A concise formal synthesis of the potent HIV protease inhibitor nelfinavir mesylate

Full text of DOI:10.1021/jo9705778

8546
J . Org. Chem. 1997, 62, 8546-8548
A Con cise F or m a l Syn th esis of th e P oten t
HIV P r otea se In h ibitor Nelfin a vir Mesyla te
Dale L. Rieger
Chemical Development, Agouron Pharmaceuticals, Inc.,
3565 General Atomics Court, San Diego, California 92121
Received March 31, 1997
Nelfinavir mesylate (AG1343) is a potent, orally active
inhibitor of HIV protease and has recently been approved
by the US FDA as a treatment for HIV infection.1 We
required an efficient, large-scale process for production
of the large quantities of AG1343 needed for clinical
development and for eventual market launch. Here, we
report some of our studies in this area, which have led
to a concise formal synthesis of AG1343.
ketone 3 with NaBH4 (0.5 molar equiv, MeOH/THF (2/
1), 4 °C) gave 4 after aqueous workup and crystallization
from EtOAc/hexanes (1/3, 8 mL/g crude 3). The overall
yield of 4 from 1 was 70% on a 40-g scale. The ee of the
product (4) was 83%.6 The diastereomeric ratio, 82/18
in the crude product, was 98/2 in isolated 4. Overaddi-
tion of the organolithium species was not a problem, since
none of alcohol 5 was isolated from the reaction mixture.
Attempted addition of 2-lithio-1,3-dithiane to the even
less expensive diethyl amide derivative 2c did give the
desired ketone 3, but the reaction was not as clean,
resulting in 3 which was not as pure as that derived from
2b. The reason for the differing reactivity of 2b and 2c
may at least in part be due to the increased steric bulk
surrounding the carbonyl group in 2c.
As the starting material for our synthetic efforts, we
chose N-Cbz-S-phenyl-L-cysteine (1). This compound was
readily available on large scale from L-serine.2 Deriva-
tization of 1 as its Weinreb amide 2a proceeded without
racemization via the pivaloyl mixed anhydride.3 Addition
of 2-lithio-1,3-dithiane (generated from 1,3-dithiane and
n-BuLi at 0 °C) gave ketone 3, which was reduced in situ
with sodium borohydride at 0 °C to provide the desired
dithianyl alcohol 4 in 64% yield from 2a . The diastereo-
selectivity in the reduction was 82:18 in favor of 4.4 Use
of DIBAL in the reduction of 3 gave reversed stereose-
lectivity (1:2), as would be predicted by a Felkin-type
addition to 3. This indicates either that the hydride in
the NaBH4 reduction is delivered through coordination
of the reductant with the carbamate moiety or that the
reduction proceeds through an anti-Felkin-type transition
state.
Further investigation of the conversion of N-Cbz-S-
phenyl-L-cysteine to dithianyl alcohol 4 revealed that the
relatively inexpensive dimethyl amide derivative 2b
functioned equally well in the addition of 2-lithio-1,3-
dithiane as compared to the Weinreb amide 2a . Thus,
addition of 3 equiv of 2-lithio-1,3-dithiane to crude 2b
(88% ee) formed 3. The reaction was quenched with an
organic acid (HOAc) prior to aqueous workup to prevent
racemization of the chiral center.5 Reduction of the crude
Completion of the synthesis of AG1343 required re-
moval of the dithianyl group in 4 in the presence of the
phenylthio group to give R-hydroxy aldehyde 6. Reduc-
tive amination of this aldehyde with perhydroisoquinoline
77 would give AG1357 which has previously been con-
verted to AG1343.8 Several methods were studied for
removal of the dithianyl moiety (MeI, H2O; HgCl2; CAN;
MeOTs, H2O; NaIO4, H2O; OHCCOOH, HOAc, HCl; CuO,
CuCl2; DDQ).9 These methods were either too vigorous
(i.e., HgCl2; CAN; CuO, CuCl2) or too sluggish (i.e., MeI,
H2O; MeOTs, H2O) to afford high yields of 6. The method
that finally gave reasonable yields (ca. 80%) of the desired
aldehyde was Hg(ClO4)2‚3H2O in a mixture of IPA,
CHCl3, and H2O (3/6/1) at ambient temperature.9h,10 This
(1) Appelt, K.; Bacquet, R. J .; Bartlett, C.; Booth, C. L. J .; Freer, S.
T.; Fuhry, M. M.; Gehring, M. R.; Herrmann, S. M.; Howland, E. F.;
J anson, C. A.; J ones, T. R.; Kan, C. C.; Kathardekar, V.; Lewis, K. K.;
Marzoni, G. P.; Mathews, D. A.; Mohr, C.; Moomaw, E. W.; Oatley, S.
J .; Ogden, R. C.; Reddy, M. R.; Reich, S. H.; Schoettlin, W. S.; Smith,
W. W.; Varney, M. D.; Villafranca, J . E.; Ward, R. W.; Webber, S.;
Webber, S. E.; Welsh, K. M.; White, J . J . Med. Chem. 1991, 34, 1925.
Patick, A.; Hongmei, M.; Markowitz, M.; Ho, D.; Webber, S. Proc. 2nd
Nat. Conf. Human Retroviruses and Related Infections 1995, abstr.
184, 88. Shetty, B. V.; Kosa, M. B.; Khalil, D. A.; Webber, S. Antimicrob.
Agents Chemother. 1996, 40, 110.
(2) Marzoni, G.; Kaldor, S. W.; Trippe, A. J .; Shamblin, B. M.; Fritz,
J . E. Synth. Commun. 1995, 25, 2475.
(3) (a) Sibi, M. P. Org. Prep. Proc. Int. 1993, 25, 15. Nahm, S.;
Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. (b) The author would
like to thank Mr. M. Shore for development of this conversion.
(4) The ratio was determined by isolation of 4 and its diastereomer
at the carbinol center.
(5) Quenching of the reaction under two-phase conditions (2 N
aqueous HCl) resulted in 4 (after reduction) that was racemic.
(6) The chiral assay was performed on a Pirkle (S,S)-Whelk O1 4.6
× 250 mm column. Eluant: 4/4/92 IPA/CH2Cl2/hexane. Flow: 1.5 mL/
min. Detector: 254 nm. Retention times: 4, 53 min; en t-4, 57 min;
diastereomer 1, 37 min; diastereomer 2, 48 min.
(7) Houpis, I. N.; Molina, A.; Reamer, R. A.; Lynch, J . E.; Volante,
R. P.; Reider, P. J . Tetrahedron Lett. 1993, 34, 2593. Gohring, W.;
Gokhale, S.; Hilpert, H.; Roessler, F.; Schlageter, M.; Vogt, P. Chimica
1996, 50, 532. Allen, D. R.; J enkins, S.; Klein, L.; Erickson, R.; Froen,
D. U.S. Patent 5,587,481, 1996 (The Monsanto Company).
(8) Dressman, B. A.; Fritz, J . E.; Hammond, M.; Hornback, W. J .;
Kaldor, S. W.; Kalish, V. J .; Munroe, J . E.; Reich, S. H.; Tatlock, J . H.;
Shepherd, T. A.; Rodriguez, M. J . U.S. Patent 5,484,926, 1994 (Agouron
Pharmaceuticals, Inc.); Chem. Abstr. 1994, 123, 256539v.
S0022-3263(97)00577-X CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 24, 1997 8547
was performed on a VG Analytical 70SEZAB mass spectrometer.
Optical rotations were observed using a J asco DIP-370 digital
polarimeter. Melting points are uncorrected.
unstable aldehyde generally was not isolated, but was
used immediately in the subsequent reductive amination.
The use of MeOH in place of IPA in this reaction gave
almost exclusively the dimethyl acetal 8.
(1 S ,2 R )-2 -[(B e n z y l o x y c a r b o n y l )a m i n o ]-1 -[2 -(1 ,3 -
d ith ia n yl)]-3-(p h en ylth io)-1-p r op a n ol (4). N-Methylmor-
pholine (12.2 g, 13.3 mL, 0.121 mol) was added slowly to a cold
(-20 °C) suspension of N-Cbz-S-phenylcysteine (40 g, 0.121 mol)
in acetonitrile (242 mL) under Ar, keeping the internal temper-
ature below -15 °C, giving a clear solution. Pivaloyl chloride
(14.6 g, 14.9 mL, 0.121 mol) was added rapidly. There was a
mild exotherm from -20 to -15 °C, and a white precipitate
formed. After 1 h at -25 to -15 °C, a 40 wt % solution of
dimethylamine in water (13.6 g, 15.2 mL, 0.121 mol) was added,
giving a clear solution. After 1 h at -25 to -15 °C, 2 N aqueous
HCl (80 mL) was added, and the mixture was warmed to
ambient temperature. The acetonitrile was removed in vacuo.
Methyl tert-butyl ether (300 mL) was added to the residue, and
the layers were separated. Water (150 mL) and 50% aqueous
NaOH (10 mL) were added to the organic layer, and the mixture
was stirred vigorously for 1 h. The layers were separated, and
water (150 mL) and 50% aqueous NaOH (10 mL) were added to
the organic layer. After stirring vigorously for 30 min, the layers
were separated and the organic layer was washed with H2O (150
mL). The organic layer was dried (MgSO4) and evaporated in
vacuo to give crude amide 2b as a colorless oil (44.4 g, 102%).
This material contained 4.4 wt % methyl tert-butyl ether
(determined by integration of the 1H NMR spectrum), giving a
corrected yield of 98%. The enantiomeric excess was determined
Reductive amination of crude 6 with perhydroisoquino-
line 7 was also studied under a variety of conditions
(NaCNBH3; NaBH4; pyr‚BH3; Ti(O-i-Pr)4, NaBH4).12 These
methods were unsatisfactory due to low yields of AG1357
and the large amounts of diol 9 (13-26%) formed as a
byproduct through direct reduction of aldehyde 6. It was
found that the method of Katritzky (benzotriazole, 4 Å
MS; then NaBH4) was most efficient, resulting in an
overall yield of AG1357 of 74% from 4 (corrected for the
enantiomeric purity of 4).12c The only byproduct isolated
in this reaction was diol 9. AG1357 has previously been
converted to AG1343 in two steps and 41% yield, thus
completing a formal four-step synthesis of AG1343.8 The
overall yield for this synthesis of AG1343 is 21% from
N-Cbz-S-Ph-cysteine (1).
to be 88% by analysis on a Pirkle (S,S)-Whelk-O1 column.
A
22
portion of this material was used in the next step: [R]D +8.8°
(c 0.0202, CHCl3); IR (thin film) 3281, 2936, 1717, 1645, 1499,
1254, 1044, 741, 694 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.46-
7.19 (m, 10 H), 5.78 (br d, J ) 8.4 Hz, 1 H), 5.12 (s, 2 H), 4.91
(q, J ) 7.7 Hz, 1 H), 3.24 (d, J ) 5.6 Hz, 2 H), 2.94 (s, 3 H), 2.86
(s, 3 H); HRMS calcd for C19H22N2O3S1 + Cs 491.0405, found
491.0389.
n-BuLi (2.5 M in hexanes, 139 mL, 0.348 mol) was added to
a cold (-10 °C) solution of 1,3-dithiane (41.8 g, 0.348 mol) in
THF (873 mL) under Ar, keeping the internal temperature below
-1 °C, giving a yellow solution. After 1 h, a solution of crude
amide 2b (41.56 g, 0.116 mol) in THF (233 mL) was added. After
30 min, a solution of HOAc (56 g, 53 mL, 0.928 mol) in THF
(102 mL) was added, giving a thick mixture. This mixture was
warmed to ambient temperature, H2O (233 mL) was added, and
the THF and hexanes were removed in vacuo. The residue was
partitioned between EtOAc (1.2 L) and H2O (480 mL). The
organic layer was washed with H2O (1 × 480 mL) and brine (1
× 240 mL), dried (MgSO4), and evaporated in vacuo to give
ketone 3 as a yellow oil. The crude ketone 3 was dissolved in
MeOH/THF (195 mL/98 mL), cooled to 4 °C under Ar, and
NaBH4 (2.2 g, 0.0580 mol) was added in portions (gas evolution!
foaming!). After 15 min, the MeOH/THF was removed in vacuo.
The residue was diluted with EtOAc (1.2 L), washed with half-
saturated brine (2 × 480 mL) and brine (1 × 240 mL), and dried
(MgSO4). This mixture was filtered and concentrated in vacuo
to a yellow oil. This oil was dissolved in EtOAc (93 mL) and
heated to 60 °C, and hexanes (113 mL) was added. Crystalliza-
tion began, and the mixture was allowed to cool to ambient
temperature. More hexanes (166 mL) was added, and the
mixture was aged at ambient temperature overnight. The
mixture was filtered, and the cake was washed with EtOAc/
hexanes (25/75, 2 × 20 mL) and hexanes (2 × 20 mL). The white
solid was dried in vacuo (air sweep, ambient temperature) to
give 34.76 g (70% from N-Cbz-S-phenylcysteine (1)) of alcohol
4. The enantiomeric excess of 4 was determined to be 83% and
the syn/anti ratio was 98/2, both determined by chiral HPLC
on a Pirkle (S,S)-Whelk-O1 column: mp 74-77 °C; [R]22D -48.1°
(c 0.0146, CHCl3); IR (thin film) 3414, 2901, 1705, 1701, 1512,
1240, 1217, 1088, 1026, 752, 696 cm-1; 1H NMR (300 MHz, C6D6)
δ 7.40-6.87 (m, 10 H), 5.19 (br d, J ) 9.2 Hz, 1 H), 5.07 (br s,
2 H), 4.72 (m, 1 H), 4.07 (d, J ) 8.4 Hz, 1 H), 3.47 (d, J ) 8.8
Hz, 1 H), 3.04 (m, 2 H), 2.69 (br s, 1 H), 2.44 (t, J ) 11.4 Hz, 1
H), 2.21 (t, J ) 11.4 Hz, 1 H), 1.87 (m, 2 H), 1.41 (m, 1 H), 1.24
(m, 1 H); HRMS calcd for C21H25N1O3S3 + Cs 568.0051, found
568.0033.
Exp er im en ta l Section
In general, 1H NMR data were collected on a GE QE 300 MHz
spectrometer. Infrared spectra were taken on a MIDAC FTIR,
model number 101280-1. High-resolution mass spectrometry
(9) (a) MeI, H2O: Takano, S.; Hatakeyama, S.; Ogasawara, K. J .
Chem. Soc., Chem. Commun. 1977, 68. (b) HgCl2: Corey, E. J .; Boch,
M. G. Tetrahedron Lett. 1975, 2643. Seebach, D.; Beck, A. K. Organic
Syntheses; Wiley: New York, 1988; Collect. Vol. VI, p 316. (c) CAN:
Ho, T.-L.; Ho, H. C.; Wong, C. M. J . Chem. Soc., Chem. Commun. 1972,
791. (d) NaIO4, H2O: Carlson, R. M.; Helquist, P. M. J . Org. Chem.
1968, 33, 2596. Carey, F. A.; Dailey, O. D., J r., Hernandez, O.; Tucker,
J . R. J . Org. Chem. 1976, 41, 3975. (e) OHCCOOH, HOAc, HCl:
Muxfeldt, H.; Unterweger, W.-D.; Helmchen, G. Synthesis 1976, 694.
(f) CuO, CuCl2: Stutz, P.; Stadler, P. A. Org. Synth. 1977, 56, 8. (g)
DDQ: Mathew, L.; Sankararaman, S. J . Org. Chem. 1993, 58, 7576.
(h) Hg(ClO4)2‚3H2O: Fujita, E.; Nagao, Y.; Kaneko, K. Chem. Pharm.
Bull. 1978, 26, 3743.
(10) Other one-carbon homologating agents which were studied for
the conversion of 1 to 6 were benzothiazole11 and bis(methylthi-
o)methane. In the former case, the conditions for unmasking the
aldehyde (MeOSO2F; aqueous K2CO3) proved not to be amenable to
scale. Use of MeI was ineffective. In the latter case, the intermediate
corresponding to 4 was an oil, making separation of the diastereomers
at this point difficult on large scale. For the use of 2-(trimethylsi-
lyl)thiazole as a one-carbon homologating agent in a related system,
see: Parkes, K. E. B.; Bushnell, D. J .; Crackett, P. H.; Dunsdon, S. J .;
Freeman, A. C.; Gunn, M. P.; Hopkins, R. A.; Lambert, R. W.; Martin,
J . A.; Merrett, J . H.; Tedshaw, S.; Spurden, W.; Thomas, G. J . J . Org.
Chem. 1994, 59, 3656.
(11) Corey, E. J .; Boger, D. L. Tetrahedron Lett. 1978, 5,9.
(12) (a) pyr‚BH3: Bomann, M. D.; Guch, I. C.; DiMare, M. J . Org.
Chem. 1995, 60, 5995. Moormann, A. E. Synth. Commun. 1993, 23,
789. (b) Ti(O-i-Pr)4, NaBH4: Bhattacharyya, S. J . Org. Chem. 1995,
[3S-(3R*,4a R*,8a R*,2′S*,3′S*)]-N-(1,1-Dim et h ylet h yl)-
d eca h yd r o-2-[2′-h yd r oxy-3′-[(ben zyloxyca r bon yl)a m in o]-
4′-(ph en ylth io)bu tyl]-3-isoqu in olin ecar boxam ide (AG1357).
60, 4928. (c) Benzotriazole,
4 Å MS, NaBH4: Katritzky, A. R.;
Yannakopoulou, K.; Lue, P.; Rasala, D.; Urogdi, L. J . Chem. Soc.,
Perkin Trans. 1 1989, 225.

8548 J . Org. Chem., Vol. 62, No. 24, 1997
Notes
Mercuric perchlorate trihydrate (20.9 g, 0.0460 mol) was added
to a vigorously stirred mixture of dithiane 4 (10.0 g, 0.0230 mol)
in isopropyl alcohol/CHCl3/H2O (3/6/1, 200 mL) at ambient
temperature. After 1 h, the mixture was filtered, and the cake
was washed with CHCl3 (3 × 100 mL). The combined mother
liquors and filtrates were washed with half-saturated brine (2
× 100 mL), saturated aqueous NaHCO3 (1 × 100 mL), and brine
(1 × 100 mL). The organic layer was dried (MgSO4) and
evaporated in vacuo to give 6 as a colorless oil. This oil was
dissolved in THF (90 mL) and used directly in the subsquent
reductive amination.
(3S,4aS,8aS)-3-N-(tert-Butylcarbamoyl)decahydroisoquino-
line (5.5 g, 0.0230 mol), benzotriazole (2.7 g, 0.0230 mol), and 4
Å molecular sieves (7.9 g) were added to a solution of crude
aldehyde 6 in THF (90 mL) at ambient temperature. After 17
h, NaBH4 (0.87 g, 0.0230 mol) was added, and the mixture was
stirred at ambient temperature. After 25 h further, the mixture
was filtered through Celite (THF wash) and concentrated in
vacuo. The residue was dissolved in EtOAc (300 mL) and
washed with 1 N aqueous HCl (1 × 100 mL), H2O (1 × 100 mL),
saturated aqueous NaHCO3 (1 × 100 mL), and brine (1 × 100
mL). The organic layer was dried (Na2SO4) and purified by
flash chromatography (50/50 EtOAc/hexanes) to give AG1357
as a white foam (10.06 g, 77% from 4). This material contained
12 wt % benzotriazole, giving a corrected yield of 8.85 g (68%
from 4). Further correction for the enantiomeric purity of 4 (83%
ee) gave a corrected yield of AG1357 of 74% from 4. A small
portion of this mixture was purified further to afford pure
AG1357. Analytical data (IR 1H NMR, elemental analysis)
conformed to that previously reported.8
Ack n ow led gm en t. The author would like to thank
Drs. B. Borer and K. Albizati for helpful advice and
encouragement throughout this work. The author
would also like to thank Mr. J . Shanley for supplies of
amide 2a .
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectrum
of compound 4 (1 page). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O9705778