys 14/97

Rx-ID: 4552785 View in Reaxys 17/97

(2S)-2r-carboxy-4t-hydroxy-1,1dimethyl-pyrrolidinium betaine Rx-ID: 5583438 View in Reaxys 82/97

(2S)-2r-carboxy-4t-hydroxy-1,1dimethyl-pyrrolidinium betaine Rx-ID: 5583439 View in Reaxys 85/97

Potrebbero piacerti anche