WO2006075139A2 - Novel process for the preparation of substituted indoles - Google Patents

Novel process for the preparation of substituted indoles Download PDF

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Publication number
WO2006075139A2
WO2006075139A2 PCT/GB2006/000060 GB2006000060W WO2006075139A2 WO 2006075139 A2 WO2006075139 A2 WO 2006075139A2 GB 2006000060 W GB2006000060 W GB 2006000060W WO 2006075139 A2 WO2006075139 A2 WO 2006075139A2
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Prior art keywords
formula
compound
process according
methyl
vii
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PCT/GB2006/000060
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French (fr)
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WO2006075139A3 (en
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Philip Keegan
Eric Merifield
Duncan Gill
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority to MX2007008348A priority Critical patent/MX2007008348A/en
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Priority to US11/813,816 priority patent/US7781598B2/en
Priority to AU2006205697A priority patent/AU2006205697B2/en
Priority to JP2007550831A priority patent/JP2008526936A/en
Priority to BRPI0606639-9A priority patent/BRPI0606639A2/en
Priority to EP06700281A priority patent/EP1844012A2/en
Priority to CN2006800023115A priority patent/CN101102999B/en
Priority to NZ556147A priority patent/NZ556147A/en
Priority to CA002594391A priority patent/CA2594391A1/en
Publication of WO2006075139A2 publication Critical patent/WO2006075139A2/en
Publication of WO2006075139A3 publication Critical patent/WO2006075139A3/en
Priority to IL183965A priority patent/IL183965A0/en
Priority to NO20074047A priority patent/NO20074047L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring

Definitions

  • the present invention relates to a novel process for the preparation of substituted indoles which are useful as therapeutic agents.
  • WO 04/106302 discloses a series of substituted indoles useful for the treatment of respiratory diseases.
  • the invention therefore provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:
  • R is an ester forming group, and optionally thereafter forming a pharmaceutically acceptable salt or solvate.
  • the reaction can be carried out in the presence of a base followed by treatment with acid and a ketone or ester containing solvent or mixtures of said solvents or mixtures comprising said solvents.
  • the compounds of formula (II) are treated with a base such as an alkali metal hydroxide in a suitable solvent such as an organic alcohol, preferably at elevated temperature.
  • the reaction mixture is then treated with acid at elevated temperature in the presence of ketone or ester-containing solvents to give the compound of formula (I).
  • the use of ketone and ester-containing solvents has surprisingly been found to promote crystal growth.
  • Suitable solvents include ethyl acetate, n-propylacetate and MIBK and mixtures thereof.
  • MIBK is used.
  • the compound of formula (II) is treated with aqueous sodium hydroxide in n-propanol at elevated temperature, for example at about 68°C.
  • the group R is phenyl, benzyl or a C 1-6 alkyl group such as methyl or ethyl, preferably R is C 1-6 alkyl, more preferably ethyl.
  • R is hydrogen or is as defined in formula (II) by hydrogenation followed by treatment of the resulting amine with an acetylating agent such as acetyl chloride.
  • R is an ester forming group as defined in formula (II).
  • the hydrogenation can be carried out using standard conditions such as using a platinum catalyst under a hydrogen atmosphere at elevated pressure, e.g. a pressure of about 4 bar. This reduction can also be achieved with sodium dithionite.
  • the resulting amine which is optionally isolated, for example by crystallisation from ethyl acetate/iso-hexane, is treated with acetyl chloride in a solvent such as ethyl acetate at ambient or elevated temperature, preferably at about 4O 0 C.
  • R is as defined in formula (II) and X is halogen.
  • R is ethyl and X is bromo such that the compound (V) is ethylbromoacetate.
  • the reaction is carried out in the presence of a base such as potassium carbonate in water/acetonitrile.
  • R 1 is chloro or a group that be converted to chloro such as amino or hydrogen.
  • R 1 is chloro.
  • the reaction of compounds (VI) and (VII) can be carried out using a suitable base such as sodium methoxide in methanol at elevated temperature, or a reagent such as trichloroisocyanuric acid in a solvent such as ethyl acetate or dichloromethane.
  • R is hydrogen or is as defined in formula (II) by hydrogenation and subsequent reaction of the resulting amine using analogous conditions to those described above for the hydrogenation of compound (V).
  • R is as defined in formula (II), more preferably R is ethyl.
  • Compound (IX) can be prepared from a compound of formula (VI) by reaction with a compound such as ethylbromoacetate using analogous conditions to those described above for the reaction of compound (IV).
  • compounds of formula (IH) can be prepared from compounds of formula (IX) as defined above by reacting with a compound of formula (VII) as defined above using analogous conditions to those described above for the reaction of compounds (VI) and (VII) using TCCA.
  • Trichloroisocyanuric acid (450 mg, 1.9 mmol) was added to a solution of bis(p- chlorodiphenyl)disulphide (1.63 g, 5.7 mmol) in ethyl acetate (10 ml) at ambient temperature, resulting in the formation of an orange suspension.
  • a suspension of 2-methyl-4-nitro-lH-indole (2.0 g, 11.3 mmol) in ethyl acetate 25 (10 ml) was added followed by an ethyl acetate rinse (4 ml), using water bath cooling to control the mild exotherm. Stirring was continued at ambient temperature for 40 minutes.
  • Aqueous sodium bicarbonate (5%, 20 ml) and water (20 ml) were added and the resulting suspension stirred at ambient temperature for 45 minutes.
  • the solid was collected by filtration, washed with water (2 x 10 ml), followed by ethyl acetate (2 x 10 ml) then dried in a vacuum oven at 45 0 C to provide 3-(4-chlorophenylsulfanyl)-2-methyl-4-nitro-lH-indole, 2.9 g (81%) as a yellow / brown solid.
  • Aqueous sodium hydroxide (1 M, 11.7 kg) was added to a solution of [4-acetylamino- 3 -(4-chlorophenylsulfanyl)-2-methyl-lH-indol-l-yl] acetic acid, ethyl ester (2.20 kg, 5.28 mol) in 1-propanol (8.2 kg) and the mixture heated to 68 0 C. After cooling to 40 0 C, the solution was filtered, the filter rinsed with water (1 kg) then methyl zsobutyl ketone (17.8 kg) was added to the filtrate, which was re-heated to 80 0 C.
  • Aqueous hydrochloric acid (1 M, 12.2 kg) was added over a period of 90 minutes then the mixture cooled to 19 0 C.
  • the crystalline solid was collected by filtration, washed with water (2 x 4 kg), ethyl acetate (6 kg) then dried in a vacuum oven at 40 0 C to provide [4-acetylamino-3-(4-chlorophenylsulfanyi)-2- methyl-lH-indol-l-yl]acetic acid as white crystals, 1.87 kg (91%).
  • Trichloroisocyanuric acid (0.30 g, 1.3 mmol) was added to a solution of bis(p- chlorophenyl)disulphide (1.08 g, 3.8 mmol) in ethyl acetate (10 ml) at ambient temperature is resulting in formation of a yellow suspension.
  • a slurry of (4-nitro-2-methyl-lH-indol-l-yl)-acetic acid, ethyl ester (2.0 g, 7.6 mmol) in ethyl acetate (10 ml) was added followed by an ethyl acetate rinse (4 ml), using water bath cooling to control the mild exotherm. Stirring was continued for 35 minutes at ambient temperature.
  • Aqueous sodium bicarbonate (5%, 20 ml) was added followed by water
  • Trichloroisocyanuric acid (0.15 g, 0.65 mmol) was added to a solution of bis(p- chlorophenyl)disulphide (0.55 g, 1.9 mmol) in ethyl acetate (5.25 ml) at ambient temperature resulting in formation of a yellow suspension.
  • Trichloroisocyanuric acid (0.13 g, 0.56 mmol) was added to a solution of bis(p- chlorophenyl)disulphide (0.47 g, 1.6 mmol) in ethyl acetate (5 ml) at ambient temperature resulting in formation of a yellow suspension.
  • ethyl acetate 5 ml
  • a slurry of (4-acetylamino-2 -methyl- lH-indol-l-yl)acetic acid (0.80 g, 3.2 mmol) in ethyl acetate (10 ml) was added followed by an ethyl acetate rinse (5 ml), using water bath cooling to control the mild exotherm.
  • Aqueous sodium hydroxide (1 M, 25 ml) was added to a solution of (4-nitro-2-methyl- l/J-indol-l-yl)acetic acid, ethyl ester (5.0 g, 18.9 mmol) in ethanol (25 ml) and the mixture warmed to 40 0 C. After stirring for 70 mins at this temperature, the mixture was allowed to cool back to ambient temperature and aqueous hydrochloric acid (1 M, 27.5 ml) added causing precipitation of a solid.
  • Trichloroisocyanuric acid (0.51 g, 2.2 mmol) was added to a solution of bis(p- chlorophenyl)disulphide (1.84 g, 6.4 mmol) in ethyl acetate (15 ml) at ambient temperature resulting in formation of a yellow suspension.
  • ethyl acetate 15 ml
  • a slurry of (4-nitro-2-methyl-lH-indol-l-yl)-acetic acid (3.0 g, 12.8 mmol) in ethyl acetate (30 ml) was added followed by an ethyl acetate rinse (6 ml). Stirring was continued for 40 minutes at ambient temperature.
  • the product can be converted to a compound of formula (I) by reduction of the nitro group followed by amide formation using a process analogous to that given above for [4- Acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-lH ; -indol-l-yl] acetic acid, ethyl ester: method A

Abstract

The invention relates to a novel process for the preparation of substituted indoles which are useful as therapeutic agents.

Description

NOVEL PROCESS
The present invention relates to a novel process for the preparation of substituted indoles which are useful as therapeutic agents. WO 04/106302 discloses a series of substituted indoles useful for the treatment of respiratory diseases.
New processes have now been developed for certain compounds which are more > efficient than those disclosed in the art.
In a first aspect the invention therefore provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000002_0001
(I) which comprises de-esterification of a compound of formula (II):
Figure imgf000002_0002
(H) in which R is an ester forming group, and optionally thereafter forming a pharmaceutically acceptable salt or solvate. The reaction can be carried out in the presence of a base followed by treatment with acid and a ketone or ester containing solvent or mixtures of said solvents or mixtures comprising said solvents. The compounds of formula (II) are treated with a base such as an alkali metal hydroxide in a suitable solvent such as an organic alcohol, preferably at elevated temperature. The reaction mixture is then treated with acid at elevated temperature in the presence of ketone or ester-containing solvents to give the compound of formula (I). The use of ketone and ester-containing solvents has surprisingly been found to promote crystal growth. Suitable solvents include ethyl acetate, n-propylacetate and MIBK and mixtures thereof. Preferably MIBK is used. Preferably the compound of formula (II) is treated with aqueous sodium hydroxide in n-propanol at elevated temperature, for example at about 68°C. Preferably the group R is phenyl, benzyl or a C1-6alkyl group such as methyl or ethyl, preferably R is C1-6alkyl, more preferably ethyl.
Compound of formula (II) are prepared by reaction of compounds of formula (III):
Figure imgf000003_0001
(III) in which R is hydrogen or is as defined in formula (II) by hydrogenation followed by treatment of the resulting amine with an acetylating agent such as acetyl chloride. Preferably R is an ester forming group as defined in formula (II). The hydrogenation can be carried out using standard conditions such as using a platinum catalyst under a hydrogen atmosphere at elevated pressure, e.g. a pressure of about 4 bar. This reduction can also be achieved with sodium dithionite. The resulting amine, which is optionally isolated, for example by crystallisation from ethyl acetate/iso-hexane, is treated with acetyl chloride in a solvent such as ethyl acetate at ambient or elevated temperature, preferably at about 4O0C.
Compounds of formula (III) can be prepared by reacting compounds of formula (TV):
Figure imgf000003_0002
(IV) with compounds of formula (V):
XCH2CO2R (V) in which R is as defined in formula (II) and X is halogen. Preferably R is ethyl and X is bromo such that the compound (V) is ethylbromoacetate. The reaction is carried out in the presence of a base such as potassium carbonate in water/acetonitrile.
Compounds of formula (IV) can be prepared by reacting compounds of formula (VI):
Figure imgf000004_0001
(VI) with compounds of formula (VII):
Figure imgf000004_0002
(VII) . in which R1 is chloro or a group that be converted to chloro such as amino or hydrogen. Preferably R1 is chloro. The reaction of compounds (VI) and (VII) can be carried out using a suitable base such as sodium methoxide in methanol at elevated temperature, or a reagent such as trichloroisocyanuric acid in a solvent such as ethyl acetate or dichloromethane.
In an alternative embodiment of the invention compounds of formula (II) can be prepared from compounds of formula (VIII):
Figure imgf000004_0003
(VIII) in which R is hydrogen or is as defined in formula (II) by reacting with a compound of formula (VII). The reaction can be carried out using trichloroisocyanuric acid as described above. This reaction is advantageous where R is hydrogen as it can be used for the direct preparation of compounds of formula (I).
Compounds of formula (VIII) can be prepared from compounds of formula (IX):
Figure imgf000005_0001
(IX) in which R is hydrogen or is as defined in formula (II) by hydrogenation and subsequent reaction of the resulting amine using analogous conditions to those described above for the hydrogenation of compound (V). Preferably R is as defined in formula (II), more preferably R is ethyl. Compound (IX) can be prepared from a compound of formula (VI) by reaction with a compound such as ethylbromoacetate using analogous conditions to those described above for the reaction of compound (IV).
In a still further embodiment of the invention compounds of formula (IH) can be prepared from compounds of formula (IX) as defined above by reacting with a compound of formula (VII) as defined above using analogous conditions to those described above for the reaction of compounds (VI) and (VII) using TCCA.
All novel intermediates disclosed herein form a further aspect of the invention, hi a further aspect the invention therefore provides a compound of formula (VIII) and (IX).
The following examples illustrate the invention.
Example 1 3-(4-ChlorophenylsuIfanyl)-2-methyl-4-nitro-lH-indole
Figure imgf000006_0001
Method A
Sodium methoxide in methanol (4.1 kg, 25% w/w, 19 mol) was added to a stirred suspension of 2-methyl-4-nitro-17i-indole (1.52 kg, 8.6 mol) and bis(p- io chlorophenyl)disulphide (2.48 kg, 8.6 mol) in methanol (6.47 kg) followed by a methanol line rinse (0.67 kg). The mixture was then heated at 60 - 65 0C for 3.5 hours. Water (6.1 kg) was added to the reaction mixture, which was then cooled to 20 0C and stirred at this temperature for 7 minutes. The solid was collected by filtration, washed with water (2 x 4 kg) followed by ethyl acetate (2 x 4 kg) then dried in a vacuum oven at 40 0C. 3-(4-Chlorophenylsulfanyl)-2-
I5 methyl-4-nitro-lH'-indole was obtained as a bright yellow solid, 2.57 kg (93% yield).
1H NMR (400 MHz, D6-DMSO) δ 7.77 (d, J= 7.9 Hz, IH), 7.63 (d, J= 7.6 Hz, IH), 7.27 (m, 3H), 6.92 (d, J= 8.8 Hz, 2H), 2.48 (s, 3H). LC-MS (ES+): 319 (100%, MH+).
20 Method B
Trichloroisocyanuric acid (450 mg, 1.9 mmol) was added to a solution of bis(p- chlorodiphenyl)disulphide (1.63 g, 5.7 mmol) in ethyl acetate (10 ml) at ambient temperature, resulting in the formation of an orange suspension. After stirring at ambient temperature for 30 minutes, a suspension of 2-methyl-4-nitro-lH-indole (2.0 g, 11.3 mmol) in ethyl acetate 25 (10 ml) was added followed by an ethyl acetate rinse (4 ml), using water bath cooling to control the mild exotherm. Stirring was continued at ambient temperature for 40 minutes. Aqueous sodium bicarbonate (5%, 20 ml) and water (20 ml) were added and the resulting suspension stirred at ambient temperature for 45 minutes. The solid was collected by filtration, washed with water (2 x 10 ml), followed by ethyl acetate (2 x 10 ml) then dried in a vacuum oven at 45 0C to provide 3-(4-chlorophenylsulfanyl)-2-methyl-4-nitro-lH-indole, 2.9 g (81%) as a yellow / brown solid.
f3-(4-ChlorophenvIsuIfanyl)-2-methyl-4-nitro-ljΗ-indoI-l-yl1 acetic acid, ethyl ester: method A
Figure imgf000007_0001
3-(4-Chlorophenylsulfanyl)-2-methyl-4-nitro-l/f-indole (3.76 kg, 11.8 mol) and potassium carbonate (1.80 kg, 13.0 mol) were suspended in acetonitrile (32.7 kg). Water (0.53 kg) and a solution of ethyl bromoacetate (2.17 kg, 13.0 mol) in acetonitrile (5.75 kg) were added followed by an acetonitrile line rinse (2.97 kg). The mixture was heated at 50 0C for 6 hours then allowed to cool to 20 0C and held at this temperature overnight. Water (35.4 kg) was added to the reaction mixture and stirring continued for 30 minutes at 15 0C. The solid product was collected by filtration, washed with acetonitrile (2.95 kg) then dried in a vacuum oven at 40 0C to afford [3-(4-chlorophenylsulfanyl)-2-methyl-4-nitro-lH-indol-l- yl]acetic acid, ethyl ester as a bright yellow solid, 4.33 kg (91%).
1H NMR (300 MHz, D6-DMSO) δ 7.97 (dd, J- 8.3, 0.8 Hz, IH), 7.65 (dd, J= 7.9, 0.8 Hz, IH), 7.34 (t, J= 8.1 Hz, IH), 7.26 (m, 2H), 6.92 (m, 2H), 5.40 (s, 2H), 4.19 (q, J= 7.0 Hz, 2H), 2.45 (s, 3H), 1.22 (t, J= 7.1 Hz, 3H). LC-MS (ES+): 405 (100%, MH+), 407 (MH+). |4-Acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-lJ3r-indoI-l-vn acetic acid, ethyl ester: method A
Figure imgf000008_0001
A solution of [3-(4-chlorophenylsulfanyl)-2-methyl-4-nitro-lHr-indol-l-yl]acetic acid, ethyl ester (1.99 kg, 4.92 mol) in ethyl acetate (24.2 kg) was hydrogenated in the presence of a 1% Pt / C catalyst paste (1.39 kg 44% w/w) under 4 bar A hydrogen pressure. After 2 hours hydrogen uptake had ceased so the reaction mixture was inerted then filtered through Celite o (2.60 kg). The solids were washed with ethyl acetate (3 x 8 kg) and the combined filtrates distilled until a volume of 26 L remained to leave a solution of [4-amino-3-(4- chlorophenylsulfanyl)-2-methylindol-l-yl] acetic acid, ethyl ester in ethyl acetate. This solution was cooled to 4 0C then triethylamine (0.50 kg, 4.94 mol) added, followed by an ethyl acetate line wash (0.82 kg). A solution of acetyl chloride (0.39 kg, 4.97 mol) in ethyl s acetate (3 kg) was added followed by an ethyl acetate line wash (0.76 kg). The reaction mixture was heated at 40 0C for 17 hours then water (16.9 kg) added. The reaction mixture was distilled down until 24.6 kg of distillate had been removed then cooled to 200C. The solid product was collected by filtration, washed with water (1.9 kg) followed by acetonitrile (1.6 kg) then dried in a vacuum oven at 400C to afford [4-acetylamino-3-(4- 0 chlorophenylsulfanyl)-2-methyl-lH-indol-l-yl] acetic acid, ethyl ester, 1.69 kg (82%) as an off white solid.
1H NMR (300 MHz, DMSO) δ 9.51 (s, IH), 7.46 (d, J= 7.5 Hz, IH), 7.36 - 7.25 (m, 3H), 7.11 (t, J= 8.0 Hz, IH), 6.97 (d, J= 8.7 Hz, 2H), 5.24 (s, 2H), 4.18 (q, J= 7.1 Hz, 2H), 2.39 (s, 3H)5 1.86 (s, 3H), 1.21 (t, J= 7.1 Hz, 3H). s LC-MS (ES+): 417 (100%, MH+), 419 (MH+). f4-AcetvIamino-3-(4-chlorophenvlsulfanvlV2-methvl-lH-indol-l-vllacetic Acid
Figure imgf000009_0001
Aqueous sodium hydroxide (1 M, 11.7 kg) was added to a solution of [4-acetylamino- 3 -(4-chlorophenylsulfanyl)-2-methyl-lH-indol-l-yl] acetic acid, ethyl ester (2.20 kg, 5.28 mol) in 1-propanol (8.2 kg) and the mixture heated to 68 0C. After cooling to 40 0C, the solution was filtered, the filter rinsed with water (1 kg) then methyl zsobutyl ketone (17.8 kg) was added to the filtrate, which was re-heated to 80 0C. Aqueous hydrochloric acid (1 M, 12.2 kg) was added over a period of 90 minutes then the mixture cooled to 19 0C. The crystalline solid was collected by filtration, washed with water (2 x 4 kg), ethyl acetate (6 kg) then dried in a vacuum oven at 40 0C to provide [4-acetylamino-3-(4-chlorophenylsulfanyi)-2- methyl-lH-indol-l-yl]acetic acid as white crystals, 1.87 kg (91%).
1H NMR (400 MHz, D6-DMSO) δ 9.51 (s, IH), 7.47 (d, J= 7.6 Hz, IH), 7.38 - 7.24 (m, 3H), 7.11 (t, J= 8.1 Hz, IH), 6.98 (d, J= 8.5 Hz, 2H), 5.12 (s, 2H), 2.40 (s, 3H), 1.86 (s, 3H).
LC-MS (ES+): 389 (100%, MH+), 391 (MH+).
(4-Nitro-2-methyl-lH-indol-l-yl)-acetic acid, ethyl ester
Figure imgf000009_0002
Water (4.5 ml), potassium carbonate (25.9 g, 187 mmol) and ethyl bromoacetate (20.8 ml, 188 mmol) were added sequentially to a suspension of 2-methyl-4-nitro-lH-indole (30 g, 170 mmol) in acetonitrile (225 ml) and the mixture heated at 60 0C for 16 hours. After allowing to cool to ambient temperature, water (225 ml) was added and the resulting mixture was broken up and then filtered. The solid was washed with water (2 x 75 ml), followed by IMS (2 x 75 ml) then dried in a vacuum oven to give (4-nitro-2-methyl-lH-indol-l-yl)-acetic acid, ethyl ester, 32.15 g (72%).
1H-NMR (300 MHz, D6-DMSO) δ 8.04 (d, J= 8.1 Hz, IH), 7.93 (d, J= 8.1 Hz, IH), 5 7.27 (t, J= 8.1 Hz, IH), 6.93 (s, IH), 5.25 (s, 2H), 4.17 (q, J= 7.1 Hz, 2H), 2.44 (s, 3H), 1.21 (t, J = 7. I Hz, 3H)
LC-MS (ES+): 263 (100%, MH+)
[3-(4-ChlorophenylsuIfanyl)-2-methvI-4-nitro-l£f-indol-l-vIl acetic acid, ethyl ester: it) method B
Figure imgf000010_0001
Trichloroisocyanuric acid (0.30 g, 1.3 mmol) was added to a solution of bis(p- chlorophenyl)disulphide (1.08 g, 3.8 mmol) in ethyl acetate (10 ml) at ambient temperature is resulting in formation of a yellow suspension. After stirring for 30 minutes at this temperature, a slurry of (4-nitro-2-methyl-lH-indol-l-yl)-acetic acid, ethyl ester (2.0 g, 7.6 mmol) in ethyl acetate (10 ml) was added followed by an ethyl acetate rinse (4 ml), using water bath cooling to control the mild exotherm. Stirring was continued for 35 minutes at ambient temperature. Aqueous sodium bicarbonate (5%, 20 ml) was added followed by water
20 (20 ml). After stirring for 45 minutes, ethyl acetate was removed by evaporation, the solid product collected by filtration, washed with water (2 x 10 ml), followed by 50% v/v aqueous acetonitrile (2 x 10 ml) then dried overnight in a vacuum oven at 45 0C to provide [3-(4- chlorophenylsulfanyl)-2-methyl-4-nitro-lH-indol-l-yl] acetic acid, ethyl ester as a bright yellow solid, 2.95 g (96%).
25 (4-Amino-2-methyl-lHr-indol-l-yl)-acetic acid, ethyl ester
Figure imgf000011_0001
5 A solution of (4-nitro-2-methyl-lJi-indol-l-yl)-acetic acid, ethyl ester (5.0 g, 19 mmol) in ethyl acetate (75 ml) was hydrogenated under 3 bar hydrogen pressure in the presence of a wet 1% Pt / C catalyst paste (38 w/w, 0.7 g) until hydrogen uptake ceased (3 hours). The reaction mixture was filtered through kieselguhr and the solids washed with ethyl acetate (75 ml). The filtrate and wash were combined with solutions obtained from 2 o previous experiments which had been carried out in a similar manner, each on a 2 g scale, and evaporated to dryness to provide (4-amino-2-methyl-lH-indol-l-yl)-acetic acid, ethyl ester, 8.59 g, >100% as a brown oil which solidified on standing.
1H NMR (300 MHz, D6-DMSO) δ 6.73 (t, J= 7.9 Hz, IH), 6.49 (d, J= 8.1 Hz, IH), 6.28 (s, IH), 6.15 (d, J= 7.5 Hz, IH), 5.05 (br s, 2H), 4.89 (s, 2H), 4.13 (q, J= 7.1 Hz, 2H), s 2.27 (s, 3H), 1.20 (t, J= 7.1 Hz, 3H). LC-MS (ES+): 233 (100%, MH+).
(4-Acetylamino-2-methyl-lH-indol-l-yl)-acetic acid ethyl ester
Figure imgf000011_0002
o The (4-amino-2-methyl-lH-indol-l-yl)-acetic acid, ethyl ester prepared above (8.59 g) was dissolved in ethyl acetate (175 ml) then triethylamine (5.2 ml, 37 mmol) added followed by acetyl chloride (2.6 ml, 37 mmol). An exotherm to 35 0C was observed and a thick suspension resulted. After stirring for 4 hours during which the mixture was allowed to cool back to ambient temperature, water (85 ml) was added and the ethyl acetate removed by evaporation under vacuum. The solid was collected by filtration, washed with water (25 ml) followed by 50% v/v aqueous acetonitrile (50 ml) then dried in a vacuum oven at 50 0C overnight to provide (4-acetylamino-2-methyl-lH-indol-l-yl)-acetic acid, ethyl ester, as an off-white solid, 7.26 g (77% from (4-nitro-2-methyl-lH-indol-l-yl)-acetic acid, ethyl ester). 1H NMR (300 MHz, D6-DMSO) δ 9.51 (s, IH), 7.55 (d, J= 7.7 Hz, IH), 7.07 (d, J= 8.1 Hz, IH), 6.96 (t, J= 7.9 Hz, IH), 6.50 (s, IH), 5.02 (s, 2H), 4.14 (q, J= 7.1 Hz, 2H), 2.33 (s, 3H)5 2.12 (s, 3H), 1.20 (t, J= 7.1 Hz, 3H). LC-MS (ES+): 275 (100%, MH+).
[4-Acetylamino-3-(4-chloro-phenvIsulfanyl)-2-methyl-lHr-indol-l-yll-acetic acid, ethyl ester: method B
Figure imgf000012_0001
Trichloroisocyanuric acid (0.15 g, 0.65 mmol) was added to a solution of bis(p- chlorophenyl)disulphide (0.55 g, 1.9 mmol) in ethyl acetate (5.25 ml) at ambient temperature resulting in formation of a yellow suspension. After stirring for 15 minutes at this temperature, a slurry of (4-acetylamino-2 -methyl- lH-indol-l-yl)-acetic acid, ethyl ester (1.05 g, 3.8 mmol) in ethyl acetate (5.25 ml) was added, followed by an ethyl acetate rinse (2 ml), using water bath cooling to control the mild exotherm. Stirring was continued for Ih 15 minutes at ambient temperature. Aqueous sodium bicarbonate (5%, 10.5 ml) was added followed by water (10.5 ml). After stirring for 35 minutes, the solid product was collected by filtration, washed with water (2 x 5 ml) then dried in a vacuum oven at 45 0C overnight to give [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-lH-indol-l-yl]-acetic acid, ethyl ester as a grey solid, 1.13 g, 71%). (4-Acetylamino-2-methyl-lJH-indol-l-yI)acetic acid
Figure imgf000013_0001
(4-Acetylamino-2-methyl-lH-indol-l-yl)-acetic acid, ethyl ester (2.0 g, 7.3 mmol) was slurried in ethanol (10 ml) at ambient temperature. Aqueous sodium hydroxide (I M, 10 ml, 10 mmol) was added and the mixture heated to 50 0C. The solution obtained at was then allowed to cool back to ambient temperature and aqueous hydrochloric acid (1 M, 11 ml, 11 mmol) added. The resulting solid was collected by filtration, washed with water (2 x 10 ml) then dried in a vacuum oven at 45 0C overnight to provide (4-acetylamino-2-methyl-lH- indol-l-yl)acetic acid as an off-white solid, 1.66 g (92%).
1H NMR (300 MHz, D6-DMSO) δ 12.97 (s, IH), 9.49 (s, IH), 7.54 (d, J= 7.5 Hz, IH), 7.07 (d, J= 8.1 Hz, IH), 6.95 (t, J= 7.9 Hz, IH), 6.49 (s, IH), 4.91 (s, 2H), 2.33 (d, J= 0.8 Hz, 3H), 2.12 (s, 3H) LC-MS (ES+): 247 (100%, MH+).
f4-Acetylamino-3-(4-chlorophenylsuIfanvI)-2-methyl-lH-indol-l-yIl acetic Acid: method B
Figure imgf000013_0002
Trichloroisocyanuric acid (0.13 g, 0.56 mmol) was added to a solution of bis(p- chlorophenyl)disulphide (0.47 g, 1.6 mmol) in ethyl acetate (5 ml) at ambient temperature resulting in formation of a yellow suspension. After stirring for 15 minutes at this temperature, a slurry of (4-acetylamino-2 -methyl- lH-indol-l-yl)acetic acid (0.80 g, 3.2 mmol) in ethyl acetate (10 ml) was added followed by an ethyl acetate rinse (5 ml), using water bath cooling to control the mild exotherm. Stirring was continued for 1 h 15 minutes at ambient temperature. The solid product was collected by filtration, washed with ethanol (2 x 10 ml) then dried overnight in a vacuum oven at 45 0C to provide [4-acetylamino-3-(4- chlorophenylsulfanyl)-2-methyl-lH-indol-l-yl] acetic acid as an off-white solid, 1.22 g (97%).
Example 2 (2-Methyl-4-nitro-lH-indoI-l-yI)acetic acid
Figure imgf000014_0001
Aqueous sodium hydroxide (1 M, 25 ml) was added to a solution of (4-nitro-2-methyl- l/J-indol-l-yl)acetic acid, ethyl ester (5.0 g, 18.9 mmol) in ethanol (25 ml) and the mixture warmed to 40 0C. After stirring for 70 mins at this temperature, the mixture was allowed to cool back to ambient temperature and aqueous hydrochloric acid (1 M, 27.5 ml) added causing precipitation of a solid. This was collected by filtration, washed with water (2 x 25 ml) then dried in a vacuum oven at 50 0C overnight to leave (2-methyl-4-nitro-lH-indol-l- yl)acetic acid as a yellow solid, 4.18 g (94%). 1H-NMR (300 MHz, D6-DMSO) δ 13.2 (s, IH), 8.03 (d, J= 8.1 Hz, IH), 7.93 (d, J=
8.1 Hz, IH), 7.26 (t, J= 8.1 Hz, IH), 6.92 (s, IH), 5.13 (s, 2H), 2.45 (s, 3H) LC-MS (ES+): 235 (100%, MH+) f3-(4-ChIorophenylsulfanyl)-2-methyl-4-nitro-li?-indol-l-yll acetic acid
Figure imgf000015_0001
Trichloroisocyanuric acid (0.51 g, 2.2 mmol) was added to a solution of bis(p- chlorophenyl)disulphide (1.84 g, 6.4 mmol) in ethyl acetate (15 ml) at ambient temperature resulting in formation of a yellow suspension. After stirring for 5 minutes at this temperature, a slurry of (4-nitro-2-methyl-lH-indol-l-yl)-acetic acid (3.0 g, 12.8 mmol) in ethyl acetate (30 ml) was added followed by an ethyl acetate rinse (6 ml). Stirring was continued for 40 minutes at ambient temperature. The solid product was collected by filtration, washed with ethyl acetate (2 x 10 ml) then dried overnight in a vacuum oven at 50 0C to provide [3-(4- chlorophenylsulfanyl)-2-methyl-4-nitro-lH-indol-l-yl] acetic acid as a bright yellow solid, 2.93 g. The by-product, cyanuric acid, was not removed during the work up.
1H NMR (300 MHz, D6-DMSO) δ 13.4 (s, IH), 7.97 (dd, J= 8.3, 0.8 Hz, IH), 7.64 (dd, J= 7.7, 0.8 Hz, IH), 7.34 (t, J= 8.1 Hz, IH), 7.25 (m, 2H), 6.92 (m, 2H), 5.28 (s, 2H), 2.45 (s, 3H).
LC-MS (ES+): 377 (100%, MH+), 379 (MH+).
The product can be converted to a compound of formula (I) by reduction of the nitro group followed by amide formation using a process analogous to that given above for [4- Acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-lH;-indol-l-yl] acetic acid, ethyl ester: method A

Claims

Claims
1. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000016_0001
(I) which comprises de-esterification of a compound of formula (II):
Figure imgf000016_0002
(H) in which R is an ester forming group, in the presence of a base followed by treatment with an acid and a ketone or ester containing solvent, and optionally thereafter forming a pharmaceutically acceptable salt or solvate.
2. A process according to claim 1 in which R is C1-6alkyl.
3. A process according to claim 1 or 2 in which R is ethyl.
4. A process according to any one of claims 1 to 3 which is carried out using an alkali metal hydroxide in an organic alcohol solvent.
5. A process according to any one of claims 1 to 4 which is carried out using aqueous sodium hydroxide in n-propanol.
6. A process according to any one of claims 1 to 5 which is carried out at a temperature 5 of about 68°C.
7. A process according to any one of claims 1 to 5 in which the acid treatment is carried out in the presence of ethyl acetate, n-propylacetate and MIBK and mixtures thereof.
Q 8. A process according to any one of claims 1 to 5 which the acid treatment is carried out in the presence of MIBK.
9. A compound of formula (I) prepared using the process according to any one of claims l to 8. s
10. A process for the preparation of a compound of formula (I) or (II) which comprises reaction of a compound of formula (VIII):
Figure imgf000017_0001
Q (VIII) in which R is hydrogen or is as defined in formula (II) by reacting with a compound of formula (VII).
Figure imgf000017_0002
5
(VII) in which R1 is chloro or a group that can be converted to chloro, and optionally thereafter forming a pharmaceutically acceptable salt or solvate.
11. A process for the preparation of a compound of formula (II) or the corresponding 5 carboxylic acid which comprises reducing a compound of formula (III):
Figure imgf000018_0001
(III) in which R is hydrogen or is as defined in formula (II) with sodium dithionite or by Q hydrogenation followed by amide formation.
12. A process for the preparation of a compound of formula (III) or the corresponding carboxylic acid which comprises reaction of a compound of formula (IX):
s
Figure imgf000018_0002
(IX) in which R is hydrogen or is as defined in formula (II) with a compound of formula
(VII): Q
Figure imgf000018_0003
(VII). in which R1 is chloro or a group that can be converted to chloro.
13. A process for the preparation of compounds of formula (IV) by reacting compounds of formula (VI):
Figure imgf000019_0001
(VI) with compounds of formula (VII):
-s-s R'
^ // Q
(VII) in which R1 is chloro or a group that can be converted to chloro.
14. A compound of formula (VIII) : s
Figure imgf000019_0002
(vπi) in which R is hydrogen, phenyl, benzyl or C1-6 alkyl.
Q 15. A compound of formula (IX) :
Figure imgf000020_0001
(IX) in which R is hydrogen, phenyl, benzyl or C1-6 alkyl.
PCT/GB2006/000060 2005-01-13 2006-01-09 Novel process for the preparation of substituted indoles WO2006075139A2 (en)

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