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J. D. Hull et al. / Tetrahedron: Asymmetry 14 (2003) 567–576
1
2774 (CH), 2229 (CN). H NMR (250 MHz, CDCl3) l
7.38 (10H, m, CHar), 2.70 (1H, dd, J 13.6, 6.4,
CHCHACHBCPh2), 2.54 (1H, sextet, 6.3,
CH3CHCHACHB), 2.25 (1H, dd, 13.6, 6.0,
CHCHACHBCPh2), 2.15 (6H, s, N(CH3)2), 0.92 (3H, d,
J 6.5, CH
3CH). 13C NMR (63 MHz, CDCl3) l 141.2,
140.6 (ipso-Ar), 128.7, 128.6, 127.8, 127.6, 127.3, 127.1
(CHar), 122.8 (CN), 55.4 (CH3CH), 49.6 (CPh2CN),
43.2 (N(C
(1H, brd, J 14.0, CHCHA
CH3CHCHACHB), 2.67 (6H, brd, N(CH3 2
m, CHCHACHBCPh2), 2.20 (2H, q, J 7.3, CH3CH2
0.73 (3H, t, J 7.2, CH3CH2CO), 0.43 (3H, d, J 6.6,
CH
3CH). 13C NMR (63 MHz, DMSO-d6) l 140.7,
140.3 (ipso-Ar), 129.4, 129.2, 129.0, 128.7, 127.8, 127.0
(CHar), 64.8 (CH3CH), 59.1 (CPh2CO), 38.5, 38.3
(CHCH2CPh2 and N(CH3)2), 32.6 (CH2CO), 14.9, 9.5
(CH3CH and C
H3CH2). m/z (FAB) 310 (100%, MH+),
6
CHBCPh2), 2.93 (1H, m,
) ), 2.40 (1H,
CO),
6
6
6
6
J
6
6
6
J
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
H3)2), 39.9 (C6 H2), 13.1 (C6 H3CH). m/z (FAB)
6
6
289 (4.9%, MH+), 279 (100), 154 (23, Ph2), 137 (14), 72
(45, CH3CHN(CH3)2).
265 (11, M−N(CH3)2), 154 (19, Ph2), 72 (15,
CH3CHN(CH3)2). Chiral HPLC shows no evidence of
(S)-isomer (S)-15—e.e. >99%.
6.11. (S)-(+)-Methadone hydrochloride, (S)-1515
6.8. (S)-(+)-1-Dimethylamino-2-propanol, (S)-9
This was prepared following the same procedure as the
(R)-isomer. 10 g of (S)-13 were used and 6.6 g (53%) of
(S)-(+)-methadone hydrochloride (S)-15 were obtained.
Rt 12.6 (99.9%)—racemic—10.0, 13.1. Mp 240–241°C
[lit.19 239–241°C]. [h]D +136 (c 2.02, EtOH), wmax
Racemic 1-dimethylamino-2-propanol 8 (100 g, 0.97
mol) was stirred with vinyl propionate (63.6 ml, 0.58
mol) at 40°C and Novozyme® 435 (5 g) was added. The
reaction mixture was stirred slowly for 75 h and after
this time TLC (10% methanol/dichloromethane—visu-
alise KMnO4 solution) indicated that the reaction had
gone to at least 50% conversion. The enzyme was
removed by filtration and the filtrate was distilled at
reduced pressure. (S)-(+)-1-Dimethylamino-2-propanol
(S)-9 was obtained as a colourless oil (31.6 g, 64%) bpt
35°C, 5 mmHg. [h]D +23 (c 2.10, EtOH) [lit.5 +24 (c
2.17, EtOH)]. Rf (methanol:dichloromethane, 1:9) 0.19.
1
(solid)/cm−1 2935 (CH), 2462, 1702 (CꢀO). H NMR
(250 MHz, DMSO-d6) l 7.07–7.57 (10H, m, CHar), 3.08
6
(1H, brd, J 14.0, CHCH
CH3CHCHACHB), 2.67 (6H, brd, N(CH3 2
m, CHCHACHBCPh2), 2.20 (2H, q, J 7.3, CH3CH2
0.73 (3H, t, J 7.2, CH3CH2CO), 0.43 (3H, d, J 6.6,
CH
3CH). 13C NMR (63 MHz, DMSO-d6) l 140.7,
140.3 (ipso-Ar), 129.4, 129.2, 129.0, 128.7, 127.8, 127.0
(CHar), 64.8 (CH3CH), 59.1 (CPh2CO), 38.5, 38.3
(CHCH2CPh2 and N(CH3)2), 32.6 (CH2CO), 14.9, 9.5
(CH3CH and C
H3CH2). m/z (FAB) 310 (100%, MH+),
6
ACHBCPh2), 2.93 (1H, m,
) ), 2.40 (1H,
CO),
6
6
6
6
6
6
6
6
6
wmax (neat)/cm−1 3419 (OH) 2969, 2819, 2772 (CH). H
1
6
6
6
NMR (250 MHz, CDCl3)
CH3CH(OH)), 3.49 (1H, brs, OH
N(CH3)2), 2.15 (2H, m, NCH2
CH3
CH(OH)). 13C NMR (63 MHz, CDCl3) l 67.0
(CH(OH)), 63.0 (CH2-N), 45.4 ((CH3)2N), 20.0
(CH3CH).
l
3.76 (1H, m,
6
6
6
6 ), 2.24 (6H, s,
265 (11, M−N(CH3)2), 154 (19, Ph2), 72 (15,
CH3CHN(CH3)2) Chiral HPLC shows no evidence of
(R)-isomer (R)-15, e.e. >99%.
6
6 ) 1.10 (3H, d, J 6.1,
6
6
6
6
6
6.12. Preparation of racemic 1-dimethylamino-2-propyl
propanoate, rac-10 (R1=COEt)
6.9. (R)-(−)-1-Dimethylamino-2-chloropropane hydro-
chloride, (R)-125
To a solution of 1-dimethylamino-2-propanol 8 (5 g,
48.5 mmol) in dichloromethane (125 ml) was added
slowly with stirring a solution of propanoyl chloride (5
g, 54.1 mmol) in dichloromethane (75 ml). When the
addition was complete stirring was continued for a
further 30 min and then the solvent was removed at
reduced pressure to leave the hydrochloride salt of the
product as a white solid. This was dissolved in water
(50 ml) and the solution treated with saturated sodium
hydrogen carbonate solution (50 ml). The free base was
extracted with ethyl acetate (3×70 ml) and the com-
bined organic layers were washed with brine (120 ml)
and dried (MgSO4). The ethyl acetate was removed by
rotary evaporation at reduced pressure and the product
purified by distillation at reduced pressure (bpt 132°C/
ꢀ10 mmHg) to afford a colourless oil (5.7 g, 74%). Rt
This was prepared following the same procedure as the
(S)-isomer (Section 6.5). 30.6 g of (S)-9 were used and
45.0 g (96%) of crude product was isolated. This was
recrystallised from 2-propanol as in the other series to
give 30.9 g (65%) of (R)-12. Mp 192–193°C [lit.9 192–
193°C]. [h]D −65.8 (c 2.0, H2O) [lit.9 −65 (c 2.01, H2O)].
wmax (solid)/cm−1 2962 (CH). 1H NMR (250 MHz,
CDCl3) l 4.42 (1H, sextet, J 7.0, CH2CH
(2H, d, J 8.0, NCH2CHCl), 2.88 (6H, d, J 8.4,
N(CH3)2), 1.49 (3H, d, J 6.5, CH3
CHCl). 13C NMR (63
MHz, CDCl3) l 64.3 (CHCl), 52.0 (CH2N), 45.6
6 ClCH3), 3.40
6
6
6
6
6
(C6 H3N), 41.8 (C6 H3N), 22.3 (C6 H3CH). m/z (FAB) 124
(26.7%, MH+, 37Cl), 122 (100, MH+, 35Cl), 86 (8.5,
M−Cl), 44 (11.0, N(CH3)2).
1
13.4, 14.0. H NMR (250 MHz, CDCl3) l 5.09 (1H, m,
CH3CH
CH2CH(OCOCH2
(3H, d, J 6, CH3CH(OCOC2H5)), 1.13 (3H, t, J 7.5,
OCOCH2CH3).
6
(OCOC2H5)),
2.10–2.60
(4H,
m,
N-
6.10. (S)-(+)-2,2-Diphenyl-4-dimethylaminopentaneni-
trile, (S)-13
6
6
CH3)), 2.25 (6H, s, N(CH3 2
6 ) ), 1.21
6
6
This was prepared following the same procedure as the
(R)-isomer (Section 6.6). 30 g of (R)-12 were used and
6.13. Lipase screen for the resolution of 1-dimethyl-
amino-2-propanol, 8
14.65
g
(33%) of (S)-(+)-2,2-diphenyl-4-dimethyl-
aminopentanenitrile (S)-13 were obtained. Mp 100–
101°C [lit.9 100–101°C]. [h]D +52.9 (c 0.66, EtOH) [lit.9
+49 (c 0.68, EtOH)]. wmax (solid)/cm−1 2972, 2938, 2819,
Racemic 1-dimethylamino-2-propanol 8 (103 mg, 1
mmol) was stirred with vinyl propanoate (2 ml) and a