FACILE AND EFFICIENT SYNTHESIS OF d
3
-LABELLED REYATAZTM
1045
to give a syrup which was purified by column chromatography on silica gel
(
elution with 40% EtOAc/hexanes, TLC R ¼ 0:2) to give the desired product
f
1
(9) (4.97 g, 25%) as a white solid. H NMR (CDCl ): 8.67(d, J ¼ 4:8 Hz, 1H),
3
7
.92(d, J ¼ 8:1 Hz, 2H), 7.74(m, 2H), 7.42(d, J ¼ 8:0 Hz, 2H), 7.21(m, 6H),
.3(bs, 1H), 5.1(bs, 1H), 4.8(bs, 1H), 4.1(d, J ¼ 13:9 Hz, 1H), 3.91
5
(
d, J ¼ 13:8 Hz, 1H), 3.62(m, 6H), 2.90(m, 3H), 2.63(d, J ¼ 11:6 Hz, 1H),
.10(bs, 1H), 1.34(s, 9H), 0.72 (s, 9H). C NMR (CDCl ): 171.3, 157.3, 157.2,
3
13
2
1
1
56.3, 150.0, 139.3, 138.8, 137.1, 136.9, 129.8, 129.6, 128.6, 127.4, 126.5, 122.5,
20.8, 79.4, 67.3, 62.8, 61.9, 61.7, 53.5, 52.8, 39.6, 34.6, 28.7, 26.5. Analytically
calculated for C H N O .0.39 H O: C, 65.60; H, 7.52; N, 10.93; found: C,
3
5
47
5
6
2
6
5.60; H, 7.57; N, 10.84.
0
0
Preparation of {(S)-1-[N -((2S,3S)-3-amino-2-hydroxy-4-phenyl-butyl)-N -
4-pyridin-2-yl-benzyl)-hydrazinocarbonyl]-2,2-dimethyl-propyl}-carbamic acid
methyl ester (4)
(
To a stirring solution of compound 9 (2.20 g, 3.47 mmol) in THF (20 ml) was
added HCl (12 M, 1.0 ml) under nitrogen at room temperature. The reaction
mixture was heated to 508C, stirred for 5 h at that temperature, and cooled to
room temperature. The THF was decanted from the mixture and the resulting
yellow solid was washed with THF (2 ꢀ 20 ml) and dried in vacuo to give the
1
product (4) (1.85 g, 100%). HNMR (DMSO-d ): 8.61(d, J ¼ 5:5 Hz, 1H),
6
8
.32(t, J ¼ 8:2 Hz, 1H), 8.15(m, 1H), 7.86(d, J ¼ 8:2 Hz, 3H), 7.71
(t, J ¼ 6:6 Hz, 1H), 7.31(d, J ¼ 8:2 Hz, 2H), 7.04(m, 3H), 6.81(m, 1H),
3
1
5
.93(bs, 1H), 3.70(d, J ¼ 3:7 Hz, 1H), 3.38(m, 4H), 3.16(s, 3H), 2.76(m, 3H),
þ
.5(bs, 3H), 0.37(s, 9H) ESIMS m/z 534.3 (½M þ H ꢁ, C H N O requires
3
0
39
5
4
33.3.
Preparation of N-(d -methoxycarbonyl)-l-tert-leucine (2b)
3
A stirred solution of l-tert-leucine 10 (11.4 g, 87.2 mmol) in dioxane (40 ml)
and sodium hydroxide (2 M, 145 ml) was cooled in ice and d -methyl
3
chloroformate (17 g, 174.3 mmol) was added dropwise over 45 min, maintain-
ing the internal temperature between 15 and 188C. The reaction flask was
warmed to 608C, stirred at this temperature for 18 h, and extracted with
dichloromethane (2 ꢀ 50 ml). The organic solution was acidified to pH ¼ 2 by
aqueous HCl (6 M) and extracted with ethyl acetate (3 ꢀ 50 ml). The extracts
were dried over Na SO , filtered and concentrated in vacuo. The residue was
2
4
crystallized from hexanes (80 ml) to give the product (2b) (14.2 g, 85%) as a
1
white solid. H NMR (300 MHz, CDCl ): d 9.9 (s, 1H), 5.2 (bs, 1H), 4.1 (bs,
3
1
3
1
H), 0.9 (s, 9H); C NMR (100 MHz, CDCl ): d 176.5, 156.9, 62.1, 34.5, 26.4;
3
þ
ESIMS m/z 193.1 (½M þ H ꢁ, C H D NO requires 193.12.
8
13
3
4
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 1041–1047