An alternative synthesis of a potent GPIIb/IIIa receptor antagonist

Article abstract of DOI:10.1055/s-1999-3094

A key intermediate to SB-214857 was prepared via an oxidative cyclization of a hydroquinone with a flanking aspartate side chain using Fremy's salt.

Full text of DOI:10.1055/s-1999-3094

LETTER
865
An Alternative Synthesis of a Potent GPIIb/IIIa Receptor Antagonist
Jerome F. Hayes
SmithKline Beecham Pharmaceuticals, Old Powder Mills, Nr Leigh, Tonbridge, Kent, TN11 9AN, England
Received 28 January 1999
Dedicated to Professor Albert Eschenmoser
Abstract: A key intermediate to SB-214857 was prepared via an
oxidative cyclization of a hydroquinone with a flanking aspartate
side chain using Fremy’s salt.
Key words: benzodiazepine, cyclization, quinone, hydroquinone,
oxidation
Benzodiazepine SB-214857 is a potent GPIIb/IIIa recep-
tor antagonist and as a consequence disrupts the binding
Scheme 1
interaction of fibrinogen with the GPIIb/IIIa receptor on
activated platelets.1 This results in inhibition of platelet
Reagents and conditions: (a) DMSO, toluene, 3Å molecular sieves,
128-130 °C, 22h.
aggregation and possibly thrombosis. In fact SB-214857
has just completed successful phase II clinical trials and is
targeted to enter phase III for the prevention of secondary
thrombotic events such as heart attack and stroke.
For the oncoming phase III clinical trials we required
several hundreds of kilograms of SB-214857 and there-
fore an efficient and robust route of synthesis. The medic-
inal chemistry route2 that was used to prepare the initial
supplies of SB-214857 was not suitable for the quantities
we now required. This was due in part, to the facile β-
elimination of ammonia to form fumarate 1 during the flu-
oride displacement reaction. This resulted in low yields
(30–40%) of the key intermediate 2 (Scheme 1). We
therefore engaged ourselves in a program of research to
discover alternative, novel and efficient synthetic routes
to SB-214857. Our initial targets were benzodiazepines 3
or 4 (Scheme 2) since we had an efficient method to con-
vert these intermediates to SB-214857 using an inventive
palladium catalysed aminocarbonylation process.3,4
Scheme 2
The unusual structure of SB-214857 with regards to the
chiral 2S-acetic acid side chain limited our scope to apply
known procedures for the preparation of the 1,4-benzodi-
azepine nucleus.5,6 Notwithstanding one potential route
we considered involved exploitation of Teuber's oxidative
cyclisation reaction using Fremy's salt7 to prepare 2-phe-
nyl-5-hydroxy indole 5.8 Using this methodology we
hoped to convert phenol 6 or hydroquinone 7 to imino-
quinone 8. Subsequent hydrogenation of this would give
us the required benzodiazepine 4 (Scheme 2).
Reagents and conditions: (a) potassium nitrosodisulfonate (Fremy's
salt), 2.2 equiv., HCl conc., 1.0 equiv., CHCl3, AcOH, H2O (b) cata-
lytic hydrogenation (c) resolution.11
The phenol 6 and hydroquinone 7 were readily prepared
(Scheme 3). Condensation of aldehydes 9, 10 and 11 with
methylamine in ethanol gave the Schiffs bases 12, 13 and
14 and these were hydrogenated over 10% palladium on
charcoal to afford amines 15, 16 and 17 respectively in
Synlett 1999, S1, 865–866 ISSN 0936-5214 © Thieme Stuttgart · New York

866
J. F. Hayes
LETTER
quantitative yield. The amines were then coupled with N- In conclusion SB-214857 can be prepared from cheap and
Z-L-aspartic acid-β-methyl ester 18 using DCC to give readily available starting materials. The key oxidative cy-
amides 19, 20 and 21 in 81%, 46% and 100% yields re- clisation of 7 is novel for the preparation of 2-substituted
spectively. Hydrogenation of 19 and 20 over 10% palladi- 1,4-benzodiazepines and should be applicable to the prep-
um on charcoal produced the required substrates 6 and 7 aration of several analogous benzazepine systems.
in 91% and 70% yields respectively after purification by
chromatography on silica gel. Hydroquinone 7 was also
prepared from 21 via the quinone 22. Oxidative demethy-
References and Notes
(1) Nichols, A.J.; Vasko, J.A.; Koster, P.F.; Valocik, R.E.;
Samanen, J.M. In Cellular Adhesion:Molecular Definition to
Therapeutic Potential; Metcalf, B.W.; Dalton, B.J.; Poste, G.
Eds.; Plenum: New York, 1994, pp213-237.
lation of 21 with ammonium cerium(IV) nitrate furnished
the quinone 22 and hydrogenation of this over 10% palla-
dium on charcoal gave 7 in 50% yield.
(2) a) Bondinell, W.E.; Callahan, J.F.; Huffman, W.F.; Keenan,
R.M.; Ku, T.W.; Newlander, K.A.; Samanen, J.M.; Uzinskas,
I.N. WO 9414776, Chem. Abstr. 1994, 123, 112082; b) Miller,
W.H.; Ku, T.W.; Ali, F.E.; Bondinell, W.E.; Calvo, R.R.;
Davis, L.D.; Erhard, K.F.; Hall, L.B.; Huffman, W.F.;
Keenan, R.M.; Kwon, C.; Newlander, K.A.; Ross, S.T.;
Samanen, J.M.; Takata, D.T.; Yuan, C.-K. Tetrahedron Lett.
1995, 36, 9433.
(3) Etridge, S.K.; Hayes, J.F.; Walsgrove, T.C.; Wells, A.S. WO
9724336, 1997; Chem. Abstr. 1997, 127, 135814.
(4) Etridge, S.K.; Hayes, J.F.; Walsgrove, T.C.; Wells, A.S.
Organic Process Research and Development, 1999, 3, 60-63.
AN 1998:768608.
(5) Katritski, A.; Rees, C. Comprehensive Heterocyclic
Chemistry, Lwowski, W., Ed.; Pergamon: Oxford, 1984; Vol
7, p 608.
(6) Walser, A., Fryer, R. I.; Chem. Heterocycl. Compd. 1991, 50,
849-946.
(7) For a review concerning the reaction of Fremy’s salt with
aromatic hydroxy compounds see Zimmer, H.; Lankin, D.C.;
Horgan, S.W. Chem. Rev. 1971, 71, 229-246.
(8) Teuber, H.-J; Glosauer, O. Chem. Ber. 1965, 98, 2648.
(9) Experimental procedure for the reaction of 7 with Fremy’s
salt. To a solution of (3S) methyl-3-amino-4-{N-methyl-N-
(2,5-dihydroxybenzyl) carbamoyl} butanoate 7 (30.30g at ca
45% purity, 0.048mol) in water (2.08 L) and acetic acid (233
ml) and chloroform (5.0 L) was added HCl (9.7 ml of an
11.0M aqueous solution, 0.107mol) followed by Fremy’s salt
(63.4g, 0.237 mol) in water (3.0 L) at room temperature. The
reaction mixture was stirred for 3h after which time the
chloroform layer was separated, was washed with water
(1.0 L) and then was concentrated to dryness. The resultant
dark foamy residue was chromatographed on silica gel using
AcOEt : hexane - 3:1 as eluant. The title compound was
obtained as a white solid (7.29g, 56%); HRMS, Found M++H
263.1016. C13H15N2O4 requires 263.1032. δH (CDCl3, 270
MHz) 3.00 (3H, s), 3.75 (3H, s), 4.25 (2H, s br), 5.40 (1H, s),
5.80 (1H, s), 6.70 - 6.80 2H, m), 6.85 (1H, d) and 10.50 (1H,
s).
Scheme 3
Reagents and conditions: (a) MeNH2 (8.03M solution in EtOH), 1.5
equiv., toluene (b) 10% Pd-C, EtOH, H2 (c) 18, 1.1 equiv., DCC, 1.1
equiv., (HOBT for the preparation of 15 only, 1.1 equiv.), (d) Am-
monium cerium(IV) nitrate, 2.5 equiv., MeCN, H2O, -10 – 10 °C, 3h.
With the required amines in hand, they were treated with
Fremy’s salt under the acidic conditions described by
Teuber for the conversion of 23 to 5-hydroxyindole 5.8,9
Interestingly compound 24 was formed in 18% yield from
the phenol 6 and in 56% yield from the hydroquinone 7.
Oxidation of 7 with potassium ferricyanide also gave 24
but in only 14% yield. It appears that the required imino-
quinone 8 does form but it readily tautomerizes to the ar-
(10) Cyclization of an amide group onto a hydroquininone in the
presence of silver (I) oxide to give a 3,4-dihydro-1,4-
benzodiazepine-2,5-dione has been recently published.
However, precise details concerning conditions and yields
were not disclosed; Kraus, G.A.; Melekhov, A. Tetrahedron
Lett., 1998, 39, 3957.
omatic benzodiazepine. Although the chirality was lost, (11) Wells, A.S.; WO 9829561. Chem. Abstr. 1998, 129, 121708.
the application of this oxidative cyclization methodology
to the synthesis of a 3-oxo-1,4-benzodiazepine derivative
Article Identifier:
is completely novel.10 The product 24 can be successfully
1437-2096,E;1999,0,S1,0865,0866,ftx,en;W03799ST.pdf
converted to SB-214857 in good yield and with high opti-
cal purity (Scheme 2); precise details for this conversion
will be published in due course.
Synlett 1999, No. S1, 865–866 ISSN 0936-5214 © Thieme Stuttgart · New York