A convenient method for the N-acylation and esterification of hindered amino acids: Synthesis of ultra short acting opioid agonist, remifentanil

Article abstract of DOI:10.1055/s-1999-2978

A general method has been devised for the one step preparation of N- acylamino acid esters of type 7 from the corresponding a-amino acids in high yield under mild conditions and a probable mechanism is proposed.

Full text of DOI:10.1055/s-1999-2978

LETTER
1923
A Convenient Method for the N-Acylation and Esterification of Hindered
Amino Acids: Synthesis of Ultra Short Acting Opioid Agonist, Remifentanil
Mark J. Coleman, Michael D. Goodyear, David W. S. Latham, Andrew J. Whitehead*
Chemical Development Division, Glaxo Wellcome Research and Development, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY,
UK
Received 12 October 1999
Abstract: A general method has been devised for the one step prep-
aration of N-acylamino acid esters of type 7 from the corresponding
a-amino acids in high yield under mild conditions and a probable
mechanism is proposed.
Key words: acylation, esterification, amino acids
Reagents: (i) KCN, PhNH2; (ii) aq H2SO4; (iii) aq HCl; (iv) NaOH;
(v) MeI; (vi) (EtCO)2O; (vii) Pd/C, H2; (viii) methyl acrylate
Opiate analgesics of the 4-acylanilinopiperidine type are
important adjuncts for anaesthesia. Fentanyl (1) is the pro-
Scheme 1
totype of the series but many analogues have been pre-
pared, including the more potent carboxylate derivative,
The reaction of 5 with aliphatic anhydrides to activate the
carfentanil (2). Recently the development by Glaxo
carboxylate function towards nucleophilic attack by
Wellcome of the ultra short acting opioid agonist,
alcohols5 produced N-acylated products even at room
temperature. Treatment of the hydrochloride salt of 5 with
remifentanil (3)1, has led us to re-evaluate synthetic ap-
proaches to 4-carboxypiperidine esters (Figure 1).
excess propionic anhydride in the presence of triethy-
lamine in ethyl acetate at reflux followed by the addition
of methanol gave the desired 4-propionylaminopiperi-
dine-4-carboxylate ester 6 in high yield. These mild con-
ditions were extended to a range of acids, anhydrides and
alcohols and the results of these investigations are sum-
marised in the Table6.
In most cases yields of the 4-acylaminopiperidine-4-car-
boxylate esters 7 were high, the acylation and esterifica-
tion reactions were rapid (ca. 1h and 2h respectively at
reflux in ethyl acetate) and the products were convenient-
Figure 1
ly isolated as oxalate salts. The intermediate acid 7a-l was
The reported syntheses2 of the piperidine amino acid class
of opiate agonists are based on a classical Strecker reac-
tion of N-benzyl-4-piperidone (4) leading via stepwise hy-
drolysis of the nitrile and amide functions to the acid 5
(Scheme 1). Both the 4-carboxylate and the 4-anilino
groups at the piperidine quaternary carbon of 5 are rela-
tively unreactive, probably due to a combination of steric
and electronic factors. Conventional acid catalysed ester-
ification is very slow3 and acylation of the aniline requires
drastic conditions4. Generation of the propion amide 6
was initially achieved by alkylation of the sodium salt of
5 with methyl iodide, followed by acylation in neat propi-
onic anhydride at reflux (Scheme 1). In the development
of a practical process for the manufacture of remifentanil
improvements to existing reaction conditions provided us
with a satisfactory process for both the early and final
steps of the synthesis but a new approach to the conver-
sion of 5 into 6 was required.
Table Preparation of N-acylamino acid esters 7
Synlett 1999, No. 12, 1923–1924 ISSN 0936-5214 © Thieme Stuttgart · New York

1924
M. J. Coleman et al.
LETTER
isolated in 79% yield by quenching the acylation reaction
mixture with water instead of an alcohol.
Attempts to prepare the trifluoromethyl compound 8 us-
ing trifluoroacetic anhydride gave instead the oxazolidone
9 in 80% yield (Figure 2). The structure of 9 was con-
firmed by the single crystal X-ray analysis of its oxalate
salt. The desired amide 8 was prepared by treatment of the
methyl ester of 5 with trifluoroacetic anhydride in toluene
at reflux.
Figure 2
A possible mechanism for the N-acylation and esterifica-
tion reactions is depicted in Scheme 2. The mild condi-
tions of the N-acylation step compared with those required
to acylate the esters of 5 suggest that the reaction is
intramolecular4. A related N-O intramolecular transposi-
tion has been proposed by Colapret2b in the preparation of
4-acyloxypiperidines related to fentanyl. Support for a
spiro intermediate is also provided by the structure 9. In
this case the electronegativity of the trifluoromethyl group
favours attack by methanol at C2 of the oxazolinium ion.
The related 2-hydroxy-2-trifluoromethyl-5,5-diphenyl-4-
oxazolidone has been reported by Ketcha7 and this com-
pound was converted via an oxazolinone into the corre-
sponding 2-ethoxy compound by heating in anhydrous
ethanol.
Scheme 2
(3) Taber D.F. and Rahimizadeh M. J. Org. Chem. 1992, 57,
4037.
(4) Van Deale P. G.; De Bruyn M. F.; Boey J M.; Agten J. T. and
Janssen P. A. Arzneim.-Forsch. Drug Res. 1976, 26, 1521.
(5) Parish R. C. and Stock L. M. J. Org. Chem. 1965, 30, 927.
(6) General procedure for the preparation of N-acylamino
esters of type 7: Triethylamine (0.3 mol, 41.8 mL) was added
slowly to a stirred suspension of the acid 5 (0.1 mol, 34.7 g)
and propionic anhydride (0.7 mol, 89.8 mL) in ethyl acetate
(260 mL) at reflux and the resulting solution was heated at
reflux for 1 h. The reaction mixture was cooled to 70°C,
methanol (70 mL) added, the reaction heated at reflux for a
further 2 h, cooled to room temperature and then basified with
5 M aqueous sodium hydroxide. The biphasic mixture was
separated and the aqueous extracted with ethyl acetate, the
combined ethyl acetate solution was washed with 2M aqueous
sodium hydroxide and water. Water was then added followed
by aqueous phosphoric acid (2.5 M) until the pH of the
aqueous reached 6. The layers were separated and a solution
of oxalic acid dihydrate (0.1 mol, 12.6 g) in methanol (34.7
mL) was added to the organic layer. The resulting solid was
isolated by filtration and washed with ethyl acetate and dried
in vacuo at 40°C to afford the product 7b (43.5 g, 92%).
(7) Ketcha D. M.; Abou-Gharbia M.; Smith F. X. and Swern D.
Tetrahedron Lett. 1983, 24, 2811.
In conclusion this easily performed sequence provides a
convenient method for the preparation of N-acylamino
acid esters of type 7 from α-amino acids in high yields un-
der mild conditions.
Acknowledgement
The authors would like to thank Paul Feldman (Glaxo Wellcome
Inc.) for the preparation of 7a-l and Wayne Brailsford (University
of East Anglia) for the preparation of 9.
References and Notes
(1) Feldman P. L.; James M. K.; Brakeen M. F.; Bilotta J. M.;
Schuster S. V.; Lahey A. P.; Lutz M. W.; Johnson M. R. and
Leighton H. J. J. Med. Chem. 1991, 34, 2202.
(2) For recent examples see: a) Janssens F.; Torremans J. and
Janssen P. J. Med. Chem. 1986, 29, 2290. b) Colapret J. A.;
Diamantidis G.; Spencer H. K.; Spalding T.C. and Rudo F. G.
J. Med. Chem. 1989, 32, 968. c) Feldman P.L. and Brakeen M.
F. J. Org. Chem.,. 1990, 55, 4207 and references cited therein.
Article Identifier:
1437-2096,E;1999,0,12,1923,1924,ftx,en;L14799ST.pdf
Synlett 1999, No. 12, 1923–1924 ISSN 0936-5214 © Thieme Stuttgart · New York