Preparation of aminoalkyl chlorohydrin hydrochlorides: Key building blocks for hydroxyethylamine-based HIV protease inhibitors

Journal of Organic Chemistry

Volumn 61, Issue 11, 1996, Pages 3635-3645

  Beaulieu, Pierre L ^a   Wernic, Dominik ^a  

^a Bio Mega Boehringer Ingelheim R   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

AMINE; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; ANTIVIRUS AGENT; ETHANOLAMINE DERIVATIVE; PROTEINASE INHIBITOR;

ARTICLE; CHIRALITY; DRUG SYNTHESIS; REACTION ANALYSIS;

EID: 0029891972     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo960109i     Document Type: Article

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47. 16
48. 19d
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53. While our work was in progress, the addition of (chloromethyl)-lithium (generated in situ from alkyllithium and chloroiodomethane) to chiral N,N-dibenzyl-α-amino aldehydes was reported: (a) Barluenga, J.; Baragaña, B.; Alonso, A.; Concellón, J. M. J. Chem. Soc., Chem. Commun. 1994, 969. (b) Barluenga, J.; Baragaña, B.; Concellón, J. M. J. Org. Chem. 1995, 60, 6696. (c) Ng, J. S.; Przybyla, C. A.; Mueller, R. A.; Vazquez, M. L.; Getman, D. P. World Patent Appl. no. WO 93/ 23388. publ. November 25, 1993. Ng, J. S.; Przybyla, C. A.; Liu, C.; Yen, J. C.; Muellner, F. W.; Weyker, C. L. Tetrahedron 1995, 51, 6397. In both cases, diastereomerically pure epoxides were obtained only after careful chromatography. In addition, the use of highly pyrophoric alkyllithiums in the metal-halogen exchange reaction, high cost of chloroiodomethane, and the fact that iodoalkanes are generated as byproduct made these procedures less attractive on a large scale.
54. While our work was in progress, the addition of (chloromethyl)-lithium (generated in situ from alkyllithium and chloroiodomethane) to chiral N,N-dibenzyl-α-amino aldehydes was reported: (a) Barluenga, J.; Baragaña, B.; Alonso, A.; Concellón, J. M. J. Chem. Soc., Chem. Commun. 1994, 969. (b) Barluenga, J.; Baragaña, B.; Concellón, J. M. J. Org. Chem. 1995, 60, 6696. (c) Ng, J. S.; Przybyla, C. A.; Mueller, R. A.; Vazquez, M. L.; Getman, D. P. World Patent Appl. no. WO 93/ 23388. publ. November 25, 1993. Ng, J. S.; Przybyla, C. A.; Liu, C.; Yen, J. C.; Muellner, F. W.; Weyker, C. L. Tetrahedron 1995, 51, 6397. In both cases, diastereomerically pure epoxides were obtained only after careful chromatography. In addition, the use of highly pyrophoric alkyllithiums in the metal-halogen exchange reaction, high cost of chloroiodomethane, and the fact that iodoalkanes are generated as byproduct made these procedures less attractive on a large scale.
55. While our work was in progress, the addition of (chloromethyl)-lithium (generated in situ from alkyllithium and chloroiodomethane) to chiral N,N-dibenzyl-α-amino aldehydes was reported: (a) Barluenga, J.; Baragaña, B.; Alonso, A.; Concellón, J. M. J. Chem. Soc., Chem. Commun. 1994, 969. (b) Barluenga, J.; Baragaña, B.; Concellón, J. M. J. Org. Chem. 1995, 60, 6696. (c) Ng, J. S.; Przybyla, C. A.; Mueller, R. A.; Vazquez, M. L.; Getman, D. P. World Patent Appl. no. WO 93/ 23388. publ. November 25, 1993. Ng, J. S.; Przybyla, C. A.; Liu, C.; Yen, J. C.; Muellner, F. W.; Weyker, C. L. Tetrahedron 1995, 51, 6397. In both cases, diastereomerically pure epoxides were obtained only after careful chromatography. In addition, the use of highly pyrophoric alkyllithiums in the metal-halogen exchange reaction, high cost of chloroiodomethane, and the fact that iodoalkanes are generated as byproduct made these procedures less attractive on a large scale.
56. While our work was in progress, the addition of (chloromethyl)-lithium (generated in situ from alkyllithium and chloroiodomethane) to chiral N,N-dibenzyl-α-amino aldehydes was reported: (a) Barluenga, J.; Baragaña, B.; Alonso, A.; Concellón, J. M. J. Chem. Soc., Chem. Commun. 1994, 969. (b) Barluenga, J.; Baragaña, B.; Concellón, J. M. J. Org. Chem. 1995, 60, 6696. (c) Ng, J. S.; Przybyla, C. A.; Mueller, R. A.; Vazquez, M. L.; Getman, D. P. World Patent Appl. no. WO 93/ 23388. publ. November 25, 1993. Ng, J. S.; Przybyla, C. A.; Liu, C.; Yen, J. C.; Muellner, F. W.; Weyker, C. L. Tetrahedron 1995, 51, 6397. In both cases, diastereomerically pure epoxides were obtained only after careful chromatography. In addition, the use of highly pyrophoric alkyllithiums in the metal-halogen exchange reaction, high cost of chloroiodomethane, and the fact that iodoalkanes are generated as byproduct made these procedures less attractive on a large scale.
57. (a) A high-intensity 600W ultrasonic processor equipped with a 1-in. low intensity horn (available from Ace glass or Aldrich Co.) and operating at 20-30% maximum power was used.
58. (b) The intermediate chlorohydrin alkoxides could also be quenched at low temperature. The free base of 8a was isolated as a mixture of diastereomers. These chlorohydrins could be purified in low yield by flash chromatography, but were found to be unstable in the free-base state.
59. (a) Mason, T. J. Practical Sonochemistry. User's Guide to Applications in Chemistry and Chemical Engineering; Ellis Horwood Ltd.: Chichester, 1991.
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61. 18d who found that yields decreased substantially (by as much as 40%) under stirring conditions (i.e. no sonication), we obtained similar results for both methods, provided the Li metal was crushed prior to using. Reactions performed with sonication proceeded at faster rates then under stirring conditions, but the end result was comparable.
62. 16 by treatment with 6 N HCl. HPLC analysis gave clean separation of all four isomers and allowed detection limits <0.5%.
63. 20b
64. The free base of 9a-e must be generated in the presence of the acylating agent to prevent decomposition.