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Query

Query Results Date

1. Query

H N

O

O ALK

HO

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

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

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HO

H N

OH

O

HO

H N

O

O

HO

Cl H

Rx-ID: 3821891 View in Reaxys 1/97Yield Conditions & References

100 % Example Name 90.1Example Title Preparation of 1-(3,4-dimethoxy-5-trifluoromethylthiobenzoyl)-4S-fluoropyrrolidine-2R-carboxylic acidhydroxyamide; Step 1To 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 towarm to [23 .deg.C.] After 16 h the reaction mixture was concentrated in vacuo to give 4R-hydroxypyrrolidine-2R-carboxylic 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) EnglishView 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 AmericanChemical Society; vol. 118; nb. 29; (1996); p. 6826 - 6840View in Reaxys

90 % Example Name 31To a solution of (2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid 31.1 (1.0 eq) in MeOH (31 eq) at 0 .deg.C was addedS0C12 (1.2 eq) dropwise. The reaction solution was stirred at rt for 72 h. The resulting mixture was concentrated invacuo 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; SUNESISPHARMACEUTICALS, INC.; LUGOVSKOY, Alexey, A.; WO2011/29046; (2011); (A1) EnglishView 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 ofMedicinal Chemistry; vol. 31; nb. 8; (1988); p. 1598 - 1611View 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 MedicinalChemistry; vol. 42; nb. 26; (1999); p. 5426 - 5436View in Reaxys

With thionyl chloride, Time= 6h, Heating

Marusawa, Hiroshi; Setoi, Hiroyuki; Sawada, Akihiko; Kuroda, Akio; Seki, Jiro; Motoyama, Yukio; Tanaka, Hir-okazu; Bioorganic & Medicinal Chemistry; vol. 10; nb. 5; (2002); p. 1399 - 1416View in Reaxys

With thionyl chloride, Time= 6h, T= 20 °C , Methylation

Merino, Pedro; Anoro, Sonia; Franco, Santiago; Merchan, Francisco L.; Tejero, Tomas; Tunon, Victoria; Journalof Organic Chemistry; vol. 65; nb. 5; (2000); p. 1590 - 1596View in Reaxys

http://www.reaxys.com/reaxys/secured/hopinto.do?context=R&query=RX.ID=3821891&origin=ReaxysOutput&ln=

http://www.reaxys.com/reaxys/secured/hopinto.do?context=C&query=CNR.CNR=8940130&origin=ReaxysOutput&ln=







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With thionyl chloride

D'Costa, Moneesha; Kumar, Vaijayanti A.; Ganesh, Krishna N.; Organic Letters; vol. 1; nb. 10; (1999); p. 1513 -1516View in Reaxys

With thionyl chloride, T= 0 - 20 °C

Garrabou, Xavier; Gomez, Livia; Joglar, Jesus; Bujons, Jordi; Clapes, Pere; Gil, Sergi; Parella, Teodor; Chem-istry--A European Journal; vol. 16; nb. 35; (2010); p. 10691 - 10706View 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 inertatmosphere. To this was added a solution of Cis-4-Hydroxy-D- proline (3.235g, 24.67 mmol) and refluxed for 8h. Thereaction mixture was cooled to room temperature, and poured into ether (200mL). The precipitated solid was suctionfiltered and dried to yield (2R,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride in quantitative yield. Thiswas 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) EnglishView in Reaxys

HO

H N

OH

O

HO

H N

O

O

HO


100 % With thionyl chloride

Barrett, Anthony G. M.; Pilipauskas, Daniel; Journal of Organic Chemistry; vol. 55; nb. 18; (1990); p. 5194 - 5196View in Reaxys

100 % With hydrogenchloride, Heating

Zhang, Xiaojun; Schmitt, Aaron C.; Jiang, Wen; Tetrahedron Letters; vol. 42; nb. 32; (2001); p. 5335 - 5338View 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 - 225View in Reaxys

100 % Example Name 1.1Example 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, CDCl3): δ 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, 14.6Hz, 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) EnglishView in Reaxys









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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 ofOrganic Chemistry; vol. 59; nb. 18; (1994); p. 5192 - 5205View 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 - 7816View 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 MedicinalChemistry Letters; vol. 21; nb. 12; (2011); p. 3771 - 3773View in Reaxys


Emery, Fabienne; Bisang, Christian; Favre, Michel; Jiang, Luyong; Robinson, John A.; Journal of the ChemicalSociety, Chemical Communications; nb. 18; (1996); p. 2155 - 2156View 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 - 484View 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 - 5190View in Reaxys

75 % in thionyl chloride

Kemp, D. S.; Curran, Timothy P.; Tetrahedron Letters; vol. 29; nb. 39; (1988); p. 4931 - 4934View in Reaxys

With hydrogenchloride

Poroschin et al.; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; (1959); p. 1851; engl. Ausg. S. 1768, 1769View in ReaxysSmith; Bergmann; Journal of Biological Chemistry; vol. 153; (1944); p. 627,649View in Reaxys


Kaname, Mamoru; Yoshifuji, Shigeyuki; Tetrahedron Letters; vol. 33; nb. 52; (1992); p. 8103 - 8104View in ReaxysCurran, Timothy P.; Chandler, Nicole M.; Kennedy, Robert J.; Keaney, Meghan T.; Tetrahedron Letters; vol. 37;nb. 12; (1996); p. 1933 - 1936View in ReaxysQiu, Xiao-Long; Qing, Feng-Ling; Synthesis; nb. 3; (2004); p. 334 - 340View in Reaxys

With thionyl chloride, Yield given

Blanco, M. Jesus; Sardina, F. Javier; Tetrahedron Letters; vol. 35; nb. 45; (1994); p. 8493 - 8496View in Reaxys

With hydrogenchloride, Time= 1h, Ambient temperature














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Iso, Yasuyoshi; Irie, Tadashi; Nishino, Yutaka; Motokawa, Kiyoshi; Nishitani, Yasuhiro; Journal of Antibiotics;vol. 49; nb. 2; (1996); p. 199 - 209View in Reaxys


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 - 1181View in Reaxys


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 - 590View in Reaxys


Cossy, Janine; Mirguet, Olivier; Pardo, Domingo Gomez; Synlett; nb. 10; (2001); p. 1575 - 1577View in Reaxys

Stage 1: With thionyl chloride, Time= 0.5h, T= -10 °CStage 2:T= 20 °C

Arakawa, Yasushi; Ohnishi, Masafumi; Yoshimura, Norikazu; Yoshifuji, Shigeyuki; Chemical & PharmaceuticalBulletin; vol. 51; nb. 8; (2003); p. 1015 - 1020View 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 - 3837View 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 - 2394View in Reaxys


Kamal, Ahmed; Shankaraiah, N.; Devaiah, V.; Reddy, K. Laxma; Tetrahedron Letters; vol. 47; nb. 37; (2006); p.6553 - 6556View in Reaxys


Ishino, Takeru; Oriyama, Takeshi; Chemistry Letters; vol. 36; nb. 4; (2007); p. 550 - 551View in ReaxysMetro, Thomas-Xavier; Pardo, Domingo Gomez; Cossy, Janine; Journal of Organic Chemistry; vol. 72; nb. 17;(2007); p. 6556 - 6561View in Reaxys

Example Name 13Example 13 Bis-{2-[(S)-2-methylene-7-methoxy-5-oxo-1,3,,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yloxy]-ethyl}-carbamic acid tert-butyl esterCompound 1. Thionyl chloride (5.6 mL, 76.3 mmol) was added dropwise to dry methanol (76 mL) at -20 .deg.C, followingby 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 providetrans-4-hydroxy-L-proline methyl ester 1 as a white solid: 1H-NMR (300 MHz, DMSO-d6) δ 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/z146 ([M]++1).

With thionyl chloride, Time= 20h, T= -20 - 20 °C

Patent; Sanofi-Aventis; EP1813614; (2007); (A1) English











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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 - 1572View in Reaxys


Wang, Chao; Yu, Chun; Liu, Changlu; Peng, Yungui; Tetrahedron Letters; vol. 50; nb. 20; (2009); p. 2363 - 2366View in Reaxys


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 - 4057View in Reaxys

Intermediate 7: (2S.4R)-l-tert-butyl 2-methyl 4-hydroxypyrrolidine- 1.2-dicarboxylate; H Thionyl chloride (47 g, 0.393mol) 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 inDCM (200 mL) and the organic phase was washed with 10percent NaHCO3(aq) (50 mL) and brine. Next, i-tert- butyl-dicarbonate (86.6g, 0.393 mol) and triethylamine (46.3g, 0.46 mol) were added at 00C to the organic phase and stirredovernight at room temperature. The mixture was washed with IN HCl (50 mL) and brine, dried over Na2SO4, concen-trated 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) δ 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 °CStage 2: With sodium hydrogencarbonate in dichloromethane, water

Patent; GLAXOSMITHKLINE LLC; SCHMITZ, Frank Ulrich; RAI, Roopa; ROBERTS, Christopher Don; KAZ-MIERSKI, Wieslaw; GRIMES, Richard; WO2010/62821; (2010); (A1) EnglishView in Reaxys

OH H N

OH

O

HO

H N

O

O

HO


99 % 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 - 3833View 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 - 5300View in Reaxys

98 % Example Name 1Step 1: (2S, 4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid ethyl ester (2); Thionyl chloride (22.2 mL, 0.304 mol) wasadded dropwise to ethanol (92 mL) at 0.deg.C. 4-Hydroxy-proline 1 or (10 g, 0.076 mol) was added portionwise to thatsolution at 0.deg.C. The mixture was stirred at 0.deg.C for 5 min and then refluxed for 16 hrs. After completion of thereaction, the solvent was evaporated. The obtained white solid was washed with ether and filtered to yield the titledcompound 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









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View in Reaxys


Imaoka, Takuya; Akimoto, Takafumi; Iwamoto, Osamu; Nagasawa, Kazuo; Chemistry - An Asian Journal; vol. 5;nb. 8; (2010); p. 1810 - 1816View in Reaxys


Kapfhammer; Matthes; Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie; vol. 223; (1934); p. 43,51View 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 - 4739View 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 - 2025View 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 - 172View 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 & MedicinalChemistry Letters; vol. 16; nb. 18; (2006); p. 4856 - 4860View in Reaxys


Shiigi, Hirofumi; Mori, Hiroyuki; Tanaka, Tomoaki; Demizu, Yosuke; Onomura, Osamu; Tetrahedron Letters;vol. 49; nb. 36; (2008); p. 5247 - 5251View 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 - 1787View in Reaxys

OH H N

OH

O

HO

H N

O

O

HO

Cl H


98 % 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 - 1739View in Reaxys


Curtis, Kim L.; Evinson, Emma L.; Handa, Sandeep; Singh, Kuldip; Organic and Biomolecular Chemistry; vol. 5;nb. 21; (2007); p. 3544 - 3553












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View in Reaxys

98 % With thionyl chloride, T= 0 °C , Reflux

Imaoka, Takuya; Iwamoto, Osamu; Noguchi, Kei-Ichi; Nagasawa, Kazuo; Angewandte Chemie, International Ed-ition; vol. 48; nb. 21; (2009); p. 3799 - 3801View in Reaxys

97 % Example Name 1.1Example 1; Step 1 :To a mechanically stirred suspension of compound 1 (100.6 g, 0.767 mol) in EtOH (1000 ml) andcooled to O 0C was added SOCI2 (136.9 g, 1.15 mol, 84.0 ml) dropwise via addition funnel such that the internaltemperature 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. Theproduct 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. 1H-NMR (DMSO) δ 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) EnglishView in Reaxys

97 % Example Name 1.1Step 1:To a mechanically stirred suspension of compound 1 (100.6 g, 0.767 mol) in EtOH (1000 ml) and cooled to0.deg. C. was added SOCl2 (136.9 g, 1.15 mol, 84.0 ml) dropwise via addition funnel such that the internal temperaturewas <15.deg. C. The reaction mixture was heated at reflux for 2.5 h, then cooled to 0.deg. C. Ether (1000 ml) wasadded, and a white solid precipitated. The solid was isolated by vacuum filtration and washed with ether. The product2 (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) δ 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 (broads, 1H).

With thionyl chloride, T= 0 °C , Reflux

Patent; SCHERING CORPORATION; US2011/3780; (2011); (A1) EnglishView 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 - 809View in Reaxys


Baker, Gregory L.; Fritschel, Scott J.; Stille, John R.; Stille, John K.; Journal of Organic Chemistry; vol. 46; nb.14; (1981); p. 2954 - 2960View in Reaxys

94 % With thionyl chloride, Esterification

Yanagi, Toshiharu; Kitajima, Akihiko; Anzai, Kinsei; Kodama, Kazuya; Mizoguchi, Jun-ichi; Fujiwara, Hiromi-chi; Sakiyama, Hideyo; Kamoda, Osamu; Kamei, Chiaki; Chemical & Pharmaceutical Bulletin; vol. 47; nb. 11;(1999); p. 1650 - 1654View 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 OrganicChemistry; vol. 75; nb. 5; (2010); p. 1620 - 1629View in Reaxys


Tanaka, Ken-ichi; Sawanishi, Hiroyuki; Tetrahedron: Asymmetry; vol. 6; nb. 7; (1995); p. 1641 - 1656View in Reaxys










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80 % With thionyl chloride, T= 20 °C

Watanabe, Akiko; Yamasaki, Tetsuo; Tanda, Kazuhiro; Miyagoe, Tatsunori; Sakamoto, Masanori; Kiyota, Nao-toshi; Otsuka, Masami; Journal of Heterocyclic Chemistry; vol. 48; nb. 5; (2011); p. 1132 - 1139View in Reaxys


Watanabe, Kiyoko; Fukumura, Toshimitsu; Sasaki, Shigeki; Maeda, Minoru; Takehara, Shuzo; Chemical & Phar-maceutical Bulletin; vol. 39; nb. 12; (1991); p. 3211 - 3214View in Reaxys


Heindl, Cornelia; Huebner, Harald; Gmeiner, Peter; Tetrahedron: Asymmetry; vol. 14; (2003); p. 3141 - 3152View in Reaxys

Example Name 23.AExample 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)-4-hydroxy-pyrrolidine-2-carboxylic acid) (13.1 g, 100 mmol), and 50 mL absolute ethanol. The above mixture was cooleddown to 0 .deg.C and saturated with HC1 gas until all of the suspension was dissolved. The mixture was refluxed undernitrogen for 2 h. The mixture was cooled down to rt, and all solvent was removed by vacuum. The residue was kept inthe 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) EnglishView in Reaxys


Patent; Athena Neurosciences, Inc.; American Home Products; US6362341; (2002); (B1) EnglishView 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:S02011STView in Reaxys

N

O

O O O

HO

H N

O

O

HO


100 % Example Name 1A solution of 4.0 N HCl in dioxane (50 mL) was added to a solution of commercially available 4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (30 g, 206 mmol) in dichloromethane (200 mL). After the reactionmixture was stirred at room temperature for 4 hours, it was concentrated to get a quantitative yield of crude intermediateXI, 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) EnglishView in Reaxys

Example Name B.85.1Boc-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









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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. Thereaction was then quenched with water, dilutedwith DCM, washed with sat. NaHCOs, and sat. NHO. The organic layerwasthen 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 dilutedwith water and the pH wasadjusted to 3 using IN HC1. The mixture was then extracted with EtOAc,dried, and concen-trated 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) EnglishView in Reaxys

H N

OH

O

HO

H N

O

O

OH

HCl


87.6 % [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 toRT (room temperature) and 500 ml of ether was added to form white crystal followed by filtration and drying undervacuum 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) EnglishView in Reaxys

H N

OH

O

HO

HN

O O

OH

H Cl H


98.0% Example Name R.5Example Title Trans-4-Hydroxy-L-Proline Methyl Ester HydrochlorideREFERENCE EXAMPLE 5Trans-4-Hydroxy-L-Proline Methyl Ester HydrochlorideA 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 crystalsthus precipitated, washing the crystals with ether and drying them to give 18.86 g (yield 98.0percent) of the title com-pound.1H-N.M.R. (DMSO-d6) δ: 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(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) νcm-1: 3370, 2950, 1740, 1585, 1360,1285, 1245.


Patent; Wakamoto Pharmaceutical Co., Ltd.; US6225306; (2001); (B1) EnglishView in Reaxys

92% Example Name 50Example Title trans-4-Hydroxy-L-proline, Methyl Ester, Hydrochloridetrans-4-Hydroxy-L-proline, Methyl Ester, Hydrochloride






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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) EnglishView in Reaxys

92% Example Name 50Example Title trans-4-Hydroxy-L-proline, methyl ester, hydrochloridetrans-4-Hydroxy-L-proline, methyl ester, hydrochlorideTo 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) EnglishView in Reaxys

HO

N

O O

OH

O

HO

H N

O

O

HO

Cl H


~ 100 % 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).


Patent; Mioskowski, Charles; Marin, Sandra De Lamo; Maruani, Martine; Gill, Manjinder; US2006/199853; (2006);(A1) EnglishView 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 theabove solution, 1.8 equivalents of thionyl chloride was added. The solution was heated to 45.deg. C. for 4 hours, andwas 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 filteredoff and washed several times with ether. The crystals were finally dried in a vacuum oven for 24 hours (40.deg. C.) toyield 76 (354 mg, 100percent). 76: MS: M+H+=146. 1H NMR (500 MHz, D2O): δ 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.


Patent; Chapal, Nicolas; McNicol, Patricia; Jette, Lucie; US2006/223884; (2006); (A1) EnglishView in Reaxys






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N

O

O O O

HO

O

O NH

HO


Example Name 11-(2-{2-Cyclohexyl-2-[(pyrazine-2-carbonyl)-amino]- acetylamino}-3, 3-dimethyl-butyryl)-4-hydroxy-pyrr olidine-2-car-boxylic acid tert-butyl ester (6) [0156] Mixed (3) in EtOH, and added catalytic amount of 10percent Pd on carbon, thenstirred 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 givethe amine as a yellow solid, which was carried on into the next step. Z-Tbg-OH (8.3g, 31. lmmols) was dissolved inNMP and to it was added EDC (6. 0g, 31. lmmols), HOBT (4.2g, 31. 1mmols), DMAP (340mgs, 2.8mmols), and cooledto 0.deg.C using and ice-water bath. To this mixture was added the amine as a solution in NMP, and the reaction wasstirred for 2 days. The reaction was poured over ice and acidified with 0.5N hydrochloric acid to pH 5, and then extractedwith 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. Purificationwas carried out using chromatography on Si02, eluting with 50percent EtOAc-Hexanes. Concentration of the homo-geneous 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) EnglishView in Reaxys

H N

OH

O

HO

H N

O

O

HO

Cl H


94.5% Example Name 22Example Title Example 22Example 223.27 g (27.5 mmol) of thionyl chloride was added dropwise to a suspension of cis-4-hydroxy-D-proline (3.00 g, 2.9mmol) 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 hydrochloridewas obtained as colorless needles (94.5percent).

With thionyl chloride in ethanol, acetone

Patent; Ajinomo Co., Inc.; US6127361; (2000); (A1) EnglishView in Reaxys

H N

OH

O

HO

H N

O

O

HO

Cl H


113% Example Name P.7.A.1Example Title Step A-1.Step A-1.






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13/47 2012-01-31 07:06:55

Preparation of an ester compoundTo a suspension of cis-4-hydroxy-D-proline (16.46 g: 125.5 mmole) in methanol (66 ml), thionylchloride (9.16 ml: 125.5mmole) is added in a nitrogen atmosphere under ice cooling, and the mixture is stirred at room temperature for 30minutes.The mixture is further stirred to react at 40.deg. C. for 4 hours to give (2R,4R)-4-hydroxy-2-methoxycarbonylpyrrolidinehydrochloride as crude crystals (25.74 g). Yield: 113percent.Colorless crystals. NMR δ(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 ν (KBr) cm-1: 3320, 2980, 1728.


Patent; Shionogi Seiyaku Kabushiki Kaisha; US5317016; (1994); (A1) EnglishView in Reaxys

OH H N

OH

O

HO

NH O

O HO

HCl


100 % Example Name 7Example Title Intermediate 7.; ISO-PROPVL-4R)-4-HVDROXY-D-PROLINATE HVDROCHLORIDETo a suspension of cis-4-hydroxy-D-proline [(1.] [0G)] in dry iso-propanol (25ml) under nitrogen cooled to [0C] wasadded dropwise thionyl chloride (0. [8MI).] The reaction mixture was heated at [100C] for 6 hours. The mixture wasconcentrated 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).


Patent; CELLTECH R and D LIMITED; WO2004/22554; (2004); (A1) EnglishView in Reaxys

H N

OH

O

HO

Cl O H N

O

O

HO

Cl H


88% Example Name P.7.C.1Example Title Step C-1.Step C-1.Preparation of an ester compoundTo a suspension of trans-4-hydroxy-L-proline (200 g: 1.525 mole) in methanol (800 ml), acetylchloride (163 ml: 2.288mole) 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 hoursat 40.deg. C. to give (2S,4R)-4-hydroxy-2-methoxycarbonylpyrrolidine hydrochloride (244.27 g). Yield: 88percent.Colorless crystals. NMR δ(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=3.6Hz, 1H), 3.49(s, 3H), 4.2 to 4.4(m, 2H). IR ν (KBr) cm-1: 3380, 3330, 2695, 2960, 1742.


Patent; Shionogi Seiyaku Kabushiki Kaisha; US5317016; (1994); (A1) EnglishView in Reaxys

HN HO

O OH

Cl H

HN

O

O

OH HCl

Rx-ID: 24887302 View in Reaxys 14/97







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Yield Conditions & References

77.5% Example Name 8.2Example 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 acetoneto 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) EnglishView in Reaxys

H N

OH

O

HO

H N

O

O

HO


95% Example Name 110.1Example Title (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dihydro-pyr-role-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) asa white solid. MS: APCI (AP+): 146 (M)+.

in hydrogenchloride, methanol, diethyl ether

Patent; Bigge, Christopher Franklin; Casimiro-Garcia, Agustin; Dudley, Danette Andrea; Edmunds, JeremyJohn; Filipski, Kevin James; Kohrt, Jeffrey Thomas; Van Huis, Chad Alan; US2003/162787; (2003); (A1) EnglishView in Reaxys

Reaction Steps: 21: SOCl22: -5 °CWith 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 - 149View in Reaxys

Example Name 28.1Example Title (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-pi-peridin-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.





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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, JeremyJohn; Filipski, Kevin James; Kohrt, Jeffrey Thomas; Van Huis, Chad Alan; US2003/162787; (2003); (A1) EnglishView in Reaxys

HO

H N

OH

O

HO

H N

O

O

HO

Cl H


100 % 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- 2728View in Reaxys


Blanco, Maria-Jesus; Sardina, F. Javier; Journal of Organic Chemistry; vol. 61; nb. 14; (1996); p. 4748 - 4755View in Reaxys

100 % With thionyl chloride, Ambient temperature

Westwood, Nigel B.; Walker, Richard T.; Tetrahedron; vol. 54; nb. 44; (1998); p. 13391 - 13404View in Reaxys

100 % With thionyl chloride, Time= 4.16667h

Chang, Meng-Yang; Chen, Hua-Ping; Heterocycles; vol. 65; nb. 7; (2005); p. 1705 - 1711View 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 AmericanChemical Society; vol. 123; nb. 42; (2001); p. 10245 - 10254View 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 - 1244View in Reaxys

100 % With hydrogenchloride

Tamaki, Makoto; Han, Guoxia; Hruby, Victor J.; Journal of Organic Chemistry; vol. 66; nb. 10; (2001); p. 3593 -3596View in Reaxys


Koch, David; Maechling, Simon; Blechert, Siegfried; Tetrahedron; vol. 63; nb. 30; (2007); p. 7112 - 7119View in Reaxys


Chang, Meng-Yang; Chen, Shui-Tein; Chang, Nein-Chen; Heterocycles; vol. 60; nb. 5; (2003); p. 1203 - 1210View in Reaxys












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Chang, Meng-Yang; Kung, Yung-Hua; Wu, Tsun-Cheng; Journal of the Chinese Chemical Society (Taipei, Taiwan);vol. 54; nb. 3; (2007); p. 803 - 806View in Reaxys

100 % Example Name 5.ITo a stirred solution of (2S, 4i?)-4-hydroxypyrrolidine-2-carboxylic acid (13.1 g, 0.1 mol) in methanol (400 mL) cooledto 0.deg.C was added acetyl chloride (14.3 mL, 0.2 mol) over a period of 30 min. The reaction mixture was warmed toroom temperature and stirred for 2 h. The volatiles were removed under reduced pressure and the residue was trituratedwith 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 δ 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) EnglishView in Reaxys


Grygorenko, Oleksandr O.; Komarov, Igor V.; Cativiela, Carlos; Tetrahedron: Asymmetry; vol. 20; nb. 12; (2009);p. 1433 - 1436View in Reaxys


Haberhauer, Gebhard; Synlett; nb. 6; (2004); p. 1003 - 1006View 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 MedicinalChemistry; vol. 41; nb. 11; (2006); p. 1347 - 1351View in Reaxys

99 % Example Name 1.a; 12Acetyl chloride (4.14 g, 52.8 mmol) is dropped into a three neck round bottom flask containing anhydrous methanol (33ml) in ice bath and under N2 flux. [(2S,4R)-(-)-4-Hydroxypyrrolidine-2-carboxylic acid (1) (5.0 g, 37.7 mmol) is addedand 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): δ 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): δ 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. Theoreticalmass 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)EnglishView 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 Transac-tions 1: Organic and Bio-Organic Chemistry (1972-1999); nb. 22; (1998); p. 3777 - 3794View 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 - 1425View in Reaxys










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Issartel, V.; Spehner, V.; Bahaji, H.; Seilles, E.; Couquelet, J.; European Journal of Medicinal Chemistry; vol. 31;nb. 9; (1996); p. 717 - 724View 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 - 2378View in Reaxys


Diafi, Lahcen; Couquelet, Jacques; Tronche, Pierre; Gardette, Daniel; Gramain, Jean-Claude; Journal of Heter-ocyclic Chemistry; vol. 27; nb. 7; (1990); p. 2181 - 2187View in Reaxys

95 % Example Name 1.1Step 1 : (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (2). Thionyl chloride (11.6 ml, 160 mmol) wasadded to a stirred solution of (2S,4R)-4- hydroxypyrrolidine-2-carboxylic acid (10.0 g, 76.26 mmol) (1) in methanol (150ml) 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-hydroxypyrroli-dine-2-carboxylate hydrochloride (2) (17.90 g, 95percent) as a white solid. Used without further purification. MS m/z146.2 (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) EnglishView in Reaxys

95 % With acetyl chloride



Umashankara, M.; Babu, I. Ramesh; Ganesh, Krishna N.; Chemical Communications (Cambridge, United Kingdom);nb. 20; (2003); p. 2606 - 2607View in Reaxys


Kemp, D. S.; Curran, Timothy P.; Davis, William M.; Boyd, James G.; Muendel, Christopher; Journal of OrganicChemistry; vol. 56; nb. 23; (1991); p. 6672 - 6682View 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 - 1842View in Reaxys


Bisang, Christian; Jiang, Luyong; Freund, Ernst; Emery, Fabienne; Bauch, Christian; et al.; Journal of the Amer-ican Chemical Society; vol. 120; nb. 30; (1998); p. 7439 - 7449View in Reaxys

92 - 97 % Example Name 21.aAbsolute 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 suspensionobtained was added dropwise at 10-15 0C distilled thionyl chloride (1.1 equiv). Then the mixture was stirred at 45 0Cuntil TLC indicated completion (5 h) of the reaction. The suspension was cooled to 5-10 0C and then filtered and washedwith dry diethyl ether. The mother liquor was evaporated in vacuo and the residue was recrystallized from dry methanolto give the title compound in 92-97percent yield.










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18/47 2012-01-31 07:06:55


Patent; PFIZER INC.; WO2006/27694; (2006); (A1) EnglishView in Reaxys

87 % With hydrogenchloride

Jordis, Ulrich; Sauter, Fritz; Siddiqi, Suhaib M.; Kueenburg, Bernhard; Bhattacharya, Kaberi; Synthesis; nb. 10;(1990); p. 925 - 930View in Reaxys


Jordis, Ulrich; Sauter, Fritz; Siddiqi, Suhaib M.; Indian Journal of Chemistry, Section B: Organic Chemistry IncludingMedicinal Chemistry; vol. 28; nb. 1-11; (1989); p. 294 - 296View in ReaxysCheng, Xian-Chao; Wang, Qiang; Fang, Hao; Tang, Wei; Xu, Wen-Fang; Bioorganic and Medicinal Chemistry;vol. 16; nb. 10; (2008); p. 5398 - 5404View in ReaxysCheng, Xian-Chao; Wang, Qiang; Fang, Hao; Tang, Wei; Xu, Wen-Fang; European Journal of Medicinal Chemistry;vol. 43; nb. 10; (2008); p. 2130 - 2139View in ReaxysCheng, Xian-Chao; Wang, Qiang; Fang, Hao; Tang, Wei; Xu, Wen-Fang; Bioorganic and Medicinal Chemistry;vol. 16; nb. 17; (2008); p. 7932 - 7938View in Reaxys

79.5 % With acetyl chloride

Gong, Jianzhi; Xu, Wenfang; Gong, Yanqing; Journal of Chemical Research, Synopses; nb. 11; (2009); p. 668 - 670View 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 -4187View in Reaxys


Schumacher, Kelly K.; Jiang, Jianjun; Joullie, Madeleine M.; Tetrahedron: Asymmetry; vol. 9; nb. 1; (1998); p. 47- 54View in Reaxys


Marusawa, Hiroshi; Setoi, Hiroyuki; Sawada, Akihiko; Kuroda, Akio; Seki, Jiro; Motoyama, Yukio; Tanaka, Hir-okazu; Bioorganic & Medicinal Chemistry; vol. 10; nb. 5; (2002); p. 1399 - 1416View in Reaxys

With thionyl chloride, Time= 32h

Greenwood, E. S.; Hitchcock, P. B.; Parsons, P. J.; Tetrahedron; vol. 1859; (2003); p. 3307 - 3314View in Reaxys


Kamal, Ahmed; Reddy, P. S. M. M.; Reddy, D. Rajasekhar; Laxman, E.; Murthy, Y. L. N.; Bioorganic & MedicinalChemistry Letters; vol. 14; nb. 22; (2004); p. 5699 - 5702View in ReaxysEvans, Paul; Journal of Organic Chemistry; vol. 72; nb. 5; (2007); p. 1830 - 1833View 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 - 7709View in Reaxys















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With hydrogenchloride, Time= 2.5h, Heating

Barkallah, Salim; Schneider, Stephen L.; McCafferty, Dewey G.; Tetrahedron Letters; vol. 46; nb. 30; (2005); p.4985 - 4987View in Reaxys


Li, Ya-Lin; XU, Wen-Fang; Bioorganic & Medicinal Chemistry; vol. 12; nb. 19; (2004); p. 5171 - 5180View in Reaxys


Mollica, Adriano; Paradisi, Mario Paglialunga; Varani, Katia; Spisani, Susanna; Lucente, Gino; Bioorganic &Medicinal Chemistry; vol. 14; nb. 7; (2006); p. 2253 - 2265View in Reaxys

With thionyl chloride, Time= 6h, T= 20 °C , Methylation

Merino, Pedro; Anoro, Sonia; Franco, Santiago; Merchan, Francisco L.; Tejero, Tomas; Tunon, Victoria; Journalof Organic Chemistry; vol. 65; nb. 5; (2000); p. 1590 - 1596View 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 - 2941View in Reaxys


D'Costa, Moneesha; Kumar, Vaijayanti A.; Ganesh, Krishna N.; Organic Letters; vol. 1; nb. 10; (1999); p. 1513 -1516View in Reaxys


Liu, Feng-Zhi; Fang, Hao; Zhu, Hua-Wei; Wang, Qiang; Yang, Yue; Xu, Wen-Fang; Bioorganic and MedicinalChemistry; vol. 16; nb. 1; (2008); p. 578 - 585View in Reaxys

Example Name 7.4Example 7-4 Methyl (2S, 4R) -4-hydroxy-2-pyrrolidinecarboxylate hydrochloride Hydroxy proline (155g) was dissolvedin"Hydrogen Chloride, MethanolReagentlO" (TokyoKaseiKogyoCo., Ltd. 900mL), and this mixture was heated at refluxfor 2hrs. The resulting mixture was cooled to room temperature, and the solvent was removed in vacuo to give thetarget 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) EnglishView in Reaxys

Example Name 7

With thionyl chloride, Time= 4h

Patent; Shionogi Co., Ltd.; EP1852436; (2007); (A1) EnglishView in Reaxys


Palomo, Claudio; Landa, Aitor; Mielgo, Antonia; Oiarbide, Mikel; Puente, Angel; Vera, Silvia; AngewandteChemie, International Edition; vol. 46; nb. 44; (2007); p. 8431 - 8435; Angewandte Chemie; vol. 119; nb. 44; (2007);p. 8583 - 8587View in Reaxys












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Dhudshia, Bhartesh; Cooper, Benjamin F. T.; MacDonald, Charles L. B.; Thadani, Avinash N.; Chemical Com-munications (Cambridge, United Kingdom); nb. 4; (2009); p. 463 - 465View in Reaxys

Example Name 24PREPARATION 24(2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl esterAdd thionyl chloride (1.07 mol, 128.2 g) drop wise to a solution of (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid (0.70mol, 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.


Patent; GAVARDINAS, Konstantinos; Jadhav, Prabhakar Kondaji; US2009/163472; (2009); (A1) EnglishView in Reaxys

Example Name 1-1Example Title Preparation 1-1; Methyl (2S, 4R)-4-hydroxy-2-pyrrolidinecarboxylate hydrochlorideHydroxyproline (155g) was dissolved in Hydrogen Chlororide, Methanol Reagent 10 (TCI, 900mL), and this mixturewas heated at reflux for 2hrs. The resulting mixture was cooled to room temperature, and the solvent was removed invacuo 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) EnglishView in Reaxys

Example Name 244.1To 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 wasremoved 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) EnglishView 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; Chem-istry--A European Journal; vol. 16; nb. 18; (2010); p. 5333 - 5342View in Reaxys


Garrabou, Xavier; Gomez, Livia; Joglar, Jesus; Bujons, Jordi; Clapes, Pere; Gil, Sergi; Parella, Teodor; Chem-istry--A European Journal; vol. 16; nb. 35; (2010); p. 10691 - 10706View 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 - 5711View in Reaxys

OH H N

OH

O

HO

H N

O

O

HO

Rx-ID: 4552785 View in Reaxys 17/97









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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 ofMedicinal Chemistry; vol. 39; nb. 15; (1996); p. 2990 - 3000View 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 - 172View in Reaxys


Renau, Thomas E.; Leger, Roger; Filonova, Lubov; Flamme, Eric M.; Wang, Michael; Yen, Rose; Madsen, Dei-dre; Griffith, David; Chamberland, Suzanne; Dudley, Michael N.; Lee, Ving J.; et al.; Bioorganic & MedicinalChemistry Letters; vol. 13; nb. 16; (2003); p. 2755 - 2758View 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 & MedicinalChemistry Letters; vol. 16; nb. 18; (2006); p. 4856 - 4860View in Reaxys

Example Name 17.1Step 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 addeddropwise 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-d6): δ 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(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 Jo-seph; US2009/286798; (2009); (A1) EnglishView in Reaxys

HO

H N

OH

O

HO

H N

O

O

HO



Zhang, Haile; Mitsumori, Susumu; Utsumi, Naoto; Imai, Masanori; Garcia-Delgado, Noemi; Mifsud, Maria; Al-bertshofer, Klaus; Cheong, Paul Ha-Yeon; Houk, K. N.; Tanaka, Fujie; Barbas, Carlos F.; Journal of the AmericanChemical Society; vol. 130; nb. 3; (2008); p. 875 - 886View 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 - 2496View in Reaxys









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Dios, Alfonso de; Prieto, Lourdes; Martin, Jose Alfredo; Rubio, Almudena; Ezquerra, Jesus; Tebbe, Mark; Ur-alde, Beatriz Lopez de; Martin, Justina; Sanchez, Ana; LeTourneau, Deborah L.; McGee, James E.; et al.; Journalof Medicinal Chemistry; vol. 45; nb. 20; (2002); p. 4559 - 4570View in Reaxys

Stage 1: With thionyl chloride, Time= 0.5h, T= -10 °CStage 2:T= 20 °C

Arakawa, Yasushi; Ohnishi, Masafumi; Yoshimura, Norikazu; Yoshifuji, Shigeyuki; Chemical & PharmaceuticalBulletin; vol. 51; nb. 8; (2003); p. 1015 - 1020View in Reaxys

Example Name 80.AEXAMPLE 80; Step A; A solution of cis-hydroxy-D-proline (2.98 g, 22.7 mmol) in methanol (20 mL) was treated withthionyl chloride (1.78 mL, 24.4 mmol) and stirred at room temperature for 1 h. The reaction mixture was then heatedto 65.deg. C. overnight. Evaporation of the volatiles gave the crude methyl ester (4.0816 g), which was dissolved indichloromethane (50 mL) and diisopropyl ethyl amine (9.59 mL, 55.1 mmol) was added. The reaction mixture wascooled 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 ofcitric acid (10percent, 50 mL) and the product was extracted into dichloromethane. The combined organic phases wereback-washed with brine, dried with anhydrous sodium sulfate, and the solvent was removed in vacuo. The crude productwas purified by flash chromatography (silica gel, ethyl acetate:hexanes/4:6) to yield 4.0717 g (69percent) of the pureproduct. 1H NMR (500 MHz, CDCl3): δ 7.35 m (5H), 5.21 (d, J=12.6 Hz, 2H), 5.10 (d, J=13 Hz, 1H), 5.06 (d, J=12.35Hz, 1H), 4.45 (m, 2H), 3.80 (s, 3H), 2.35 (m, 1H), 2.15 (m, 1H).


Patent; Butora, Gabor; Goble, Stephen D.; Pastemak, Alexander; Yang, Lihu; Zhou, Changyou; Moyes, Chris-topher R.; US2008/81803; (2008); (A1) EnglishView in Reaxys

Example Name 7.7.1EXAMPLE 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. Thionylchloride (18.1 ml) is subsequently added dropwise at the same temperature distributed over an hour. The reactionmixture (RM) is warmed to room temperature (RT) over 12 h, during which a clear solution forms. The solvent is removedin vacuo, and the residue obtained is recrystallised from ether, giving 50 g of methyl (2R,4R)-4-hydroxypyrrolidine-2-carboxylate; Rt.: 0.386 min; [M+H]+146.2.


Patent; Merck Patent GmbH; US2011/263561; (2011); (A1) EnglishView in Reaxys

N

O O

OH

H N

O

O

OH

HCl


Example Name 93.4Example Title Preparation of 1-(3,4-dimethoxy-5-trifluoromethylthiobenzoyl)-4S-hydroxypyrrolidine-2R-carboxylic acidhydroxyamide; Step 4[4S-HYDROXYOXY-1-TRITYLPYRROLIDINE-2R-CARBOXYLIC] acid methyl ester (510 mg, 1.32 mmol, [1] eq. ) wastreated 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






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23/47 2012-01-31 07:06:55

Patent; VICURON PHARMACEUTICALS, INC.; WO2004/7444; (2004); (A2) EnglishView in Reaxys

O HN

O

O

OH HCl


93% Example Name 8Example Title Allo-4-cis-hydroxy-D-proline ethyl ester hydrochlorideEXAMPLE 8Allo-4-cis-hydroxy-D-proline ethyl ester hydrochloride80 g of 4-cis-hydroxy-D-proline (0.61 mol) was suspended in 500 ml of anhydrous ethanol and anhydrous HC1 gaswas 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 ofproduct (93percent yield). M.P. 152.deg.-153.deg. C.

in ethanol

Patent; Braish; Tamim F.; Fox; Darrell E.; US5036153; (1991); (A1) EnglishView in Reaxys

N

O O

O

O

HO

H N

O

O

HO

Cl H


Example Name 1.AExample Title A.A.4-Hydroxy-L-Proline Ethyl Ester HydrochlorideTo a solution of N-Cbz-4-hydroxy-L-proline ethyl ester (3.29 g) in 40 ml ethanol was added 6 ml of ethanol saturatedwith 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) EnglishView in Reaxys

N O

O OH O

OH

H I H N

O

O

HO


Example Name 11Example Title EXAMPLE 11[0057] The compound 4-OH-L-proline methyl ester, described supra, is believed to be a new compound, representativeof a new group of compounds. The synthesis, of the compound and guidelines for synthesis of other members of this







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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 protected4-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] Deprotectionof tert-butyl dicarbonate was then carried out using trifluoroacetic acid, and standard methods. [0061] The key com-ponent 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 °CStage 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) EnglishView in Reaxys

HO

H N

OH

O

HO

H N

O

O

HO


Example Name 1Intermediate 1 methyl (4S)-4-hydroxy-D-prolinateIn a three necked flask under argon atmosphere equipped with amagnetic stir bar and a reflux condenser was placed MeOH (7 ml_). To the system was added acetyl chloride (0.898g, 11.4 mmol) in an ice bath followed by (4S)-4-hydroxy-D-proline (1 g, 7.6 mmol). The resultant mixture was heatedat reflux for 12 hours and cooled down to room temperature. Ether was added to cause precipitation and the resultingbrown 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) EnglishView 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 - 147View in Reaxys

With acetyl chloride


OH H N

OH

O

HO

H N

O

O

HO

Cl H


98 % With thionyl chloride, T= 0 °C , Reflux

Delunafreire, Kristerson R.; Tormena, Claudio F.; Coelho, Fernando; Synlett; nb. 14; (2011); p. 2059 - 2063; Art.No:S02011STView in Reaxys








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25/47 2012-01-31 07:06:55


Braish, Tamim F.; Fox, Darell E.; Journal of Organic Chemistry; vol. 55; nb. l; (1990); p. 1684 - 1687View 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 - 809View in Reaxys

HO

H N

OH

O

HO

H N

O

O

HO


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 wasevaporated under reduced pressure. The resulting solid was suspended in DCM (500 ml), and Et3N (127 ml, 0.915mol) and BnBr (33 ml, 0.275 mol) were added. The mixture was refluxed for 10 h. The solvent was evaporated and theproduct purified by flash chromatography using a linear gradient of EtOH in CHCl3. The product was obtained as a lightyellow oil in a 70percent yield (37.00 g, 0.160 mol). All spectral data recorded were in accordance with the literaturedata.


Kovackova, Sona; Dracinsky, Martin; Rejman, Dominik; Tetrahedron; vol. 67; nb. 7; (2011); p. 1485 - 1500View in Reaxys

HO

H N

OH

O

HO

Cl H

H N

O

O

HO

Cl H


93 % 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 - 519View in Reaxys

Example Name 26PREPARATION 26(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl esterAdd thionyl chloride (1.81 mol, 213.8 g, 1.5 eq) drop wise to a solution of (2R,4R)-4-hydroxy-pyrrolidine-2-carboxylicacid 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.


Patent; GAVARDINAS, Konstantinos; Jadhav, Prabhakar Kondaji; US2009/163472; (2009); (A1) EnglishView in Reaxys









SIG1


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OH H N

OH

O

HO

Cl H H N

O

O

HO

Cl H




69 % With thionyl chloride, Etherification

Yanagi, Toshiharu; Kitajima, Akihiko; Anzai, Kinsei; Kodama, Kazuya; Mizoguchi, Jun-ichi; Fujiwara, Hiromi-chi; Sakiyama, Hideyo; Kamoda, Osamu; Kamei, Chiaki; Chemical & Pharmaceutical Bulletin; vol. 47; nb. 11;(1999); p. 1650 - 1654View 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 - 4101View in Reaxys



N

O O

O

O

HO

H N

O

O

HO

Cl H


96 % 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 - 1757View in Reaxys

N O

O O O

OH

H H N

O

O

HO


With hydrogen, palladium on activated charcoal in ethanol, Time= 2.5h, p= 3102.9Torr , Ambient temperature











SIG1


27/47 2012-01-31 07:06:55

H N

OH

O

HO NH

O

O HO

HCl


Example Name 11Example Title Preparation of (2R-trans)-4-fluoro-2-pyrrolidinecarboxylic AcidEXAMPLE 11Preparation of (2R-trans)-4-fluoro-2-pyrrolidinecarboxylic AcidA 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 110mL (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 gof crude cis-4-hydroxy-D-proline methyl ester hydrochloride as a white solid.


Patent; Degussa AG; US6384234; (2002); (B1) EnglishView in Reaxys

H N

OH

O

HO

H N

O

O

HO


Example Name 3.1Example 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.


Patent; ACHILLION PHARMACEUTICALS, INC.; US2009/82261; (2009); (A1) EnglishView in Reaxys

N

O O

O

O

OH

H H N

O

O

HO

Cl H


Example Name 1Scheme 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-hydroxyproline1.-1 with HCl in dioxane followed by coupling with acid 1.-2 using HATU, afforded intermediate 1.-3. Other amino acidderivatives 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 cy-clopropyl-containing amine 1.-4 yielded tri-peptide 1.-5. Finally, ring-closing metathesis with a ruthenium-based catalystsuch as dichloro(o- isopropoxyphenylmethylene) (tricyclohexylphosphine)ruthenium(II) gave the desired key inter-mediate 1.-6 (for further details on ring closing metathesis see recent reviews: Grubbs et al, Ace. Chem. Res., 1995,






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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) EnglishView in Reaxys

N

O

O O O

HO

O

O

HN

OH

H


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 - 3625View in Reaxys

2.4 g With hydrogen, palladium on activated charcoal in methanol, Time= 10h, p= 760Torr , Ambient temperature


HO

H N

OH

O

HO

H N

O

O

HO


Example Name 82Thionyl chloride (612 ml) was added dropwise to a solution of L-hydroxyproline (1.0 g) in methanol (10 ml) at roomtemperature, and the resulting mixture was stirred overnight at room temperature. The reaction solution was concen-trated under reduced pressure, followed by adding thereto chloroform (10 ml) and a saturated aqueous sodium hydro-gencarbonate solution and then di-tert-butyl dicarbonate (2.5 g), and the resulting mixture was stirred at room temper-ature for 2 hours. The organic layer was concentrated under reduced pressure to obtain the title compound as a crudeproduct (3.38 g). 1H NMR (400 MHz, CDCl3) δ 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).


Patent; Dainippon Sumitomo Pharma Co., Ltd.; EP1659123; (2006); (A1) EnglishView in Reaxys

O

Cl

O H N

O

O

HO

Cl H

N

O O

O

O

HO


Example Name R.3.1








SIG1


29/47 2012-01-31 07:06:55

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 thendropwise 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 withchloroform.The chloroform extract was after-treated to obtain (2R,4R)-N-benzyloxycarbonyl-2-ethoxycarbonyl-4-hydroxy pyrroli-dine as an oily product.Yield 114.5 g.NMR (CDCl3)δ(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) EnglishView in Reaxys

N

O

O O O

HO

F

F F

HO

O F

F

F HO

O H N

O

O

HO


Example Name 4.1Step 4-1:Synthesis of methyl (4R)-4-hydroxy-L-prolinate trifluoroacetateTo a solution of 2.00 g of 1-tert-butyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate in CHCl3 (20 ml) wasadded TFA (10 ml) under ice cooling, the reaction mixture was warmed to room temperature, then was stirred for 3hours at the same temperature.Thereafter, the reaction solution was concentrated under reduced pressure to obtain 3.82 g of the title compound (crudeform, 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-d6) δ (ppm); 2.05-2.29 (m, 2H), 3.04-3.16 (m, 1H), 3.27-3.41 (m, 1H), 3.77 and 3.78 (each-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) EnglishView in Reaxys

NH

O O

I

H N

O

O

HO


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 - 830View in Reaxys






SIG1


30/47 2012-01-31 07:06:55

N

O

O

HO

H N

O

O

HO


With hydrogen, palladium dihydroxide in ethanol, Time= 5h, p= 1861.7Torr , Ambient temperature


N O O

O

O

H N

O

O

HO


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 - 3872View in Reaxys

N O

O

O

O

H N

O

O

HO




N O O

O

O

H N

O

O

HO












SIG1


31/47 2012-01-31 07:06:55

N

O O

OH

O

HO

H N

O

O

HO


Reaction Steps: 21: 81 percent / Et3N / acetonitrile / 55 °C2: H2 / 5percent Pd/C / ethanol / 2.5 h / 3102.9 Torr / Ambient temperatureWith hydrogen, triethylamine, palladium on activated charcoal in ethanol, acetonitrile


H N

OH

O

HO

H N

O

O

HO


Example Name 56.AExample Title Step AStep A4(R)-Hydroxyproline methyl esterA suspension of 4(R)-hydroxyproline (35.12 g, 267.8 mmol) in methanol (500 ml) was saturated with gasseous hydro-chloric acid.The resulting solution was allowed to stand for 16 hrs and the solvent evaporated in vacuo to afford the title compoundas a white solid.1 H NMR CD3 OD δ 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)and 2.21(1H, m) ppm.

in methanol

Patent; Merck and Co., Inc.; US5756528; (1998); (A1) EnglishView in Reaxys

N

O O

O

O

OH

H H N

O

O

HO


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 - 10657View in Reaxys







SIG1


32/47 2012-01-31 07:06:55

H N

OH

O

HO

O

O

HN

OH

H


Reaction Steps: 31: NaHCO3 / H2O / 2 h2: tetrahydrofuran / 1.) r.t., 30 min, 2.) 55 deg C, 20.5 h3: H2 / 10percent Pd/C / methanol / 2 hWith hydrogen, sodium hydrogencarbonate, palladium on activated charcoal in tetrahydrofuran, methanol, water


N

O O

OH

O

HO

O

O

HN

OH

H


Reaction Steps: 21: tetrahydrofuran / 1.) r.t., 30 min, 2.) 55 deg C, 20.5 h2: H2 / 10percent Pd/C / methanol / 2 hWith hydrogen, palladium on activated charcoal in tetrahydrofuran, methanol


Cl O H N

OH

O

HO

H N

O

O

HO


Example Name 30Example 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 (40ml) 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 driedunder 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) EnglishView in Reaxys







SIG1


33/47 2012-01-31 07:06:55

H N

O

O

HO

F

F F

HO

O F

F F

OH

O

N H

O

O

HO


Example Name B.102.1To a solution of ez's-hydroxyprolinemethyl ester (20 g, 81 mmol) inDCM (200 mL) was added TFA (40 mL). The reactionwas stirred for 2 h withmonitoring by LC/MS. Strip solvent and coevaporate with toluene 2X thenchloroform 3X. Removeexcess TFA by placing the reaction mixture underhigh vacuum for 5 h which afforded TFA salt (~ 21 g) as an orangeviscous oil.LC/MS: 260 (M+ + l).To a solution of TFA salt (10.0 g, 40.7 mmol) in DMF (125 mL) was addedcyclopenty-loxycarbonyl-fert-leucinecarboxylic acid (12g, 48 mmol), andHATU (23g, 61 mmol). The reaction mixture was cooledto 0 .deg.C and Hunig'sbase (28 mL, 163 mmol) was added slowly over 5 min. The reaction wasallowed to warm toroom temperature and stirred for 1 h. Remove solventunder reduced pressure and dilute with ethyl acetate. Extract theorganicswith 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) EnglishView in Reaxys

Cl H

HN HO

O OH

Cl H

HN

O

O

OH HCl


212.1 g(75%)

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 withdry 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. [α]D =+20.37.deg. (c=2, H2 O).

in ethanol

Patent; Bristol-Myers Company; US4954507; (1990); (A1) EnglishView in Reaxys

OH H N

OH

O

HO

H N

O

O

HO


Example Name 132Example 132. (4R)-4-Hydroxy-D-proline, Ethyl Ester (132); [0518] In accordance with the procedure of Shunji Sakurabaet al. (Chem. Pharm. Bull,1995, 43, 738), 4-hydroxy-L-proline (10 g, 76.3 mmol) was treated with Ac2O (72 mL, 0.763mol, d 1.087) in AcOH followed by HCl in EtOH to afford the title compound as a white gum: 1H NMR δH (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 acidStage 2: With hydrogenchloride






SIG1


34/47 2012-01-31 07:06:55

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) EnglishView in Reaxys

O

Cl O H N

OH

O

HO

H N

O

O

HO


Example Name 41.AExample Title A.A.(2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid methyl esterAcetyl 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 themixture 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) EnglishView in Reaxys

NH

O NH 2

H N

O

O

HO


Reaction Steps: 21: iodine / tetrahydrofuran; H2O / 0.5 h / Ambient temperature2: H2 / Pd(OH)2 / ethanol / 5 h / 1861.7 Torr / Ambient temperatureWith hydrogen, iodine, palladium dihydroxide in tetrahydrofuran, ethanol, water


NH

O O

I

H N

O

O

HO


Reaction Steps: 21: 90 percent / Na2CO3 / 24 h / Ambient temperature2: H2 / Pd(OH)2 / ethanol / 5 h / 1861.7 Torr / Ambient temperatureWith hydrogen, sodium carbonate, palladium dihydroxide in ethanol









SIG1


35/47 2012-01-31 07:06:55

N

O

O

O

H N

O

O

HO


Reaction Steps: 31: NH3 / ethanol / 0.5 h / 0 °C2: iodine / tetrahydrofuran; H2O / 0.5 h / Ambient temperature3: H2 / Pd(OH)2 / ethanol / 5 h / 1861.7 Torr / Ambient temperatureWith ammonia, hydrogen, iodine, palladium dihydroxide in tetrahydrofuran, ethanol, water


OH H N

OH

O

HO

Cl H H N

O

O

HO


73 % With thionyl chloride, T= 20 °C


Cl O H N

OH

O

HO

H N

O

O

HO

Cl H


100 % in methanol, Time= 8h, Heating

Rosen, Terry; Fesik, Stephen W.; Chu, Daniel T. W.; Pernet, Andre G.; Synthesis; nb. 1; (1988); p. 40 - 44View in Reaxys

OH H N

OH

O

HO

H N

O

O

HO

Cl H



Karim, A.; Mortreux, A.; Petit, F.; Buono, G.; Pfeiffer, G.; Siv, C.; Journal of Organometallic Chemistry; vol. 317;(1986); p. 93 - 104View in Reaxys









SIG1


36/47 2012-01-31 07:06:55

H N

OH

O

HO

H N

O

O

HO

Cl H


Reaction Steps: 21.1: Ac2O; AcOH / 5.5 h / Heating1.2: 65 percent / aq. HCl / 3 h / Heating2.1: 67 percent / HCl / ethanol / 5 h / HeatingWith 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 - 4101View in Reaxys

Reaction Steps: 21.1: Ac2O / acetic acid / 5.5 h / Heating1.2: 96 percent / aq. HCl / 3 h / Heating2.1: 82 percent / SOCl2 / 6 h / HeatingWith thionyl chloride, acetic anhydride in acetic acid


Reaction Steps: 21: 1.) acetic anhydride, 2.) 2N HCl / 1.) glacial acetic acid, reflux, 5.5 h, 2.) reflux, 3 h2: 77 percent / HCl (gas) / 5 h / HeatingWith hydrogenchloride, acetic anhydride


OH N

O

OH

O

HO

H N

O

O

HO

Cl H


57 % With hydrogenchloride, Heating


Cl O H N

OH

O

HO

H N

O

O

HO

Cl H


92 % in methanol, Time= 8h, Heating

Cho, Han-Won; Oh, Chang-Hyun; Lee, Ju-Shin; Lee, Soo-Chul; Choi, Jung-Hoon; Cho, Jung-Hyuck; Archiv derPharmazie (Weinheim, Germany); vol. 336; nb. 11; (2003); p. 495 - 503View in Reaxys









SIG1


37/47 2012-01-31 07:06:55

N

O

O

HO

S

HO

O O

H N

O

O

HO

S

HO

O O


85 % 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 - 251View in Reaxys

HO

H N

Cl

O

HO

H N

O

O

HO

Cl H


Example Name 44-(R)-Hydroxypyrrolidine-2-(R)-carboxylic acid methyl ester hydrochloride Add thionyl chloride (5.5 mL, 75.8 mmol) toan ice-cold suspension of 4-(R)- hydroxypyrrolidine-2- (R)-carboxylic acid (4.97 g, 31.9 mmol) in methanol (60 mL). Stir10 min, then warm to room temperature and stir 3.5 h. Concentrate, add methanol, and concentrate again. Dissolve inabsolute ethanol (25 mL) and precipitate with diethyl ether (50 mL) and filter. Dry cake under vacuum to give the titlecompound 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) EnglishView in Reaxys

HO

NH Cl

O HO H N

O

O

HO


Example Name 7Add 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, addmethanol 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) EnglishView in Reaxys

O O

H N

OH

O

HO

H N

O

O

HO

Cl H


83 % With hydrogenchloride, Ambient temperature










SIG1


38/47 2012-01-31 07:06:55

N

O

O

HO

H N

O

O

HO


With formic acid in 1,2-dichloro-ethane

Demange, Luc; Menez, Andre; Dugave, Christophe; Tetrahedron Letters; vol. 39; nb. 10; (1998); p. 1169 - 1172View in Reaxys

H N

O

O

HO

Cl H

H N

O

O

HO


Reaction Steps: 31: 76 percent / Et3N / CHCl3 / 0 °C2: 1.) PPh3, DEAD, PhCO2H; 2.) KOH / 1.) toluene; 2.) MeOH3: HCO2H / 1,2-dichloro-ethaneWith potassium hydroxide, formic acid, triethylamine, triphenylphosphine, benzoic acid, diethylazodicarboxylate inchloroform, 1,2-dichloro-ethane


N

O

O

HO

H N

O

O

HO


Reaction Steps: 21: 1.) PPh3, DEAD, PhCO2H; 2.) KOH / 1.) toluene; 2.) MeOH2: HCO2H / 1,2-dichloro-ethaneWith potassium hydroxide, formic acid, triphenylphosphine, benzoic acid, diethylazodicarboxylate in 1,2-dichloro-ethane


N

O

O

H N

O

O

HO

S

HO

O O


Reaction Steps: 2








SIG1


39/47 2012-01-31 07:06:55

1: 85 percent / triphenylphosphine (TPP), diethyl azodicarboxylate (DAED) / tetrahydrofuran / 48 h / Ambient temper-ature2: 85 percent / tetrahydrofuran; propan-2-ol / 0.25 h / Ambient temperatureWith triphenylphosphine, diethylazodicarboxylate in tetrahydrofuran, isopropyl alcohol


N

OH

O

HO

H N

O

O

HO

S

HO

O O


Reaction Steps: 31: triphenylphosphine (TPP), diethyl azodicarboxylate (DAED) / tetrahydrofuran / 0.08 h / 0 °C2: 85 percent / triphenylphosphine (TPP), diethyl azodicarboxylate (DAED) / tetrahydrofuran / 48 h / Ambient temper-ature3: 85 percent / tetrahydrofuran; propan-2-ol / 0.25 h / Ambient temperatureWith triphenylphosphine, diethylazodicarboxylate in tetrahydrofuran, isopropyl alcohol


H N

O

O

HO

Cl H H N

O

O

HO


Example Name 1

With ammonia in methanol, chloroform, Time= 0.0833333h

Patent; SALAMA, Zoser, B.; WO2005/58816; (2005); (A1) GermanView in Reaxys

OH H N

OH

O

HO

H N

O

O

HO



Adams et al.; Journal of Biological Chemistry; vol. 208; (1954); p. 573,577View in Reaxys








SIG1


40/47 2012-01-31 07:06:55

HO

H N

Cl

O

HO

H N

O

O

HO


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 - 149View in Reaxys

OH trans-4-hydroxy-DL-proline-hydrochlor‐ide

H N

O

O

HO racemate


Gaudry; Godin; Journal of the American Chemical Society; vol. 76; (1954); p. 139,141View in Reaxys

OH cis-4-hydroxy-DL-proline-hydrochlor‐ide

H N

O

O

HO racemate


Gaudry; Godin; Journal of the American Chemical Society; vol. 76; (1954); p. 139,141View in Reaxys

OH H N

OH

O

HO

H N

O

O

HO

Cl H




HO

H N

OH

O

HO racemate

N H O

O

HO

racemate


With acetyl chloride, Time= 24h

Asari, Asnuzilawati; Angelov, Plamen; Auty, James M.; Hayes, Christopher J.; Tetrahedron Letters; vol. 48; nb.14; (2007); p. 2631 - 2634View in Reaxys











SIG1


41/47 2012-01-31 07:06:55

HO

H N

OH

O

HO

Cl H

H N

O

O

HO



Stevens, Kirk L.; Alberti, Jennifer G. Badiang; Caferro, Thomas R.; Chamberlain, Stanley D.; Dickson, HamiltonD.; 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 - 26View in Reaxys

OH H N

OH

O

HO

H N

O

O

HO


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 - 747View in Reaxys

H N

OH

O

HO

H N

O

O

HO


Reaction Steps: 21.1: acetic anhydride; acetic acid / 5.5 h / 50 °C / Reflux1.2: 3 h / Reflux2.1: thionyl chloride / 20 °CWith thionyl chloride, acetic anhydride, acetic acid


OH H N

OH

O

HO

H N

O

O

HO


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 - 2025View in Reaxys









SIG1


42/47 2012-01-31 07:06:55

HO

H N

OH

O

HO

H N

O

O

HO

Cl H


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 andBio-Organic Chemistry (1972-1999); nb. 22; (1998); p. 3767 - 3776View in Reaxys

N N

H N

OH

O

HO

H N

O

O

HO

(2S)-2r-carboxy-4t-hydroxy-1,1-dimethyl-pyrrolidinium betaine


With diethyl ether

Kuhn; Brydowna; Chemische Berichte; vol. 70; (1937); p. 1333,1339View in Reaxys

OH

H N

OH

O

HO

H N

O

O

HO

Cl H


Example Name 1

With hydrogenchloride, Time= 24h


N N

H N

OH

O

HO

H N

O

O

HO

N +

O

O –

HO


With diethyl ether


N N O

H N

OH

O

HO

H N

O

O

HO

(2S)-2r-carboxy-4t-hydroxy-1,1-dimethyl-pyrrolidinium betaine













SIG1


43/47 2012-01-31 07:06:55

HN

O

O

OH


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) EnglishView in Reaxys

H N

O

O

HO

Cl H


Example Name 1Example Title Preparation 1Preparation 1In 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 addeddropwise 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 thistemperature 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 hydro-chloride (134.8 g).IR (Nujol): 3320, 1740, 1590, 1080, 1620, 900 cm-1

NMR (DMSO-d6, δ): 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) EnglishView in Reaxys

H N

O

O

HO


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; andtrans-4-hydroxy-L-proline methyl ester;






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Patent; Arris Pharmaceutical Corporation; US5525623; (1996); (A1) EnglishView in Reaxys

HN

O O

OH

H Cl H


20.05 g(93.1%)

Example Name 5.AExample Title A.A.(cis)-4-Hydroxy-L-proline, methyl ester hydrochlorideInto a 1 liter Parr hydrogenation bottle was placed 29.90 g (107.12 mmol) of (cis)-1-benzyloxycarbonyl-4-hydroxy-L-proline, methyl ester (reference: J. Am. Chem. Soc., 79, 185, (1957)), 400 ml of methanol, 9.83 ml (117.90 mmol) ofconcentrated 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; thepalladium 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, whichcaused a white precipitate to form.The solids were filtered, washed twice with ethyl acetate and once with hexane, and dried under vacuum to yield 20.05g (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) EnglishView in Reaxys

OH

O

H N

O

O

HO


Example Name R.5.2Example Title REFERENCE EXAMPLE 5-2 STR134REFERENCE EXAMPLE 5-2 STR134To 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) EnglishView in Reaxys

H N

O

O

HO

Cl H


Example Name R.2.1Example Title REFERENCE EXAMPLE 2(1)







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To a mixture of 100 g of 4-hydroxy-L-proline[α]D 20 =-76.5.deg. (c=2.5, H2 O) and 380 ml of ethanol, 109 g of thionylchloride 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. to154.deg. C.[α]D 20 =-29.85.deg. (c=1.0, H2 O).NMR (DMSO-d6)δ(TMS ppm): 1.25 (3H, t), 1.9-2.4 (2H), 2.8-4.7 (4H), 4.23 (2H, q).


H N

O

O

HO

Cl H


Example Name R.4.1Example Title REFERENCE EXAMPLE 4Into a solution of 5 g of thus obtained crystals in 25 ml of ethanol, 6.49 g of thionyl chloride were dropwise added andthe 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.[α]D 20 =-20.34.deg. (c=1, H2 O).NMR (DMSO-d6)δ(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).


S

O

O

O

N O

O

O O

H N

O

O

HO

Cl H


Example Name R.3.3Example Title REFERENCE EXAMPLE 31.47 g of thus obtained crystalline material were suspended in 6 ml of ethanol and the suspension was added dropwisewith 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 obtaincrystals, which were recrystallized from ethanol to obtain (2R,4S)-2-ethoxycarbonyl-4-hydroxy pyrrolidine hydrochlor-ide.Yield 1.08 g M.p. 153.deg. to 153.5.deg. C.[α]D 20 =+29.78 (c=1, H2 O).







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N O

O

OH

H N

O

O

HO

Cl H


Example Name R.3.4Example 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-ethox-ycarbonyl-4-hydroxy pyrrolidine hydrochloride obtained in the preceeding para. (3), to obtain 7.54 g of (2R,4S)-2-ethoxycarbonyl-N-ethyl-4-hydroxy pyrrolidine NMR datas were identical with those of the compound obtained in Ref-erence Example 2 (2).


N H

O

O

HO


78.6 % Example Name 1


H N

O

O

HO


4-Hydroxyprolin

Grimm,L.; Grassmann,W.; Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie; vol. 337; (1964); p. 161 - 171View in Reaxys

Hydroxyprolin, Me., HCl

Heyns,K.; Legler,G.; Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie; vol. 321; (1960); p. 161 - 183View in Reaxys

Hydroxyprolin, Me., SOCl2

Heyns,K.; Legler,G.; Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie; vol. 321; (1960); p. 161 - 183View in Reaxys

H N

O

O

HO


Example Name 1

Patent; FAUST PHARMACEUTICALS; WO2005/118533; (2005); (A1) English










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