Practical asymmetric synthesis of Efavirenz (DMP 266), an HIV-1 reverse transcriptase inhibitor

Article abstract of DOI:10.1021/jo981170l

A highly enantioselective and practical synthesis of the HIV-1 reverse transcriptase inhibitor efavirenz (1) is described. The synthesis proceeds in 62% overall yield in seven steps from 4-chloroaniline (6) to give efavirenz (1) in excellent chemical and optical purity. A novel, enantioselective addition of Li-cyclopropyl acetylide (4a) to p-methoxybenzyl-protected ketoaniline 3a mediated by (1R,2S)-N-pyrrolidinylnorephedrine lithium alkoxide (5a) establishes the stereogenic center in the target with a remarkable level of stereocontrol.

Full text of DOI:10.1021/jo981170l

8536
J . Org. Chem. 1998, 63, 8536-8543
P r a ctica l Asym m etr ic Syn th esis of Efa vir en z (DMP 266), a n HIV-1
Rever se Tr a n scr ip ta se In h ibitor
Michael E. Pierce,* Rodney L. Parsons, J r., Lilian A. Radesca, Young S. Lo, Stuart Silverman,
J ames R. Moore, Qamrul Islam, Anusuya Choudhury, J oseph M. D. Fortunak, Dieu Nguyen,
Chi Luo, Susan J . Morgan, Wayne P. Davis, and Pat N. Confalone
Chemical Process R&D Department, Process Research Facility, The DuPont Pharmaceuticals Company,
Deepwater, New J ersey 08023-0999
Cheng-yi Chen,* Richard D. Tillyer,* Lisa Frey, Lushi Tan, Feng Xu, Dalian Zhao,
Andrew S. Thompson, Edward G. Corley, Edward J . J . Grabowski, Robert Reamer, and
Paul J . Reider
Department of Process Research, Merck Research Laboratories, P.O. Box 2000,
Rahway, New J ersey 07065
Received J une 17, 1998
A highly enantioselective and practical synthesis of the HIV-1 reverse transcriptase inhibitor
efavirenz (1) is described. The synthesis proceeds in 62% overall yield in seven steps from
4-chloroaniline (6) to give efavirenz (1) in excellent chemical and optical purity. A novel,
enantioselective addition of Li-cyclopropyl acetylide (4a ) to p-methoxybenzyl-protected ketoaniline
3a mediated by (1R,2S)-N-pyrrolidinylnorephedrine lithium alkoxide (5a ) establishes the stereogenic
center in the target with a remarkable level of stereocontrol.
Sch em e 1
In tr od u ction
Inhibition of HIV-1 (human immunodeficiency virus
type 1) reverse transcriptase by nucleosides such as AZT,
DDC, DDI, D4T, and 3TC is a proven therapy for
delaying the progression to AIDS. However, the rapid
viral mutation to resistant strains requires the develop-
ment of new therapeutic agents.1-3 The recent develop-
ments of both protease inhibitors and non-nucleoside
reverse transcriptase inhibitors offer hope of effective
treatment, especially when coadministered.4 Efavirenz
(1) is a non-nucleoside reverse transcriptase inhibitor
that shows high potency against a variety of HIV-1
mutant strains5 and is currently undergoing clinical
studies.6 The importance of efavirenz has prompted us
to design and develop a practical enantioselective syn-
thesis of the compound.7-9
(1) Romero, D. L. Ann. Rep. Med. Chem. 1994, 29, 123.
(2) Tucker, T. J .; Lyle, T. A.; Wiscount, C. M.; Britcher, S. F.; Young,
S. D.; Sanders, W. M.; Lumma, W. C.; Goldman, M. E.; O’Brien, J . A.;
Ball, R. G.; Homnick, C. F.; Schlief, W. A.; Emini, E. A.; Huff, J . R.;
Anderson, P. S. J . Med. Chem. 1994, 37, 2437.
(3) Quinn, T. C. Lancet 1996, 348, 99.
(4) De Clercq, E. J . Med. Chem. 1995, 38, 2491.
(5) Young, S. D.; Britcher, S. F.; Tran, L. O.; Payne, L. S.; Lumma,
W. C.; Lyle, T. A.; Huff, J . R.; Anderson, P. S.; Olsen, D. B.; Carroll, S.
S.; Pettibone, D. J .; O’Brien, J . A.; Ball, R. G.; Balani, S. K.; Lin, J . H.;
Chen, I.-W.; Schleif, W. A.; Sardana, V. V.; Long, W. J .; Byrnes, V.
W.; Emini, E. A. Antimicrob. Agents Chemother. 1995, 39, 2602.
(6) Mayers, D.; Riddler, S.; Bach, M.; Stein, D.; Havlir, M. D.; Kahn,
J .; Ruiz, N.; Labriola, D. F.; and the efavirenz clinical development
team. Durable Clinical Anti-HIV-1 Activity and Tolerability for
efavirenz in Combination with Indinavir (IDV) at 24 Weeks. Clinical
data presented at the ICAAC meeting, Toronto, 1997, I-175.
(7) Thompson, A. S.; Corley, E. G.; Huntington, M. F.; Grabowski,
E. J . J . Tetrahedron Lett. 1995, 36, 8937.
(8) Thompson, A.; Corley, E. G.; Hungtington, M. F.; Grabowski, E.
J . J .; Remenar, J . F.; Collum, D. B. J . Am. Chem. Soc. 1998, 120, 2028.
(9) A synthesis of racemic efavirenz, followed by resolution, has been
reported. Radesca, L. A.; Lo, Y. S.; Moore, J . R.; Pierce, M. E. Synth.
Commun. 1997, 27, 4373.
Resu lts a n d Discu ssion
Establishment of the quarternary carbon center in an
asymmetric manner presented a unique challenge during
the synthesis of efavirenz. We envisioned that the most
efficient route to efavirenz would involve enantioselective
addition of a metal cyclopropylacetylide to a trifluoro-
methyl ketone 3 (with or without N-protection) mediated
by a chiral additive as depicted in Scheme 1.10 The
enantioselective addition of Li-acetylides to cyclic N-
acetylketimines mediated by stoichiometric amounts of
quinine Li-alkoxide has been reported previously.10e
(10) (a) Mukaiyama, T.; Suzuki, K.; Soai, K.; Sato, T. Chem. Lett.
1979, 447. (b) Mukaiyama, T.; Suzuki, K. Chem. Lett. 1980, 255. (c)
Niwa, S.; Soai, K. J . Chem. Soc., Perkin Trans. 1 1990, 937-943. (d)
Tombo, G. M. R.; Didier, E.; Loubinoux, B. Synlett 1990, 547-548. (e)
Corey, E. J .; Cimprich, K. A. J . Am. Chem. Soc. 1994, 116, 3151-3152.
(f) Huffman, M. A.; Nobuyoshi, Y.; DeCamp, A. D.; Grabowski, E. J . J .
J . Org. Chem. 1995, 60, 1590.
10.1021/jo981170l CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/21/1998

Asymmetric Synthesis of Efavirenz
J . Org. Chem., Vol. 63, No. 23, 1998 8537
Sch em e 2
Sch em e 4
which was directly crystallized from the reaction mixture
at 5 °C and was isolated in 84% yield (from 4-chloro-
aniline) and >98% purity. Treatment of the salt 9 with
aqueous NaOAc in MTBE provided the corresponding
free base 3b in preparation for the p-methoxybenzyl
protection. Previously, this transformation was carried
out using p-methoxybenzyl chloride in the presence of
basic alumina.7 A more efficient and economical method
has been developed using p-methoxybenzyl alcohol under
mild acid catalysis.13 Thus, a mixture of ketoaniline 3b
and a catalytic amount of p-TsOH in acetonitrile was held
at 70 °C while p-methoxybenzyl alcohol was slowly added
(over 3 h). Slow addition was used to minimize the
formation of p-methoxybenzyl alcohol self-condensation
products. Under these conditions, p-methoxybenzyl al-
cohol is also converted into its symmetrical ether;14
however, this intermediate is an equally effective alky-
lating agent for the conversion 3b to 3a . The product
3a was then directly crystallized from the reaction
mixture by addition of water and was isolated in 90%
yield and in >99% purity. Alternatively, this p-meth-
oxybenzylation reaction could be carried out using tolu-
ene as solvent and the product 3a employed directly in
the next step, as a solution in toluene, without further
purification. Although this method simplifies the pro-
cessing, the procedure employing acetonitrile as solvent,
and isolation of 3a , is preferred since the use of purified
3a leads to more reproducible results in the enantiose-
lective addition reaction.
The preparation of (1R,2S)-N-pyrrolidinylnorephedrine
(5b) and its application as a ligand in asymmetric
synthesis has been reported in the literature.10c,15 While
the alkylation of (1R,2S)-norephedrine (10) with 1,4-
dibromobutane using K2CO3 as base was reported to give
5b in only 33% yield, it was found that reproducibly
excellent yields and product purity could be obtained
using NaHCO3 as base and toluene as solvent (Scheme
4).16 At reaction completion, inorganic salts were filtered
and the filtrate was washed with water to give the
product 5b as a solution in toluene (97% yield, >99.9%
purity). This solution can be used directly in the chiral
addition step or may be solvent switched to heptane and
the product 5b isolated by crystallization at <0 °C.
Alternatively, the hydrochloride salt of 5b may be
isolated by the addition of HCl and 2-propanol (96% yield,
>99% purity).
Sch em e 3
Subsequent studies on the use of chiral Li-alkoxides as
mediators for addition of Li-cyclopropyl acetylide (4a ) to
ketones of general structure 3 identified (1R,2S)-N-
pyrrolidinylnorephedrine Li-alkoxide (5a ) as the optimal
chiral mediator and the p-methoxybenzyl-protected ke-
toaniline 3a as the substrate of choice (Scheme 2).7 The
enantioselective alkynylation reaction proceeded rapidly
and efficiently in THF at low temperature (<-50 °C) to
give the product amino alcohol 2a with excellent enan-
tioselectivity (96-98% ee). This key transformation is
the cornerstone of an efficient asymmetric synthesis of
efavirenz, which is described in detail in this paper.
P r ep a r a tion of Sta r tin g Ma ter ia ls. The synthesis
of efavirenz required the preparation of p-methoxybenzyl
ketoaniline 3a , cyclopropylacetylene (4b), and (1R,2S)-
N-pyrrolidinylnorephedrine (5b). The ketoaniline 3a was
prepared from 4-chloroaniline (6) in 76% overall yield as
shown in Scheme 3. Reaction of 4-chloroaniline with
pivaloyl chloride in a two-phase mixture of tert-butyl
methyl ether (MTBE) and aqueous sodium hydroxide
afforded pivaloylamide 7 in 97% yield. Directed ortho-
metalation of 7 (2 equiv of n-BuLi or n-hexylLi, MTBE,
TMEDA) generated the corresponding dianion, which
was quenched with ethyl trifluoroacetate to afford ke-
toamide 8.11 The use of MTBE avoids the competitive
attack of n-butyllithium on THF at the required reaction
temperature of 0 °C.12 Hydrolysis of the amide in situ
(HOAc-HCl) provided the hydrochloride hydrate 9,
(12) Bates, R. B.; Kroposki, L. M.; Potter, D. E. J . Org. Chem. 1972,
37, 560.
(13) A similar acid-catalyzed benzylation of amides was reported.
Henneuse, C.; Boxus, T.; Tesolin, L.; Pantano, G.; Marchand-Brynaert,
J . Synthesis 1996, 495.
(14) Emert, J .; Goldenberg, M.; Chiu, G. L.; Valeri, A. J . Org. Chem.
1977, 42, 2012.
(15) (a) Soai, K.; Yokoyama, S.; Hayasaka, T. J . Org. Chem. 1991,
56, 4264. (b) Syntheses of pyrrolidyl alkanols using NaHCO3 as a base
was reported to give pyrrolidyl derivatives in moderate yields. Moffett,
R. B. J . Org. Chem. 1949, 14, 2.
(16) This simple and efficient alkylation procedure has now been
used to prepare a wide variety of N,N-cycloalkyl derivatives of amino
alcohols.
(11) Fuhrer, W.; Gschwend, H. W. J . Org. Chem. 1979, 44, 1133,.

8538 J . Org. Chem., Vol. 63, No. 23, 1998
Pierce et al.
Ta ble 1. Asym m etr ic Ad d ition of 4A to N-P r otected
Ketoa n ilin es
Ta ble 2. Effect of Tem p er a tu r e on En a n tioselectivity
T (°C)
2a (ee, %)
-30
-40
-50
-60
-70
91
95
97-98
99
99
Ta ble 3. Asym m etr ic Am p lifica tion
additive 5b (ee, %) product 2a (ee, %)
99 98
2, 3
R group
solution (ee, %)
a
b
c
d
p-methoxybenzyl
hydrogen
3,4-dimethoxybenzyl
triphenylmethyl
96-98
72
99
90
80
70
50
95.5
91.5
88
90
77
Cyclopropylacetylene (4b) is readily prepared by treat-
ing 5-chloropentyne with 2 equiv of n-butyllithium or
n-hexyllithium in cyclohexane or THF.17 Alternative
procedures from methyl cyclopropyl ketone have also
been published.18
Sch em e 5
En a n tioselective Alk yn yla tion . The intial report
describing the enantioselective alkynylation of keto-
aniline 3a with Li-cyclopropyl acetylide (4a ) in the
presence of chiral additive 5a defined the key parameters
leading to optimal results.7 The enantioselectivity of this
reaction is highly dependent on the N-protecting group
(Table 1). Excellent enantioselectivities were obtained
using the p-methoxybenzyl-protected ketoaniline 3a (98%
ee) and the 3,4-dimethoxybenzyl-protected ketoaniline 3c
(99% ee), and useful results were obtained using trityl-
protected ketoaniline 3d (90% ee). Although the trityl
protecting group is easier to remove than p-methoxyben-
zyl, the use of 3a is preferred due to the high enantiose-
lectivity in the addition reaction, the low cost of p-meth-
oxybenzyl alcohol, and the high yield in the protection
step.
In addition to the requirement for p-methoxybenzyl
protection, it was shown that 2 equiv of (1R,2S)-N-
pyrrolidinylnorephedrine Li-alkoxide (5a ) and 2 equiv of
Li-cyclopropyl acetylide (4a ) are required for maximum
selectivity and conversion (>97%) and that THF is the
solvent of choice (used as cosolvent with hydrocarbons
from alkyllithium reagent).7 Most importantly, it was
shown that the alkoxide-acetylide mixture is best gener-
ated at -25 to 0 °C in order to establish aggregate
equilibration prior to reaction with the ketoaniline 3a .
Generation of the alkoxide-acetylide mixture below -50
°C followed by reaction with 3a at this temperature
provided the addition product 2a in only 82-85% ee.7
Finally, it was found that the reaction is complete within
minutes of addition of the ketoaniline 3a to the preequili-
brated alkoxide-acetylide mixture and shows some
dependence of enantioselectivity on reaction temperature
(Table 2).
aggregate was fully characterized as the C2-symmetrical
2:2 cubic tetramer 11 (Scheme 5).8 Additionally, the level
of asymmetric amplification observed in this reaction
(Table 3) is very close to that predicted for reaction
proceeding via cubic tetramer 11.7,19
It is clear from the above discussion that optimal
reaction conversion and enantioselectivity require strict
control of reagent stoichiometry and reaction conditions.
Experimentally, the chiral complex 11 was prepared by
reaction of n-butyllithium (or n-hexyllithium) with a
mixture of (1R,2S)-N-pyrrolidinylnorephedrine (5b) and
cyclopropyl acetylene (4b) at -10 to 0 °C (aggregate
equilibration) in a THF-toluene-hexane mixture (Scheme
5). After the mixture was cooled below -50 °C, keto-
aniline 3a was added. After ∼60 min, the reaction was
quenched with aqueous citric acid.20 The organic layer
was then solvent switched into toluene, and the product
2a was crystallized by the addition of heptane (91-93%
isolated yield, >99.5% ee).21 The chiral additive 5b is
easily recycled from the aqueous layer by basification
with NaOH and extraction into toluene to give (1R,2S)-
N-pyrrolidinylnorephedrine (5b) (>99% purity, 98% yield).
The ligand has been recycled up to nine times in
Many of these observations are now understood as a
6
result of extensive Li NMR studies of the Li alkoxide-
acetylide mixture.8 It is clear that the 2:2 alkoxide-
acetylide mixture generated at low temperature exists
as a complex mixture of species, which rapidly equili-
brates to a single aggregate above -40 °C. This stable
(19) Bolm, C.; Bienewald, F.; Seger, A. Angew. Chem., Int. Ed. Engl.
1996, 35, 1657.
(17) Thompson, A.; Corley, E. G. Org. Synth. 1997, in press.
(18) (a) Schoberth, W.; Hanack, M. Synthesis 1972, 703. (b) Scott,
L. T.; Cooney, M. J .; Otte, C.; Puls, C.; Haumann, T.; Boese, R.; Carroll,
P. J .; Smith, A. B., III; de Meijere, A. J . Am. Chem. Soc. 1994, 116,
10275. (c) Lambert, J . B.; Papay, J . J .; Mark, H. W. J . Org. Chem.
1975, 40, 633.
(20) The reaction may alternately be quenched into 2 N aqueous
HCl without loss of 2a into the aqueous phase. Aqueous HCl may also
be used interchangeably with citric acid in purifying and recycling the
ligand 5b.
(21) The product 2a readily upgrades in optical purity upon crystal-
lization.

Asymmetric Synthesis of Efavirenz
J . Org. Chem., Vol. 63, No. 23, 1998 8539
Sch em e 6
Sch em e 7
subsequent chiral addition reactions to give product 2a
with typical chemical and optical purity.
Sch em e 8
Com p letion of th e Syn th esis. Two routes were
employed for conversion of the amino alcohol 2a into the
target compound, efavirenz. Initially, 2a was converted
into the benzoxazinone 12 (COCl2, Et3N, toluene), which
was isolated in 95% yield upon crystallization from
methanol. Compound 12 was then deprotected (CAN)
to give efavirenz (Scheme 6).7 Although this reaction
proceeds cleanly and efficiently and is suitable for the
small-scale synthesis of efavirenz, there were several
features that are not attractive for the large-scale prepa-
ration of this drug. First, an equal amount of p-
methoxybenzaldehyde was generated in this reaction,
which was not efficiently removed from efavirenz upon
crystallization. Also, a significant quantity of waste
cerium salts was generated in the reaction, which is an
environmental concern upon scale-up.
A more practical route to efavirenz was realized by
simply reversing the order of ring closure (benzoxazinone
formation) and N-deprotection. The most efficient method
for the de-p-methoxybenzylation of compound 2a involved
oxidative cleavage using quinones, such as DDQ (Scheme
7).22 Reaction of compound 2a with 1 equiv of DDQ
(toluene, 0-10 °C) proceeded quantitatively to give an
11.5:1 mixture of diastereomeric cyclic aminals 13a and
13b.23 The DDHQ (dichlorodicyanohydroquinone) byprod-
uct from this reaction is essentially insoluble in toluene,
enabling removal by filtration and efficient recycling back
to DDQ using established literature procedures.24 The
cyclic aminals 13a /13b were then directly converted into
the desired amino alcohol 2b without isolation or further
purification. Reaction of 13a /13b with NaOH in MeOH
effected clean dissociation to the amino alcohol 2b (as
its Na alkoxide) and p-methoxybenzyaldehyde. Since
direct isolation of 2b in the presence of p-methoxybenz-
aldehyde was not feasible, this was reduced in situ
(NaBH4) to p-methoxybenzyl alcohol. The amino alcohol
2b was then directly crystallized from the reaction
mixture, upon neutralization (HOAc), and was isolated
in 94% yield and >99.9% purity (after recrystallization
from toluene-heptane).
Conversion of the amino alcohol 2b into efavirenz was
most conveniently and economically accomplished using
phosgene (THF-heptane, 0 to 25 °C) in the absence of
base. This reaction presumably proceeds via intermedi-
ate 14a followed by ring closure (Scheme 8). After
aqueous workup (aqueous NaHCO3), efavirenz was crys-
tallized from THF-heptane and was isolated in excellent
yield (93-95%) and purity (>99.5%, >99.5% ee). Two
nonphosgene, ring-closure methods using chloroformates
were also developed (Scheme 8). A two-step procedure
involving formation and isolation of the methyl carbam-
ate 14c, followed by base-promoted ring closure, provided
efavirenz in 83% overall yield. Aside from the lower
yield, it was difficult to completely remove residual 14c
from efavirenz prepared by this method. A more conve-
nient one-pot process was also developed, involving
formation of the p-nitrophenylcarbamate 14b followed by
in situ ring closure.25 The organic layer was then washed
with brine, the solvent was switched to isopropyl alcohol,
(22) The less expensive quinone chloranil was also used for the
deprotection step. However, the initial oxidation of 2a to give the cyclic
aminals 13a /13b is not as efficient as the reaction involving DDQ, and
aminals 13a /13b required purification (by crystallization) prior to
conversion into the amino alcohol 2b. The isolated yield of 2b from
this two-step procedure was 75-80%.
(23) The structure of 13b was determined by comprehensive het-
eronuclear NOE (HOESY) experiments. Yu, C.; Levy, G. C. J . Am.
Chem. Soc. 1984, 106, 6533.
(24) Newman, M. S., Khanna, V. K. Org. Prep. Proced. Int. 1985,
17(6), 422-423.

8540 J . Org. Chem., Vol. 63, No. 23, 1998
Pierce et al.
N-(4′-Meth oxyben zyl)-4-ch lor o-2-(tr iflu or oa cetyl)a n i-
lin e (3a ). Into a 50 L extractor was charged a solution of
sodium acetate (1.4 kg, 17.6 mol) in water (3.6 L) and tert-
butyl methyl ether (18 L). The HCl salt 9 (3.0 kg, 10.8 mol)
was added. The heterogeneous mixture was stirred at ambient
temperature for 30 min or until solids disappeared. The pH
of the aqueous layer should be in the range of 4.0-6.0,
otherwise HCl (6 N) or NaOH (5 N) was used to adjust the
pH to the desired range. The organic layer was separated,
washed with water (3.6 L), and transferred to a 50 L, three-
necked, round-bottom reaction flask equipped with mechanical
stirrer and a thermocouple. The solution was concentrated
to ∼8 L and flushed with acetonitrile (2 × 12 L) to give
ketoaniline 3b (2.24 kg, 10.0 mol, 99% yield) as a free base in
acetonitrile (8 L), which was directly used in the next step. A
small sample of ketoaniline 3b was isolated as yellow needles
by crystallization from heptane: mp 98-99 °C; 1H NMR (300
MHz, CDCl3) δ 7.70 (d, J ) 2 Hz, 1 H), 7.32 (dd, J ) 2, 9 Hz,
1H), 6.7 (d, J ) 9 Hz, 1H), 6.44 (brs, 2H); 13C NMR (75 MHz,
CDCl3) δ 180.0, 151.6, 136.9, 1301.1, 120.9, 119.0, 116.8, 111.4;
19F NMR (282 MHz, CDCl3) δ 70.3; IR (cm-1) 3498, 3380, 1663,
1625, 1589, 1533, 1138; HRMS calcd for C8H5ClF3NO 223.0001,
found 223.0012. Anal. Calcd for C8H5ClF3NO: C, 42.98; H,
2.25; N, 6.26. Found: C, 43.01; H, 2.14; N, 6.09.
To the solution of ketoaniline 3b in acetonitrile, under
nitrogen, was added p-toluenesulfonic acid monohydrate (28.65
g, 0.15 mol). The reaction mixture was heated to 70 °C with
stirring. 4-Methoxybenzyl alcohol (1.53 kg, 11.0 mol) in
acetonitrile (3 L) was added over 4-5 h, keeping the reaction
temperature at 70 °C. The reaction was monitored by HPLC
until reaction completion (typically 2 h after the addition of
the alcohol). The batch was cooled to room temperature and
seeded. A bright yellow crystalline solid gradually formed. The
slurry was then aged at ambient temperature for 1-2 h with
stirring. Water (11 L) was added slowly over 2 h. After being
aged at room temperature for another 1-2 h, the solid was
filtered and washed with 50/50 acetonitrile/water (2 × 10 L).
The wet cake was dried under vacuum (50 °C, 70 mmHg, 24
h) to give ketoaniline 3a (3.17 kg, 90% yield) as a bright yellow
solid: mp 82-84 °C; 1H NMR (300 MHz, CDCl3) δ 9.04 (s, 1H),
7.74 (d, J ) 2 Hz, 1H), 7.35 (dd, J ) 2, 9 Hz, 1H), 7.24 (d, J )
8 Hz, 2H), 6.91 (d, J ) 8 Hz, 2H), 6.75 (d, J ) 9 Hz, 1H), 4.43
(d, J ) 6 Hz, 2H), 3.79 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
180.5, 159.2, 151.9, 137.4, 130.8, 128.9, 128.4, 119.9, 117.0,
114.5, 114.4, 111.3, 55.3, 46.6; IR (cm-1) 3355, 1659, 1608,
1565, 1510, 1431, 1407, 1357, 1245, 1160, 1133; HRMS calcd
for C16H13ClF3NO2 343.0587, found 343.0588. Anal. Calcd for
and the product was crystallized by addition of water to
give efavirenz in 94% yield and >99.5% purity, free of
the 14b intermediate.
Su m m a r y
A highly efficient, practical, enantioselective synthesis
of the HIV reverse transcriptase inhibitor efavirenz is
now available, which is suitable for the manufacture of
this important compound. The synthesis provides ana-
lytically pure efavirenz in an overall yield of 62%, in
seven steps from 4-chloroaniline. A novel, chiral Li-
alkoxide-mediated, enantioselective acetylide addition
reaction is used to establish the chiral center in the target
with a remarkable level of stereocontrol.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. 1H,
13C, and 19F NMR spectra were collected at 300, 75, and 282
MHz, respectively. Analytical HPLC were run with Zorbax
RX-C18 columns at 215, 240, or 250 nm. Chiral HPLC were
run with a ChiralPak AD column. All reactions were run
under nitrogen, and all reagents were plant grade unless
otherwise noted. Combustion analyses were performed by
Quantitative Technologies, Inc., Bound Brook, NJ .
N-(4-Ch lor op h en yl)-2,2-d im eth ylp r op a n a m id e (7). 4-
Chloroaniline (6, 1.0 kg, 7.8 mol) was charged into a mixture
of tert-butyl methyl ether (4.6 L) and 30% aqueous sodium
hydroxide (1.17 kg, 8.78 mol), and the mixture was cooled to
15 °C. To the resulting slurry was added trimethylacetyl
chloride (1.0 kg, 8.5 mol) over 1 h, keeping the temperature
below 40 °C. After being stirred for 30 min at 30 °C, the slurry
was cooled to -10 °C and held for 2 h. The product was
collected by filtration, washed with a solution of 90/10 water/
methanol (2.5 L) and water (5 L), and dried in vacuo to give
pivaloylamide 7 (1.61 kg, 97% yield) as a crystalline solid: mp
1
152-153 °C (lit.11 mp 145 °C); H NMR (300 MHz, CDCl3) δ
7.48 (d, J ) 9 Hz, 2H), 7.37 (s, 1H), 7.28 (d, J ) 9 Hz, 2H),
1.30 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 176.7, 136.6, 129.1,
128.9, 121.4, 39.6, 27.6.
4-Ch lor o-2-tr iflu or oa cetyla n ilin e, Hyd r och lor id e Hy-
d r a te (9). Compound 7 (3.7 kg, 17.3 mol) was charged to a
solution of TMEDA (2.0 kg, 17.4 mol) in anhydrous tert-butyl
methyl ether (35 L), and the mixture was cooled to -20 °C.
To the cold slurry was added 2.7 N n-butyllithium in hexane
(10.2 kg, 39.3 mol) while the temperature was kept below 5
°C. The mixture was aged at 0-5 °C for 2 h and cooled below
-15 °C, and ethyl trifluoroacetate (3.45 kg, 24.3 mol) was
added rapidly. After 30 min, the resulting solution was
quenched into 3 N HCl (20 L, 58.9 mol), keeping the temper-
ature below 25 °C. The organic solution was separated and
concentrated by distilling approximately 20 L of solvent.
Acetic acid (33 L) was added while 35 L of solvent was distilled
under vacuum (∼100 mmHg). The solution was cooled to 30
°C, 12 N HCl (3.6 L, 43.4 mol) was added, and the mixture
was heated to 65-70 °C and held for 4 h. The resulting slurry
was cooled to 5 °C, and the product was collected by filtration,
washed with ethyl acetate (5.5 L), and dried in vacuo to give
4.2 kg (87%) of the salt 9 as a white crystalline solid: mp 159-
162 °C dec; 1H NMR (300 MHz, DMSO-d6) δ 7.65-7.5 (m, 2H),
7.1 (d, J ) 8 Hz, 1H), 7.0 (brs, 3H); 19F NMR (282 MHz, DMSO-
d6) δ -69.5; IR (cm-1) 3201(broad), 1929, 1795 (weak), 1626,
1595, 1558, 1509, 1486, 1174. Anal. Calcd for C8H8Cl2F3-
NO2: C, 34.56; H, 2.90; N, 5.04; Cl, 25.50. Found: C, 34.56;
H, 2.76; N, 4.91; Cl, 25.26.
C
16H13ClF3NO2: C, 55.91; H, 3.81; N, 4.07. Found: C, 56.07;
H, 3.87; N, 3.99.
N-(3′,4′-Dim eth oxyben zyl)-4-ch lor o-2-(tr iflu or oa cetyl)-
a n ilin e (3c). Compound 3a (4.96 g, 40 mmol) and 3,4-
dimethoxybenzyl alcohol (7.39 g, 44 mmol) were added to
2-propanol (40 mL). TsOH (76 mg, 0.4 mmol) was added and
the mixture heated to 60 °C and held 3.5 h. The solution was
concentrated in vacuo to one half the original volume, diluted
with water (10 mL), and stirred at 25 °C. The resulting slurry
was filtered and the product dried in vacuo at 30 °C to give
10.16 g (68%) of 3c as a yellow powder. An analytically pure
sample was obtained by recrystallization from acetonitrile: mp
1
82-84 °C; H NMR (CDCl3) δ 9.05 (brs, 1H), 7.75 (brt, J ) 2
Hz, 1H), 7.35 (dd, J ) 2, 8 Hz, 1H), 6.8 (d, J ) 8 Hz, 3H), 6.75
(d, J ) 8 Hz, 1H), 4.43 (d, J ) 5 Hz, 2H), 3.88 (s, 3H), 3.87 (s,
3H); 13C NMR (CDCl3) δ 179.9, 151.9, 149.4, 148.7, 137.4,
130.8, 130.8, 130.7, 129.4, 119.4, 114.5, 111.5, 111.4, 110.3,
56.1, 56.0, 47.0; 19F NMR (CDCl3) δ -69.61; IR (cm-1) 3343,
1656, 1612, 1566, 1512, 1464, 1141, 1264, 1195, 1140, 1028;
HRMS calcd for C17H15F3ClNO3 373.0692, found 373.0698.
N-(Tr ip h en ylm et h yl)-4-ch lor o-2-(t r iflu or oa cet yl)a n i-
lin e (3d ). To a solution of NaOAc (1.42 kg, 17.3 mol) in water
(3.6 L) was added tert-butyl methyl ether (5.0 L), cyclohexane
(13.7 L), and compound 9 (3.00 kg, 10.8 mol). After dissolution
the phases were separated. The organic phase was partially
concentrated by distilling 7.5 L of solvent. Trityl alcohol (3.03
kg, 11.6 mol) and p-TsOH (20 g, 0.11 mol) were added and
the mixture heated to reflux with distillation of 6.5 L of solvent
(25) Two bases are used in this reaction (KHCO3, followed by KOH),
since the reaction does not proceed to completion if run at initially
high pH (pH > 11). In this case, ring closure is rapid and K-
nitrophenylate competes with 2b for nitrophenyl chloroformate (form-
ing nitrophenyl carbonate as a byproduct). Use of KHCO3 ensures pH
< 8.5 and complete formation of the carbamate 14b before addition of
KOH to effect ring closure.

Asymmetric Synthesis of Efavirenz
J . Org. Chem., Vol. 63, No. 23, 1998 8541
over 6 h. Diisopropylethylamine (28 g, 0.22 mol) and aceto-
nitrile (12.5 L) were added followed by distillation of 7.5 L of
solvent. The mixture was cooled to -5 °C and the product
isolated by filtration to give 4.4 kg (88%) of 3d as a bright
yellow solid. An analytically pure sample was obtained by
recrystallization from acetonitrile: mp 165-167 °C; 1H NMR
(CDCl3) δ 10.4 (brs, 1H), 7.71 (brt, J ) 2 Hz, 1H), 7.3 (brs, 15
H), 6.9 (dd, J ) 2, 8 Hz, 1H), 6.27 (d, J ) 8 Hz, 1H). 13C NMR
(75 MHz, CDCl3) δ 180.5, 151.2, 144.1, 135.7, 130.7, 130.6,
129.2, 128.9, 128.7, 128.6, 128.5, 128.2, 128.0, 127.7, 127.5,
122.9, 120.3, 119.3, 119.1, 115.2, 112.3, 111.3, 71.9; 19F NMR
(282 MHz, CDCl3) δ -69.5; HRMS calcd for C27H19ClF3NO
465.1107, found 465.1099. Anal. Calcd for C27H19ClF3NO: C,
69.60; H, 4.11; N, 3.01. Found: C, 69.66; H, 4.24; N, 2.95.
(1R,2S)-N-P yr r olid in yln or ep h ed r in e (5b). A 22 L three-
necked round-bottom flask equipped with a mechanical stirrer,
a condenser with a Dean-Stark trap, and a thermocouple was
charged with toluene (8 L), (1R,2S)-(-)-norephedrine (10) (1.50
kg, 10 mol), 1,4-dibromobutane (2.38 kg, 11 mol), and sodium
bicarbonate (1.85 kg, 22 mol). The heterogeneous mixture was
heated under reflux (110-118 °C) for 20 h or until the
completion of the reaction (as judged by HPLC). The batch
was cooled to ambient temperature and filtered through a
sintered glass funnel to remove inorganic solids. The waste
cake was washed with 3 L of toluene. The combined filtrate
and wash was washed with water (6 L). The organic layer
was transferred to a 50 L extractor and extracted with 30%
aqueous citric acid solution at room temperature. The aqueous
layer was separated and transferred into another extractor
containing 10 L of toluene. NaOH (50 wt %, 3.57 kg) was
added, slowly, keeping the temperature below 30 °C. The
mixture was stirred for 15 min, and the layers were separated.
The aqueous layer (pH of the aqueous layer was 12-12.5) was
extracted with toluene (5 L). The organic layers were com-
bined and washed with water (2 × 5 L). The organic solution
was concentrated in vacuo to about 5 L to afford 5b (1.97 kg,
38 wt %, 96%) in toluene as a pale yellow solution. An
analytically pure sample was obtained by concentrating the
toluene solution of 5b in vacuo followed by crystallization from
heptane: mp 46-48 °C. Spectral data were consistent with
those previously reported for this compound.15a
130.2, 128.6, 124.0, 121.6, 119.5, 114.8, 114.1, 94.0, 75.0, 70.6,
55.3, 48.0, 8.6, 8.5, - 0.6; 19F NMR (282 MHz, CDCl3) δ -80.19;
IR (cm-1) 3428, 3294, 2235, 1601, 1574, 1507, 1457, 1399, 1323,
1305, 1256, 1233, 1166, 1135. Anal. Calcd for C21H19F3-
ClNO2: C, 61.54; H, 4.67; N, 3.42. Found: C, 61.26; H, 4.62;
N, 3.24.
Recycle of (1R,2S)-N-P yr r olid in yln or ep h ed r in e. To
3.8 L of pyrrolidinylnorephedrine (284 g) in citric acid (∼1 M)
was added 500 mL of toluene, and the mixture was stirred at
25 °C for 30 min. The organic layer was removed, 1.5 L of
toluene was added to the aqueous layer, and 50% NaOH was
added until pH 12. The organic layer was separated, and the
aqueous layer was extracted with 1.5 L of toluene. The toluene
layers were combined and washed with 500 mL water and
dried azeotropically to give a solution of pure (1R,2S)-N-
pyrrolidinylnorephedrine in approximately 500 mL of toluene
(278.3 g, 98% yield).
(S)-5-Ch lor o-r-(cyclop r op yleth yn yl)-2-[(3,4-d im eth ox-
yph en yl)m eth yl]-am in o]-r-(tr iflu or om eth yl)ben zen em eth -
a n ol (2c). A 17.2 wt % solution of 5b (254 g, 213 mmol) was
concentrated by distilling 160 mL of solvent at atmospheric
pressure. Triphenylmethane (0.2 g, 0.8 mmol) was added, and
the solution was cooled to 25 °C. THF (130 mL) was added,
and the solution was cooled to -20 °C. n-Hexyllithium (2.0
M solution in hexane, 203 mL, 0.406 mol) was added while
the temperature was maintained below 0 °C. The mixture
turned red after the addition of 108 mL. A 16 wt % solution
of 4b (103 g, 0.25 mol) was added until the solution decolorized.
The solution was stirred at -5 to 0 °C for 20 min and then
cooled to -45 °C, at which point compound 3c (29.7 g, 81.8
mmol) predissolved in 50 mL THF was added. After 1 h at
-45 °C, the mixture was quenched into 2 N HCl (400 mL).
The organic layer was washed twice with 2 N HCl (100 mL)
and then concentrated in vacuo. Toluene (150 mL) was added,
and the mixture was concentrated to a volume of 80 mL.
Heptane (100 mL) was added, and the solvent ratio (deter-
mined by GC analysis) heptane/toluene was adjusted to 60:40
by adding 43 mL of toluene. After crystallization, the product
was filtered and recrystallized from toluene/heptane (3:1) to
give 23.1 g (64%) of 2c as a pale yellow solid: mp 128-129.5
°C; [R]25D + 11.00° (c 0.300, MeOH); 1H NMR (300 MHz, CDCl3)
δ 7.56 (m, 1H), 7.13 (dd, J ) 9, 3 Hz, 1H), 6.84 (m, 3H), 6.58
(d, J ) 9 Hz, 1H), 4.24 (m, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 1.34
(m, 1H), 0.90-0.74 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ
148.8, 147.8, 146.3, 131.4, 129.8, 129.4, 124.3, 119.1, 118.9,
118.2, 113.4, 111.8, 110.9, 92.7, 73.8, 70.9, 55.5, 55.3, 46.5, 8.2,
8.1, -1.1; 19F NMR (282 MHz, CDCl3) δ -80.0; IR (cm-1) 3425,
2240, 1602, 1575, 1508, 1477, 1263, 1186, 1162, 1019; HRMS
calcd for C22H22ClF3NO3 (M + H) 440.1240, found 440.1228.
Anal. Calcd for C22H21ClF3NO3: C, 60.07; H, 4.78; N, 3.18.
Found: C, 60.14; H, 4.88; N, 3.07.
(S)-5-Ch lor o-r-(cyclopr opyleth yn yl)-2-[(4-m eth oxyph en -
yl)m et h yl]a m in o]-r-(t r iflu or om et h yl)b en zen em et h a n -
ol (2a ). Into dry tetrahydrofuran (4.4 L) were charged
(1R,2S)-N-pyrrolidinylnorephedrine (5b) (3.31 kg, 6.11 mol,
37.9 wt % in toluene) and Ph3CH (1 g, used as indicator). The
solution was cooled to -10 °C, and n-BuLi (1.6 M in hexanes)
was added over 1 h, keeping the temperature below 5 °C. The
amount of n-BuLi added was recorded when the solution
turned red. The same amount of n-BuLi was added to give a
deep red solution, and then cyclopropylacetylene (403 g, 6.11
mol) was added dropwise, keeping the temperature below 5
°C. The mixture was aged at 0-5 °C for 30 min, to give the
tetrameric complex 11, and was cooled to -55 °C. Ketone 3a
(1.05 kg, 3.0 mol) in dry THF (2.2 L) was added to the complex
over 60 min, allowing the internal temperature to rise to -50
°C during the addition. The resulting red solution was aged
at -55 °C for 60 min and quenched by addition into 1 M citric
acid (4.4 L). The mixture was warmed to ambient tempera-
ture, and the layers were separated. The organic layer was
washed with 1 M citric acid (4.4 L). The organic solution was
concentrated to ∼3.2 L and flushed with 2 × 4 L of toluene to
give a pale yellow slurry. Heptane (2.4 L) was added dropwise
to complete the crystallization. The slurry was aged at
ambient temperature for 1 h. The solid was filtered and
washed with heptane/toluene (4:1 by volume, 3 L) and heptane
(1.5 L). The product was dried at 45 °C under vacuum with a
nitrogen stream to afford the PMB-amino alcohol 2a (1.2 kg,
91% yield, >99 A%, >99.5% ee) as an off-white solid: mp 163-
5-Ch lor o-r-(cyclop r op yleth yn yl)-2-(tr ip h en ylm eth yl)-
a m in o]-r-(tr iflu or om eth yl)ben zen em eth a n ol (2d ). To a
solution of 4b (3.15 g, 48 mmol) and 5b (10.9 g, 53 mmol) in
THF (50 mL) was added 2 N n-hexyllithium (46 mL, 92 mmol),
keeping the temperature below 0 °C. Compound 3d (9.32 g,
20 mmol) dissolved in THF (20 mL) was added to the complex,
and the mixture was held at -45 to -50 °C for 1 h and then
quenched with 1 N citric acid (92 mL). The organic layer was
separated, dried with sodium sulfate, and concentrated to an
oil. Crystallization from heptane/toluene gave 6.34 g (60%)
of 2d : mp 180-182 °C; [R]25 +7.77° (c 1.004, CH3CN); 1H
D
NMR (300 MHz, CDCl3) δ 7.53 (d, J ) 2 Hz, 1H), 7.4-7.1
(complex, 16 H), 6.67 (dd, J ) 2,7 Hz, 1H), 6.05 (d, J ) 7 Hz,
1H), 3.17 (brs, 1H), 1.07 (m, 1H), 0.72 (m, 2H), 0.62 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 143.7, 129.1, 129.0, 128.8, 128.1,
126.9, 126.0, 122.2, 120.7, 118.7, 118.3, 94.7, 74.0, 71.6, 70.2,
8.4, 8.3, -0.8; 19F NMR (282 MHz, CDCl3) δ -79.9; HRMS
calcd for C32H25ClF3NO 531.1577, found 531.1566. Anal.
Calcd for C32H25ClF3NO: C, 72.24; H, 4.74; N, 2.63. Found:
C, 72.05; H, 4.94; N, 2.51.
165 °C; HPLC, 99.8%, chiral HPLC. 99.9%; [R]25 +8.15° (c
D
1
1.006, MeOH); H NMR (300 MHz, CDCl3) δ 7.55 (brs, 1H),
7.23 (d, J ) 8 Hz, 2H), 7.13 (dd, J ) 3, 9 Hz, 1H), 6.86 (d, J )
8 Hz, 2H), 6.59 (d, J ) 8 Hz, 1H), 4.95 (bs, 1H), 4.23 (s, 2H),
3.79 (s, 3H), 2.39 (m,1H), 1.34 (m, 1H), 0.84 (m, 2H), 0.76 (m,
2H); 13C NMR (75 MHz, CDCl3 ) δ 158.9, 145.5, 130.6, 130.3,
(S)-6-Ch lor o-4-(cyclop r op yleth yn yl)-1,4-d ih yd r o-4-(tr i-
flu or om eth yl)-1-[(4′-m eth oxyp h en yl)m eth yl]-3,1-ben zox-
a zin -2-on e (12). Compound 3a (2.9 kg, 7.1 mol) and trieth-
ylamine (1.52 kg, 15.0 mol) were dissolved in 11.5 L of toluene.

8542 J . Org. Chem., Vol. 63, No. 23, 1998
Pierce et al.
A 20% solution of phosgene (0.84 kg, 8.5 mol) in toluene (4 L)
was added at a rate that the temperature remained below 25
°C. The mixture was aged at this temperature for 1 h, and
methanol (90 g, 2.8 mol) was added to quench excess phosgene.
After 15 min, water (9.0 L) was added, and the layers were
separated. The organic layer was washed with water (6.0 L)
and concentrated by distilling about 14 L of solvent in vacuo.
Methanol (29 L) was added, and the mixture was concentrated
by distilling about 18.5 L of solvent. The solution was cooled
to -15 °C, and the resulting solids were filtered, washed with
cold methanol (2 L), and dried in vacuo at 50 °C to give 2.82
kg (91%) of benzoxazinone 12 as a white solid: mp 115-116.5
°C; [R]25D -93.67° (c 0.300, MeOH); 1H NMR (300 MHz, CDCl3)
δ 7.52 (m, 1H), 7.26 (dd, J ) 9, 2 Hz, 1H), 7.17 (d, J ) 9 Hz,
2H), 6.85 (d, J ) 9 Hz, 2H), 6.83 (d, J ) 9 Hz, 1H), 5.08 (s,
2H), 3.77 (s, 3H), 1.40 (m, 1H), 0.96-0.82 (m, 4H); 13C NMR
(75 MHz, DMSO-d6) δ 158.6, 147.5, 134.9, 131.8, 128.1, 127.8,
127.0, 126.7, 122.1, 117.3, 116.6, 114.1, 96.0, 76.8, 65.6, 54.9,
46.6, 8.5, 8.4, -1.3; 19F NMR (282 MHz, CDCl3) δ -81; IR
(cm-1) 2248, 1735, 1605, 1515, 1497, 1314, 1252, 1187; HRMS
calcd for C22H18ClF3NO3 (M + H) 436.0927, found 436.0931.
Anal. Calcd for C22H17ClF3NO3: C, 60.62; H, 3.90; N, 3.21.
Found: C, 60.51; H, 3.89; N, 3.18.
(S)-6-Ch lor o-4-(cyclop r op yleth yn yl)-1,4-d ih yd r o-4-(tr i-
flu or om eth yl)-2H-3,1-ben zoxa zin -2-on e (1). To a solution
of compound 12 (250 g, 0.57 mol) in acetonitrile (2.5 L) was
added a solution of CAN (960 g, 1.75 mol) in water (1 L). The
mixture was stirred at ambient temperature for 1 h and
quenched with Na2S2O5 (200 g) to remove anisaldehyde. The
organic layer was separated and washed with 1 L of water.
To the organic solution was added another portion of Na2S2O5
(700 g), and the mixture was aged at ambient temperature
for 12 h to give a slurry. The slurry was filtered, and the waste
cake was washed with EtOAc (2 L). The filtrate was concen-
trated in vacuo, and the residue was crystallized from EtOAc-
heptane (5/95) to give efavirenz (1, 140 g, 76% yield) as white
solid.
(S)-5-Ch lor o-r-(cyclop r op yleth yn yl)-2-a m in o-r-(tr iflu -
or om eth yl)ben zen em eth a n ol (2b). DDQ (0.85 kg, 3.74 mol)
was dissolved in toluene (4.52 L, 5.31 mL/1 g of DDQ) at 30
°C and was charged dropwise to a slurry of the PMB-protected
amino alcohol 2a (1.51 kg, 3.68 mol) in toluene (6.62 L) at 0
°C over 20 min. The resulting mixture was aged at ambient
temperature for 2 h. The mixture was filtered, and the waste
solid (mainly DDHQ) was washed with toluene (3 × 0.5 L).
The filtrate and wash were combined and washed with
aqueous 5% NaHCO3 (3.3 L). The resulting toluene solution
contained mainly the cyclic aminals 13: 1H NMR (major
isomer, 300 MHz, DMSO-d6) δ 7.46 (d, J ) 9 Hz, 2H), 7.28-
7.21 (m, 3H), 7.0 (d, J ) 9 Hz, 2H), 6.85 (d, J ) 9 Hz, 1H),
5.52 (s, 1H), 3.78 (s, 3H), 1.52-1.47 (m, 1H), 0.90-0.84 (m,
2H), 0.72-0.68 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 160.3,
143.8, 129.6, 129.3, 128.9, 125.8, 123.1, 121.7, 118.1, 117.8,
113.8, 93.6, 80.9, 74.1, 70.3, 55.2, 8.5, 8.4, -1.07; 19F NMR
(282 MHz, CDCl3) δ -80.9; IR (cm-1) 2226, 1610, 1513, 1492,
1458, 1303, 1279, 1256, 1174. HRMS calcd for C21H17NO2ClF3
407.0899, found 407.0885. Anal. Calcd for C21H17NO2ClF3:
C, 61.99; H, 3.89; N, 3.41. Found: C, 61.68; H, 4.16; N, 3.34.
The toluene solution was concentrated in vacuo to ∼3 L at
∼40 °C. MeOH (9 L) was added portionwise, and the solution
was concentrated in vacuo to ∼3 L (toluene content in the final
solution should be <2 vol %). The total volume of the solution
was adjusted to 6.6 L with methanol. The solution was heated
at 40 °C, and 5 N NaOH (3.3 L) was added over 10 min. The
The crude product was dissolved in toluene (2.7 L) and
MTBE (0.85 L). The solution was concentrated in vacuo to
∼1.5 L. Heptane (2.6 L) was added over 1 h. The resulting
slurry was aged at ambient temperature for 1 h. The solid
was collected by filtration, washed with heptane (1 L), and
dried in vacuo to give 1.0 kg (94% yield) of the amino alcohol
2b as a white solid: mp 141-143 °C; [R]25 -28.3° (c 0.106,
D
1
MeOH); H NMR (300 MHz, CDCl3) δ 7.54 (d, J ) 2 Hz, 1H),
7.13 (dd, J ) 9, 2 Hz, 1H), 6.61 (d, J ) 9 Hz, 1H), 4.50 (brs,
3H), 1.44-1.35 (m, 1H), 0.94-0.78 (m, 2H), 0.72-0.68 (m, 2H);
13C NMR (75 MHz, DMSO-d6) δ 146.7, 129.4, 129.0, 124.3,
118.4, 118.07, 118.05, 92.3, 72.6, 71.0, 8.2, 8.1, -1.1; 19 F NMR
(282 MHz, CDCl3) δ -80.5; IR (cm-1) 3421, 3331, 2237, 1612,
1490, 1410, 1289, 1264, 1169, 1092; HRMS calcd for C13H11
NOClF3 289.0481, found 289.0497. Anal. Calcd for C13H11
-
-
NOClF3: C, 53.80; H, 3.77; N, 4.72. Found: C, 53.65; H, 3.63;
N, 4.81.
(S)-6-Ch lor o-4-(cyclop r op yleth yn yl)-1,4-d ih yd r o-4-(tr i-
flu or om et h yl)-2H -3,1-b en zoxa zin -2-on e (1)-P h osgen e.
Compound 2b (1.57 kg, 5.43 mol) was dissolved in a mixture
of heptanes (4 L) and THF (6 L), and the solution was cooled
to below -10 °C. Phosgene (0.8 kg, 8.0 mol) was directly fed
below the surface over about 1 h, keeping the temperature
below 0 °C. The resulting slurry was warmed to 20-25 °C
and held for 1 h. Methanol (0.65 kg, 20.3 mol) was added and
the solution stirred for ∼30 min. Heptanes (14 L) was added,
and ∼14 L of solvent was distilled under reduced pressure.
Heptanes (14 L) and THF (2.5 L) were added, and the solution
was washed with 5% aqueous sodium bicarbonate (1.5 L)
followed by water (1.5 L). The solution was warmed to 50 °C
and filtered into a clean reactor, followed by a 5 L heptanes
rinse. The solution was concentrated under reduced pressure,
diluted with heptanes (2.5 L), and cooled below -10 °C. The
product was filtered, washed with heptanes (4.5 L), and dried
in vacuo at 90-100 °C to give 1.6 kg (95% yield) of 1 as white
solid: mp 139-141 °C; [R]25D -94.1° (c 0.300, MeOH); 1H NMR
(400 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.54 (dd, J ) 2.5, 7 Hz,
1H), 7.43 (d, J ) 2.5 Hz, 1H), 6.99 (d, J ) 7 Hz, 1H), 1.58 (m,
1H), 0.92 (m, 2H), 0.77 (m, 2H); 13C NMR (100 MHz, DMSO-
d6) δ 146.23, 134.71, 132.04, 126.93, 126.57, 122.24, 116.83,
114.08, 95.63, 77.62, 65.85, 8.48, 8.44, -1.32; 19F NMR (282
MHz, DMSO-d6) δ -81.1; IR (cm-1) 3316, 2250, 1752, 1602,
1498, 1196, 1186; HRMS calcd for C14H10F3ClNO2 (M + H)
316.0352, found 316.0338. Anal. Calcd for C14H9F3ClNO2: C,
53.27; H, 2.87; N, 4.45; Cl 11.23; F, 18.05. Found: C, 53.15;
H, 2.73; N, 4.37; Cl, 11.10; F, 17.84
(S)-6-Ch lor o-4-(cyclop r op yleth yn yl)-1,4-d ih yd r o-4-(tr i-
flu or om et h yl)-2H -3,1-b en zoxa zin -2-on e (1)-Non p h os-
gen e. To a solution of the amino alcohol 2b (35.38 mmol,
10.25 g) in toluene (100 mL) were added water (100 mL),
potassium bicarbonate (2 equiv, 7.08 g), and methyl chloro-
formate (2 equiv, 5.46 mL). The biphasic mixture was stirred
vigorously at 20-25 °C until <0.5% amino alcohol 2b remained
by HPLC analysis (approximately 8.5 h). The layers were
separated, and the organic layer was washed with brine (100
mL) and dried over magnesium sulfate. After filtration, the
solution was concentrated (50-60 °C under vacuum), and
heptane was added to adjust the final solvent ratio to ap-
proximately 10% toluene/90% heptane and a final volume of
100 mL. During the solvent ratio adjustment, the methyl
carbamate 14c crystallized. After the slurry was aged at 20-
25 °C for approximately 30 min, the material was filtered, and
the cake was washed with one cake volume of heptane. The
solid was dried by suction to give 11.32 g of methyl carbamate
14c (92% yield) as a white solid: mp 112.5-114.5 °C; 1H NMR
(300 MHz, CDCl3) δ 8.70 (brs, 1H), 8.03 (d, J ) 8.5 Hz, 1H),
7.67 (d, J ) 2.4 Hz, 1H), 7.32 (dd, J ) 8.9, 2.5 Hz, 1H), 4.54
(brs, 1H), 3.76 (s, 3H), 1.36 (m, 1H), 0.90 (m, 2H), 0.81 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 154.7, 136.2, 130.2, 130.1,
128.1, 124.3, 123.6 (q, J ) 286.9, 1C), 122.9, 94.7, 74.8 (q, J )
33.5, 1C), 69.6, 52.7, 8.5, 8.4, -0.7.
resulting clear solution was held at 40 °C for 30 min.
A
solution of NaBH4 (39.1 g, 1.03 mol) in 0.5 N NaOH (390 mL)
was added dropwise, maintaining the temperature at 40-45
°C. The mixture was stirred at ambient temperature for 15
min and cooled to 19 °C. The solution was neutralized with
glacial acetic acid (∼ 1.0 L) to pH 8.4, keeping the temperature
at 20-25 °C. Water (10 L) was added dropwise over 30 min.
The mixture was aged at ambient temperature for 1 h and
filtered. The solid was washed with water (1 L) and dried in
vacuo to give crude amino alcohol 2b as a pale yellow solid
(1.04 kg).
To a solution of methyl carbamate 14c (32.55 mmol, 11.32
g) in MTBE (170 mL) was added a solution of LiO-t-Bu in
hexanes (1 equiv, 32.6 mL of a 1 M solution). The reaction
mixture immediately became a slurry, which became a clear

Asymmetric Synthesis of Efavirenz
J . Org. Chem., Vol. 63, No. 23, 1998 8543
yellow solution within 30 min. The reaction mixture was aged
at 20-25 °C until <0.3% methyl carbamate 14c remained by
HPLC analysis (approximately 16 h). The reaction was
quenched into 0.5 N HCl (150 mL), the layers were separated,
and the organic layer was washed with brine (150 mL), dried
over magnesium sulfate, and filtered. The solution was solvent
switched into IPA (56 mL), and the product was crystallized
by the addition of water (106 mL). The product was filtered
and dried to give 9.22 g (90% yield, 83% from 2b) of 1.
(S)-6-Ch lor o-4-(cyclop r op yleth yn yl)-1,4-d ih yd r o-4-(tr i-
flu or om et h yl)-2H -3,1-b en zoxa zin -2-on e (1)-Non p h os-
gen e. To a three necked round-bottom flask equipped with a
mechanical stirrer, N2 line, and thermocouple were charged
amino alcohol 2b (500 g, 1.73 mol), MTBE (2.5 L), water (5.0
L), and solid KHCO3 (225 g, 2.25 mol). The resulting mixture
was stirred at ambient temperature, and then solid 4-nitro-
phenyl chloroformate (365 g, 1.82 mol) was added over 3 h.
The mixture was stirred at 20-25 °C for 1 h. The pH of the
reaction was adjusted to 11 by addition of aqueous KOH (1.94
M). At approximately pH 9.2, the carbamate dissolved. More
KOH was added until the pH was 11-11.5. The resulting two-
phase mixture was stirred vigorously at 25 °C. The total
aqueous volume was adjusted to 100 mL by addition of water.
The layers were separated, and 2.5 L of brine (15 wt %) was
added to the organic phase. HOAc (0.1 N) was added until
the pH was 6-7 (approximately 350-700 mL of HOAc was
added). The organic layer was then washed with 2.5 L of brine
and solvent switched to IPA (3 L). H2O (5.7 L) was added to
crystallize compound 1 (94% yield) as a white solid.
Ack n ow led gm en t. DuPont Pharmaceuticals: We
are thankful to Dr. Rodger Stringham, Barbara Lord,
Bill Cummings, and Tom Sholz for their analytical
support and to Hank J ackson and Dr. Charles Ray for
performing thermochemical hazards analyses through-
out the process. Merck: We would like to acknowledge
the efforts of Charles Moeder, Tom O’Brien, and Dr. P.
Yehl in Analytical Research and J . Kukura for the
development of the isopropyl alcohol-water crystalliza-
tion of efavirenz.
J O981170L