solubility properties of the intermediates and the need for
multiple chromatographies make scale-up of this synthesis
problematic. Another short route uses the reaction of (S)-
benzylglycidyl ether with 2-aminoethyl hydrogen sulfate and
base to generate the morpholine in a one-pot sequence.7 BOC
protection and debenzylation yields 1. Unfortunately, tars are
formed in this process which are difficult to remove. On a
kilogram scale, the overall yield of 1 was 38%, but two
distillations and three chromatographies were required to give
material of acceptable quality, which seriously detracts from
the chemical brevity of this synthesis. A more straightforward
route also starting from (S)-benzylglycidyl ether has been
described.8 This route has also been scaled but has seven isolated
intermediates, three chromatographies, and a distillation, which
limit throughput. A similar but even longer route starting with
D-mannitol has also been described.9
Concise Synthesis of
(S)-N-BOC-2-Hydroxymethylmorpholine and
(S)-N-BOC-Morpholine-2-carboxylic Acid
Kevin E. Henegar*
Pfizer Global Research and DeVelopment, Groton
Laboratories, Eastern Point Road, Groton
Connecticut 06340
keVin.e.henegar@pfizer.com
ReceiVed February 12, 2008
Given the utility of 1 and 2, there remains a need for a more
efficient and scalable route to these valuable compounds. We
describe herein a concise synthesis that can be used to make
either enantiomer starting from inexpensive chiral epichloro-
hydrin. The basic synthetic approach is shown in Scheme 1.
An operationally simple synthesis of N-BOC-2-hydroxy-
methylmorpholine (1) and N-BOC-morpholine-2-carboxylic
acid (2) from epichlorohydrin has been developed. No
chromatography is required in the processing, which allows
high process throughput.
(4) (a) Baldwin, J. J.; Claremon, D. A.; Tice, C.; Cacatian, S.; Dillard, L. W.;
Ishchenko, A. V.; Yuan, J.; Xu, Z.; McGeehan, G.; Zhao, W.; Simpson, R. D.;
Singh, S. B.; Flaherty, P. T.; Wery, J.-P. WO2006/042150, Apr. 20, 2006; CAN
144:432692. (b) Ko, S. S.; Delucca, G. V.; Duncia, J. V.; Santella, J. B., III;
Wacker, D. A. WO 2000/035877, Dec. 17, 2000; CAN 133:58720. (c) Ackerman,
J.; Banner, D.; Gubernator, K.; Hadvary, P.; Hilpert, K.; Mueller, K.; Labler,
L.; Schmid, G.; Tschopp, T. EP468231, July 2, 1991; CAN 116:214908. (d)
Amegadzie, A. K.; Beck, J. P.; Gardinier, K. M.; Hembre, E. J.; Ruble, J. C.;
Savin, K. A.; Wakefield, B. DWO 2006/066174, June 22, 2006; CAN 145:83313.
(e) Bower, J. F.; Poyser, J. P.; Turner, P.; Waterson, D.; Winter, J. WO2006/
067401, June 29, 2006; CAN 145:103720. (f) Gudmundsson, K.; Miller, J. F;
Turner, E. M. WO2006/020415, Feb. 23, 2006; CAN 144:233072. (g) Fink, B. E.;
Gavai, A. V.; Vite, G. D.; Chen, P.; Mastalerz, H.; Norris, D. J.; Tokarski, J. S.;
Zhao, Y.; Han, W.-C. WO2005/066176, July 21, 2005; CAN 143:153408. h)
Gavai, A. V.; Han, W.-C.; Chen, P.; Ruediger, E. H.; Mastalerz, H.; Fink, B. E.;
Norris, D. J. WO2005/065266, July 21, 2005; CAN 143:133402. (i) Kato, S.;
Yamazaki, H.; Hirokawa, Y.; Suga, Y.; Yoshida, N.; Morikage, Y.; Morikage,
K.; Oku, S. JP2004/277319, Oct. 7, 2004; CAN 141:307556. (j) Munson, M.;
Mareska, D. A.; Kim, Y.; Groneberg, R. D.; Rizzi, J.; Rodriguez, M.; Kim, G.;
Vigers, G.; Rao, C.; Balachari, D.; Harvey, D. US2004/192653, Sept. 30, 2004;
CAN 141:314320. (k) Bhide, R.; Cai, Z.-w.; Qian, L.; Barbosa, S. WO2004/
009784, Jan. 29, 2004; CAN 140:124558. (l) Luckhurst, C.; Perry, M.; Sanganee,
H.; Springthorpe, B. WO2003/078395, Sept. 25, 2003; CAN 139:276907. (m)
Mastalerz, H.; Zhang, G.; Tarrant, J. G.; Vite, G. D. WO2003/042172, May 22,
2003; CAN 138:401758. (n) Sanganee, H.; Springthorpe, B. WO2003/024962,
Mar. 6, 2003; CAN 138:271690. (o) Gustafsson, J.; Hossain, N.; Nilsson, S.
WO2003/018576, Mar. 6, 2003; CAN 138:221591. (p) Gustafsson, J.; Hossain,
N.; Nilsson, S. WO2003/018566, Mar. 6, 2003; CAN138:221472. (q) Ko, S. S.;
Delucca, G. V.; Duncia, J. V.; Santella, J. B., III; Wacker, D. A. WO2000/
035877, June 22, 2000; CAN 133:58720. (r) Miyake, H.; Take, K.; Shigenaga,
S.; Azami, H.; Sasaki, H.; Eikyu, Y.; Nakai, K.; Ishida, J.; Manabe, T.; Konishi,
N.; Terasaka, T. WO98/57954, Dec. 22, 1998; CAN 130:81525. (s) Yanagisawa,
H.; Fujimoto, K.; Shimoji, Y.; Kanezaki, T.; Iwata, N.; Kubo, Y. JP 04120021,
1992; CAN 117:251362. (t) Ackerman, J.; Banner, D.; Gubernator, K.; Hadvary,
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B.; Noren, R.; Grabowska, U.; Jackson, P.; Fallon, P.; Carr, A.; Liley, M.; Tozer,
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N-BOC-2-Hydroxymethylmorpholine (1) and the closely
related N-BOC-morpholine-2-carboxylic acid (2) have been used
extensively in the preparation of pharmacologically active
compounds, both as the racemates and as single enantiomers.
These include a number of CNS compounds such as reboxetine
and related norepinephrine and norepinephrine-serotonin re-
uptake inhibitors (NRI and NSRI, respectively),1 NRI and NSRI
indazoles,2 and other CNS structural classes.3 In addition, 1 and
2 have been used to prepare a wide variety of other pharma-
ceutically active compounds.4
Despite their widespread use, synthetic routes to these
valuable compounds, either racemic or single enantiomer, are
limited by expensive starting materials, processing issues, and
lengthy and/or inefficient routes. For example, a 4-step synthesis
of (S)-1 starting with (S)-3-amino-1,2-propanediol was recently
reported as part of a synthesis of reboxetine.5 Although the
starting material is commercially available, its high cost makes
this route economically unattractive.6 In addition, the poor
* Corresponding author.
(1) (a) Fish, P. V.; Mackenny, M. C.; Stobie, A.; Wakenhut, F.; Whitlock,
G. A. U.S. 2005/250775, Nov. 10, 2005; CAN 143:460166. (b) Fish, P. V.;
Mackenny, M. C.; Stobie, A.; Wakenhut, F.; Whitlock, G. A WO 2005/105100,
(Nov. 10, 2005; CAN 143:460165. (c) Barta, N. S.; Glase, S. A.; Gray, D. L.;
Reichard, G. A.; Simons, L. J.; Xu, WU.S. 2005/245519, Nov. 3, 2005; CAN
143:440426.
(5) Brenner, E.; Baldwin, R. M.; Tamagnan, G. Org. Lett. 2005, 7, 937–
939.
(2) Schelkun, R. M.; Yuen, P.-W. WO2006/056873, Jun. 1, 2006; CAN 145:
27985.
(6) The lowest bulk quote we received for (S)-3-amino-1,2-propanediol was
10 kg at $6000/kg).
(3) (a) Ono, S.; Yamafuji, T.; Chaki, H.; Maekawa, M.; Todo, Y.; Narita,
H. EP383281, Aug. 8, 1994; CAN 114:81222. (b) Carruthers, N. I.; Gomez,
L. A.; Jablonowski, J. A.; Keith, J. M.; Letavic, M. A.; Ly, K. S.; Miller, J. M. B.;
Stocking, E. M.; Wolin, R. LWO2006/066197, Jun. 22, 2006; CAN 145:83244.
(c) Kojima, T.; Niigata, K.; Fujikura, T.; Tachikawa, S.; Nozaki, Y.; Kagami,
S.; Takahashi, K. Chem. Pharm. Bull. 1985, 33, 3766–74.
(7) Ackerman, J.; Banner, D.; Gubernator, K.; Hadvary, P.; Hilpert, K.;
Mueller, K.; Labler, L.; Schmid, G.; Tschopp, T. EP468231, Jan 29, 1992; CAN
116:214908.
(8) Berg, S.; Larsson, L.-G.; Renyi, L.; Ross, S. B.; Thorberg, S.-O.; Thorell-
Svantesson, G. J. Med. Chem. 1998, 41, 1934–1942.
(9) Yanagisawa, H.; Kanazaki, T. Heterocycles 1993, 35, 105–9.
3662 J. Org. Chem. 2008, 73, 3662–3665
10.1021/jo800356q CCC: $40.75 2008 American Chemical Society
Published on Web 03/26/2008