A. Schmidt et al. / Tetrahedron 60 (2004) 11487–11492
11491
gave 680 mg (1.5 mmol, 100% yield) of aminoalcohol 4f as
a white solid. Mp 80 8C. IR (disk): n [cm ]Z3391, 3204,
concentrated hydrochlorid acid in 50 mL ethanol was
refluxed for 4 h. The solution was neutralised with a diluted
solution of NaOH and extracted with dichloromethane.
K1
3
1
958, 2926, 2848, 1705, 1600, 1502, 1371, 1308, 1264,
1
189, 748, 698. H NMR (400 MHz, CDCl ): dZ1.60–1.77
The extraction was dried over MgSO and evaporated at
4
3
3
3
(
m, 4H), 2.48 (dd, 2H, JZ5.1, 5.2 Hz), 2.54 (dd, 2H, JZ
reduced pressure to obtain 293 mg (0.62 mmol, 100% yield)
of 8-[4,4-bis-(4-fluorophenyl)-but-3-enyl]-1-phenyl-1,3,8-
triazaspiro[4.5]-decan-4-one (12).
5
6
.2, 5.3 Hz), 2.64–2.91 (m, 6H), 3.70 (s, 1H), 4.72 (s, 2H),
.87–7.60 (m, 15 H), 9.05 (s, 1H). C NMR (100 MHz,
1
3
CDCl ): dZ22.1, 28.3, 42.4, 49.3, 58.8, 58.9, 59.2, 76.2,
3
1
1
14.3, 118.5, 125.9, 126.0, 127.9, 129.4, 142.9, 148.8,
77.9. MS (ESI): m/z (%)Z456 (100, M ).
The olefin 12 (280 mg, 0.59 mmol) was dissolved in 50 mL
ethanol, palladium on charcoal (150 mg, 10 wt%) was
added and the suspension was stirred for 3 days at room
temperature under a hydrogen atmosphere (1.5 bar). The
catalyst was removed by suction and the filtrate was
evaporated at reduced pressure to obtain 275 mg
C
4
1
1
5
.3.7. 1,1-Bis-(p-fluorophenyl)-4-morpholin-4-yl-butan-
-ol (4g). Hydroaminomethylation of olefin 6b (407 mg,
.7 mmol) with morpholine (10a; 0.15 mL, 1.7 mmol) gave
4
85 mg (1.7 mmol, 99% yield) of aminoalcohol 4g. IR
(0.58 mmol, 98% yield) of Fluspirilene (1).
K1
(
film): n [cm ]Z3410, 3068, 2956, 2921, 2856, 2818,
1
1
662, 1601, 1506, 1457, 1446, 1305, 1268, 1223, 1158,
1
117, 1013, 837. H NMR (400 MHz, CDCl ): dZ1.62
3
3
3
(
quint, 2H, JZ5.5 Hz), 2.29 (br s, 4H), 2.40 (dd, 2H, JZ
3
5
.5, 5.5 Hz), 2.43 (dd, 2H, JZ5.5, 5.5 Hz), 3.69 (t, 4H,
3
3
References and notes
JZ4.8 Hz), 6.97 (td, 4H, JZ2.0, 8.8 Hz), 7.43 (m, 4H).
1
3
C NMR (100 MHz, CDCl ): dZ21.1, 42.8, 53.0, 59.4,
3
1
. Nakachi, N.; Kiuchi, Y.; Inagaki, M.; Inazu, M.; Yamazaki,
Y.; Oguchi, K. Eur. J. Pharmacol. 1995, 281, 195–204.
6
6.2, 76.0, 114.7 (JC,FZ21 Hz), 127.7 (JC,FZ8 Hz), 143.8
(
JC,FZ3 Hz), 161.4 (JC,FZ243 Hz). MS (ESI): m/z (%)Z
C
48 (100, M C1).
2. Sindelar, K.; Rajsner, M.; Cervena, I.; Valenta, V.; Jilek, J. O.;
Kakay, B.; Holubek, J.; Svatek, E.; Miksik, F.; Protiva, M.
Collect. Czech. Chem. Commun. 1973, 38, 3879–3901.
3
4
.3.8. 8-[4,4-Bis(-p-fluorophenyl)-4-hydroxybutyl]-1-
3
. Janssen, P. A. J. Fr. M3059 (Janssen Pharmaceutical N.V.),
965; Chem. Abstr. 1965, 63, 9955.
. Botteghi, C.; Marchetti, M.; Paganelli, S.; Persi-Paoli, F.
phenyl-1,3,8-triazaspiro[4.5]decan-4-one (4h). Hydro-
aminomethylation of olefin 6b (369 mg, 1.5 mmol) with
1
4
1
1
-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (10f; 400 mg,
.7 mmol) gave 730 mg (1.5 mmol, 99% yield) of aminoal-
Tetrahedron 2001, 57, 1631–1637.
5. Botteghi, C.; Paganelli, S.; Marchetti, M.; Pannocchia, P.
J. Mol. Catal. A: Chem. 1999, 143, 233–241.
K1
cohol 4h as a white solid. Mp 203 8C. IR (disk): n [cm ]Z
3
1
381, 3118, 3072, 2973, 2952, 2930, 2857, 1707, 1599,
502, 1369, 1223, 1155, 822, 748, 558. H NMR (500 MHz,
1
6. Kleemann, A.; Engel, J. Pharmazeutische Wirkstoffe; Georg
Thieme Verlag: Stuttgart, 1987.
CDCl ): dZ1.63–1.69 (m, 4H), 2.48 (m, 4H), 2.65–2.85 (m,
3
7
. (a) Rische, T.; Eilbracht, P. Tetrahedron 1999, 55, 1915–1920.
6
7
H), 3.71 (s, 1H), 4.74 (s, 2H), 6.88–7.06 (m, 7H), 7.36–
.39 (m, 3H), 7.50–7.52 (m, 4H). C NMR (125 MHz,
1
3
(
(
b) Donsbach, M.; Eilbracht, P.; Buss, C.; Schmidt, A.
Schwarz Pharma AG, Monheim Germany), Pat. DE 100 33
CDCl ): dZ22.1, 28.3, 42.7, 49.3, 58.8, 58.8, 59.2, 75.6,
3
0
16.9, July 7, 2000. For a stepwise version see: (c) Botteghi,
1
14.5, 114.7 (JC,FZ20 Hz), 118.7, 127.5 (JC,FZ9 Hz),
C.; Corrias, T.; Marchetti, M.; Paganelli, S.; Piccolo, O. Org.
Proc. Res. Develop. 2002, 6, 379–383.
1
29.4, 142.9, 144.5, 161.3 (JC,FZ233 Hz), 177.9. MS
C
(ESI): m/z (%)Z492 (100, M ). C H F N O (491.6):
calcd. C 70.9, H 6.4, N 8.6; found C 70.4, H 6.6, N 8.4.
29 31 2 3 2
8
. Eilbracht, P.; B a¨ rfacker, L.; Buss, C.; Hollmann, C.; Kitsos-
Rzychon, B. E.; Kranemann, C. L.; Rische, T.; Roggenbuck,
R.; Schmidt, A. Chem. Rev. 1999, 99, 3329–3365.
. Miescher, K.; Marxer, A. U.S. Pat. 2,411,664, 1946; Chem.
Abstr. 1947, 41, P6276e.
4
(
.4. Direct synthesis of 4-(4,4-diphenylbutyl)-morpholin
11) from 4a
9
1
1
0. Yevich, J. P.; Neu, J. S.; Lobeck, W. G.; Dextraze, P.;
Brenstein, E. J. Med. Chem. 1992, 35, 4516–4525.
A suspension of aminoalcohol 4a (65 mg, 0.21 mmol) and
palladium on charcoal (200 mg, 10 wt%) in 50 mL ethanol
and 1 mL concentrated hydrochlorid acid was stirred for
1. (a) Vitale, A. A.; Doctorovich, F.; Nudelman, N. S.
J. Organomet. Chem. 1987, 332, 9–18. (b) Tacke, R.;
Terunuma, D.; Tafel, A.; M u¨ hleisen, M.; Forth, B.;
Waelbroeck, M.; Gross, J.; Mutschler, E.; Friebe, T.;
Lambrecht, G. J. Organomet. Chem. 1995, 501, 145–154.
3 days under a hydrogen atmosphere (1.5 bar). The catalyst
was removed by suction, the filtrate was neutralised with a
diluted solution of NaHCO and extracted with ether. The
3
etheral solution was dried over MgSO and evaporated at
4
reduced pressure to obtain 60 mg (0.20 mmol, 97% yield) of
12. Breit, B.; Seiche, W. Synthesis 2001, 1–36.
1
amine 11. H NMR (400 MHz, CDCl ): dZ1.47 (quint, 2H,
13. (a) Anastasiou, D.; Jackson, W. R. Aust. J. Chem. 1992, 45,
21–37. (b) Roggenbuck, R.; Eilbracht, P., in preparation.
14. Van Leeuwen, P. W. N. M.; Claver, C. Rhodium Catalysed
Hydroformylation; Kluwer Academic: Dordrecht, 2000.
15. Andrews, A. F.; Mackie, R. K.; Walton, J. C. J. Chem. Soc.,
Perkin Trans. 2 1980, 96–102.
3
3
3
JZ7.8 Hz), 2.07 (q, 2H, JZ7.8 Hz), 2.35–2.41 (m, 6H),
3
3
3
(
.69 (t, 4H, JZ4.5 Hz), 3.89 (t, 1H, JZ7.8 Hz), 7.14–7.29
13
m, 10H). C NMR (100 MHz, CDCl ): dZ24.9, 33.4,
3
5
1.3, 53.6, 58.8, 66.8, 126.1, 127.8, 128.4, 144.9.
4
.5. Synthesis of Fluspirilene (1)
16. Reitz, A. B.; Baxter, E. W.; Codd, E. E.; Davis, C. B.;
Jordan, A. D.; Maryanoff, B. E.; Maryanoff, C. A.; McDonnell,
M. E.; Powell, E. T.; Renzi, M. J.; Schott, M. R.; Scott, M. K.;
A solution of 4h (305 mg, 0.62 mmol) and 1 mL