Synthesis of high-specific activity tritium and optically pure [14C]CP 101,606. Enantioselective crystallization of a radiochemically racemic mixture.

Journal of Labelled Compounds and Radiopharmaceuticals

Volumn 39, Issue 12, 1997, Pages 973-985

  McCarthy, K E ^a   Miller, S A ^a   Chenard, B L ^a   Butler, T W ^a   Dumont, M L ^a   Stemple, J Z ^a  

^a PFIZER INC   (United States)

Author keywords

Carbon 14; CP 101,606; Enantioselective crystallization; NMDA antagonist; Tritium

Indexed keywords

CARBON; ENANTIOMERS; ENANTIOSELECTIVITY; KETONES; SODIUM BOROHYDRIDE;

BOND-FORMING STEP; CARBON 14; CARBON-CARBON BOND; CP-101,606; ENANTIOSELECTIVE; ENANTIOSELECTIVE CRYSTALLIZATION; HIGH SPECIFIC ACTIVITIES; NMDA ANTAGONIST; RACEMIC MIXTURES; RADIOLABEL;

TRITIUM;

CARBON 14; KETONE; METHYL IODIDE; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT; PHENOL; SODIUM BOROHYDRIDE; TRAXOPRODIL; TRITIUM; UNCLASSIFIED DRUG;

ALKYLATION; ARTICLE; CONTROLLED STUDY; CRYSTALLIZATION; DRUG PURITY; DRUG SYNTHESIS; ENANTIOMER; ISOTOPE LABELING; OPTICAL ROTATION; RACEMIC MIXTURE; REDUCTION; STEREOCHEMISTRY; STEREOSPECIFICITY;

EID: 0030828193     PISSN: 03624803     EISSN: None     Source Type: Journal    
DOI: 10.1002/(SICI)1099-1344(199712)39:12<973::AID-JLCR40>3.0.CO;2-O     Document Type: Article

References (16)

1. Chenard, B.L., Bordner, J., Butler, T. W., Chambers, L. K., Collins, M. A., DeCosta, D. L., Ducat, M. F., Dumont, M. L., Fox, C. B., Mena, E. E., Menniti, F. S., Nielson, J., Pagnozzi, M. J., Richter, K. E. G., Ronau, R. T., Shalaby, I. A., Stemple, J. Z., White, W. F., J. Med. Chem., 38, 3138, (1995).
2. (a) Jacques, J., Collet, A., Wilen, S.H., "Enantiomers, Racemates and Resolutions", John Wiley and Sons, 1981.
3. (b) Eliel, E.L., Wilen, S.H., "Stereochemistry of Organic Compounds", John Wiley and Sons, 1994.
4. (c) Collet, A., Jacques, J., Brienne, M.J., Chem. Rev., 80, 215, (1980).
5. Chen, G.J., Tamborski, C., Chen, L.S., J. Organomet. Chem., 215, 281, (1981).
6. th Street, Tampa, Florida.
7. King, L.C., Ostrum, G.K., J. Org. Chem., 29, 3459, (1964).
8. Protection of the tertiary hydroxyl was considered, however since yield of desired product was reasonable and both 10 and 12 result from bis-methylation of the enolate, it was felt that any effort invested screening protecting groups would offset any potential increase in the overall yield.
9. The auto-oxidation of α-aminoketones under basic conditions has been previously reported. See Schirmann, P.J., Matthews, R.S., Dittmer, D.C. J. Org. Chem., 48, 4426, (1983).
10. Compounds 13 and 14 were formed in ca. 80% yield based on NMR and mass spectral data of the crude reaction mixture.
11. The instability of this intermediate was unexpected since both the desired product 9 and the related intermediate 5 were known to be stable. Apparently, the additional substitution at the alpha position of the aminoketone leads to enhanced stability. For example, over 20 aminoketones of type 9 were prepared in reference 1 and no mention of their instability was made.
12. 4 and 0.7 mL water.
13. See references 2a, p.p. 88 - 92 and 2b, p.p. 381 - 389.
14. The relationship between the chemical and radiochemical requirements which must be satisfied can be described by the equation: eutectic point x specific activity required < specific activity of the racemate.
15. 2O, and remove the EtOH in vacuo. After stirring the residue in water for ∼ 3 hours to remove any borate salts, the product can be isolated by extraction with either methylene chloride or ethyl acetate.
16. The ULTRON-ES OVM column was purchased from Mac-Mod Analytical Inc., 127 Commons Court, Chadds Ford, Pennsylvania 19317.