A new asymmetric 1,4-addition method: Application to the synthesis of the HIV non-nucleoside reverse transcriptase inhibitor DPC 961

Article abstract of DOI:10.1016/S0040-4039(00)00331-2

The asymmetric synthesis of the HIV non-nucleoside reverse transcriptase inhibitor (NNRTI) DPC 961 is achieved in three steps with an overall yield of >55%. The asymmetry is induced by the chiral auxiliary (R)-(+)-α- methylbenzylamine, utilizing a new asymmetric 1,4-addition protocol. (C) 2000 DuPont Pharmaceuticals Company. Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00331-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3015–3019
A new asymmetric 1,4-addition method: application to the
synthesis of the HIV non-nucleoside reverse transcriptase
inhibitor DPC 961
Nicholas A. Magnus,∗ Pat N. Confalone and Louis Storace
DuPont Pharmaceuticals Company, Chemical Process R & D, Chambers Works, PRF Bldg. (S1), Deepwater, NJ 08023, USA
Received 2 February 2000; accepted 21 February 2000
Abstract
The asymmetric synthesis of the HIV non-nucleoside reverse transcriptase inhibitor (NNRTI) DPC 961 is
achieved in three steps with an overall yield of >55%. The asymmetry is induced by the chiral auxiliary (R)-(+)-α-
methylbenzylamine, utilizing a new asymmetric 1,4-addition protocol. © 2000 DuPont Pharmaceuticals Company.
Published by Elsevier Science Ltd. All rights reserved.
The dihydroquinazolinone DPC 9611a 1 is a second generation HIV non-nucleoside reverse trans-
criptase inhibitor (NNRTI) with enhanced potency when compared to Efavirenz (Sustiva™) which has
been approved for the treatment of HIV.2 DPC 9611a is currently undergoing clinical evaluation due
to its activity against wild-type HIV-1 and increased potency toward the K103N-containing human
immunodeficiency virus as well as a variety of NNRTI-resistant mutant viruses. This communication
describes a highly stereoselective synthesis of DPC 961.1a,b
Although the general synthetic transformations outlined in Scheme 1 have literature precedent,3,4 no
examples are known in which R2 is chiral or 1,4-additions to 3 yield 4 diastereoselectively. We decided
to investigate the synthesis of DPC 9611a using the approach outlined in Scheme 1 with R2 as an acid
labile chiral auxiliary to direct a diastereoselective 1,4-addition of R3M to the 2(3H)-quinazolinone 3.
∗
Corresponding author. Tel: (856)-540-4986; fax: (856)-540-4876; e-mail: nicholas.a.magnus@dupontpharma.com (N. A.
Magnus)
0040-4039/00/$ - see front matter © 2000 DuPont Pharmaceuticals Company. Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00331-2
tetl 16611

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Scheme 1.
The keto-aniline 1a2 (Scheme 1) where R1=CF3 is unreactive towards (R)-(+)-α-methylbenzyl iso-
cyanate 7 (Scheme 2), presumably due to delocalization of the nitrogen lone pair of 1a into the
trifluoromethyl ketone. The hydrate hydrochloride keto-aniline 6 (Scheme 2) is a known compound2b
and reacts with isocyanate 7 in aqueous acidic solvents, preferably THF containing 7% vol. 1N HCl.
A >95% conversion of hydrate hydrochloride 6 into acyclic urea 8 (which cyclizes to give hemiaminal
9) requires two equivalents of isocyanate 7, because one of the equivalents is hydrolyzed to give (R)-
(+)-α-methylbenzylamine hydrochloride and CO2 under the reaction conditions. Temperatures in excess
of 25°C prior to consumption of the isocyanate 7 led to its decomposition to give the corresponding
symmetric urea 9a which is difficult to separate from the product. After consumption of the isocyanate
7, the acyclic urea 8 is converted rapidly (within 1 h) to the hemiaminal 9 by increasing the temperature
to 60°C. The hemiaminal moiety of 9 is formed diastereoselectively in a ratio of 93:7. The absolute
configuration of the major diastereomer of 9 was determined by X-ray. After washing the (R)-(+)-
α-methylbenzylamine hydrochloride away with water, crystallization of hemiaminal 9 is effected by
exchanging the THF for toluene via azeotropic distillation to give a 94% isolated yield of hemiaminal 9
as a 96:4 ratio of diastereomers.
Scheme 2.
The literature describes 1,4-dehydration of cyclic hemiaminals related to 9 under acidic, basic, or
thermal conditions.3–5 Although the hemiaminal 9 did not dehydrate thermally, exposure to acid caused
1,2-dehydration to form the corresponding iminium ion, and the benzyl group was cleanly lost via
ionization, generating styrene/polystyrene and the ketimine 9b (Scheme 3). Treatment of 9 with base
generated the alkoxide which eliminated fluoroform to give the corresponding imide 9c (Scheme 3) at
room temperature in excellent yield.

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Scheme 3.
In order to prevent the fluoroform elimination pathway and promote the 1,4-dehydration, the alkoxide
of 9 was generated at low temperature and trapped with an activating agent. The first example of this
procedure was to dissolve 9 in THF, in the presence of excess TEA at 0°C, and treat the colorless
mixture with methanesulfonyl chloride. This produced a bright orange mixture that became colorless
upon exposure to air and returned the starting material 9. Extended imines of type 10 (Scheme 4), known
as substituted 2(3H)-quinazolinones, are reported to be highly colored compounds ranging from yellow
to red.3–5 2(3H)-Quinazolinones have been isolated,3,4 but this particular analog bearing a trifluoromethyl
group has proven too reactive for practical isolation. Therefore, 2(3H)-quinazolinone 10 was treated in
situ with cyclopropylacetylide which afforded the desired dihydroquinazolinone 11 with a high degree
of diastereoselectivity.
Scheme 4.
Scheme 4 depicts the optimized preparation of dihydroquinazolinone 11.6 The hemiaminal 9 is sus-
pended in toluene, and treated with an excess of TEA as solvent and base. Exposure of this mixture at 0°C
to an equivalent of thionyl chloride rapidly generates intermediate 10 which is trapped instantaneously at
−50°C by an excess of cyclopropylacetylene magnesium chloride to give 11. Employing the optimized
procedure, the conversion of 9 into 11 is 97%, and the diastereomeric excess is routinely around 92%.
The dihydroquinazolinone 11 is crystallized from methanol to give an 86% isolated yield of the desired
diastereomer exclusively (absolute configuration confirmed by X-ray). The reaction has been run with a
ReactIR 1000 DiComp® probe submerged into a mixture of 9 in toluene containing triethylamine at 0°C.
The absorptions corresponding to the carbonyl and NH stretching vibrations were recorded at 1681 cm−1

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and 3200 cm−1, respectively. Addition of thionyl chloride to the mixture caused the carbonyl absorption
at 1681 cm−1 to disappear (as well as the NH absorption) and a new carbonyl absorption to appear at
1696 cm−1. The increased carbonyl absorption of 15 cm−1, indicating a lessening mesomerism or more
carbonyl characteristic, and the disappearance of the NH absorption supports intermediate 10.
As illustrated in Scheme 5, the conversion of dihydroquinazolinone 11 into DPC 9611a is effected by
acid. Trifluoroacetic acid (TFA) is the usual acid used for such transformations.4 Exposure of 11 to wet
TFA at 18°C causes complete deprotection within 1 h. We have obtained an 80% isolated yield of DPC
9611a using this procedure. Warm formic acid also induces ionization of the benzyl group to transform
11 into DPC 961,1a in 85% isolated yield.
Scheme 5.
This paper describes the first 1,4-asymmetric additions to substituted 2(3H)-quinazolinones to afford
chiral dihydroquinazolinones. The HIV NNRTI DPC 9611a is prepared in three steps in >55% isolated
yield using this methodology. This chemistry is amenable to large scale and has provided metric ton
quantities of DPC 961.1a Further applications of this chemistry are under investigation and will be
reported in due course.
Acknowledgements
Charles W. Ray and Robert G. Wethman are thanked for conducting and interpreting the IR experiment.
References
1. (a) Corbett, J. W.; Ko, S. S.; Rodgers, J. D.; Bacheler, L. T.; Diamond, S.; Lai, C.-M.; Jeffery, S.; Klabe, R. M.; Rabel, S. R.;
Saye, J. A.; Adams, S. P.; Trainor, G. L.; Anderson, P. S.; Erickson-Viitanen, S. K. Antimicrob. Agents Chemother. 1999, 43,
2893. (b) Asymmetric syntheses of dihydroquinazolinones have been reported which involve the use of chiral amino alkoxides
to mediate the enantioselective addition of acetylides to cyclic N-acyl ketimines. Huffman, M. A.; Yasuda, N.; DeCamp, A.
E.; Grabowski, E. J. J. J. Org. Chem. 1995, 60, 1590.
2. (a) 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. (b) Pierce, M. E.; Parsons Jr.,
R. L.; Radesca, L. A.; Young, S. L.; Silverman, S.; Moore, J. R.; Islam, Q.; Choudhury, A.; Fortunak, J. M. D.; Nguyen, D.;
Luo, C.; Morgan, S. J.; Davis, W. P.; Confalone, P. N. J. Org. Chem. 1998, 63, 8536 and references cited therein. (c) Patel,
M.; Ko, S. S.; McHugh, R. J.; Markwalder, J. A.; Srivastava, A. S.; Cordova, B. C.; Klabe, R. M.; Erickson-Viitanen, S. K.;
Trainor, G. L.; Seitz, S. P. Bioorg. Med. Chem. Lett. 1999, 9, 2805. (d) Patel, M.; McHugh, R. J.; Cordova, B. C.; Klabe, R.
M.; Erickson-Viitanen, S. K.; Trainor, G. L.; Ko, S. S. Bioorg. Med. Chem. Lett. 1999, 9, 3221. (e) Thompson, A. S.; Corely
E. G.; Huntington, M. F.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 8937. (f) Tan, L.; Cheng-Yi, C.; Tillyer, R. D.;
Grabowski, E. J. J.; Reider, P. J. Angew. Chem., Int. Ed. Engl. 1999, 38, 711.
3. Sternbach, L. H.; Metlesics, W.; Silverman, G.; Toome, V. J. Org. Chem. 1966, 31, 1007.

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4. Britcher, S. F.; Lumma Jr., W. C.; Goldman, M. E.; Lyle, T. A.; Huff, J. R.; Payne, L. S.; Quesada, M. L.; Young, S. D.;
Sanders, W. M.; Tucker, T. J.; Sanderson, P. E. Merck & Co., Inc.: USA Patent. International Publication Number: WO
93/04047; International Application Number: PCT/US92/06576; International publication date: 4 March 1993.
5. (a) Reissert, A.; Schaaf, H. Chem. Ber. 1926, 39, 2494. (b) Gheorghui, C. V. Chem. Ber. 1943, 76, 994.
6. Preparation of dihydroquinazolinone 11: under N2, the hemiaminal 9 (1.0 g, 2.70 mmol) is suspended in toluene (10 mL)
and treated with triethylamine (TEA) (1.88 mL, 13.49 mmol) to give a colorless homogeneous mixture. The resulting mixture
is cooled to 0°C, and thionyl chloride (206 µL, 2.83 mmol) added slowly. This produces a bright orange mixture with TEA
hydrochloride salt as a precipitate. After 1 h at 0°C, the mixture is cooled to −50°C. A 2N cyclopropylacetylene magnesium
chloride solution in THF (6.47 mL, 10.79 mmol) is added to the mixture over 0.5 h. The resulting mixture is quenched into
12% aqueous citric acid (10 mL). The organic phase is concentrated via distillation and the remaining solvent subsequently
exchanged for methanol employing azeotropic distillation. This induces crystallization of the product 11 in 86% (970 mg)
isolated yield. The de of 11 in the crude reaction mixture was determined to be 92% by HPLC using a Zorbax RX-C18
column.