Concise synthesis of sibrafiban and lamifiban, two non-peptide fibrinogen receptor (GP IIb/IIIa) antagonists

Article abstract of DOI:10.1002/jccs.200100024

The total synthesis of the non-peptide fibrinogen receptor antagonists, sibrafiban (1) (Ro 48-3657) and lamifiban (2) (Ro 44-9883), is described. Both contain 4-hydroxypiperidine unit and the same solid-phase synthesis method was used as a key step. Conne

Full text of DOI:10.1002/jccs.200100024

JournaloftheChineseChemicalSociety, 2001, 48, 133-135
133
Communication
Con cise Syn the sis of Sibrafiban and Lamifiban, Two Non-Peptide
FibrinogenReceptor(GPIIb/IIIa)Antagonists
Meng-Yang Chang (
) and Shui-Tein Chen* (
)
InstituteofBiologicalChemistry,AcademiaSinica,Taiwan
The to tal syn the sis of the non-peptide fibrinogen re cep tor an tag o nists, sibrafiban (1) (Ro 48-3657) and
lamifiban (2) (Ro 44-9883), is de scribed. Both con tain 4-hydroxypiperidine unit and the same solid-phase
synthesismethodwasusedasakeystep.ConnectionofasecondaryalcoholtotheDHP-resin, fol lowed by it-
erativesaponificationandcouplingsequences,providednoveldrugs.
INTRODUCTION
Dihydropyran (DHP)-linked poly sty rene resin has be-
plateletaggregation. Theyarecurrentlyinclinicaldevelop-
ment as in ject able antithrombotic agents for the treat ment
andpreventionofacutecoronarysyndromes.
come a valu able solid sup port for the high-throughput syn-
thesisofoxygen-linkedsubstrates.1-9 The acetal, which in
fact cor re sponds to a tetrahydropyran ether, should with stand
a wide range of con di tions in clud ing strong bases. The DHP-
resin has pro vided the “traceless” linker in this solid phase
peptidesynthesis(SPPS)ofliterature. Sincetheintegrityof
thechiralcentercanbecompromisedinpeptidesynthesisus-
ing this ap proach, it is usu ally only used for side chain at tach-
mentornonpeptidesynthesis. Inthisletter, wereportanO-at-
tach ment/saponification ap proach by em ploy ing DHP HM
resin that pro vides a gen eral and straight for ward method for
the syn the sis of sibrafiban (1)10,11 and lamifiban (2)12,13 (see
Diagram1).Compounds1 and 2were both de signed based on
the integrin tripeptide recognition motif, Arg-Gly-Asp
(RGD).Accordingtorecentstudies14 these com pounds must
have a carboxylate and an am mo nium func tion al ity within a
dis tance of 11-15 Å to be ef fec tive in hib i tors. More over, it
has been shown that the ba sic func tion can be ei ther a gua-
nidine,whichisthenaturalfunctionoftheRGDsequence,or
an amine such as piperidine or a benzamidine moi ety. They
are also small or ganic mo lec u lar in hib i tors of all platelet
fibrinogen re cep tor glycoprotein IIb/IIIa (GPIIb/IIIa) block-
ers15 and have been eval u ated for their abil ity to pre vent
RESULTS AND DISCUSSION
As shown in Di a gram 2, 4-hydroxypiperidine re acted
with N-(9H-fluoren-2-yl-methoxycarbonyloxy)succinimide
(Fmoc-Osu, 1.0 eq) to give Fmoc-protected 4-hydroxy-
piperidine in 97% yield, then the re sul tant prod uct (1.2 eq)
was cou pled to DHP HM poly sty rene resin (0.98 mmole/g)
us ingp-toluenesulfonic acid (p-TsOH, 1.2 eq) in di chloro-
methane/dimethylformamide (1/1 = v/v) for 20 h to give the
Fmoc-amine resin. Deprotection of the Fmoc-amine resin
(20% piperidine in DMF, 30 min) fol lowed by acylation with
Fmoc-Ala-OH or Fmoc-Tyr-(OBut)-OH (2.0 eq) and PyBOP
(2.1 eq) for two hours gave the resin-bound am ide. This was
fol lowed by deprotection of the Fmoc-amine am ide (20%
piperidine in DMF, 30 min) and acylation with 4-cyano-
benzoic acid (2 eq) and PyBOP (2 eq) for 2 h. When the de-
siredcyano-alcoholwasobtained, cleavageoftheacetalfrom
the DHP HM resin was per formed in acidic con di tions. Treat-
ment of the crude al co hol, 1a or 2a, with so dium hy dride
(NaH, 2.2 eq) and tert-butyl bromoacetate (1.2 eq) gave the
Ala-CO2But-ester 1b and Tyr-CO2But-ester.Toeasilypurify
the Tyr-(OBut)-CO2But-es ter2b, we pro tected the hydroxy
group of phe nol us ing ex cess iso bu tyl ene in acidic con di-
Diagram 1
t
tions16,17 to give the Tyr-(OBu )-CO2But-ester 2b. The re sul-
tant cyano es ters,1b and 2b, were ob tained in 36% and 30%
yield, re spec tively, from Fmoc-protected piperidine. With 1b
and 2b in hand, we re quired an ef fi cient con ver sion of the
nitrile into the amidine or amidoxime.15,18-24 Conversionof
the benzonitrile, 1b or 2b, into the benzamidoxime, 1c or 2c,
was successfully achieved by amidoxime formation of
R1N
H2N
O
O
CO2R2
N
O
HN
R3
sibrafiban (1) R1=OH, R2= Et, R3=Me
lamifiban (2) R1=R2=H, R3=
OH

134 J. Chin. Chem. Soc., Vol. 48, No. 2, 2001
Chang and Chen
Diagram 2
Key Words
Sibrafiban; Lamifiban; Integrin; Fibrinogen;
DHP HM resin; Phase III; GPIIb/IIIa.
ODHP-resin
OH
1) Fm oc-OSu,rt,1h
dioxane:H 2O=10:1(97%)
stepwise elongation
2) p-TsOH,DC M,rt,16h
and final deprotection
C O2 But
N
N
H
O
Fmoc
O
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