TEPZZ_ 

767 _B_T
(19)

(11) EP 1 276 721 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.:

of the grant of the patent: C07D 209/18 (2006.01) C07D 209/42 (2006.01)
18.12.2013 Bulletin 2013/51 C07D 209/08 (2006.01) C07D 209/12 (2006.01)
C07D 403/14 (2006.01)
(21) Application number: 01927909.0
(86) International application number:
(22) Date of filing: 10.04.2001 PCT/EP2001/004113

(87) International publication number:

WO 2001/081305 (01.11.2001 Gazette 2001/44)

(54) METHYLATION OF INDOLE COMPOUNDS USING DIMETHYL CARBONATE

METHYLIERUNG VON INDOL- VERBINDUNGEN MIT DIMETHYLCARBONAT
METHYLATION DE COMPOSES D’INDOLE A L’AIDE DE DIMETHYLCARBONATE

(84) Designated Contracting States: (56) References cited:

AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU EP-A- 0 208 622 FR-A- 2 478 639
MC NL PT SE TR US-A- 4 443 615

(30) Priority: 19.04.2000 US 198203 P • ONO, YOSHIO: "Catalysis in the production and
reactions of dimethyl carbonate, an
(43) Date of publication of application: environmentally benign building block" APPL.
22.01.2003 Bulletin 2003/04 CATAL., A (1997), 155(2), 133-166, XP001042285
• BOSCH ET AL: "Rearrangement under alkaline
(73) Proprietor: F. Hoffmann-La Roche AG conditions of compounds related to tetracyclic
4070 Basel (CH) strychnos indole alkaloids" HETEROCYCLES,
vol. 22, no. 3, 1984, pages 561-564, XP001042267
(72) Inventor: JIANG, Xinglong • LISSEL M: "LIEBIGS ANNALEN DER CHEMIE,
Plainsboro, New Jersey 08536 (US) VERLAG CHEMIE GMBH. WEINHEIM, DE"
LIEBIGS ANNALEN DER CHEMIE, VERLAG
(74) Representative: Klein, Thomas CHEMIE GMBH. WEINHEIM, DE, 1987, pages
F. Hoffmann-La Roche AG 77-79, XP002125053 ISSN: 0170-2041
Patent Department • GRAY; ARCHER: "The pyridylethylation of indole
Grenzacherstrasse 124 and related reactions" JOURNAL OF THE
4070 Basel (CH) AMERICAN CHEMICAL SOCIETY., vol. 79, 1957,
pages 3554-3559, XP002186538 AMERICAN
CHEMICAL SOCIETY, WASHINGTON, DC., US
ISSN: 0002-7863
EP 1 276 721 B1

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent
Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the
Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been
paid. (Art. 99(1) European Patent Convention).

Printed by Jouve, 75001 PARIS (FR)

 EP 1 276 721 B1

Description

[0001] The invention relates to the use of dimethyl carbonate ("DMC") for the N-methylation of indole compounds.
[0002] The compound 3-(1-methylindol-3-yl)-4-(1-methyl-6-nitroindol-3-yl)-1H-pyrrole-2,5-dione is a selective inhibitor
5 of protein kinase C ("PKC") and is useful as an antimitotic agent for oral treatment of solid tumors as well as treating
autoimmune diseases such as rheumatoid arthritis. This compound is described in U.S. Patent No. 5,057,614. A synthetic
route for preparing this compound uses methyl iodide as a methylating agent (see for example, U.S. Patent No. 6,048,887,
which shows the use of methyl iodide for the N-methylation of an indole to synthesize similar compounds). Unfortunately,
methyl iodide is highly toxic and has a low boiling point The release of methyl iodide into the air is highly restricted.
10 Accordingly, there exists a need for environmentally friendly methods for methylating indole compounds.
[0003] FR 2478639 relates to a methylation of a specific indole compound. EP 0 208 622 relates to a process for
preparing an N-methyl derivatives of ergoline.
[0004] The following scheme shows a method for preparing 3-(1-methyl-3-indolyl)-4-(1-methyl-6-nitro-3-indolyl)-1H-
pyrrole-2,5-dione.
15

20

25

30

35

40

45

50

55

[0005] Common methylating agents, such as methyl halides (MeX; X=Cl, Br, I) and dimethylsulfate ("DMS"), can be

2
 EP 1 276 721 B1

used to methylate O-, C- and N- under mild reaction conditions. However, as described above for methyl iodide, these
agents pose severe concerns from environmental and process safety standpoints. On the other hand, dimethyl carbonate
is a comparatively safe, non toxic and environmentally friendly methylating agent. The by-products of its use, methanol
and carbon dioxide, are not associated with disposal problems. Moreover, for the manufacture of antimitotic agents of
5 the above class, which require two indole ring methylations, the need is double. Although it has been reported (Tondo,
P., Selva, M., and Bomben, A., Org. Synth. 1998, 76, 169) that DMC can be used to methylate the alpha position of an
arylacetonitrile, nowhere has it been suggested to use DMC for methylating indole ring containing compounds, much
less the N-methylation of indole rings.
[0006] Unfortunately, the use of DMC in prior art processes typically requires high reaction, temperatures (>180 °C),
10 a stainless steel autoclave, high pressure, and a large excess of dimethyl carbonate (as solvent and methylating agent).
With the help of catalysts, lower reaction temperatures (100 °C) can be used. However, such catalysts (e.g. crown ether)
are generally very toxic and pressurized reaction chambers are required.
[0007] The inventive use of dimethyl carbonate for N-methylation of an indole ring forms a part of the subject invention
and was disclosed in the European Patent Application WO 01/46178.
15 [0008] Therefore, the subject invention fulfills a need in the art for a green process for methylating the nitrogen atom
in an indole compound under conditions that do not require high pressure or temperature.
[0009] The subject invention provides a process for manufacturing a methylated indole compounds of the formula I

20

25

where R1 is selected from the group consisting of halogen, C1-C6 alkyl, C1-C 6 alkenyl, -OCH3, -NO2, -CHO, -CO2CH3,
and -CN, and R2 is selected from the group consisting of C1-C6 alkyl, -CO2CH3, -CN, -CHO, -NH2, -N(C1-C6 alkyl)2,
30 -(CH2)nCOOH, and -(CH 2)nCN, where n is an integer from 1 to 4, inclusive. The process comprises reacting a compound
of the formula :

35

40

wherein R1 and R2 are as above, with dimethyl carbonate in the presence of a suitable base or catalyst at ambient
pressure as defined in claim 1.
[0010] The present application also provides a process for manufacturing a compound of the formula I wherein R1 is
45 nitro and at position 6, R2 is hydrogen. The present application also provides a process for manufacturing a compound
of the formula I wherein R1 is hydrogen, R2 is acetonitrile.
[0011] Furthermore, the present application provides a process disclosed in Examples 1-4 and 6-19.
[0012] In the present description the term "alkyl", alone or in combination, signifies a straight-chain or branched-chain
alkyl group with 1 to 6 carbon atom. Examples of straight-chain and branched C1-C6 alkyl groups are methyl, ethyl,
50 propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentyls, and the isomeric hexyls.
[0013] The term "alkenyl" refers to a hydrocarbon chain as defined for alkyl having at least one olefinic double bond
(including for example, vinyl, allyl and butenyl).
[0014] The reacting is at a temperature between 120 °C and 134 °C, more preferrably between 126 °C and 130 °C.
[0015] It is preferred that the reacting is in the presence of a solvent, such as N,N-dimethylformamide and 1-methyl-
55 2-pyrrolidinone, the most preferred solvent being N,N-dimethylformamide.
[0016] Favorably, the reacting is in the presence of a phase transfer catalyst, such as tetrabutylammonium bromide
or 18-crown-6, the most favorable catalyst being tetrabutylammonium bromide. Phase transfer catalysts are known in
the art and described e.g. in Surv. Prog Chem. 9, 1-54 (1980); Chem. Unserer Zeit 12, 161-168 (1978); Makosza, in

3
 EP 1 276 721 B1

Scheffold, Modem Synthetic Methods, Bd. 1, S. 7-100, Frankfurt: Salle u. Sauerländer 1976. Polymer 20, 1048 ff. (1979).
Angew. Chem. 91, 464-472 (1979).
[0017] The process can involve reacting in the presence of potassium carbonate.
[0018] Of course the reacting can be in the presence of both potassium carbonate and tetrabutylammonium bromide
5 as catalyst.
[0019] The reaction time can vary but is readily determined by the skilled artisan. Favorable reaction times are between
0.75 hour and 36 hours, preferably between 1 hour and 26 hours, and most preferably between 1 hour and 10 hours.
[0020] Favored compounds include those where R1 is at position 6 and R2 is hydrogen (R1 is favorably nitro) and
those where R 1 is hydrogen and R2 is acetonitrile.
10 [0021] The present invention concerns also the use of the above described process for the preparation of compounds
of formula I and for the preparation of 3-(1-methylindol-3-yl)-4-(1-methyl-6-nitroindol-3-yl)-1H-pyrrole-2.5-dione.
[0022] Especially the present invention concerns a process for the preparation of 3-(1-methylindol-3-yl)-4-(1-methyl-
6-nitroindol-3-yl)-1H-pyrrole-2.5-dione comprising

15 a) a methylation of the nitrogen atom in an indole compound wherein R1 is at position 6 and R2 is hydrogen as
presently described; followed by

b) a reaction of the compound of formula I

20

25
with (COCI)2 to obtain a compound of formula II;

30

and
35
c) coupling a compound of formula II with a compound of formula III

40

[0023] Finally the present invention concerns the compound of formula I prepared by the process as presently described
45 and claimed.
[0024] The invention will now be described in terms of its preferred embodiments. These embodiments are set forth
to aid in understanding the invention but are not to be construed as limiting.
[0025] The subject N-methylation process typically requires only 2.2 equivalents of dimethyl carbonate, reasonable
temperature, and ambient pressure. The term "ambient pressure" is used herein to reflect normal atmospheric pressure.
50 The exemplified processes below generally needs only catalytic amounts of tetrabutylammonium bromide ("TBAB") or
18-crown-6 without the use of a base. Alternatively, or additionally, a base such as potassium hydroxide, sodium hy-
droxide, or potassium carbonate can by utilized. Both potassium carbonate and TBAB are easily eliminated from the
product by the following an isolation procedure that involves the addition of water. Catalytic amounts of TBAB or 18-
crown-6, as well as appropriate amounts of base, for example potassium hydroxide, sodium hydroxide or potassium
55 carbonate, are readily determinable by the skilled artisan. Generally, these amounts will be for TBAB in the range of
about five percent (5%) by weight to about eighty percent (80%) by weight of catalyst to substrate. A preferred range is
from about twenty percent (20%) by weight to about forty percent (40%) by weight of catalyst to substrate, with the range
of from about twenty percent (20%) by weight to about thirty percent (30%) by weight of catalyst to substrate being most

4
 EP 1 276 721 B1

preferred. For 18-crown-6, the amounts will generally be in the range of about five percent (5%) by weight to about ten
percent (10%) by weight of catalyst to substrate. Preferably, the 18-crown-6 is present at about five percent (5%) by
weight of catalyst to substrate.
[0026] The subject process can proceed by mixing an indole substrate with dimethyl carbonate in the presence of a
5 base or a catalyst in a suitable solvent, such as N,N-dimethylformamide ("DMF") or 1-methyl-2-pyrrolidinone ("NMP"),
followed by heating the reaction mixture to reflux for a short time (normally 2 to 3 hours). The choice of reaction temperature
is readily determinable by the skilled artisan. The reaction temperature will normally be above the boiling point of the
reagent, around 90 °C for DMC. The reaction can be quenched by adding water, after which the product can be obtained
either by filtration or by extraction with a suitable solvent. The subject process typically results in the desired product in
10 good yield with high quality. For example, when 6-nitroindole was used to conduct the reaction, 96% of 1-methyl-6-
nitroindole was obtained in 99.5% (by weight) purity. Only 0.3 % of one impurity was detected.
[0027] The process described below is a general procedure. If the product is not solid, filtration is not necessary,
instead, the desired product can be extracted from the aqueous mixture by using a suitable solvent, for example, tert-
butyl methyl ether, or ethyl acetate.
15 [0028] The effect of various substituents on the methylation of an indole system using DMC was investigated. Table
1 records the effects of several electron-withdrawing functional groups on the N-methylation reaction. There was not
much difference found in terms of either reaction time or the yields obtained of N-methylated indoles when the functional
groups are present on the phenyl ring or the pyrrole ring of the indole system. All substrates tested with this method
afforded high yields (>95%), except in the case of indole-3-carboxaldehyde where the corresponding N-methylated
20 indole was obtained in 85% yield.

Table 1. Effect of Electron Withdrawing Substituents of the N-Methylation of Indoles

25

30 R reaction time (h) Desired product yield (%)

3-CN 3.5 97
4-NO2 2 96
5-NO2 3 97
35
6-NO2 2 97
5-Br 3.5 95
6-Cl 3.5 96

40 3-CHO 3.5 85
3-CO2CH3 3.5 96

[0029] The R group can be at any position of the indole system except position 1. The reaction between indole-3-
45 carboxylic acids and dimethyl carbonate was also investigated. The selectivity between O-methylation and N-methylation
was not as high as would be expected. However, as expected, under the reaction conditions, esterfication of a carboxyl
group was somewhat faster than N-methylation. For example, the reaction of indole-3-propionic acid with dimethyl
carbonate in the presence of potassium carbonate in DMF afforded both an O,N-dimethylated substance in 65% yield
after 4 hours at refluxing temperature, together with 30% of the O-methylated product. After the reaction mixture was
50 heated to reflux for another 4 hours, only O,N-dimethylated product was obtained in 93% isolated yield. As demonstrated
in Table 2, similar results were observed with indole-3-acetic acid. But when indole-3-carboxylic acid was subjected to
the typical reaction conditions, along with 50% of the dimethylated product obtained, 45% of N-methylindole was isolated,
formed as a result of decarboxylation of indole-3-carboxylic acid at the reaction temperature (128 °C).

55

5
 5

55
50
45
40
35
30
25
20
15
10
Table 2. Differences in the Rates of N- and O-Methylation of Indolecarboxylic acids with dimethyl carbonate.

n Reaction time (h) Product yield (%)

0 5 R = R1 = Me (50)
N-Methylindole (45)
1 6 R = R1 = Me (89)
R = Me, R1 = H (8)
8 R = R1 = Me: 95
2 4 R = R1 = Me (65)

6
R = Me, R1 = H (30)
8 R = R1 = Me (93)
EP 1 276 721 B1
 EP 1 276 721 B1

[0030] As above, the substituent could be attached at any position of the indole nucleus except at position 1.
[0031] With dimethyl carbonate as a methylating agent, the N-methylation of indole system containing electron-donating
groups was also studied. For an example, N-methylation of 5-methoxyindole with dimethyl carbonate at reflux temperature
for 5 hours gave 1-methyl-5-methoxyindole in 97% isolated yield. However, other indole substrates, such as gramine,
5 indole-3-methanol, indole-3-ethanol and tryptamine gave a complex mixture of unidentified products. These results
indicated that N-methylation with dimethyl carbonate is not applicable to such indole systems.
[0032] One apsect of the invention is also the use of a process of the present invention for the preparation of compounds
of formula I

10

15

[0033] To further illustrate the utility of this method, indole-3-acetonitrile was used as a substrate to examine the
20 selectivity between methylation of an indole nitrogen and C-methylation of an activated methylene group present in the
molecule. As can be seen in Table 3 however, dimethyl carbonate can be used to preferentially N-methylate indole-3-
acetonitriles with only a small amount of concurrent C-methylation by varying the reaction conditions. In the presence
of potassium carbonate, indole-3-acetonitrile gave, along with 89% of the expected product 1-methylindol-3-acetonitrile,
the C,N-dimethylated by-product, rac.- 2-(1-methylindol-3-yl)propionitrile in 8% yield. With the assistance of a phase
25 transfer catalyst ("PTC"), such as 18-crown-6 or tetrabutylammonium bromide, the formation of the dimethylated by-
product was suppressed to about 3%. Under the latter reaction conditions, about 90% of the desired product, 1-meth-
ylindole-3-acetonitrile was isolated.

30

35

40

45 Table 3. Selectivity between N- and C-methylation of indole-3-acetonitrile

base catalyst Composition of crude reaction product (anal. HPLC) Isolated yield
I II I+II
K2CO3 89% 8% 89%
50
K2CO3 n-Bu4NBr 86.6% 9.7% 90.5%
n-Bu4NBr 93.8% 2.9% 91.5%
KOH n-Bu4NBr 94.4 % 3.1 % 80%
55 NaOH 18-crown-6 91% 3% 78%

7
 EP 1 276 721 B1

EXAMPLES

[0034] The experiments in the following examples have actually been performed.

5 Example 1

Preparation of 1-methylindole-3-acetonitrile

[0035]
10

15

20 A 500 mL, three-necked flask equipped with a thermocouple, condenser, and addition funnel was charged with indole-
3-acetonitrile (10.0g, 0.064 mol), potassium carbonate (5.0g, 36 mmol), N,N-dimethylformamide (60 mL) and dimethyl
carbonate (11.0 mL, 0.13 mol). The resulting mixture was heated to 12461°C. The progress of the reaction was monitored
by HPLC. After 10 h at this temperature, the presence of the starting indole could not be detected. The reaction mixture
was then cooled to zero to -5°C. Water (140mL) was added which resulted in the formation of a precipitate. The mixture
25 was stirred at -5 °C for 1 hour, then the solid was collected by filtration, washed with water (150 mL), and dried under
high vacuum at 45°C for 24 h to give 1-methylindole-3-acetonitrile (I and II, 9.69g, 89%) as a brown solid.

Example 2

30 Synthesis of 1-methylindole-3-acetonitrile and rac.-2-(1-methylindol-3-yl)propionitrile.

[0036]

35

40

45
A mixture of indole-3-acetonitrile (5.0g, 32.01 mmol), potassium carbonate (powder, 2.5g), dimethyl carbonate (10 mL,
118.8 mmol), N,N-dimethylformamide (40 mL) and tetrabutylammonium bromide 0.5g were mixed together and heated
to 126 °C for 6 h. Then a second portion of dimethyl carbonate (3 mL, 35.6 mmol) was added and mixture was refluxed
for another 17 h. Starting material was still present, so an third portion of dimethyl carbonate (3 mL, 35.6 mmol) was
50 added and the reaction mixture was refluxed for another 3 h. Analysis of the reaction mixture at this point showed it to
be mainly a mixture of two compounds, 1-methylindole-3-acetonitrile (86.6%) along with a second minor component
identified as rac.-2-(1-methylindol-3-yl)propionitrile (9.7%). Starting indole could not be detected. The reaction mixture
was cooled to room temperature, then was diluted with water (80 mL) and extracted with tert-butyl methyl ether (100
mL) The separated organic layer was washed twice with water (100 mL) then the solution was concentrated under
55 vacuum to ~20 mL. The concentrate was cooled in an ice-bath as heptane (100 mL) was added drop-wise with vigorous
stirring. The mixture was cooled to -15 °C and the resulting solid was filtered off, washed with heptane (50 mL) and dried
under vacuum at 25 °C to give 1-methylindole-3-acetonitrile (I) and rac.-2-(1-methylindol-3-yl)propionitrile (II).

8
 EP 1 276 721 B1

Example 3

Preparation of 1-methylindole-3-acetonitrile.

5 [0037]

10

15
A 1 L, three-necked flask equipped with a thermocouple, condenser, and addition funnel was charged with indole-3-
acetonitrile (58.0g, 90% pure = 0.334 mol), tetrabutylammonium bromide (11.6g, 36 mmol), N,N-dimethylformamide
(348 mL) and dimethyl carbonate (92.8 mL, 1.10 mol) and the resulting mixture was heated to 12661°C. The progress
of the reaction was monitored by HPLC and after 3 h at this temperature, the presence of remaining starting indole could
20 not be detected. After the reaction mixture was then cooled to zero to -5°C, water (696 mL) was added which resulted
in the formation of a precipitate. The mixture was stirred at -5 °C for 1 hour, then the solid was collected by filtration,
washed with water (150 mL) and dried under high vacuum at 45°C for 24 h to give 1-methylindole-3-acetonitrile (52.0g,
91.5%) as a brown solid.

25 Example 4

Synthesis of 1-methylindole-3-acetonitrile and rac.-2-(1-methylindol-3-yl)propionitrile.

[0038]
30

35

40

A mixture of indole-3-acetonitrile (4.0g, 25.6 mmol), potassium hydroxide (pallet, 2.5g), dimethyl carbonate (8 mL, 94.9
45 mmol), N,N-dimethylformamide (50 mL) and tetrabutylammonium bromide 0.5g were mixed together and heated to 128
°C for 10 h. Analysis of the reaction mixture at this point showed it to be mainly a mixture of two compounds, 1-methylindole-
3-acetonitrile (94.4%) along with a second minor component identified as rac.-2-(1-methylindol-3-yl)propionitrile (3.1%).
Starting indole could not be detected. The reaction mixture was cooled to room temperature, then was diluted with water
(120mL). The mixture was cooled to -15 °C ,and the precipitate was formed. The mixture was stirred at this temperature
50 for 1 h. The resulting solid was filtered off, washed with heptane (50 mL) and dried under vacuum at 25 °C to give 3.60g
of 1-methylindole-3-acetonitrile(I) and C,N-dimethylated by-product (II).

ReferenceExample 5

55 Synthesis of 1-methylindole-3-acetonitrile and rac.-2-(1-methylindol-3-yl)propionitrile.

[0039]

9
 EP 1 276 721 B1

10

A 250 mL, three-necked flask was charged with indole-3-acetonitrile (5.0g, 32.0 mmol), sodium hydroxide (pallet, 2.5g),
dimethyl carbonate (6.6. mL, 78.3 mmol), N,N-dimethylformamide (40 mL), and 25 mg of 18-crown-6. The resulting
15 mixture was heated to 127 °C for 10 h. Analysis of the reaction mixture at this point showed it to be mainly a mixture of
two compounds, 1-methylindole-3-acetonitrile (90.8%) along with a second minor component identified as rac.-2-(1-
methylindol-3-yl)propionitrile (3.0%). No starting indole was detected. The reaction mixture was cooled to room temper-
ature, then was diluted with water (100mL). The mixture was cooled to -15 °C, and a precipitate formed. The mixture
was stirred at this temperature for 1 h. The resulting solid was filtered off, washed with heptane (50 mL), and dried under
20 vacuum at 25 °C to give 4.3g of 1-methylindole-3-acetonitrile(I) and C,N-dimethylated by-product (II).

Example 6

Preparation of 1-methylindole-3-carbonitrile.
25
[0040]

30

35

A mixture of indole-3-carbonitrile (1.0g, 7.03 mmole), potassium carbonate (0.5g), N,N-dimethylformamide (10 mL) and
dimethyl carbonate (1.8 mL, 21.4 mmol) was stirred and heated to reflux, (~130 °C). The reaction (monitored by HPLC)
was complete within 3.5 h. The reaction mixture was then cooled to 3 °C and ice cold water (25 mL) was added slowly.
40 The resulting oily suspension was extracted with tert-butyl methyl ether (40 mL) and the organic phase was washed
with water (3 x 25 mL), dried and evaporated in vacuo to obtain 1.07g of the product, 1-methylindole-3-carbonitrile, as
a dark oil (97.4% yield).

Example 7
45
Preparation of 5-bromo-1-methylindole.

[0041]

50

55

5-Bromoindole (3.0g, 15.38 mmol), potassium carbonate (1.5g), N,N-dimethylformamide (20 mL) and dimethyl carbonate

10
 EP 1 276 721 B1

(3.9 mL, 46 mmol) were stirred and heated to reflux (~130 °C) for 3.5 h. The reaction was monitored by HPLC. The
mixture was then cooled to ~3 °C, and the slow addition of ice cold water (50 mL) resulted in the separation of the
product as a light brown oil. The mixture was extracted with tert-butyl methyl ether (40 mL) and the organic layer was
washed with water (3 x 25 mL). The solvent was evaporated under reduced pressure to furnish 3.06 g of 5-bromo-1-
5 methylindole as a light brown oil (94.8% yield).

Example 8

Preparation of 6-chloro-1-methylindole.
10
[0042]

15

20
6-Chloroindole (1.0g, 6.59 mmol), potassium carbonate (0.5g), N,N-dimethylformamide (10 mL) and dimethyl carbonate
(1.7 mL, 20.21 mmol) were stirred and heated to reflux (~130 °C). The starting indole was consumed within 3.5 h (as
determined by HPLC). After the mixture was then cooled to ~3 °C, ice cold water (50 mL) was added and the resulting
oily suspension was extracted with tert-butyl methyl ether (40 mL). The separated organic layer was washed with water
25 (3 x 25 mL), then was evaporated under vacuum to furnish 5-chloro-1-methylindole as a light yellow oil (1.05g, 96.1%
yield).

Example 9

30 Preparation of 1-methylindole-3-carboxaldehyde.

[0043]

35

40

A mixture of indole-3-carboxaldehyde (3g, 20.67 mmol), potassium carbonate (1.5g), N,N-dimethylformamide (20 mL)
45 and dimethyl carbonate (5.2 mL, 61 mmol) were stirred and heated to reflux (~130 °C). At various time intervals, the
progress of the reaction was monitored by HPLC and it was shown to be complete within 3.5 h. The reaction mixture
was cooled down to ~ 3 °C and ice cold water (60 mL) was slowly added. The resulting dark oily suspension was extracted
with tert-butyl methyl ether (60 mL) and the organic layer was washed with water (2 x 50 mL). The organic extract was
evaporated under reduced pressure to provide 1-methylindole-3-carboxalehyde as a dark brown oil (1.98g, 85% yield).
50
Example 10

Preparation of 1-methylindole-3-carboxylic acid methyl ester.

55 [0044]

11
 EP 1 276 721 B1

10
Indole-3-carboxylic acid methyl ester (5.0g, 28.54 mmol), potassium carbonate (2.5g), N,N-dimethylformamide (35 mL)
and dimethyl carbonate (7.2 mL, 85 mmol) were combined and the stirred mixture was heated to reflux (~130 °C). Within
3.5 h, the reaction had gone to completion as determined by HPLC analysis. After the reaction mixture was cooled to ~
3 °C, ice cold water (100 mL) was slowly added. The resulting slightly off-white solid was recovered by filtration and was
15 washed with water (2 x 50 mL). The solid was not purified further, but was dried in vacuo at 45 °C for 24 h to provide
5.2g of 1-methylindole-3-carboxylic acid methyl ester (96.3% yield).

Example 11

20 Preparation of 5-methoxy-1-methylindole.

[0045]

25

30

A mixture of 5-methoxyindole (1g, 6.79 mmol), potassium carbonate (0.5g), N,N-dimethylformamide (10 mL) and dimethyl
carbonate (1.7 mL, 20 mmol) was stirred and heated to reflux (~130 °C). The progress of the reaction was monitored
by HPLC. Within 5 h, the starting indole had been consumed and after the mixture was cooled to ~3 °C, it was treated
35 with ice cold water (30 mL). The formed precipitate was filtered off, then was washed in turn with water (2 x 30 mL) and
hexanes (30 mL). The colorless product was dried under vacuum at 25 °C for 48 h to afford 5-methoxy-1-methylindole
(1.067g, 97.4% yield).

Example 12
40
Preparation of 1-methylindole.

[0046]

45

50

Indole (10g, 85.4 mmole), potassium carbonate (5g), N,N-dimethylformamide (70 mL) and dimethyl carbonate (11 mL,
0.13 mol) were mixed together and refluxed (~130 °C) for 2 h. At this point TLC analysis of the reaction showed two
55 compounds, the N-methylated indole along with a significant amount of starting material. The reaction mixture was
cooled down to ~50 °C and a second portion of dimethyl carbonate (5.5 mL, 0.065 mol) was added. The mixture was
heated at reflux for another 7 h until TLC analysis indicated total consumption of starting indole. The reaction mixture
was cooled down to room temperature and it was slowly diluted with water (150 mL). The resulting mixture was extracted

12
 EP 1 276 721 B1

with tert-butyl methyl ether (150 mL) and the separated organic layer was washed with water (2 x 100 mL). The solvent
was evaporated in vacuo to furnish 10.8g of 1-methylindole as light yellow oil (96.5% yield).

Example 13
5
Preparation of 1-methylindoline.

[0047]

10

15

Indoline (3g, 0.025 mol), potassium carbonate (1.5g), N,N-dimethylformamide (20 mL) and dimethyl carbonate (6.4 mL ,
0.076 mol) were mixed together and heated to reflux (around 130 °C) for 14 h. The reaction, monitored by HPLC, went
20 to completion within 14 h. The reaction mixture was cooled down to room temperature, then was slowly diluted with
water (50 mL) and extracted with tert-butyl methyl ether (60 mL). The organic extract was washed with water (3 x 50
mL) and the solution was evaporated to constant weight under reduced pressure to furnish 3.13g of the product, N-
methylindoline as a light yellow oil (95% yield).

25 Example 14

Synthesis of 1-methyl-5-nitroindole.

[0048]
30

35

A 500 mL, three-necked flask equipped with a thermocouple, condenser, and addition funnel was charged with 5-
40 nitroindole (20.0g, 12.3 mmol), potassium carbonate (4.0g, 29 mmol), N,N-dimethylformamide (80 mL) and dimethyl
carbonate (22 mL, 26.14 mmol). The resulting mixture was heated to reflux. The reaction was monitored by HPLC or
TLC (solvent system: 30% ethyl acetate in heptane). An analysis of the reaction mixture after 3 h at reflux, by the above
methods, failed to detect any remaining 5-nitroindole. The reaction mixture was then cooled to 1065°C and diluted with
water (160 mL) which resulted in the formation of a yellow precipitate. After the mixture was stirred at room temperature
45 for 2 h, the solid was collected by filtration, then was washed with water (100 mL) and dried under high vacuum at
60-65°C for 24 h to give 1-methyl-4-nitroindole (21.1g, 97.1%) as a yellow solid.

Example 15

50 Synthesis of 1-methyl-4-nitroindole.

[0049]

55

13
 EP 1 276 721 B1

10 1-methyl-4-nitroindole was prepared from 4-nitroindole in 96% yield using the same experimental conditions and isolation
procedure described in Example 11 for the preparation of the isomeric 1-methyl-4-nitroindole.

Example 16

15 Preparation of 1-methylindole-3-carboxylic acid methyl ester and 1-methylindole.

[0050]

20

25

30
To a three-necked round bottom flask was charged 3-indolecarboxylic acid (2.5g, 15.51 mmol), potassium carbonate
(powder, 1.25g), N,N-dimethylformamide (20 mL) and dimethyl carbonate (3.9 mL, 46.3 mmol). As the stirred mixture
was heated to reflux (~130°C), the disappearance of starting indole was monitored by HPLC. After 5 h the reaction was
complete, then the mixture was cooled to room temperature and was partitioned between water (50 mL) and tert-butyl
35 methyl ether (100 mL). The separated organic layer was washed with water (2 x 50 mL) and the volatiles were evaporated
under reduced pressure. Purification of the obtained crude by using column chromatography over silica gel furnished
1-methylindole-3-carboxylic acid methyl ester (50 % yield) and the decarboxylated byproduct 1-methylindole (45% yield).

Example 17
40
Preparation of 1-methylindole-3-acetic acid methyl ester and 1-indole-3-acetic acid methyl ester.

[0051]

45

50

55

To a three-necked round bottom flask was charged indole-3-acetic acid (3.0g, 17.12 mmol), potassium carbonate (pow-
der, 1.5g), N,N-dimethylformamide (20 mL) and dimethyl carbonate (4.3 mL, 51.07 mmol). The resulting mixture was

14
 EP 1 276 721 B1

heated to reflux (~130°C) for 6 h at which time analysis of the reaction by HPLC indicated the starting material had been
consumed. After the reaction mixture was cooled to room temperature, it was partitioned between water (50 mL) and
tert-butyl methyl ether (60 mL). The separated organic layer was washed with water (2 x 50 mL) and the solvent was
evaporated under reduced pressure. The crude product, shown by HPLC analysis to contain 1-methylindole-3-acetic
5 acid methyl ester (89%) and 1-indole-3-acetic acid methyl ester (8%), was separated into the individual components by
using column chromatography over silica gel. Total yield 3.2 g, 2.8g for 1-methylindole-3-acetic acid methyl ester and
0.40g for 1-indole-3-acetic acid methyl ester.

Example 18
10
Preparation of 1-methylindole-3-propionic acid methyl ester and 1-indole-3-propionic acid methyl ester.

[0052]

15

20

25

A stirred mixture of indole-3-propionic acid (1.0g, 5.28 mmol), potassium carbonate (powder, 0.25g), N,N-dimethylfor-
mamide (10 mL) and dimethyl carbonate (1.33 mL , 15.7 mmol) was heated to reflux (~130°C). After the reaction had
30 been stirred for 5 h at reflux, no detectable levels of starting material remained, as determined by HPLC analysis. The
reaction mixture was cooled to room temperature, then was diluted with water (25 mL) and extracted with tert-butyl
methyl ether (40 mL). The organic layer was washed with water (2 x 50 mL) and the solution was concentrated under
reduced pressure. The crude product, shown by HPLC analysis to contain 1-methylindole-3-propionic acid methyl ester
(65%) and 1-indole-3-propionic acid methyl ester (30%), was separated into the individual products by using column
35 chromatography over silica gel. Total yield 1.01 g, 0.66 g for 1-methylindole-3-propionic acid methyl ester. 0.35 g for 1-
indole-3-propionic acid methyl ester.

Example 19

40 Preparation of 1-methyl-6-nitroindole.

[0053]

45

50

A 1L, three-necked flask equipped with a thermocouple, condenser, and addition funnel was charged with 6-nitroindole
(60.0g, 0.37 mol), potassium carbonate (12.0g, 87 mmol), N,N-dimethylformamide (240 mL) and dimethyl carbonate
(66 mL, 0.784 mol) and the resulting stirred mixture was heated to 12663°C. The progress of the reaction was monitored
55 by HPLC or TLC (solvent system: 30% ethyl acetate in heptane). After 1 h at this temperature, residual 6-nitroindole
could not be detected. Then, the reaction mixture was cooled to 1065°C and slowly diluted with water (480 mL). As the
water was added, a yellow precipitate formed. The resulting mixture was stirred at room temperature for 2 h, then the
solid was recovered by filtration, washed with water (250 mL) and dried under high vacuum at 60-65°C for 24 h to give

15
 EP 1 276 721 B1

62.6g of 1-methyl-6-nitroindole (96.1% yield) as a yellow solid.

Claims
5
1. A process for manufacturing a methylated indole compound of the formula I

10

15

where R1 is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkenyl, -OCH3, -NO2, -CHO, -CO2CH3,
20 and -CN, and R2 is selected from the group consisting of C1-C 6 alkyl, -CO2CH3, -CN, -CHO, -NH2, -N(C1-C6 alkyl)2,
-(CH2)nCOOH, and -(CH2)nCN, where n is an integer from 1 to 4, inclusive; or a compound of the formula I in which
R1 is at position 6 and R2 is hydrogen; or a compound of the formula I in which R2 is acetonitrile and R1 is hydrogen,
which comprises reacting a compound of the formula:

25

30

35
wherein R1 and R2 are as above, with dimethyl carbonate in the presence of potassium carbonate (K2CO3) and/or
tetrabutylammonium bromide (TBAB) as phase transfer catalyst, and at a temperature between 120°C and 134°C
at ambient pressure, or a process for manufacturing a compound of the formula:

40

45

50
which comprises reacting a compound of the formula:

55

16
 EP 1 276 721 B1

10
with dimethyl carbonate in the presence of potassium carbonate (K2CO3) and at a temperature between 120°C and
134°C at ambient pressure,
or a process for manufacturing a compound of the formula:

15

20

which comprises reacting a compound of the formula:

25

30

with dimethyl carbonate in the presence of potassium carbonate (K2CO3) and at a temperature between 120°C and
35 134°C at ambient pressure, or
a process for manufacturing a compound of the formula:

40

45

which comprises reacting a compound of the formula:

50

55

17
 EP 1 276 721 B1

10

with dimethyl carbonate in the presence of potassium carbonate (K2CO3) and at a temperature between 120°C and
134°C at ambient pressure, or
15 a process for manufacturing a compound of the formula:

20

25

which comprises reacting a compound of the formula:

30

35

40
with dimethyl carbonate in the presence of potassium carbonate (K2CO3) and at a temperature between 120°C and
134°C at ambient pressure, or
a process for manufacturing a compound of the formula:

45

50

which comprises reacting a compound of the formula:

55

18
 EP 1 276 721 B1

with dimethyl carbonate in the presence of potassium carbonate (K2CO3) and at a temperature between 120°C and
10 134°C at ambient pressure, or
a process for manufacturing a compound of the formula:

15

20
which comprises reacting a compound of the formula:

25

30
with dimethyl carbonate in the presence of potassium carbonate (K2CO3) and at a temperature between 120°C and
134°C at ambient pressure, or
a process for manufacturing a compound of the formula:

35

40

which comprises reacting a compound of the formula:

45

50

with dimethyl carbonate in the presence of potassium carbonate (K2CO3) and at a temperature between 120°C and
134°C at ambient pressure, or
55 a process for manufacturing a compound of the formula:

19
 EP 1 276 721 B1

10 which comprises reacting a compound of the formula:

15

20 with dimethyl carbonate in the presence of potassium carbonate (K2CO3) and at a temperature between 120°C and
134°C at ambient pressure, or
a process for manufacturing a compound of the formula:

25

30

35 which comprises reacting a compound of the formula:

40

45

with dimethyl carbonate in the presence of potassium carbonate (K2CO3) and at a temperature between 120°C and
134°C at ambient pressure, or
50 a process for manufacturing compounds of the formulae:

55

20
 EP 1 276 721 B1

10 which comprises reacting a compound of the formula:

15

20

with dimethyl carbonate in the presence of potassium carbonate (K2CO3) and at a temperature between 120°C and
134°C at ambient pressure, or
a process for manufacturing compounds of the formulae:
25

30

35
which comprises reacting a compound of the formula:

40

45

with dimethyl carbonate in the presence of potassium carbonate (K2CO3) and at a temperature between 120°C and
50 134°C at ambient pressure, or
a process for manufacturing compounds of the formulae:

55

21
 EP 1 276 721 B1

10

which comprises reacting a compound of the formula:

15

20

25
with dimethyl carbonate in the presence of potassium carbonate (K2CO3) and at a temperature between 120°C and
134°C at ambient pressure.

2. The process of claim 1, wherein the reaction is at a temperature between 126°C and 130°C.
30
3. The process of claims 1-2, wherein the reaction is in the presence of a solvent selected from the group consisting
of N,N-dimethylformamide and 1-methyl-2-pyrrolidinone.

4. The process of claims 1-3, wherein the reaction is in the presence of N,N-dimethylformamide.
35
5. The process of claims 1-4, wherein the reaction is in the presence of both potassium carbonate and tetrabutylam-
monium bromide.

6. The process of claims 1-5, wherein R1 is at position 6 and R2 is hydrogen.

40
7. The process of claims 1-6, wherein R1 is nitro.

8. The process of claims 1-5, wherein R1 is hydrogen and R 2 is acetonitrile.

45 9. A process for the preparation of 3-(1-methylindol-3-yl)-4-(1-methyl-6-nitroindol-3-yl)-1H-pyrrole-2.5-dione compris-

ing

d) a reaction as defined in claims 1 to 8 wherein R1 is at position 6 and R2 is hydrogen;

followed by
50 e) a reaction of the compound of formula I

55

22
 EP 1 276 721 B1

10 with (COCI)2 to obtain a compound of formula II;

15

20 and
f) coupling a compound of formula II with a compound of formula III

25

30
10. Use of a process of claims 1 to 8 for the preparation of compounds of formula I.

11. Use of a process of claims 1 to 9 for the preparation of 3-(1-methylindol-3-yl)-4-(1-methyl-6-nitroindol-3-yl)-1H-

pyrrole-2.5-dione.
35

Patentansprüche

1. Ein Verfahren zur Herstellung einer methylierten Indolverbindung der Formel I

40

45

50 wobei R1 aus der Gruppe bestehend aus Halogen, C1-C6-Alkyl, C1-C6-Alkenyl, -OCH3, NO 2, -CHO, -CO2CH3 und
-CN ausgewählt ist und R2 aus der Gruppe bestehend aus C1-C6-Alkyl, -CO2CH3, -CN, -CHO, -NH 2, -N(C1-C6-Alkyl)2,
-(CH2)nCOOH und -(CH2)nCN ausgewählt ist, wobei n eine ganze Zahl von 1 bis einschließlich 4 ist; oder einer
Verbindung der Formel I, wobei sich R1 an der Position 6 befindet und R2 Wasserstoff ist; oder einer Verbindung
der Formel I, wobei R2 Acetonitril ist und R1 Wasserstoff ist,
55 welches Umsetzen einer Verbindung der Formel:

23
 EP 1 276 721 B1

wobei R 1 und R2 wie vorstehend sind, mit Dimethylcarbonat in Gegenwart von Kaliumcarbonat (K2CO3) und/oder
10 Tetrabutylammoniumbromid (TBAB) als Phasentransferkatalysator und bei einer Temperatur zwischen 120°C und
134°C bei Umgebungsdruck umfasst,
oder ein Verfahren zur Herstellung einer Verbindung der Formel:

15

20

welches Umsetzen einer Verbindung der Formel:

25

30

mit Dimethylcarbonat in Gegenwart von Kaliumcarbonat (K2CO 3) und bei einer Temperatur zwischen 120°C und
35 134°C bei Umgebungsdruck umfasst,
oder ein Verfahren zur Herstellung einer Verbindung der Formel:

40

45
welches Umsetzen einer Verbindung der Formel:

50

55
mit Dimethylcarbonat in Gegenwart von Kaliumcarbonat (K2CO 3) und bei einer Temperatur zwischen 120°C und
134°C bei Umgebungsdruck umfasst, oder
ein Verfahren zur Herstellung einer Verbindung der Formel:

24
 EP 1 276 721 B1

10
welches Umsetzen einer Verbindung der Formel:

15

20

mit Dimethylcarbonat in Gegenwart von Kaliumcarbonat (K2CO 3) und bei einer Temperatur zwischen 120°C und
134°C bei Umgebungsdruck umfasst, oder
25 ein Verfahren zur Herstellung einer Verbindung der Formel:

30

35
welches Umsetzen einer Verbindung der Formel:

40

45

mit Dimethylcarbonat in Gegenwart von Kaliumcarbonat (K2CO 3) und bei einer Temperatur zwischen 120°C und
134°C bei Umgebungsdruck umfasst, oder
ein Verfahren zur Herstellung einer Verbindung der Formel:
50

55

25
 EP 1 276 721 B1

welches Umsetzen einer Verbindung der Formel:

10
mit Dimethylcarbonat in Gegenwart von Kaliumcarbonat (K2CO 3) und bei einer Temperatur zwischen 120°C und
134°C bei Umgebungsdruck umfasst, oder
ein Verfahren zur Herstellung einer Verbindung der Formel:

15

20

welches Umsetzen einer Verbindung der Formel:

25

30

mit Dimethylcarbonat in Gegenwart von Kaliumcarbonat (K2CO 3) und bei einer Temperatur zwischen 120°C und
134°C bei Umgebungsdruck umfasst, oder
35 ein Verfahren zur Herstellung einer Verbindung der Formel:

40

45 welches Umsetzen einer Verbindung der Formel:

50

55 mit Dimethylcarbonat in Gegenwart von Kaliumcarbonat (K2CO 3) und bei einer Temperatur zwischen 120°C und
134°C bei Umgebungsdruck umfasst, oder
ein Verfahren zur Herstellung einer Verbindung der Formel:

26
 EP 1 276 721 B1

10 welches Umsetzen einer Verbindung der Formel:

15

20
mit Dimethylcarbonat in Gegenwart von Kaliumcarbonat (K2CO 3) und bei einer Temperatur zwischen 120°C und
134°C bei Umgebungsdruck umfasst, oder
ein Verfahren zur Herstellung einer Verbindung der Formel:

25

30

35 welches Umsetzen einer Verbindung der Formel:

40

45

mit Dimethylcarbonat in Gegenwart von Kaliumcarbonat (K2CO 3) und bei einer Temperatur zwischen 120°C und
134°C bei Umgebungsdruck umfasst, oder
50 ein Verfahren zur Herstellung von Verbindungen der Formeln:

55

27
 EP 1 276 721 B1

10
welches Umsetzen einer Verbindung der Formel:

15

20

mit Dimethylcarbonat in Gegenwart von Kaliumcarbonat (K2CO 3) und bei einer Temperatur zwischen 120°C und
25 134°C bei Umgebungsdruck umfasst, oder
ein Verfahren zur Herstellung von Verbindungen der Formeln:

30

35

welches Umsetzen einer Verbindung der Formel:

40

45

50
mit Dimethylcarbonat in Gegenwart von Kaliumcarbonat (K2CO 3) und bei einer Temperatur zwischen 120°C und
134°C bei Umgebungsdruck umfasst, oder
ein Verfahren zur Herstellung von Verbindungen der Formeln:

55

28
 EP 1 276 721 B1

10
welches Umsetzen einer Verbindung der Formel:

15

20

25 mit Dimethylcarbonat in Gegenwart von Kaliumcarbonat (K2CO 3) und bei einer Temperatur zwischen 120°C und
134°C bei Umgebungsdruck umfasst.

2. Das Verfahren nach Anspruch 1, wobei die Umsetzung bei einer Temperatur zwischen 126°C und 130°C stattfindet.

30 3. Das Verfahren nach den Ansprüchen 1 - 2, wobei die Umsetzung in Gegenwart eines Lösungsmittels, ausgewählt
aus der Gruppe bestehend aus N,N-Dimethylformamid und 1-Methyl-2-pyrrolidinon, stattfindet.

4. Das Verfahren nach den Ansprüchen 1 - 3, wobei die Umsetzung in Gegenwart von N,N-Dimethylformamid statt-
findet.
35
5. Das Verfahren nach den Ansprüchen 1 - 4, wobei die Umsetzung in Gegenwart von sowohl Kaliumcarbonat als
auch Tetrabutylammoniumbromid stattfindet.

6. Das Verfahren nach den Ansprüchen 1 - 5, wobei sich R 1 an der Position 6 befindet und R2 Wasserstoff ist.
40
7. Das Verfahren nach den Ansprüchen 1 - 6, wobei R 1 Nitro ist.

8. Das Verfahren nach den Ansprüchen 1 - 5, wobei R 1 Wasserstoff ist und R2 Acetonitril ist.

45 9. Ein Verfahren zur Herstellung von 3-(1-Methylindol-3-yl)-4-(1-methyl-6-nitroindol-3-yl)-1H-pyrrol-2.5-dion, umfas-

send

d) eine Umsetzung wie in den Ansprüchen 1 bis 8 definiert, wobei sich R1 an der Position 6 befindet und R2
Wasserstoff ist;
50 gefolgt von
e) einer Umsetzung der Verbindung der Formel I

55

29
 EP 1 276 721 B1

10 mit (COCl)2, um eine Verbindung der Formel II zu erhalten;

15

20 und
f) Kuppeln einer Verbindung der Formel II mit einer Verbindung der Formel III

25

30
10. Verwendung eines Verfahrens nach den Ansprüchen 1 bis 8 zur Herstellung von Verbindungen der Formel I.

11. Verwendung eines Verfahrens nach den Ansprüchen 1 bis 9 zur Herstellung von 3-(1-Methylindol-3-yl)-4-(1-methyl-
6-nitroindol-3-yl)-1H-pyrrol-2.5-dion.
35

Revendications

1. Procédé de préparation d’un composé d’indole méthylé de formule I

40

45

50
où R1 est choisi dans le groupe constitué par halogène, alkyle en C1-C6, alcényle en C1-C 6, -OCH 3, -NO 2, -CHO,
-CO 2CH3 et -CN, et R2 est choisi dans le groupe constitué par alkyle en C1-C6, -CO2CH3, -CN, -CHO, -NH2, -N
(alkyle en C1-C6)2, -(CH2)nCOOH et -(CH2)nCN où n est un entier de 1 à 4 inclus ; ou d’un composé de formule 1
dans lequel R1 est en position 6 et R2 est un hydrogène ; ou d’un composé de formule 1 dans lequel R2 est un
55 acétonitrile et R1 est un hydrogène,
qui comprend la réaction d’un composé de formule :

30
 EP 1 276 721 B1

10 où R1 et R2 sont comme ci-dessus, avec du carbonate de diméthyle en présence de carbonate de potassium

(K2CO3) et/ou de bromure de tétrabutylammonium (TBAB) comme catalyseur de transfert de phase, et à une
température entre 120°C et 134°C sous pression atmosphérique,
ou procédé de préparation d’un composé de formule :

15

20

25 qui comprend la réaction d’un composé de formule :

30

35
avec du carbonate de diméthyle en présence de carbonate de potassium (K2CO3) et à une température entre 120°C
et 134°C sous pression atmosphérique,
ou procédé de préparation d’un composé de formule :

40

45

qui comprend la réaction d’un composé de formule :

50

55

avec du carbonate de diméthyle en présence de carbonate de potassium (K2CO3) et à une température entre 120°C

31
 EP 1 276 721 B1

et 134°C sous pression atmosphérique,

ou procédé de préparation d’un composé de formule :

10

15 qui comprend la réaction d’un composé de formule :

20

25

avec du carbonate de diméthyle en présence de carbonate de potassium (K2CO3) et à une température entre 120°C
et 134°C sous pression atmosphérique,
30 ou procédé de préparation d’un composé de formule :

35

40

qui comprend la réaction d’un composé de formule :

45

50

avec du carbonate de diméthyle en présence de carbonate de potassium (K2CO3) et à une température entre 120°C
55 et 134°C sous pression atmosphérique,
ou procédé de préparation d’un composé de formule :

32
 EP 1 276 721 B1

qui comprend la réaction d’un composé de formule :

10

15

avec du carbonate de diméthyle en présence de carbonate de potassium (K2CO3) et à une température entre 120°C
20 et 134°C sous pression atmosphérique,
ou procédé de préparation d’un composé de formule :

25

30
qui comprend la réaction d’un composé de formule :

35

40
avec du carbonate de diméthyle en présence de carbonate de potassium (K2CO3) et à une température entre 120°C
et 134°C sous pression atmosphérique,
ou procédé de préparation d’un composé de formule :

45

50

qui comprend la réaction d’un composé de formule :

55

33
 EP 1 276 721 B1

avec du carbonate de diméthyle en présence de carbonate de potassium (K2CO3) et à une température entre 120°C
10 et 134°C sous pression atmosphérique,
ou procédé de préparation d’un composé de formule :

15

20
qui comprend la réaction d’un composé de formule :

25

30
avec du carbonate de diméthyle en présence de carbonate de potassium (K2CO3) et à une température entre 120°C
et 134°C sous pression atmosphérique,
ou procédé de préparation d’un composé de formule :

35

40

45 qui comprend la réaction d’un composé de formule :

50

55

avec du carbonate de diméthyle en présence de carbonate de potassium (K2CO3) et à une température entre 120°C
et 134°C sous pression atmosphérique,

34
 EP 1 276 721 B1

ou procédé de préparation de composés de formule :

10

qui comprend la réaction d’un composé de formule :

15

20

25 avec du carbonate de diméthyle en présence de carbonate de potassium (K2CO3) et à une température entre 120°C
et 134°C sous pression atmosphérique,
ou procédé de préparation de composés de formule :

30

35

qui comprend la réaction d’un composé de formule :

40

45

50
avec du carbonate de diméthyle en présence de carbonate de potassium (K2CO3) et à une température entre
120°C et 134°C sous pression atmosphérique, ou procédé de préparation de composés de formule :

55

35
 EP 1 276 721 B1

10
qui comprend la réaction d’un composé de formule :

15

20

avec du carbonate de diméthyle en présence de carbonate de potassium (K2CO3) et à une température entre 120°C
25 et 134°C sous pression atmosphérique.

2. Procédé selon la revendication 1, dans lequel la réaction s’effectue à une température entre 126°C et 130°C.

3. Procédé selon les revendications 1-2, dans lequel la réaction s’effectue en présence d’un solvant choisi dans le
30 groupe constitué par le N,N-diméthylformamide et la 1-méthyl-2-pyrrolidinone.

4. Procédé selon les revendications 1-3, dans lequel la réaction s’effectue en présence de N,N-diméthylformamide.

5. Procédé selon les revendications 1-4, dans lequel la réaction s’effectue en présence à la fois de carbonate de
35 potassium et de bromure de tétrabutylammonium.

6. Procédé selon les revendications 1-5, dans lequel R1 est en position 6 et R2 est un hydrogène.

7. Procédé selon les revendications 1-6, dans lequel R1 est un groupe nitro.
40
8. Procédé selon les revendications 1-5, dans lequel R1 est un hydrogène et R2 est un acétonitrile.

9. Procédé de préparation de 3-(1-méthylindol-3-yl)-4-(1-méthyl-6-nitroindol-3-yl)-1H-pyrrole-2,5-dione, comprenant

45 d) une réaction telle que définie dans les revendications 1 à 8, où R1 est en position 6 et R2 est un hydrogène ;
suivie
e) d’une réaction du composé de formule I

50

55

avec (COCI)2 pour l’obtention d’un composé de formule II :

36
 EP 1 276 721 B1

et
f) du couplage d’un composé de formule II avec un composé de formule III
10

15

10. Utilisation d’un procédé selon les revendications 1 à 8 pour la préparation de composés de formule I.

11. Utilisation d’un procédé selon les revendications 1 à 9 pour la préparation de 3-(1-méthylindol-3-yl)-4-(1-méthyl-6-
20 nitroindol-3-yl)-1H-pyrrole-2,5-dione.

25

30

35

40

45

50

55

37
 EP 1 276 721 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European
patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be
excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 5057614 A [0002] • EP 0208622 A [0003]

• US 6048887 A [0002] • EP WO0146178 A [0007]
• FR 2478639 [0003]

Non-patent literature cited in the description

• TONDO, P. ; SELVA, M. ; BOMBEN, A. Org. Synth., • MAKOSZA. Modem Synthetic Methods, 1976, vol.
1998, vol. 76, 169 [0005] 1, 7-100 [0016]
• Surv. Prog Chem., 1980, vol. 9, 1-54 [0016] • Polymer, 1979, vol. 20, 1048 ff [0016]
• Chem. Unserer Zeit, 1978, vol. 12, 161-168 [0016] • Angew. Chem., 1979, vol. 91, 464-472 [0016]

38