Dilevalol via resin-mediated epimerization: A case study. Reaction mechanism to reactor design to a viable process

Organic Process Research and Development

Volumn 4, Issue 2, 2000, Pages 107-121

  Cerami, J ^a   Gala, D ^a   Hou, D ^a   Kalliney, S ^a   Mas, J L ^a   Nyce, P ^a   Peer, L ^a   Wu, G ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0034395155     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op990185y     Document Type: Article

References (53)

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3. Hartley, D. Chem. Ind. 1981, 551.
4. GC: (a) Fused silica capillary column (4 m × 0.25 mm) coated with SP-2250 with film thickness of 0.2 μm, FID detector. Injector and detector ports at 250 °C, column oven at 240 °C. Helium as a carrier gas with 20-30 cm/sec/linear velocity. Inject 1 μL. Run time of 10 min. Sample prepared by derivatization with methylboronic acid (GLC grade) in pyridine and allowed to stand at room temperature for 20 min; or (b) in an alternative GC method the column used was 10% OV-17 on 100/120 mesh Gas Chrom Q packed in a 6 ft × 1/4 in glass column, or equivalent. The carrier gas was helium at a flow rate of 30 mL/min. Both injector and detector temperature were about 340 °C. The oven temperature was about 300 °C. Detection was with flame ionization. Derivatization of the amino alcohols were made with 1-butaneboronic acid in dry pyridine (over 4 Å molecular sieves) before injection on the column.
5. Umino, N.; Iwakuma, T.; Itoh, N. Chem. Pharm. Bull. 1979, 27, 1479.
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7. BINOL is 1,1′-bi-2-naphthol. See Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem. Soc. 1984, 106, 6709.
8. Chirald is (2S,3R)-(+)-4-(dimethylamino)-1,2-diphenyl-3-methyl-2-butanol. See Yamaguchi, S.; Mosher, H. S. J. Org. Chem. 1973, 38, 1870.
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11. (R)-(S)-BPPF - OH is (R)-α-[(S)-2-bis(diphenylphosphine)ferrocenyl]ethanol. See Hayashi, T.; Katsumura, A.; Kinishi, M.; Kumada, M. Tetrahedron Lett. 1979, 20, 425.
12. (S,S)-BPPM is (2S,4S)-(-)-1-tert-butoxycarbonyl-4-(diphenylphosphino)-2- (diphenylphosphinomethyl)pyrrolidine. See Achiwa, K.; Kagure, T.; Ojima, I. Tetrahedron Lett. 1977, 18, 4431.
13. (-)-DIOP is (2R,3R)-(-)-2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane. See Kagan, H. B.; Dang, T.-P. J. Am. Chem., Soc. 1972, 94, 6429.
14. (S)-BINAP is (S)-(-)-2, 2′-bis(diphenylphosphino)-1, 1′-binaphthyl. See Takaya, H.; Noyori, R. et al. J. Org. Chem. 1986, 51, 629.
15. (R)-PROPHOS is (2R)-(+)-bis(1,2-diphenylphosphino)propane. See Fryzuk, M. D.; Bosnich, B. J. Am. Chem. Soc. 1978, 100, 5491.
16. Mitsunobu, O. Synthesis 1981, 1.
17. Protection of the phenolic OH, and the amine nitrogen could have overcome some of these problems and the ones perceived for the oxidations. However, from a commercial point of view this need for extra protection/deprotection was unattractive.
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35. (b) Easthan, J. F.; Teranishi, R. Organic Syntheses; Wiley & Sons: New York, 1963; Collect. Vol. IV, p 192.
36. (b) Easthan, J. F.; Teranishi, R. Organic Syntheses; Wiley & Sons: New York, 1963; Collect. Vol. IV, p 192.
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45. Personal communication with Dr. Esther Babad. The author (D.G.) greatly appreciates many stimulating discussions with Dr. Babad on this project.
46. It is possible that this process may be favored by protonation of the amine under the acidic conditions which could enhance the proton transfer to the benzylic hydroxy group, accelerating the quinonemethide formation. (formula presented)
47. 4 (55:45) adjusted to pH 7.5 with 1 N aqueous NaOH, flow rate 1 mL/min, 254 nm detection. Internal standard: o-phenylphenol; or (b) Waters phenyl column 25 cm × 4 mm; 40% acetonitrile/water containing 0.01% sodium decanesulfonic acid; flow rate 1 mL/min; 254 nm.
48. HPLC: Under the system described in ref 35 above, the butyl ethers (resolved) had an average RRt of 3.95, whereas the ethyl ethers (a broad hump) had a RRt of 1.8 (compared to 1 with Rr of 1.0). GC: Under the system described in ref 4a, the butyl ethers had a RRt of 1.28, whereas the ethyl ethers had RRt of 0.84 (compared to 1 with Rr of 1.0).
49. The IR resins were obtained from Rohm and Haas Co, Philadelphia, Pa. The rest of the resins were obtained from the Dow Chemical Co, Larkin Laboratory, Midland, Michigan.
50. In a typical crystallization, 1.1 mol of L-DBTA and the amino alcohol in 15-20 volumes of n-BuOH saturated with water was heated at 50 °C (pH of solution was 3.4-3.6). The mixture was cooled to 25 °C with agitation and filtered. Typically the crystallized product (33-37% yield) contained >97: 3 ratio of the isomers as determined by GC.
51. Laboratory optimum of 40 °C would necessitate capital investment, which was ruled out from commercial point of view. The necessary loading was achieved by controlling the rate of loading.
52. Teflon is a registered trademark of E. I. du Pont de Nemours and Company.
53. Dilevalol hydrochloride was prepared from the L-DBTA salt as follows: To a slurry of dilevalol dibenzoyl-L-tartrate in methyl-isobutyl ketone (MIBK) and water was added aqueous NaOH to a pH of 8.4-9.8. The MIBK layer containing the free base was combined with fresh water and then treated with concentrated HCl to pH ≤ 1, maintaining a temperature of 50-60 °C. The resultant slurry was cooled to about 20 °C, filtered, washed with MIBK and water, and dried at 75 °C. The yield was 85-95%. Typical purity of this material was >97%, producing quality material that passed a battery of tests.