A Practical Synthesis of Nelfinavir, an HIV-Protease Inhibitor, Using a Novel Chiral C4 Building Block: (5R,6S)-2,2-Dimethyl-5-hydroxy-l,3-dioxepan-6-ylammonium Acetate

Full text of DOI:10.1021/jo981472n

7582
J . Org. Chem. 1998, 63, 7582-7583
SN2 ring opening7 to provide a diastereomeric mixture of
trans-amino alcohol. The more polar isomer (4) was easily
and consistently isolated from the one-pot reaction by
crystallization in 37-40% yield with >99% de.8 Reduction
of the methylbenzyl group of 4 in the presence of 1 equiv of
acetic acid gave enantiomerically pure 5.9
A P r a ctica l Syn th esis of Nelfin a vir , a n
HIV-P r otea se In h ibitor , Usin g a Novel Ch ir a l
C4 Bu ild in g Block : (5R,6S)-2,2-Dim eth yl-5-
h yd r oxy-1,3-d ioxep a n -6-yla m m on iu m Aceta te
Takashi Inaba,*,† Angela G. Birchler,‡ Yasuki Yamada,†
Shoichi Sagawa,† Katsuyuki Yokota,† Koji Ando,† and
Itsuo Uchida†
Central Pharmaceutical Research Institute, J apan Tobacco,
Inc., 1-1, Murasaki-cho Takatsuki Osaka, 569-1125, J apan, and
Agouron Pharmaceuticals, Inc., 3565 General Atomics Court,
San Diego, California 92121
The employment of 5 as a chiral C4 unit in the synthesis
of 1 required (a) differentiation of the two acetonide pro-
tected primary hydroxyl groups and (b) inversion of the
asymmetric center possessing the secondary hydroxyl group.
Differentiation of the primary hydroxyl groups was antici-
pated to be accomplished by the coupling of 5 with the
benzoic acid moiety with subsequent intramolecular oxazo-
line ring formation involving the adjacent primary hydroxy
group. Inversion of the secondary hydroxyl group was
expected to be achieved by mesylation followed by intramo-
lecular SN2 displacement by the R-hydroxyl group. This
strategy was successfully executed using simple and reliable
synthetic methodologies that yielded 1 with high and
reproducible yields.
The coupling of 5 with acid chloride 6 gave amide alcohol
7, which was subsequently treated with methanesulfonyl
chloride to afford mesylate 8 (Scheme 1). When 8 was
treated with BF3‚Et2O followed by quenching with acetic
anhydride, 10 was obtained in 65-71% yield from 5.
Alternatively, the unstable alcohol 9 was isolated by quench-
ing the BF3‚Et2O reaction with water. Oxazoline ring
formation and concomitant deprotection of the acetonide
group achieved complete differentiation of the two primary
hydroxyl groups generated by the deprotection. A plausible
mechanism for the oxazoline formation is the concerted
nucleophilic attack of the amide oxygen with the acetone of
the acetonide protecting group serving as a leaving group.
Quenching the reaction with acetic anhydride10 or water
provided 10 or 9, respectively. Treatment of 10 with K2CO3
in the presence of perhydroisoquinoline 123 in aqueous
methanol gave 13 via the unstable epoxide 11. Under these
reaction conditions, saponification of the two acetate groups
of 10, epoxide formation, and nucleophilic attack at the
terminal carbon of the epoxide by 12 took place successively
with inversion of the asymmetric center bearing the meth-
anesulfonyloxy group. Compound 13 crystallized from the
reaction mixture and was isolated in 62-65% yield from 5.
All of the above reactions proceeded cleanly, and no isolation
or purification was required for any of the intermediates
between 5 and 13.
Received J uly 28, 1998
Nelfinavir mesylate,1 one of the most potent HIV-protease
inhibitors,2 comprises three retrosynthetic components: a
chiral C4 unit, a perhydroisoquinoline derivative unit, and
a benzoic acid derivative unit. The preparation of the
perhydroisoquinoline derivative has been previously ad-
dressed in the literature,3 and the substituted benzoic acid
derivative can be prepared using well-known chemistry.4
However, the design of a chiral C4 unit that could be
efficiently constructed and coupled to the two aforemen-
tioned units has proven to be nontrivial. This C4 unit was
previously prepared from L-serine via multiple steps, includ-
ing C1 elongation and diastereomeric reduction, which
required low-temperature reaction conditions and expensive
reagents.5 Described herein is a practical synthesis of
nelfinavir free base (1), in which (5R,6S)-2,2-dimethyl-5-
hydroxy-1,3-dioxepan-6-ylammonium acetate (5) is employed
as a new chiral C4 building block.
As the starting material for the C4 unit we focused on
epoxide 2.6 Despite its lack of chirality, 2 provided several
advantages, including the desired four-carbon arrangement
with the correct oxidation state for all four carbons. Ad-
ditionally, as a meso compound, 2 avoided the necessity for
a regioselective aminolysis. Upon refluxing in 2-propanol
with 1 equiv of (R)-R-methylbenzylamine (3), 2 underwent
† J apan Tobacco Inc.
‡ Agouron Pharmaceuticals, Inc.
The final transformation in the synthesis of 1 was the ring
(1) Kaldor, S. W.; Kalish, V. J .: Davies, J . F., II; Shetty, B. V.; Fritz, J .
E.; Appelt, K.; Burgess, J . A.; Campanale, K. M.; Chirgadze, N. Y.; Clawson,
D. K.; Dressman, B. A.; Hatch, S. D.; Khalil, D. A.; Kosa, M. B.; Lubbehusen,
P. P.; Muesing, M. A.; Patick, A. K.; Reich, S. H.; Su, K. S.; Tatlock, J . H.
J . Med. Chem. 1997, 40, 3979.
(2) For a review of recent HIV-protease inhibitors, see: Babine, R. E.;
Bender, S. L. Chem. Rev. 1997, 97, 1359.
(3) (a) Houpis, I. N.; Molina, A.; Reamer, R. A.; Lynch, J . E.; Volante, R.
P.; Reider, P. J . Tetrahedron Lett. 1993, 34, 2593. (b) Gohring, W.; Gokhale,
S.; Hilpert, H.; Roessler, F.; Schlageter, M.; Vogt, P. Chimia 1996, 50, 532.
(4) See the Experimental Section in the Supporting Information.
(5) (a) Marzoni, G.; Kaldor, S. W.; Trippe, A. J .; Shamblin, B. M.; Fritz,
J . E. Synth. Commun. 1995, 25, 2475. (b) Rieger, D. L. J . Org. Chem. 1997,
62, 8546.
(6) Elliott, W. J .; Fried, J . J . Org. Chem. 1976, 41, 2469. 2 was prepared
by the oxidation of 2,2-dimethyl-4,7-dihydro-1,3-dioxepin with H2O2/MeCN
in place of m-CPBA, which was used in the reported method. The detailed
procedure is shown in the Supporting Information.
opening of the oxazoline ring with PhSH.11 This reaction
(7) (a) Bair, K. W.; Tuttle, R. L.; Knick, V. C.; Cory, M.; McKee, D. D. J .
Med. Chem. 1990, 33, 2385. (b) Aube, J .; Wolfe, M. S.; Yantiss, R. K.; Cook,
S. M., Takusagawa, F. Synth. Commun. 1992, 22, 3003.
(8) The stereochemistry of 4 (>99% de; mp 108-109 °C; [R]25 +96.2 (c
D
1.00, MeOH)) was determined by X-ray crystallographic analysis (see the
Supporting Information). The atomic coordinates have been deposited with
CCDC (Cambridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK).
(9) Experimental data: >99% ee (HPLC); mp 133-134 °C; [R]25 +29.6
D
(c 1.05, MeOH). See the Supporting Information.
(10) Nagao, Y.; Fujita, E.; Kohno, T.; Yagi, M. Chem. Pharm. Bull. 1981,
29, 3202.
(11) Padgette, S. R.; Herman, H. H.; Han, J . H.; Pollock, S. H.; May, S.
W. J . Med. Chem. 1984, 27, 1354.
10.1021/jo981472n CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/10/1998

Communications
J . Org. Chem., Vol. 63, No. 22, 1998 7583
Sch em e 1a
16 could be explained by the formation of epoxide 15 through
a transient cyclic quaternary amine 14, although it was
unable to observe the formation of 15 under the reaction
conditions in the presence or absence of PhSH.13 It has been
speculated that 14 arises from 13 via an intramolecular ring
opening of the oxazoline by nucleophilic attack of the
perhydroisoquinoline nitrogen atom. The choice of solvent
and base may effect the stabilization of intermediate 14 and
the nucleophilicity of PhSH, thus influencing the ultimate
regioselectivity of the reaction.
a
Reaction conditions: (a) 3-acetoxy-2-methylbenzoyl chloride (6),
NaHCO3, CH2Cl2, H2O; (b) MeSO2Cl, NEt3, CH2Cl2; (c) BF3‚Et2O,
CH2Cl2; (d) H2O (for 9); (e) Ac2O (for 10); (f) K2CO3, MeOH, H2O, 12.
In summary, a concise synthesis of the potent anti-HIV
drug nelfinavir (1) was accomplished using a novel chiral
C4 unit (5). A key component in this synthetic strategy was
the utilization of an oxazoline intermediate. First, the two
protected primary hydroxyl groups of 5 were differentiated
using a unique BF3‚Et2O-mediated intramolecular oxazoline
ring formation (8 to 10). This oxazoline ring then served as
an electrophilic center for the introduction of the phenylthio
group (13 to 1). The aromatic substituent group on the
oxazoline remained in the structure of the final product 1.
This practical synthesis provides 1 from an easily accessible
starting material (5) in greater than 50% overall yield. It
is expected that 5 should also be useful in the production of
other chiral synthetic targets of biological interest.
Ta ble 1. Regioselectivity of th e Rea ction of 13 w ith
P h SHa
base
T
time ratiob
entry
(equiv)
solvent
(°C)
(h)
(1:16)
1
2
3
4
none
none
HOCH2CH2OH
DMF
DMF
120
85
80
20
16
10
4
18:82
71:29
84:16
92:8
NEt3 (4.0)
KHCO3 (2.0) MIBKc
115
a
All reactions were performed using 4.0 equiv of PhSH, except
b
that 2.0 equiv of PhSH was employed in entry 4. Regioisomer
ratio, by HPLC of the reaction mixture at completion. c Methyl
isobutyl ketone.
was accompanied by a byproduct, the undesired regioisomer
16.12 The regioselectivity (1:16) of the process was effected
by the selection of solvents and bases, as shown in Table 1.
When the reaction was conducted in ethylene glycol (entry
1), 16 was the predominate product. Use of a less polar
solvent (DMF) reversed the selectivity, and the desired
compound 1 became the predominant product (entry 2). The
selectivity was further improved when the reaction was
carried out in the presence of an organic or inorganic base
in the less polar solvents (entries 3 and 4). The reaction
conditions outlined in entry 4 provided pure isolated 1 in
81-84% yield from 13. Desired 1 could be generated
through the direct ring opening of the oxazoline moiety of
13 by the nucleophilic attack of PhSH. The generation of
Ack n ow led gm en t. The authors would like to thank
Drs. H. Cho, A. Miyama, Y. Shinoo, M. Shiozaki, N.
Shimoyama, S. Miyazaki, T. Matsui, and G. Marzoni for
helpful discussions and Mr. E. Inagaki for performing the
X-ray crystallographic analyses of 4 and 17. The authors
also express their appreciation to Mr. Masami Tsuboshima
for his encouragement.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures, analytical and spectral data for all new compounds, and
crystal structure data for 4 and 17 (31 pages).
J O981472N
(13) The nucleophilic attack of PhSH on 14 was ruled out as a mechanism
for the formation of 1 and 16 because it seemed unlikely that PhSH
selectively cleaved two of four C-N+ bonds in 14 to form 1 and 16. No
byproduct other than 16 was detected in the reactions listed in Table 1
(HPLC).
(12) The structure of 16 was confirmed by X-ray crystallographic analysis
of diacetate 17 derived from 16 (see the Supporting Information). The atomic
coordinates have been deposited with CCDC.