Organic Process Research & Development
Article
(22) (a) Schultz, O.-E.; Ziegler, A. Pharmzie 1970, 25, 472.
(b) Lunsford, C. D.; Ward, J. W.; Pallotta, A. J.; Tusing, T. W.;
Rose, E. K.; Murphey, R. S. J. Med. Pharm. Chem. 1959, 1, 73.
(23) The analogous reaction with 1,4-dichloro-2-butanol (which is
commercially available) is not published but mentioned on the WWW
saturated pyrrolidines R2N-R′ [R2= (−CH2−CH2−CH2−CH2−)].
Except the N-benzyl derivates, all compounds have low boiling points
(∼80−90 °C/760 Torr) which will separate them during the
purification of 2 by distillation, and separation by GC from 2 was
proven.
(24) Bowers Nemia, M. M.; Lee, J.; Joullie,
1983, 13, 1117.
́
M. M. Synth. Commun.
(25) Kocalka, P.; Pohl, R.; Rejman, D.; Rosenberg, I. Tetrahedron
2006, 62, 5763.
(26) Jaeger, E.; Biel, J. H. J. Org. Chem. 1965, 30, 740.
(27) (a) Liu, H.; Yuan, S. CN 101323583 A 20081217. (b) Kano, F.;
Mori, N. WO 03/091209 A1 20031106.
(40) Although it was shown that the alkylating agents (8, 9, 9a, 10,
15, 16b/c, 17b/c) could not be present in 2, they were tested by the
GC method applied for the analyses of 2 which reveals their separation
from compound 2.
(41) LOQ (limit of quantification) is 0.05%; LOD (limit of
(28) (a) Mannich, C.; Kuphal, R. Ber. Dt. Chem. Ges. 1912, 45, 314.
(b) Bao-qin, M.; Zheng-lin, Z.; Jian-zhong, Z. Jingxi Yu Zhuanyong
Huaxuepin 2005, 13, 11. (c) Bulmann, P. C.; Leach, D. C.; Hayman, C.
M.; Hamzah, A. S.; Allin, S. M.; McKee, V. Synlett 2003, 1025.
(d) Roglans, A.; Marquet, J.; Moreno-Mafias, M. Synth. Commun.
1992, 22, 1249. (e) Chen, H. from Faming Zhuanli Shenqing (2011),
CN102060743 A 20110518, (f) Li, G.; Chen, Y.; Qian, C.; Chen, X.
Huaxue Fanying Gongcheng Yu Gongyi 2010, 26, 477. (g) Pinto, A. C.;
Abdala, R. V.; Costa, P. R. R. Tetrahedron: Asymmetry 2000, 11, 4239.
(h) Casy, A. F.; Birnbaum, H.; Hall, G. H.; Everitt, B. J J. Pharm.
Pharmacol. 1965, 17, 157.
(29) 1,2,4-Tribromobutane 9a was detected in ample amounts in
commercially available samples of 1,4-dibromo-butan-2-ol 9.
(30) For example, in a 6% solution of 2 in acetonitrile an initially
spiked concentration of ethyl chloroacetate 17c (2.8% rel. to 2) is
declining to 0.01% within 21 h. Compounds 9, 9a, 10, 16b, and 17b
react vigorously when mixed with neat 2.
(31) Some of the quaternary ammonium salts are known
compounds: 28: Lunsford, C. D. (A. H. Robins Co., Inc.) GB
1170831 19691119. 29: Mandava, N.; Fodor, G. J. Lieb. Ann. Chem.
1970, 741, 167.
(32) The substitution−elimination mode of tribromobutane 9a in its
reaction with bases to form bromoalkenes like 25 is known. See:
Lespieau, P. Compt. Rend. 1908, 146, 1035.
(33) (a) 3-Hydroxy-tetrahydrofuran 31 was detected in batches of 2.
(b) 9a, 30, and 31 are commercially available. (c) The preparation of
30 from 9a is described by: Hojo, K. et al. in EP 0218 249 filed
08.10.1986. (d) The commercially available 9, contaminated with 9a,
forms a mixture of 2 and 30 when reacted with methylamine.
(34) Astonishingly, 32 was not yet reported in the literature as a
byproduct of this reaction.
(35) Its formation is explained by the base-induced transformation of
1,4-dibromo-2-butanol 9 into 4-bromo-1,2-epoxybutane which can be
attacked by methylamine at C-1 (forming 2) or C-2 forming 33; the
NaOH induced epoxide ring formation of the analogous 1,4-dichloro-
2-butanol is described in: Johnson, J. Y. Johnson, G. W. GB 692755,
June 10th, 1953. Reppe.; et al. J. Lieb. Ann. Chem. 1955, 596, 80−158
(in particular page 142).
detection) would be even smaller.
(42) 14 and 33 are not very well separated by GC.
(43) Biel, J. H.; Friedman, H. L.; Leiser, H. A.; Sprengeler, E. P. J.
Am. Chem. Soc. 1952, 74, 1485.
(44) (a) Hoffmann, K.; Schellenberg, H. Helv. Chim. Acta 1947, 30,
292. (b) Grignard, M. V.; Moissan, M. H. Comptes Rendus 1902, 135,
627.
(45) Ji, F.; Wu, W.; Dai, X.; Mori, N.; Wu, J.; Buchwald, P.; Bodor, N.
J. Pharm. Pharmacol. 2005, 57 (11), 1427−1435.
(46) This process is claimed to give higher yields than the direct
reaction with the cyclopentyl-Grignard reagent. The preparation of
cyclopentadienyl-MgBr in our hand however turned out to be very
cumbersome. (a) Waugh, T. D. US-pat. 3,381,017, April 30. 1968,
(b) Fei, Yu; Li-xin, H,; Cheng-duo, Li; Dun, W, Hecheng Huaxue
(Chin. J. Synth. Chem.) 2009, 17, 385−387.
(47) (a) Dobrina, V. A.; Ioffe, D. V. Khimiko-Farmatsevticheskii Zh.
1977, 11 (6), 90. (b) Zhong, B.; Liu, H.; Zheng, J.; Liu, K.; Li, W.; Liu,
L.; Xie, J.; Chen, L.; Han, X.; Liu, W.; Liu, C.; Ge, X.; Weng, X. CN
1673209 A 20050928.
(48) Blumberg, P.; LaMontagne, M. P.; Stevens, J. I. J. Org. Chem.
1972, 37, 1248−51.
(49) (a) Aldo, F.; Giovanni, G.; Giancarlo, T.; Marco, M.; Annalisa,
B.; Enzo, G.; Cinzia, B.; Mario, G.; Daniele, S.; Stefano, M. J. Med.
Chem. 1994, 37, 4278−87. (b) Adam, W.; Cueto, O. J. Org. Chem.
1977, 42, 38.
(50) A remark may be allowed: in view of the prior art already
published years ago, it is often not reasonable that essentially identical
processes can be patented again years later.
(51) A: 28%, B: 38%, C: 50% (86% ester), D: 53%.
(52) If they know at all, vendors and manufacturers do not readily
disclose their details, e.g., origin and structure of byproducts.
(53) The ranges for the content of product and byproduct appear to
be quite large; they are based on five experiments using different
experimental conditions varying the Grignard reagent (cyclopentyl-
magnesiumbromide and -chloride), the solvent (diethylether and
THF, as well as combinations with toluene), and the starting material
(methyl phenylglyoxylate 36a and the acid 36). The optimization was
not anticipated.
(36) (a) Preparatively aminoxides are obtained with oxygen (air)
under pressure at 100°C; hydroxen peroxide and per-carboxylic acids
react more smoothly, and organoperoxide requires transition metal
catalysts. (b) Doser, K.; Hemmer, R. In Houben Wyl − Methoden der
Organischen Chemie, Bd. E16a, G. Thieme Verlag Stuttgart: New York,
1990; p 404ff.
(54) The Grignard reaction, however, is usually complete, and no
ester 36n is left.
(55) Although its preparation needs drastic conditions, see vide infra.
(56) (a) Bobysheva, Z. I.; Volkova, V. A.; Ioffe, D. V.; Kuznetsov, S.
G.; Stepanova, A. A. Zh. Org. Khim. 1972, 8, 2062. (b) For its
preparation see vide infra.
(37) Shaikh, N. S.; Deshpande, V. H.; Bedekar, A. V. Tetrahedron
2001, 57, 9045.
(57) (a) Das, S.; Mahanti, M. K. Oxid. Commun. 2009, 32, 104−109.
(b) Zeller, K.-P.; Kowallik, M.; Haiss, P. Org. Biomol. Chem. 2005, 3,
2310−2318. (c) Marziano, N. C.; Ronchin, L.; Tortato, C.; Ronchin,
S.; Vavasori, A. J. Mol. Catal. A: Chem. 2005, 235, 26−34. (d) Favier,
I.; Dunach, E.; Hebrault, D.; Desmurs, J.-R. New J. Chem. 2004, 28,
62−66. (e) Defoin, A.; Defoin-Straatmann, R.; Kuhn, H. J. J. Labelled
Compd. Radiopharm. 1982, 19, 891−8. (f) Ando, W.; Miyazaki, H.;
Akasaka, T. Tetrahedron Lett. 1982, 23, 2655−6. (g) Moriarty, R. M.;
Gupta, S. C.; Hu, H.; Berenschot, D. R.; White, K. B. J. Am. Chem. Soc.
1981, 103, 686−8.
(38) (a) Xiao, G.; Chen, H.; Tao, Z. Faming Zhuanli Shenqing
Gongkai Shuomingshu (2006), CN 1740157 A 20060301. (b) Barbu-
lescu, N.; Bornaz, C.; Barbulescu, E.; Cuza, O.; Moga-Gheorghe, S.;
Zavoianu, D. Rev. Chim. 1983, 34, 699. (c) Frankhauser, R.; Grob, C.
A.; Krasnobajew, V. Helv. Chim. Acta 1966, 49, 690.
(39) Considering route C in Scheme 3, incomplete hydroboration−
oxidation in the last step to 13 would leave 2,5-dihydro-1H-pyrroles
R2N−R′ [R2 = (−CH2−CHCH−CH2−)] with R′ = CH2Ph, H, and
Me in 13, 14, and 2, respectively. Hydrogenolytic conditions applied
for the conversion of 13 to 14 and 2 would lead to the corresponding
(58) (a) Gough, R. G.; Dixon, J. A. J. Org. Chem. 1968, 33, 2148.
(b) Holm, T.; Crossland, I. Acta Chem. Scand. 1979, 33, 421.
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dx.doi.org/10.1021/op3001788 | Org. Process Res. Dev. 2012, 16, 1754−1769