Synthesis of trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists: Application of the cis-thermal elimination of carbonates to alkaloid synthesis

Journal of Organic Chemistry

Volumn 61, Issue 2, 1996, Pages 587-597

  Werner, John A ^a   Cerbone, Louis R ^a   Frank, Scott A ^a   Ward, Jeffrey A ^a   Labib, Parviz ^a   Tharp Taylor, Roger W ^a   Ryan, C W ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALVIMOPAN; LY 255582; N [2 BENZYL 3 [4 (3 HYDROXYPHENYL) 3,4 DIMETHYL 1 PIPERIDINYL]PROPIONYL]GLYCINE; OPIATE ANTAGONIST; PIPERIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; DRUG SYNTHESIS; REACTION ANALYSIS; STEREOCHEMISTRY;

EID: 0030023640     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo951403y     Document Type: Article

References (50)

1. (a) Zimmerman, D. M.; Nickander, H.; Horng, J. S.; Wong, D. T. Nature 1978, 275, 332.
2. (b) Zimmerman, D. M.; Leander, J. D.; Cantrell, B E.; Reel, J. K.; Snoddy, J.; Mendelsohn, L. G., Johnson, B. G ; Mitch, C. H. J. Med. Chem. 1993, 36, 2833.
3. (c) Mitch, C. H.; Leander, J. D.; Mendelsohn, L. G.; Shaw, W. N.; Wong, D. T.; Cantrell, B. E.; Johnson, B. G.; Reel, J. K.; Snoddy, J. D.; Takemori, A. E.; Zimmerman, D. M. J. Med Chem. 1993, 36, 2842.
4. (a) Zimmerman, D. M.; Leander, J. D. J. Med. Chem. 1990, 33, 895.
5. (b) Jaffe, J. H.; Martin, W. R. In Goodman and Gilman's the Pharmacological Basis of Therapeutics, 7th ed.; Gilman, A. G., Goodman, L. S., Rail, T. W., Murad, F., Eds ; Macmillan: New York, 1985; p 491.
6. For the synthesis of 1 see: Mitch, C. H.; Zimmerman, D. M.; Snoddy, J. D.; Reel, J. K.; Cantrell, B. E. J. Org. Chem. 1991, 56, 1660.
7. For a recent reference see: Shaw, W. N. Pharmacol. Biochem. Behav. 1993, 46, 653.
8. Rothman, R. B ; Xu, H.; Char, G. U.; Kim, A.; De Costa, B. R.; Rice, K. C.; Zimmerman, D. M. Peptides 1993, 14, 17.
9. (a) Zimmerman, D. M.; Gidda, J. S.; Cantrell, B. E.; Schoepp, D. D.; Johnson, B. G.; Leander, J. D. J. Med. Chem. 1994, 37, 2262.
10. (b) Zimmerman, D. M.; Gidda, J. S.; Cantrell, B. E.; Werner, J. A.; Paru, C. J.; Franklin, R. B.; Francis, P. C.; Means, J. R.; Pohland, R. C.; Leander, J. D. Drugs of the Future 1994, 19, 1078.
11. Prepared in four steps using methodology adapted from Barnett's synthesis of picenadol, a cis-3,4-dialkyl-4-arylpiperidine: Barnett, C. J.; Copley-Merriman, C. R.; Maki, J. J. Org. Chem. 1989, 54, 4795.
12. For a review of the pharmacology of MPTP and related analogs see: Markey, S. P.; Schmuff, N. R. Med. Res. Rev. 1986, 6, 389.
13. Zimmerman, D. M.; Cantrell, B. E.; Reel, J. K.; Hemrick-Luecke, S. K.; Fuller, R. W. J. Med. Chem. 1986,29, 1517 and references cited therein.
14. Fuller, R. W., Eli Lilly and Company. Unpublished results, May 21, 1986.
15. Fries, D. S.; de Vries, J.; Hazelhoff, B.; Horn, A. S. J. Med. Chem. 1986, 29, 424.
16. Casy, A. F.; Beckett, A. H.; Iorio, M. A. Tetrahedron 1967, 23, 1405 and references therein.
17. (a) Larson, D. L.; Portoghese, P. S. J. Med. Chem. 1973, 16, 195,
18. (b) The analogous reaction in a seven-membered ring nitrogen heterocycle (75%, 280-300 °C) has been reported. Diamond, J.; Bruce, W. F.; Tyson, F. T. J. Med. Chem. 1964, 7, 57.
19. For a review of pyrolytic cis-eliminations see: DePuy, C. H.; King, R. W. Chem. Rev. 1960, 431.
20. Alkylation of the metalloenamine formed by deprotonation of 20 using the conditions described in Table 2 gave only a 30% yield of the desired trans-γ-alkylation product along with significant amounts of N-deprotected starting material. Therefore, a method for effecting the elimination in the presence of the basic amine was required.
21. Werner, J. A.; Cerbone, L. R. Poster presentation at the 203rd National Meeting of the American Chemical Society, San Francisco, CA, April 1992; paper ORGN 409.
22. As expected, an ester gives only a low yield of the elimination product at this temperature. Heating the propionate ester of 23 at 190 °C for 24 h (method B) affords tetrahydropyridine 24 in only 12% yield, along with unreacted starting material (85%) and an uncharacterized impurity (3%).
23. Resolution results: 22% yield, 96% ee, 4 recrystallizations from i-PrOH at 200 mg/mL. The diastereomeric enrichment of the initial crystallization varies from 2:1 to 1:1.
24. (a) The "recrystallization" was conducted by heating a heterogeneous mixture at reflux for 2 h as described in the Experimental Section This process gives superior yields and equivalent enrichment to those obtained by a true recrystallization from a homogeneous solution.
25. 25365 +361° (c 1.1, MeOH)). The (+)-DTTA salt was the only crystalline salt obtained from the 12 chiral acids examined.
26. The introduction of an alkyl substituent at the 4-position of a piperidine ring by alkylation of a metalated enamine was first described by: Evans, D. A.; Mitch, C. H.; Thomas, R. C.; Zimmerman, D. M.; Robey, R. L. J. Am. Chem. Soc. 1980, 102, 5955.
27. 1H NMR spectrum.
28. The cis-3,4-dimethyl isomer of 29 was prepared from the cis-dimethyl isomer recovered from the purification of 45b (see Scheme 5 in the Supporting Information). The N-ethyl substituent was converted to the N-methyl substituent by dealkylation with phenyl chloroformate followed by reduction of the phenyl carbamate with Red-Al.
29. Diol 30 is prepared in two steps from cinnamyl alcohol (Sharpless asymmetric epoxidation followed by Red-Al reduction): Gao, Y.; Sharpless, K. B. J. Org. Chem. 1988, 53, 4081.
30. The enantiomeric purity of 32 varies from 90 to 99% ee depending on the reaction conditions of the hydrogenation step, the scale of the reduction, and whether or not 32 is recrystallized. Presumably the decrease in optical purity is due to the occurrence of a small amount of benzylic oxidation, via a catalytic dehydrogenation process, followed by a nonselective reduction back to diol 31.
31. The largest impurity was the C4-desmethyl isomer (0.6%), which was characterized by GC/MS: Murphy, A. T.; Breau, A. P.; Werner, J A.; Robbins, D. K. Structural Investigation of Impurities in Synthesis of LY255S82. Presented at the 41st American Society for Mass Spectrometry Conference, San Francisco, CA, May 1993.
32. This synthesis has been previously disclosed in communication format. See ref 6b.
33. (a) For a recent review of synthetic approaches to β-amino acids see: Cole, D. C. Tetrahedron 1994, 50, 9517.
34. (b) For a general review of diastereoselective alkylation strategies see: Evans, D. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press, Inc.: New York, 1984; Vol. 3, pp 2-110.
35. Excess LDA must be avoided because it rapidly reacts with benzyl bromide to give bromodiphenylethane (even at -70 °C). See: Bazukis, P.; Dynak, J. N.; Wenkert, E. Syn. Commun. 1979, 9, 11.
36. Oppolzer, W.; Moretti, R.; Thome, S. Tetrahedron Lett. 1989, 30, 6009.
37. 2O ratio is critical for a successful crystallization. At lower MeOH levels a gum is formed.
38. The isobutyl ester was used because rnultigram quantities of ester 37 were also needed for preclinical evaluation.
39. Howton, D. R. J. Org. Chem. 1945, 10, 277.
40. Procedure developed by Dr. Mary Peters, Eli Lilly and Company, unpublished results, 1987.
41. HPLC conditions for analysis of 25, 26, 27, 28: Zorbax RX-C8 (25 cm), 75% 0.1% trifluroracetic acid/25% acetonitrile, 2 mL/min, 273 nm.
42. 1H NMR using S-(+)-2,2,2-trifluoro-1-(9-anthryl)-ethanol as a chiral shift reagent showed the product to be a 95:5 ratio of enantiomers (by integration of the methyl doublets at 0.40 and 0-53 ppm).
43. R = 5.5 min (free base of 28), 6.5 min (eni-28).
44. R = 4.5 min (7), 13.6 min (free base of 28), 14.3 min (1), 22.3 min (32), 25.7 min (28b).
45. The coupling procedure with a nonaqueous workup allows for the potential recovery and recycling of sodium brosylate. John Quatroche, Eli Lilly and Company, unpublished results, 1987.
46. 1H NMR spectrum.
47. R = 5.5 mm (33), 14.6 min (35), and 16.7 min (34).
48. R = 11.5 min ((3R,4R,αS)-isomer) and 13.3 min ((3R,4R,αR)-isomer)).
49. An orange impurity is formed if any oxygen is present.
50. R = 8.3 min (2) and 11.3 min (αR,3R,4R isomer).