Abstract
A synthetic route toward new 1-alkyl-3-aminomethyl-3-fluoropiperidines,
which are of high interest as building blocks in medicinal chemistry,
is described. The successful approach consists of the fluorination
of ethyl 3-chloropropyl-2-cyanoacetate with N -fluorodibenzenesulfonimide
(NFSI) and transformation of the ester moiety into different amides,
yielding N -alkyl-5-chloro-2-cyano-2-fluoropentanamides.
Ring closure was achieved under basic conditions, yielding 1-alkyl-3-fluoro-2-oxopiperidine-3-carbonitriles.
After
reduction of the obtained lactams with borane, the desired 3-aminomethyl-3-fluoropiperidines
were obtained in good yields.
Key words
ring closure - NFSI - 3-fluoropiperidines - fluorine chemistry - heterocycles
References and Notes <A NAME="RG08009ST-1">1 </A>
Postdoctoral Fellow of the Research
Foundation - Flanders (FWO-Vlaanderen)
2a </A>
Papeo GME,
Caronni D,
Dalvit C,
Giordano P,
Mongelli N,
Veronesi M, and
Ciprandi F. inventors; Eur. Pat. Appl. EP 1923397.
;
A1 20080521
2b </A>
Grabstein KH,
Wang A,
Nairn N,
Winblade G, and
Thomas J. inventors; U.S.
Pat. Appl. Publ. US 2008096819.
; A1
20080424
2c </A>
Edmondson SD.
Mastracchio A.
Mathvink RJ.
He J.
Harper B.
Park Y.-J.
Beconi M.
Di Salvo J.
Eiermann GJ.
He H.
Leiting B.
Leone
JF.
Levorse DA.
Lyons K.
Patel RA.
Patel SB.
Petrov A.
Scapin G.
Shang J.
Roy RS.
Smith A.
Wu JK.
Xu S.
Zhu B.
Thornberry NA.
Weber AE.
J.
Med. Chem.
2006,
49:
3614
2d </A>
Celanire S,
Quere L,
Denonne F, and
Provins L. inventors; PCT Int. Appl. WO 2007048595.
;
A1 20070503
2e </A>
Keith JM.
Gomez LA.
Letavic MA.
Ly KS.
Jablonowski JA.
Seierstad M.
Barbier AJ.
Wilson SJ.
Boggs JD.
Fraser IC.
Mazur C.
Lovenberg TW.
Carruthers NI.
Bioorg.
Med. Chem. Lett.
2007,
17:
702
2f </A>
Parker JC, and
Hulin B. inventors; US Pat.
Appl. Publ. US 2005043292.
;
A1 24/02/2005; Chem. Abstr. 2005 , 142 , 261783
3a </A>
Fluorine
in Bioorganic Chemistry
Welch JT.
Eswarakrishnan S.
Wiley-Interscience;
New
York:
1991.
3b </A>
Bioorganic and
Medicinal Chemistry of Fluorine
Bégué JP.
Bonnet-Delpon D.
John
Wiley & Sons, Inc.;
New Jersey:
2008.
<A NAME="RG08009ST-4">4 </A>
Hagmann WK.
J.
Med. Chem.
2008,
51:
4359
<A NAME="RG08009ST-5">5 </A>
O" Hagan D.
Chem.
Soc. Rev.
2008,
37:
308
<A NAME="RG08009ST-6">6 </A>
Purser S.
Moore PR.
Swallow S.
Gouverneur V.
Chem. Soc. Rev.
2008,
37:
320
<A NAME="RG08009ST-7">7 </A>
Kirk KL.
Org.
Process Res. Dev.
2008,
12:
305
<A NAME="RG08009ST-8">8 </A>
Müller K.
Faeh C.
Diederich F.
Science
2007,
317:
1881
<A NAME="RG08009ST-9">9 </A>
Differding E.
Frick W.
Lang RW.
Martin P.
Schmit C.
Veenstra S.
Greuter H.
Bull.
Soc. Chim. Belg.
1990,
99:
647
<A NAME="RG08009ST-10">10 </A> inventors; Barrow J. C., Lindsley
C. W., Shipe W. D., Yang Z.: PCT Int. Appl. WO/2007/002361.
; Chem. Abstr. 2007 , 146 , 121830
<A NAME="RG08009ST-11">11 </A>
Verniest G.
Surmont R.
Van Hende E.
Deweweire A.
Deroose F.
Thuring JW.
De Kimpe N.
J.
Org. Chem.
2008,
73:
5458
<A NAME="RG08009ST-12">12 </A>
Van Niel MB.
Collins I.
Beer MS.
Broughton HB.
Cheng SKF.
Goodacre SC.
Heald A.
Locker KL.
MacLeod AM.
Morrison D.
J.
Med. Chem.
1999,
42:
2087
<A NAME="RG08009ST-13">13 </A>
Sun A.
Lankin DC.
Hardcastle K.
Snyder JP.
Chem. Eur. J.
2005,
11:
1579
<A NAME="RG08009ST-14">14 </A>
Dechamps I.
Gomez Pardo D.
Cossy J.
Eur.
J. Org. Chem.
2007,
4224
15a </A>
Ono N.
Yoshimura T.
Saito T.
Tamura R.
Tanikaga R.
Kaji A.
Bull. Chem.
Soc. Jpn.
1979,
52:
1716
15b </A>
Muthusamy S.
Gnanaprakasam B.
Tetrahedron Lett.
2005,
46:
635
<A NAME="RG08009ST-16">16 </A>
Zefirov NS.
Kuznetsova TS.
Kozhushkov SI.
Surmina LS.
Rashchupkina ZA.
Zh. Org. Khim.
1983,
19:
541
<A NAME="RG08009ST-17">17 </A>
Grossman RB.
Varner MA.
J. Org. Chem.
1997,
62:
5235
