Manufacturing synthesis of 5-hydroxy-2-methyl-1H-indole

Article abstract of DOI:10.1007/s11164-010-0210-x

The manufacturing synthesis of 5-hydroxy-2-methyl-1H-indole is described and two synthetic methods were used and the results discussed. Two small and three large runs with Nenitzescu's method were analyzed and results reported with different reaction conditions. Manufacturing issues encountered were discussed. Production scale of more than 60 kg of the 5-hydroxy-2-methyl-1H- indole-3-carboxylic acid ethyl ester and over 20 kg of the 5-hydroxy-2-methyl- 1H-indole were achieved. Based on these results, larger scale manufacturing of this product or similar products based on the optimized conditions is feasible.

Full text of DOI:10.1007/s11164-010-0210-x

Res Chem Intermed (2010) 36:975–983
DOI 10.1007/s11164-010-0210-x
Manufacturing synthesis of 5-hydroxy-2-methyl-1H-
indole
•
•
•
Yun-Sheng Huang Wen-Qing Zhang Xu Zhang
Jian-Zhong Wang
Received: 26 August 2010 / Accepted: 1 November 2010 / Published online: 18 November 2010
Ó Springer Science+Business Media B.V. 2010
Abstract The manufacturing synthesis of 5-hydroxy-2-methyl-1H-indole is
described and two synthetic methods were used and the results discussed. Two small
and three large runs with Nenitzescu’s method were analyzed and results reported
with different reaction conditions. Manufacturing issues encountered were dis-
cussed. Production scale of more than 60 kg of the 5-hydroxy-2-methyl-1H-indole-
3-carboxylic acid ethyl ester and over 20 kg of the 5-hydroxy-2-methyl-1H-indole
were achieved. Based on these results, larger scale manufacturing of this product or
similar products based on the optimized conditions is feasible.
Keywords 5-Hydroxy-2-methyl-1H-indole Á Nenitzescu Á Benzoquinone Á
Aminocrotonate
Introduction
Indole structure is one of the most important members of heterocyclic compounds
and is a ‘‘privileged scaffold’’ for many natural and pharmaceutical products [1].
For example,well known pharmaceutical/natural products Tryptophan, Indometacin,
Medmain, Serotonin, Melatonin, Oxypertine, Vinblastin, etc. contain indole
moieties. Many alkaloids from plants and from marine sources have indole
structures [2].
Numerous products of pharmaceutical interest contain the structure of 2-methyl-
5-hydroxy-1H-indole. A series of ethyl 2-alkyl-6-bromo-5-hydroxy-1H-indole-3-
carboxylate derivatives were found to be effective against influenza virus [3].
Similar structures were also demonstrated to be active against hepatitis B virus [4].
Y.-S. Huang (&) Á W.-Q. Zhang Á X. Zhang Á J.-Z. Wang
Guangdong Medical College School of Pharmacy, 1 Xincheng Ave,
Songshan Lake Technology Park, Dongguan 523808, China
e-mail: yunshenghuang@gmail.com
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Y.-S. Huang et al.
O
O
O
NH2
O
HO
b
a
HO
+
O
N
H
N
H
O
3
1
2
4
Scheme 1 Reagents and conditions: (a) acetic acid, 15 °C to RT; (b) 20%HCl/ethanol, reflux
O
O
O
O
F
NO2
a
O
F
c
b
NO2
NO2
NO2
F
F
MeO
5
6
8
7
d
f
H3CO
HO
N
H
N
H
1
9
Scheme 2 Reagents and conditions: (a) (i) t-BuOK/THF/ethyl acetoacetate/2,4-difluoronitrobenzene,
5–15 °C; (ii) 6 N HCl, \10 °C; (b) H2SO4/AcOH, 30–70 °C; (c) MeONa/MeOH, 20–35 °C;
(d) Na2S2O4/THF, RT; (e) BBr3/CH2Cl2, -5 to -8 °C
Some 5-hydroxy alkylated ethyl 2-methyl-5-hydroxy-1H-indole-3-carboxylate
derivatives were found to have anti-inflammatory and analgesic activity [5].
Several drug candidates that act on the vascular endothelial growth factor (VEGF)
related kinase insert domain receptor (KDR) with high promises in treating
angiogenesis related diseases also contain the 5-hydroxy-2-methyl-1H-indole
moiety [6–8]. Some 5-hydroxy-2-methyl-1H-indole analogues are potent prosta-
glandin D2 receptor antagonist [9].
There are a number of methods for the synthesis of indoles, such as the well
known Fischer indole synthesis [10], Bartoli indole synthesis [11], Leimgruber-
Batcho indole synthesis [12], Reissert indole synthesis [13], Larock indole synthesis
[14], Gassman indole synthesis [15], Bischler-Molau indole synthesis [16], and
Nenitzescu indole synthesis [17–19]. More recently, many new methods of
synthesizing various indoles have been published: (a) palladium (II) catalyzed ring
closure [20–27], (b) copper (I/II) catalyzed cyclization [28–30], and (c) other indole
formation [31–37]. From manufacturing standpoint, many of these methods are not
feasible due to cost, non-environmental friendliness, and scalability, etc. There are
two confirmed ways to make 5-hydroxy-2-methyl-1H-indole (1). The first one is
based on the Nenitzescu’s method (Scheme 1) with two steps via the intermediate
ethyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate (2). The second method consists
of five steps (Scheme 2), via the intermediate 5-methoxy-2-methyl-1H-indole (9).
Even though there are a number of literatures reported the synthesis of 1 [38–41],
123

Manufacturing synthesis of 5-hydroxy-2-methyl-1H-indole
977
the scales are limited in the gram level. There has been no report on scale up
synthesis of 1. No other methods toward the preparation of product 1 were reported
in the literature. We used both methods in the synthesis of product 1 and here we
report the results in scale up and manufacturing production of 1.
Results and discussion
The first method (Nenitzescu indole synthesis, Scheme 1) was to use commercially
available and less expensive ethyl 3-aminocrotonate (3) and 1,4-benzoquinone (4) in
large quantities. The generally accepted mechanism includes a Micheal addition of
ethyl 3-aminocrotonate to the 1,4-benzoquinone to form a substituted 1,4-diphenol,
oxidation of the diphenol to 1,4-benzoquinone, condensation/cyclization, and
reduction to give the indole product [42]. Due to the relatively low yield, Nenitzescu
reaction has not been extensively applied in indole synthesis, especially for
manufacturing purpose. In general, the 1,4-benzoquinone is used in excess amount
(100% excess) to drive the reaction to completion [17].
In our study, we followed the reference procedure [39], and did a couple of small
scale runs (Table 1, entries 1, 2). In the first experiment, 1,4-benzoquinone was used
100% excess and the obtained product 2 contained significant amount of unreacted
1,4-benzoquinone that was removed only by repeated recrystallization from ethyl
acetate/petroleum ether, which is the main reason that the yield in entry 1 is
significantly lower compared to the reference [39]. Therefore, 1,4-benzoquinone
was reduced to about 40% excess in the second experiment (Table 2, entry 2) and
excellent yield was obtained just by simple wash with acetic acid and petroleum
ether without recrystallization or column purification. A third small scale
experiment was conducted using equal mole ratio of the 1,4-benzoquinone and
ethyl 3-aminocrotonate. As a result, the reaction did not go completion even after
Table 1 Results from Nenitzescu reaction first step
Entry 3 (mol)a
4 (mol)a
4/3
ratiob acid
Acetic Reaction Reaction 2 (HPLC)c
temp °C time (hr)
Yield
(%)
1
2
3
4
5
a
32.5 g (0.25) 54 g (0.5)
2.0
1.4
0.5 L
1 L
15–40
15–40
2
25.3 g (96.7%)
99 g (98.5%)
46.2
90
64.5 g (0.5)
20 kg (155)
30 kg (232)
50 kg (387)
78 g (0.72)
2.5
4
25.7 kg (238) 1.53 135 kg 10–20
17.5 kg (96.8%) 51.6
32 kg (296)
50 kg (555)
1.27 220 kg 15–30
1.43 300 kg 25–40
4.5
5.5
33 kg (97.9%)
61 kg (97.8%)
64.8
71.8
Data in parentheses are the corresponding moles
b
The ratio are calculated using the mole number of 4 over that of 3
c
Data in parentheses are the results from HPLC analysis (conditions: Angilent 1100, solvent: MeOH,
injection: 20 lL, column: x-Bridge 150 mm 9 4.6 mm BDS-C18, k = 254 nm, column temp: 30 °C,
flow rate: 1.0 mL/min, mobile phase: ACN-H2O, gradient: 0–20–25 min, 15–75–75%)
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Y.-S. Huang et al.
Table 2 Results from Nenitzescu reaction second step
Entry
2 (mol)a
20%HCl
EtOH
Reaction
temp (oC)
Reaction
time (hr)
1 (HPLC)b
Yield
(%)
1
2
3
4
5
a
22 g (0.1)
200 mL
1 L
20 mL
100 mL
30 kg
80–100
80–100
75–98
2.5
2.5
3
10.4 g (96.5%)
47.5 g (97.8%)
5.9 kg (98.7%)
8.4 kg (97.5%)
22.8 kg (97.6%)
70
88 g (0.4)
17.5 kg (80)
33 kg (150)
61 kg (278)
80
170 kg
330 kg
500 kg
50
40 kg
85–95
5
37.7
55.7
80 kg
75–100
6
Data in parentheses are the corresponding moles
b
Data in parentheses are the results from HPLC analysis (conditions:same as in Table 1)
stirring overnight. When additional 1,4-benzoqinone was added (30–40% excess),
the reaction resumed and completed within 2 h and good yield was obtained as well
(data not shown). Based on the small scale experiments, we learned that 1,4-
benzoquinone should not be used in more than 60% excess (product difficult to be
purified), but no less than 20% excess (reaction too slow to proceed) relative to the
corresponding ethyl 3-aminocrotonate. Any significant amount of 1,4-benzoquinone
remaining in 2 would result in polymerization in the next step and large amount of
by-product formation by consuming both 4 and 2, resulting in low yield.
Laboratory experiments indicated that optimal mole ratio between 1,4-benzo-
quinone (4) and ethyl 3-aminocrotonate (3) should be between 1.2 and 1.6. Thus,
for the three manufacturing runs, the mole ratios were 1.27, 1.43, and 1.53,
respectively, with 1.43 giving the highest yield (Table 1, entries 3, 4, 5). In scaling
up, the reaction time should increase as well, it normally needs to stir additional
3–5 h (after the completion of addition). The progress can be easily monitored by
TLC or HPLC.
In addition to the mole ratio between 4 and 3, the reaction temperature is another
factor that might affect the outcome. Based on our small runs, the reaction
temperature should not be higher than 50 °C and not be lower than 10 °C. If the
temperature is too high, significant side reaction occurs and results in low yield. If
the temperature is below 10 °C, the reaction would not proceed as expected. The
optimal reaction temperature is around room temperature or 25–30 °C. Therefore,
external cooling is normally required due to the mild exothermic process of the
reaction. The reaction normally completes within 6 h and does not change for
extended period of time, such as stirring overnight, as long as the temperature is
kept below 40 °C. The highest yield achieved in small runs was *90%. But in
manufacturing production, the 71.8% was the best obtained.
The second step from 2 to 1 was based on acid catalyzed hydrolysis and
decarboxylation using 20% HCl (Table 2) by following the reference procedure
[41]. Though base hydrolysis should work as well [40], the reaction was
complicated and resulted in low yield (data not shown). Precaution should be
taken due to the large amount of CO2 formation when the temperature reaches
around 80 °C (especially for manufacturing scale!). Therefore the combined
reaction media should never occupy more than 50% of the reactor space. After the
123

Manufacturing synthesis of 5-hydroxy-2-methyl-1H-indole
979
peak formation of the CO2, the reaction should be heated to around 95–100 °C for
2–3 h to completion. To make the reaction go smoothly, ethanol was added to help
dissolve the intermediate 2 and, as a result, the reaction mixture was cleaner and
yield improved as well.
The two small runs gave 70 and 80% yield (Table 2, entries 1, 2), respectively,
which were close to that of the literature [41]. For the three large runs, the yields
were 50, 37.7 and 55.7% (Table 2 entries 3, 4, 5), respectively, which were
significantly lower that those of the small runs. The exact reason of the low yield of
entry 4 is most likely due to the significant polymerization (the mother liquid from
entry 4 contained significant amount of product 1 that was too difficult to be
purified). The second step normally completes within 3–6 h. Extended refluxing
(such as overnight) does not help increase the yield, but side reaction takes place,
and results in low yield. When 2 contained significant amount of 1,4-benzoquinone
([5%) was used in the second step, polymerization occurred, resulting in low yield
(data not shown). The two steps combined yield ranged from 30 to 50% with the
average around 40%.
An alternative route to 1 is outlined in Scheme 2 according to a literature
procedure [43]. This route had been used in synthesizing product 1 before the
optimized conditions of Nenitzescu’s method were achieved. It started with 2,4-
difluoronitrobenzene that was substituted with ethyl acetoacetate to afford the ortho-
fluoro replaced intermediate 6, after acid catalyzed hydrolysis and decarboxylation,
intermediate 7 was obtained in a combined yield of 53%, which was further
substituted with a methoxy group to afford intermediate 8. Reduction of the nitro
group, followed by cyclization, gave the 5-methoxy-2-methyl-1H-indole (9).
Intermediate 9 underwent demethylation with boron tribromide to afford the
desired product 1 in a combined overall yield *6% (process not optimized).
Though the synthesis of product 1 by the second route no longer has any
advantage after the first route worked out, it may still be useful for preparation of
some of the intermediates, such as 6, 7, and 8, as well as some substituted 9 or 1
other than methoxy or hydroxy at the 5 position. Unlike Nenitzescu’s method that is
only applied to produce 5-hydroxy substituted indoles, the second route can be used
to produce a range of differently substituted indoles by using various starting
materials or by functional group transformation at a later stage. Therefore, we also
included the results (largest scale conducted) from the second route in this report for
reference purpose.
In conclusion, we have conducted three manufacturing scale synthesis of the
product 5-hydroxy-2-methyl-1H-indole that is becoming increasingly important for
a number of pharmaceutical products under development. Though several literatures
reported the synthesis of 5-hydroxy-2-methyl-1H-indole or structurally similar
products, large scale production has not been reported due to the relatively low yield
of Nenitzescu method and polymerization under reaction conditions. We optimized
the reaction conditions and were able to produce many kilograms in a single batch
in good overall yield. The optimized reaction conditions may easily be applied for
production over 100 kilograms per batch as well as for production of similar
products.
123

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Y.-S. Huang et al.
Experimental section
All reagents purchased commercially were used directly without further purifica-
tion. Solvents were used directly without any treatment. Melting points were
measured using capillary method without correction. Reaction temperatures were
recorded using a regular thermometer in a tube that was attached to the reactor
without correction. TLC development solvent: PE = petroleum ether, EA = ethyl
acetate.
Ethyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate (2)
General procedure
Please refer to Table 1 for materials used: to a 500 L reactor was added acetic acid
and 1,4-benzoquinone. The mixture was stirred and cooled to 10–15 °C. Ethyl
3-aminocrotonate was added dropwise below 30 °C (3–4 h for the addition to
complete), and the reaction was stirred at RT for an additional 3–5 h. TLC indicated
the completion of the reaction with Rf = 0.4 (PE:EA = 2:1). The solid was
collected by centrifugation and washed with acetic acid, petroleum ether, and dried
to afford ethyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate as a white powder,
m.p. 206–208 °C (lit.[39] 207–208 °C).
Nenitzescu’s method synthesis of 5-hydroxy-2-methyl-1H-indole (1)
General procedure
Please refer to Table 2 for materials used: to a 1000 L reactor was added 20% HCl,
ethanol. Under stirring, ethyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate was
added and the mixture was heated to reflux (75–85 °C). As the temperature rose,
large amount of gas (CO2) evolved from the reaction. The refluxing continued until
no more gas evolution was observed (2–4 h). TLC indicated the completion of
reaction with Rf = 0.4 (PE:EA = 1:1). The ethanol was removed by distillation
and the mixture was cooled to below 10 °C and neutralized with 50% NaOH to pH
*6 below 15 °C. The precipitates were collected by centrifugation and the
crude product was dissolved in dichloromethane and added activated carbon and
heated to reflux for 2 h, filtered, and cooled to RT. The solvent was concentrated
and the solid was collected by filtration, dried to afford 2-methyl-5-hydroxy-1H-
indole as a light yellow crystal/powder. m. p. 158–160 °C (lit.[40] 158 °C).
Ethyl 2-(5-fluoro-2-nitrophenyl)-3-oxobutanoate (6)
To a 300 L reactor was added THF (96 kg), t-BuOK (25 kg, 224.5 mol). The
mixture was stirred and cooled to 5 °C, ethyl acetoacetate (29.2 kg, 224.5 mol) was
added dropwise at a temperature below 15 °C. The mixture was stirred at 20 °C for
123

Manufacturing synthesis of 5-hydroxy-2-methyl-1H-indole
981
2–2.5 h. A solution of 2,4-difluoronitrobenzene (17 kg, 106.9 mol) in THF (7 kg)
was added dropwise at a temperature not excess 15 °C and the reaction was stirred
at RT overnight. TLC indicated the completion of reaction with Rf = 0.7
(PE:EA = 10:1). The reaction mixture was cooled to below 10 °C and was added
6 N HCl to adjust pH 4–5. The organic phase was separated and the aqueous phase
was extracted with ethyl acetate (30 kg). The combined organic phase was washed
with saturated NaCl aqueous solution and dried over Na2SO4 overnight. The solvent
was removed under reduced pressure and the residual liquid (intermediate 6 and
unreacted ethyl acetoacetate) was used for the next step without purification.
1-(5-Fluoro-2-nitrophenyl) propan-2-one (7)
To a 300 L reactor was added glacial acetic acid (55.2 kg) and H2SO4 (32.5 kg)
portionwise below 30 °C, the above crude product 6 was added portionwise at a
temperature not over 30 °C. The mixture was stirred and heated to 50 °C (large
amount CO2 formed). After completion of the CO2 evolution, the mixture was
heated to 70 °C for 2–3 h. TLC indicated the completion of reaction with Rf = 0.4
(PE:EA = 10:1). The mixture was cooled to RT and poured onto 120 kg ice-water
and extracted with CH2Cl2 (2 9 30 kg). The combined organic phase was washed
with 20% NaOH, saturated aqueous NaCl, and dried over Na2SO4. The solvent was
removed under reduced pressure and the residue was dissolved in methanol (5 kg)
and cooled to 0 °C. The crystal was collected by filtration, washed with petroleum
ether to afford the intermediate 7 as a yellow solid (11.2 kg, yield 53% from 5),
m.p. 54–57 °C.
1-(5-Methoxy-2-nitrophenyl)propan-2-one (8)
To a 100 L reactor was added methanol (65 kg) and the mixture was stirred and
cooled to 10 °C and added MeONa (8.1 kg, 149 mol). The above intermediate 7
(10 kg, 50 mol) was added and the reaction was stirred at 30–35 °C for 5–6 h. TLC
indicated the completion of reaction with Rf = 0.4 (PE:EA = 4:1). The reaction
mixture was poured into 120 kg ice-water. The solid was collected by filtration and
purified by a short silica gel column (packed with *2 cm activated carbon on the
top) with ethyl acetate/petroleum ether as the eluent to afford intermediate 8 as a
yellow oil (4.5 kg, yield 43%, directly used for the next step).
5-Methoxy-2-methyl-1H-indole (9)
To a 100 L reactor was added water (55 kg), THF (7.5 kg). Under stirring, sodium
dithionite (10 kg) was added, followed by the above intermediate 8 (2.9 kg,
13.8 mol), and stirred at RT for 3–4 h. TLC indicated the completion of reaction with
Rf = 0.6 (PE:EA = 10:1). The mixture was extracted with ethyl acetate (2 9 7 kg),
washed with saturated aqueous NaCl, and dried over Na2SO4. The solvent was
removed in vacuo and the residue was dissolved in ethyl acetate (2 kg), added
petroleum ether (2 kg), and cooled to 0 °C. The solid was collected by filtration to
obtain intermediate 9 (840 g, yield 37%), m.p. 83–86 °C (Ref. Aldrich 86–88 °C).
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5-Hydroxy-2-methyl-1H-indole (1)
To a 50 L reactor was added CH2Cl2 (7.5 kg), intermediate 9 (800 g, 4.9 mol), and
cooled to -8 °C. BBr3 (4.35 kg, 17.4 mol) was added dropwise below -5 °C, the
reaction was stirred at -5–0 °C for 30 min. TLC indicated the completion of
reaction with Rf = 0.7 (PE:EA = 1:2). The mixture was poured onto ice-water
(5 kg), the organic phase was separated, and the aqueous phase was extracted with
CH2Cl2 (2 9 7 kg). The combined organic phase was washed with saturated
aqueous NaCl, dried over Na2SO4. The solvent was removed in vacuo and the
residue was dissolved in methanol (400 mL) and cooled to give product 1 as a light
yellow solid (507 g, yield 69%), HPLC 98% (conditions: same as in Table 1),
m.p. 205–206 °C (lit.[39] 207–208 °C).
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