Aziridine Indole PDF
Aziridine Indole PDF
Aziridine Indole PDF
2-Methylaziridines
Paul R. Giles,*, Mark Rogers-Evans, Milan Soukup, and John Knight
Vernalis Research Ltd., Oakdene Court, 613 Reading Road, Winnersh, Wokingham RG41 5UA, UK, and
F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland
Abstract:
An improved process for the N-alkylation of indoles using
N-protected homochiral aziridines has been developed. This
procedure allows reduced quantities of homochiral starting
material to be used and leads to improved overall yields and
operability.
Introduction
RO 60-0175 4a is a selective 5HT2C agonist with potential
therapeutic utility in the treatment of obsessive compulsive
disorder.1 Its synthesis includes a key step (Scheme 1)
involving the reaction of indole 1a with the N-protected
alaninyl mesylate 2 to give the N-alkylated indole 3a.2,3
In our hands this transformation proved to be less than
ideal for several reasons:
(1) The reaction lacked generality, giving inconsistent
yields and incomplete conversion in the synthesis of close
analogues of indole 3a.
(2) Incomplete reaction gave a mix of materials, which
proved difficult to purify without recourse to chromatography.
(3) Alaninyl mesylate 2 required very slow addition to
the reaction mixture, typically 1-2 h.
(4) The reaction conditions resulted in a partial loss of
the BOC protecting group to give indoles 4.
(5) Large solvent volumes, typically 20-50 vols, and thus
large aqueous volumes, were required during the workup of
indoles 3.
We sought a method which would circumvent these
problems and provide a scaleable, less capricious, and more
operable procedure. We therefore carried out a limited
amount of process development to improve this transformation.
Results and Discussion
The reaction illustrated in Scheme 1 using indole 1b and
literature conditions2 was monitored by HPLC to quantify
* Corresponding author. E-mail [email protected]. Telephone: + 44 118
977 3133. Fax: + 44 118 989 9300.
Vernalis Research Ltd.
F. Hoffmann-La Roche Ltd.
(1) Boes, M.; Jenck, F.; Martin, J. R.; Moreau, J.-L.; Sleight, A. J.; Wichmann,
J.; Widmer, U. J. Med. Chem. 1997, 40, 2762-2769.
(2) Rogers-Evans, M.; Soukup, M. PCT Int. Appl., WO 9747598 A1, 1997;
Chem. Abstr. 1998, 128, 75296.
(3) Adams, D. R.; Bentley, J. M.; Roffey, J. R. A.; Hamlyn, R. J.; Gaur, S.;
Duncton, M. A.; Bebbington, D.; Monck, N. J.; Dawson, C. E.; Pratt, R.
M.; George, A. R. PCT Int. Appl. WO 0012475, 2000; Chem. Abstr. 2000,
132, 194289.
10.1021/op020078v CCC: $25.00 xxxx American Chemical Society
Published on Web 00/00/0000
the amounts of indole 1b, alkylated indole 3b, and deprotected alkylated indole 4b. The HPLC method,4 using
1-methylnaphthalene as internal standard, gave baseline
separation of each of these entities.
A number of parameters were independently investigated
with the following results:
Temperature. Higher reaction temperatures increased the
loss of the BOC group to give amine 4b.
Base. Replacement of KOH with KOtBu resulted in
increased loss of the BOC group to give amine 4b. The use
of powdered KOH prepared in a blender and KOH ground
with a mortar and pestle gave similar results.
Rate and Order of Addition of Compound 2. Slow addition
of 2 gave better initial alkylation although, by the end of
the reaction, yields of each entity were similar. It was also
found that the order of addition of reagents was critical. The
desired reaction was only observed when a solution of 2 was
added to a suspension of indole and powdered KOH. The
KOH could not be added to a solution of compound 2 and
the indole.
Reaction Times. Prolonged reaction times decreased the
yield of 3b, mainly by loss of the BOC group to give 4b.
The alkylation reaction was effectively over once the addition
of mesylate 2 was complete.
Water Content. The use of dry DMSO and standard grade
DMSO gave similar results.
(4) The internal standard was weighed into the reaction vessel prior to addition
of the solvent and base. Samples (0.5 mL) of the reaction mixture were
taken for analysis and diluted with 10% aqueous acetic acid and methanol
prior to injection onto HPLC using the Vernalis conditions as described in
the Experimental Section. Typical retention times of the species are indole
1b, 3.76 min; alkylated product 3b, 5.78 min; internal standard 9.8 min;
deprotected amine 4b, 2.85 min.
Organic Process Research & Development A
entry
indole 1
yield %a
% purity
NMRb
% area
purity HPLCb
previous
yieldc
1
2
3
4
5
6
indole
6-bromoindole
5-chloroindole
6-trifluoromethylindole
5-methoxyindole
5-fluoro-6-chloroindole
80
79
86
89
85
82
85
85
92
85
90
90
85
82
93
88
75
88
not reported
56
29
11
not reported
59
a All figures are for crude reaction products. b The major impurity in each
case was the unreacted starting indole. c Yields previously obtained in-house
after chromatography using initial general procedure.9
Experimental Section
Reagents and solvents were used as received from
commercial suppliers. All equipment was inspected visually
for cleanliness and integrity before use.
Analytical HPLC was performed on a Hewlett-Packard
1050 or 1100 system with UV detection at a wavelength of
210 nm using a LiChrospher 100 RP18 endcapped (5 m)
250 mm 4 mm column (Merck) and gradient elution with
H2O-MeCN (Roche) or a Perkin-Elmer series 200 system
with UV detection at a wavelength of 210 nm using a
Supercosil ABZ+ 150 mm 6 mm column and isocratic
elution with MeOH-ammonium acetate buffer (70/30 ratio)
(Vernalis). TLCs were perfomed either with (a) isohexanesethyl acetate (1:1) and developed using KMnO4 dip or (b)
in DIPE and developed using Ninhydrin spray.
Initial General Procedure Using 5-Fluoro-6-chloroindole (1a). To a suspension of ground potassium hydroxide
(0.58 g, 10.3 mmol) in DMSO (20 mL) was added indole
1a (0.44 g, 2.6 mmol) and the resulting suspension was
stirred at 40 C. An inert atmosphere was not used. After
30 min, a solution of alaninyl mesylate 2 (1.64 g, 6.5 mmol)
in DMSO (20 mL) was added slowly over a period of 2 h,
and the resulting mixture was stirred overnight at 40 C.
The viscous gel-like suspension was poured into ice-water,
extracted with diethyl ether (2 20 mL), washed with water
and brine, dried (MgSO4), and evaporated to afford the
alkylated indole 3a, 0.5 g, 59% yield after purification).