Notes
Sch em e 1. Stu k ’s Dia m in o Alcoh ol Cor e Un it
J . Org. Chem., Vol. 61, No. 1, 1996 357
addition funnel, internal temperature monitor, and N inlet was
charged with sodium amide (97.9 g, 2.25 mole) and tetrahydro-
furan (HPLC grade, 1350 mL). The suspension was cooled to
ca. -40 °C to -45 °C, and a solution of acetonitrile (135 mL,
2
Syn th esis
2
.58 mol) and tetrahydrofuran (75 mL) was added dropwise at
such a rate that the internal temperature remained e-36 °C
ca. 22 min). The nearly homogeneous solution was stirred ca.
(
1
5
3 min and was then added via a dry ice cooled cannula to a
-L three-neck round-bottom flask equipped with an overhead
stirrer internal temperature monitor and nitrogen outlet and
charged with a solution of N-methylproline methyl ester (6)
(125.5 g, 0.876 mol) and tetrahydrofuran (1350 mL) cooled to
ca. -40 °C to -45 °C. The internal temperature was maintained
e-40 °C throughout the addition. After ca. 1 h the reaction
was quenched by the addition of solid ammonium chloride (131
g, 2.45 mole). The cold bath was removed, and the reaction was
allowed to warm to ca. +5 °C over about 1.5 h. Filter-aid (250
g) was added, and the mixture was filtered through a pad of
filter-aid (250 g, 2 in. ht × 6 in diam.) topped with sand (500 g).
The filter cake was washed with THF (ca. 1 L) to remove most
of the color. The filtrate was concentrated in vacuo, and the
foamy orange residue, 267.2 g, was used directly in the next step.
Sch em e 2. Syn th etic Rou te to ABT-418 fr om
N-Meth ylp r olin e Meth yl Ester
(
Theoretical yield is 133.4 g. The excess mass is presumably
salts and does not appear to interfere with the following step.)
TLC data: R
(1:10:90, concd NH OH/MeOH/CH Cl ): sm ) 0.5,
pdt ) 0.2; iodine stain). MS (DCI/NH ) m/ z 153 (M + H) ,
, cm ) 3000, 2790, 2180, 1727, 1570.
S)-2-(3-Am in obu t-2-en oyl)-N-m eth ylp yr r olid in e (8). A
-L three-neck round-bottom flask equipped with an overhead
f
4
2
2
+
3
-
1
1
3
00%. IR (CHCl
3
(
stirrer, addition funnel, internal temperature monitor, and N
inlet was charged with the above crude keto nitrile 7 (267 g, ca.
.87 mol) dissolved in tetrahydrofuran (1 L) and chilled to -5
C to -10 °C. Methylmagnesium chloride (930 mL, 3 M THF,
.79 mol) was added via addition funnel at such a rate as to
2
0
°
2
maintain the internal temperature e+5 °C (ca. 90 min). Fol-
lowing the addition the cold bath was removed and the reaction
allowed to warm to room temperature and stir overnight (ca.
1
5 h). The dark mixture was carefully poured into ice (1.5 kg)
and stirred 5-10 min. The aqueous portion was exhaustively
extracted with ethyl acetate (ca. 15 to 20 × 1 L). The combined
2 4
organics were dried (Na SO ), filtered, and evaporated leaving
1
58.2 g of dark oil used directly in the next step. Theoretical
yield is 147.4 g for the two steps. TLC data: R (1:10:90, concd
NH OH/MeOH/CH Cl ): sm ) 0.2, pdt ) 0.15; iodine stain.
Relative R ’s of starting material and product are very dependent
upon the amount of concd NH OH in the developing solvent.
MS (DCI/NH ) m/ z 169 (M + H) , 100%. C NMR (CDCl
2.29, 22.97, 30.68, 41.15, 56.71, 74.51, 91.79, 163.05, 199.33.
purified further. Interestingly, it was found that in the
event that all traces of residual acetonitrile were not
removed following the preparation of 7, the bis-acetoni-
trile addition product, cyanomethyl enamino ketone 9
was formed. It was apparent that the methylmagnesium
chloride deprotonated the residual acetonitrile faster
than adding to the nitrile moiety of either the acetonitrile
or the R-cyano ketone anion 10, and this chloromagne-
sium acetonitrile anion, in turn, reacted with 10 faster
than did methylmagnesium chloride. This unexpected
reactivity precluded the sequential addition of sodioac-
etonitrile and methylmagnesium chloride.
Treatment of the enamino ketone 8 with hydroxy-
lamine hydrochloride regioselectively produced the keto
oxime 11. Addition of aqueous sulfuric acid followed by
gentle heating catalyzed in situ cyclodehydration to
produce the isoxazole ring of ABT-418. By this novel
regiospecific method of 3,5-disubstituted isoxazole prepa-
ration, ABT-418 was produced in 49% overall yield from
N-methylproline methyl ester in >98% ee from economi-
cal reagents and reactions suitable for scale-up with a
single purification, the distillation of the final product.
f
4
2
2
f
4
+
13
3
3
) δ
2
1
H NMR (CDCl ) δ 1.70-1.90 (m, 3H), 1.96 (s, 3H), 2.00-2.30
3
(m, 2H), 2.33 (s, 3H), 2.70 (t, J ) 7.5 Hz, 1H), 3.14 (dt, J ) 2, 8
Hz, 1H), 5.31 (s, 1H), 5.45 (br s, 1H), 9.80 (br s, 1H).
(
S)-2-(3-Am in o-4-cya n ob u t -2-en oyl)-N-m et h ylp yr r oli-
+
d in e 9. MS (DCI/NH
3
3
) m/ z 194 (M + H) , 100%. IR (CHCl ,
-
1
13
cm ) 3250, 3160, 2200. C NMR (CDCl
3
) δ 23.11, 24.16, 30.58,
1
4
1.12, 56.64, 74.40, 92.12, 115.08, 152.96, 200.98. H NMR
(CDCl ) δ 1.70-1.95 (m, 3H), 2.05-2.15 (m, 1H), 2.20-2.40 (m,
3
1H), 2.33 (s, 3H), 2.76 (t, J ) 7.5 Hz, 1H), 3.16 (dt, J ) 2, 7 Hz,
1
H), 3.38 (s, 2H), 5.35 (br s, 1H), 5.53 (s, 1H), 9.70 (br s, 1H).
(
S)-3-Meth yl-5-(N-m eth yl-2-p yr r olid in yl)isoxa zole (ABT-
4
18). A 2-L three-neck round-bottom flask equipped with an
overhead stirrer, reflux condenser, internal temperature moni-
tor, and N inlet was charged with the above crude keto enamine
2
8 (158 g, ca. 0.87 mol), acetonitrile (HPLC grade, 1000 mL), and
hydroxylamine hydrochloride (64.0 g, 0.92 mol) and stirred at
room temperature for 6 h. Aqueous 50% sulfuric acid (9.4 M,
2
40 mL, 2.26 mol) was added, and the mixture was heated to
reflux for ca. 1 h. After cooling, the bulk of the solvents were
removed in vacuo. The residue was basified by the addition of
saturated sodium carbonate solution (ca 1.2 L, to pH 9-10),
saturated with sodium chloride, and extracted with ethyl acetate
Exp er im en ta l Section
(4 x 500 mL). The combined organics were washed with brine
Gen er a l. Reactions were routinely performed under an inert
atmosphere (nitrogen or argon). Solvents and reagents were
used as received from commercial sources. Analytical thin-layer
chromatography (TLC) was performed using E. Merck silica gel
(1 × 1 L) and then dried (MgSO4 + activated carbon). The
mixture was filtered, the filtrate was concentrated, and the
residue was distilled at reduced pressure (10 mmHg, bp 98-
101 °C) to give 71.97 g of light yellow oil (49% overall yield from
ester, g98% ee, Chiralcel AD column with 3% ethanol/hexane
6
0 F-254 glass-backed plates, 250 µm thickness.
S)-2-(Cyan oacetyl)-N-m eth ylpyr r olidin e (7). A 3-L three-
neck round-bottom flask equipped with an overhead stirrer,
(
at 1 mL/min, UV detection @ 214 nm. t
8.1 min). TLC data: R (1:10:90, concd NH
R
: (S) ) 7.1 min, (R) )
f
4
OH/MeOH/CH -
2