Synthesis of the Dopamine Agonist (-)-Quinpirole

References

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• The USAN name “quinpirole” designates the optically active (-)-4aR,8aR enantiomer. While the term “(-)-quinpirole” is thus redundant, it is used here to clearly differentiate racemic 3 from the ievorotatory isomer
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• For the original synthesis of (±)-4, see reference 2a
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• Compound 6 has also been prepared by alkylation of 5 and reduction of the resulting quinolinium salt. Personal communications, L. O. Weigel and C. L. Nichols, Lilly Research Laboratories
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• Wilds , A. L. and Nelson , N. A. 1953 . J. Am. Chem. Soc. , 75 : 5360 Use of a smaller excess of lithium or of a less acidic proton source gave incomplete reduction
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• This mixture of isomers could be purified by distillation but was not stable to column chromatography. The isomer ratio was determined by nmr
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• Birch , A. J. , Hutchinson , E. G. and Subba Rao , G. 1971 . J. Chem. Soc. , : 637 While the unconjugated diene 7 was expected to be the sole product based on analogy with the tetralin system, monocyclic anilines are known to give conjugated dienes analogous to 8 upon reduction with Li/NH3. For example, see
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• The formation of a single product upon reduction of the mixture of 7 and 8 can be explained as follows: Protonation of 7 can occur only at C-4a to give iminium salt i. In contrast, 8 may be protonated at either C-6 or C-8. Protonation at C-6 does not relieve the peri interaction between the N-1 propyl and the C-8 hydrogen. Protonation at C-8, however, does relieve this interaction and also forms i. Reduction of this common intermediate by NaCNBH3 gives the desired enol ether 9
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• Recrystallization of a sample of (±)-4 from hexanes at-78° provided a white solid (mp 40–41.5°). nmr(CDCl3): 2.97(d, J = 12Hz, 1H), 2.76–2.04 (m. 9H). 1.80–1.38 (m, 7H), 1.22–1.00 (m, 1H), 0.87 (t, J = 7Hz, 3H). ir (KBr): 1711 cm−1. ms (El): 195(20), 166(100), 165(30), 138(95), 110(45). analysis: calculated for C12H21NO: C-73.80, H-10.84, N-7.17; found: C-73.80, H-11.05, N-7.39
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• A sample of (-)-quinpirole could be recrystallized (MeOH/H2O or acetone/H2O) to give white needles (mp 111.5–113°). nmr (CDCl3): 10.4 (bs, 1H), 7.28 (s, 1H), 3.08 (dd, J = 5, 15 Hz, 1H), 2.98 (d, J = 11 Hz, 1H), 2.79 (dd, J = 5, 14 Hz, 1H), 2.75–2.65 (m, 1H), 2.60–2.47 (m, 1H), 2.40–2.16 (m, 4H), 1.92 (bd, J = 11 Hz, 1H), 1.82–1.61 (m, 3H), 1.60–1.44 (m, 2H), 1.27–1.07 (m, 1H), 0.88 (t, J = 7 Hz, 3H). ir (CHCl3): 3467, 3220 (H2O?) cm−1, uv (MeOH): 201(1500), 222(4400). ms (El): 219(70)., 191(15), 190(100), 125(25), 124(30), 96(40). OR: [α]D = -137.0° (c = 1.0, MeOH), [α]365 = -439.2° (c = 1.0, MeOH). analysis: calculated for C13H21N3 · 0.6 H2O: C-67.85, H-9.72, N-18.26; found: C-67.59, H-9.78, N-18.01
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