Novel Synthesis
Novel Synthesis
Novel Synthesis
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
a r t i c l e i n f o a b s t r a c t
Article history: In this study, a novel and convenient route for the construction of 5-((1H-1,2,4-triazol-1-yl)methyl)-1H-
Received 27 February 2014 indoles (8) is presented starting from (1H-1,2,4-triazol-1-yl)methanol (5) and indolines (6) under 98%
Revised 7 May 2014 H2SO4 at room temperature for 4–24 h, followed by deacetylation and dehydrogenation. Based on this
Accepted 15 May 2014
finding, a novel route to synthesize Rizatriptan starting from tryptamine was designed and accomplished
Available online 22 May 2014
with 48.5% overall yield in 6 steps. Compared with operational art, the new route afforded higher yield
and more pure products requiring no chromatographic purification, which may further be applied in
Keywords:
industrialization.
(1H-1,2,4-Triazol-1-yl)methanol
Tryptamine
Ó 2014 Elsevier Ltd. All rights reserved.
5-((1H-1,2,4-Triazol-1-yl)methyl)-1H-indoles
Rizatriptan
http://dx.doi.org/10.1016/j.tetlet.2014.05.063
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Y. He et al. / Tetrahedron Letters 55 (2014) 3938–3941 3939
N
NaNO2 SnCl2 N N,N-dialkylanilines by triazolylalkylating the substrates with (1H-
N N
N HCl N
NH NH 2
1,2,4-triazol-1-yl)methanol (5) in the presence of 37% HCl or CH3-
NH2
COOH. In particular, when the substrates are anilines, N-alkylani-
1 2
lines, and N,N-dialkylanilines, the substitution happened on the
N para-position. Inspired by this and for application in preparing
OMe
Me2N
Rizatriptan, we tried 5-(1H-1,2,4-triazol-1-yl)methylation of indo-
OMe
N N lines (6) under the condition of 37% HCl or CH3COOH, hoping to get
H2SO4 N N 5-((1H-1,2,4-triazol-1-yl)methyl)indulines (7) as the main product,
H
which could be further dehydrogenated to yield the 5-(1H-1,2,4-
Rizatriptan
triazol-1-yl)methyl substituted indoles (8) (Scheme 2). As the
dehydrogenation of compounds with the indoline structure has
route a(operational route). been abundantly explored9 and realized very successfully by us
later, our work mainly focused on the preparation of key interme-
diate 7.
TES
N ICI,CaCO3 N
I OTES As a model reaction, 6a was first adopted as the substrate to
N N
N
NH2 N Pd(OAc) 2, NaCO3 react with 5 under literature conditions.8 Disappointedly, as shown
NH 2 in Table 1, no 5-((1H-1,2,4-triazol-1-yl)methyl)indoline (7a) was
1 3
found under the condition of neither 37% HCl nor CH3COOH
OR N (Table 1, entries 1 and 2). Contrarily, acetylated 5-((1H-1,2,4-tria-
zol-1-yl)methyl)indoline (7b) was obtained as the main product
N
2N HCl MsCl,Et3N
N N under the condition of CH3COOH in a poor yield of 11% (Table 1,
N TES
N N
40%NHMe2 N N entry 2).
4
H H
Considering the different results described in the literature,8 we
Rizatriptan
supposed that 7b with 1-N acetylated might be more stable than
7a under the reaction condition. This may result from the elec-
route b. tron-withdrawing effect of acetyl, which makes the electron den-
sity of benzylic carbon of 7b lower than that of 7a, declining the
Scheme 1. Two main routes to prepare Rizatriptan. leave-taking of the triazol under strong acid environment which
could cause the degradation of the product described by Katritzky
et al.8,10
The purification of the final product was very tough and column
So we then chose 1-(indolin-1-yl)ethanone (6b) as the substrate
chromatography had to be adopted, leading to very low total yield
to screen the best triazolylalkylating condition in the presence of
of 11.1%.5a Houghton6 later improved total yield to 45% but column
varying proton or Lewis acids. The reaction was monitored by
chromatography was used in purification with high cost. Cheng Y.
TLC and the results are shown in Table 1. Firstly 37% HCl and CH3-
Chen et al.7 represented a process to prepare Rizatriptan, by palla-
COOH were tried as the literature procedure.8 And to ensure the
dium-catalyzed coupling ring closure of 3-iodine-4-aminobenzyl-
exhaustion of 6b, the reactant ratio (5:6b) was added to 1.5
triazol (3) with bis-TES-butynol to the corresponding tryptophol
(Table 1, entry 3 and 4). Unfortunately, only trace amount of 7b
intermediate (4) (Scheme 1, route b). This process was catalyzed
were found. We then applied several classic Friedel–Crafts acyla-
by palladium acetate in dry dimethylformamide in the presence
tion conditions, utilizing Lewis acids such as AlCl3, ZnCl2, and resin
of Na2CO3 at 100 °C for 4 h. The palladium catalyst is expensive,
in the solvent of nitrobenzene under 80 °C (Table 1, entries 5–7).
and the quite strict oxygen-free and anhydrous conditions need
But no product was formed. Then lower concentrations of acids
high-level equipment requirement, complexing the operation and
such as 15% HCl, 20% and 50% H2SO4 (Table 1, entries 8–10) were
increasing the costs. Also n-BuLi was used in preparing bis-
used. There was no desired product, which suggested that too
TES-butynol in this route, which is often eluded in industrial
much water might be negative to the reaction. Therefore, organic
production. Most of other reported routes were similar to the
acids such as HCOOH, CF3COOH, and CF3SO3H (Table 1, entries
two routes above. Obviously, neither Fisher indole reaction nor
11–13) were also tried. When CF3SO3H was tried, 7b was generated
palladium-catalyzed coupling reaction could meet the demand
in 6% yield. Encouraged by this result, we then tested some other
for high purity and yield in the preparation of Rizatriptan. We
strong acids with dehydration such as PPA and 98% H2SO4 (Table 1,
herein report a new method to prepare I starting from (1H-1,2,
entries 14–15), getting 7b in 13% and 16% yield. The positive per-
4-triazol-1-yl)methanol (5) and indolines (6).
formance of PPA and 98% H2SO4 might be the dehydration property
Katritzky et al.8 published a method to provide (1H-1,2,4-tria-
of them that can facilitate the ionization of the triazole methanol to
zol-1-yl)methyl substituted phenols, anilines, N-alkylanilines, and
smooth the reaction (Scheme 3).
As PPA is very viscous and difficult to stir at low temperature,
N OH we focused on the conditions using 98% H2SO4 to optimize the
N
N R2 reaction condition. Different temperature and reactant ratios
R2
5 N
(Table 1, entries 16–21) were tested. Even though the yield was
acid N Dehydrogenation N
N
N
N
the most optimal with a ratio of 1.5 at 25 °C for 24 h (Table 1, entry
N N
R1 18), it was still very low and not enough in application.
R2 R1
Considering that the introduction of side chain may make the
7a-c 8a-c product more stable and applied in the synthesis of Rizatriptan,
N
we attempted to choose 6c as the substrate to react with 5, expect-
R1
6a-c
a R 1=R2=H ing the high yield of 7c under specific conditions. Similarly with 6b,
b R1=Ac, R2=H
only CF3SO3H, PPA, and 98% H2SO4 generated the usable amount of
c R 1=Ac, R2=CH2CH 2N(CH 3)2
product (Table 1, entries 22–24). Encouragingly, the yields of those
Scheme 2. A novel construction of 5-((1H-1,2,4-triazol-1-yl)methyl substituted were respectively higher than that of 6b, which revealed that the
indoles (8). introduction of side chain was indeed positive to the reaction. Then
3940 Y. He et al. / Tetrahedron Letters 55 (2014) 3938–3941
Table 1
Optimization of reaction conditions for the synthesis of 7
R2 R2
N a R 1=R2=H
N OH N
N + b R1=Ac, R2=H
N N N
N c R 1=Ac, R2=CH2CH 2N(CH 3)2
R1 R1
5 6a-c 7a-c
Entry Indolines Acida Reactant ratio (5:6) Temp (°C) Timeb (h) Product Yieldc (%)
1 6a 37% HCl 1 Reflux 7 — 0
2 6a CH3COOH 1 Reflux 7 7b 11
3 6b 37% HCl 1.5 Reflux 7 7b Trace
4 6b CH3COOH 1.5 Reflux 7 7b Trace
5 6b AlCl3 1.5 80 7 — 0
6 6b ZnCl2 1.5 80 7 — 0
7 6b Resin 1.5 80 7 — 0
8 6b 15% HCl 1.5 80 7 — 0
9 6b 20% H2SO4 1.5 80 7 — 0
10 6b 50% H2SO4 1.5 80 7 — 0
11 6b HCOOH 1.5 80 7 7b Trace
12 6b CF3COOH 1.5 80 7 7b Trace
13 6b CF3SO3H 1.5 80 7 7b 6
14 6b PPA 1.5 80 7 7b 13
15 6b 98% H2SO4 1.5 80 7 7b 16
16 6b 98% H2SO4 1.5 80 3 7b 10
17 6b 98% H2SO4 1.5 50 12 7b 22
18 6b 98% H2SO4 1.5 25 24 7b 24
19 6b 98% H2SO4 1.2 25 24 7b 15
20 6b 98% H2SO4 0.5 25 36 7b 8
21 6b 98% H2SO4 5 25 18 7b 18
22 6c CF3SO3H 1.5 80 7 7c 16
23 6c PPA 1.5 80 7 7c 23
24 6c 98% H2SO4 1.5 80 2 7c 33
25 6c 98% H2SO4 1.5 25 4 7c 71
a
Typical procedure: in entries 1–4; 8–25: 1 mmol 6, n mmol 5, 1 ml acid; in entries 5–7: 1 mmol 6, 1.5 mmol 5, 1 mmol Lewis acid, 1 ml nitrobenzene.
b
Complete reaction time of substrates.
c
Isolated yield by column chromatography.
i ii iv
steps are simple reactions like acetylation–deacetylation, oxida- References and notes
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