WO2011109932A1 - Novel process for the manufacture of 5-halogenated-7-azaindoles - Google Patents

Novel process for the manufacture of 5-halogenated-7-azaindoles Download PDF

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Publication number
WO2011109932A1
WO2011109932A1 PCT/CN2010/070925 CN2010070925W WO2011109932A1 WO 2011109932 A1 WO2011109932 A1 WO 2011109932A1 CN 2010070925 W CN2010070925 W CN 2010070925W WO 2011109932 A1 WO2011109932 A1 WO 2011109932A1
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Prior art keywords
compound
formula
manufacture
toluene
azaindoles
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PCT/CN2010/070925
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French (fr)
Inventor
Hongjun Gao
Stefan Hildbrand
Christoph Hoefler
Wenfa Ye
Guoliang Zhu
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Priority to PCT/CN2010/070925 priority Critical patent/WO2011109932A1/en
Priority to US13/039,383 priority patent/US20110224438A1/en
Priority to PCT/EP2011/053252 priority patent/WO2011110479A1/en
Publication of WO2011109932A1 publication Critical patent/WO2011109932A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a new process for the manufacture of 5-bromo-7-azaindole (CAS 183208-35-7) or 5-chloro-7-azaindole (CAS 866546-07-8) of formula (I).
  • the compounds of general formula (I) are valuable starting materials in the synthesis of more complex heterocyclic molecules, which may be used in many different commercial products, and inter alia as medicaments.
  • Current methods for the synthesis of the compounds of formula (I) are disclosed in US
  • the present process is thus particularly useful in large scale manufacturing of the compounds of formula (I).
  • the present invention provides a process for the manufacture of the compound of formula I
  • R and R' are independently selected from CI -4 alkyl
  • X is -CI or -Br.
  • strong base means strong organic bases like for example alkali metal amides, in particular lithium diisopropylamide (LDA), w-butyl lithium (w-BuLi).
  • CI -4 alkyl means a saturated, linear or branched hydrocarbon containing from 1 to 4 carbon-atoms.
  • An especially preferred group is the methyl group.
  • the reaction step (a) as disclosed herein is preferably carried out using a solvent selected from heptane, toluene, xylene, dimethylsulfoxide (DMSO), dimethylformamide (DMF), chlorobenze, o-dichlorobenzene, p-dichlorobenzene, m-dichlorobenzene, 2-methyltetrahydrofuran, N-methyl-2-pyrrolidone.
  • a solvent selected from heptane, toluene, xylene, dimethylsulfoxide (DMSO), dimethylformamide (DMF), chlorobenze, o-dichlorobenzene, p-dichlorobenzene, m-dichlorobenzene, 2-methyltetrahydrofuran, N-methyl-2-pyrrolidone.
  • a solvent selected from heptane, toluene, xylene, dimethylsulfoxide (DMSO), dimethylformamide
  • the reaction step (b) as disclosed herein is preferably carried out using a solvent selected from diethyl ether, methyl t-butyl ether, w-hexane and tetrahydrofUran (THF).
  • the reaction may be carried out at temperatures ranging from -85 to 30 °C.
  • strong base as used in reaction step (b) herein means lithium diethylamide, potassium diisopropylamide (KDA), lithium hexamethyldisilazide
  • TMSCH 2 Li lithium ⁇ -(trimethylsilyl)methyl amide
  • TMS 2 CHLi lithium ⁇ -(trimethylsilyl)methyl amide
  • X is -Br (compound 1). In another particularly preferred embodiment of the present invention, X is -CI (compound la).
  • X is -Br; R and R' are both methyl, and the strong base in reaction step (b) is LDA.
  • X is -CI; R and R' are both methyl, and the strong base in reaction step (b) is LDA.
  • a particularly preferred embodiment according to the present invention is the synthesis of the compound of formula (I) wherein X is -Br, starting from the compound of formula (2) and using the specific reaction conditions described in Examples 1 and 2a.
  • This oil was heated in 40 mL of toluene until complete dissolution, and was subsequently cooled to room temperature (rt). The mixture was kept at this temperature for 10 h, then cooled and kept at 0°C for 2 h for crystallization. After filtration, the solid was washed by a small amount of toluene and dried at 50°C for 6 h. The dried solid was dissolved in 15 mL toluene and refluxed with charcoal for 1 h. After filtration, charcoal was washed with toluene. The solutions were combined, cooled to 0°C and kept at this temperature for 2 h for crystallization.
  • Phase A 10 m KH 2 P0 3 , which was adjusted to pH 2.5 with H 3 P0 4
  • sample solution A suitable amount of compound 1, about 5.4-6.2 mg, was accurately weighed and dissolved in a 25 rtiL volumetric flask with solvent by ultrasound.
  • Example 2b Synthesis of 5-bromo-7-azaindole (1): 150 mL of LDA (2.0 M in THF, 0.30 mol) was added into a flask and cooled to -30°C. Then 24.2 g (0. 10 mol) of the compound of formula (4) was dissolved in 121 mL of dry THF and the solution was slowly added (within about 2 h) to keep the reaction at constant temperature for 5-6 h until the disappearance of the compound 4 was shown by HPLC analysis. Then, 37.2 mL (0.65 mol) of acetic acid in 90 mL of THF was slowly added and the resulting solution was further vigorously stirred for 10 min. Then, 150 mL of water was injected until two clear phases appeared.
  • LDA 2.0 M in THF, 0.30 mol
  • the organic layer was separated and the aqueous phase was extracted with 4x 100 mL of hot toluene (40°C).
  • the organic phases were combined and THF was removed under vacuum at 45°C.
  • the residual toluene solution was washed with 3 x 150 mL of water and 2x 150 mL of saturated sodium chloride solution, and then dried over 8 g magnesium sulfate for 1 h. After filtration, the mixture was concentrated under vacuum to furnish 22 g of a black, sticky oil. This oil was heated in 40 mL toluene until complete dissolution, and was then cooled to room temperature. The mixture was kept at this temperature for 10 h and then cooled and kept at 0°C for 2 h for crystallization.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides a novel method for manufacturing the compound of formula (I) wherein X is -Cl or-Br.

Description

Novel process for the manufacture of 5-halogenated-7-azaindoles
The present invention relates to a new process for the manufacture of 5-bromo-7-azaindole (CAS 183208-35-7) or 5-chloro-7-azaindole (CAS 866546-07-8) of formula (I).
Figure imgf000002_0001
The compounds of general formula (I) are valuable starting materials in the synthesis of more complex heterocyclic molecules, which may be used in many different commercial products, and inter alia as medicaments. Current methods for the synthesis of the compounds of formula (I) are disclosed in US
2006/0183758 and WO03/082869. The disclosed processes are multistep synthesis routes which use environmentally hazardous reagents and/or require the use of heavy metals which are difficult to remove in the subsequent steps.
It is therefore an object of the present invention to provide a process for manufacturing the compounds of formula (I) which uses few reaction steps, in particular 2 steps, and less hazardous reagents. The present process is thus particularly useful in large scale manufacturing of the compounds of formula (I).
The present invention provides a process for the manufacture of the compound of formula I
Figure imgf000003_0001
wherein,
(a) the compound of formula (II)
Figure imgf000003_0002
is reacted in the presence of the compound of formula (III)
—0
^NRR'
— 0 (in), the compound of formula (IV)
Figure imgf000003_0003
(b) said compound of formula (IV) is further reacted in the presence of a strong base to give the compound of formula (I), and wherein
R and R' are independently selected from CI -4 alkyl; and
X is -CI or -Br. The term "strong base" as used herein means strong organic bases like for example alkali metal amides, in particular lithium diisopropylamide (LDA), w-butyl lithium (w-BuLi).
The term "CI -4 alkyl" means a saturated, linear or branched hydrocarbon containing from 1 to 4 carbon-atoms. An especially preferred group is the methyl group.
The reaction step (a) as disclosed herein is preferably carried out using a solvent selected from heptane, toluene, xylene, dimethylsulfoxide (DMSO), dimethylformamide (DMF), chlorobenze, o-dichlorobenzene, p-dichlorobenzene, m-dichlorobenzene, 2-methyltetrahydrofuran, N-methyl-2-pyrrolidone. The reaction may be carried out at temperatures within the range of 60 to 120 °C.
The reaction step (b) as disclosed herein is preferably carried out using a solvent selected from diethyl ether, methyl t-butyl ether, w-hexane and tetrahydrofUran (THF). The reaction may be carried out at temperatures ranging from -85 to 30 °C.
The term "strong base" as used in reaction step (b) herein means lithium diethylamide, potassium diisopropylamide (KDA), lithium hexamethyldisilazide
(LHMDS), Sodium hexamethyldisilazide (NaHMDS), w-butyl lithium (w-BuLi), s-Butyl lithium (s-BuLi), ?-butyl lithium (?-BuLi), lithium isopropyl cyclohexylamide (LICA), lithium 2,2,6,6-tetramethylpiperidide (TMPLi), ((trimethylsilyl)methyl)lithium
(TMSCH2Li), lithium ^-(trimethylsilyl)methyl amide (TMS2CHLi), and the like.
In a particularly preferred embodiment of the present invention, X is -Br (compound 1). In another particularly preferred embodiment of the present invention, X is -CI (compound la).
In still another preferred embodiment of the present invention, X is -Br; R and R' are both methyl, and the strong base in reaction step (b) is LDA.
In still another preferred embodiment of the present invention, X is -CI; R and R' are both methyl, and the strong base in reaction step (b) is LDA.
A particularly preferred embodiment according to the present invention is the synthesis of the compound of formula (I) wherein X is -Br, starting from the compound of formula (2) and using the specific reaction conditions described in Examples 1 and 2a.
Another particularly preferred embodiment according to the present invention synthesis of the compound of formula (I), wherein X is -Br, starting from the compound of formula (2) and using the specific reaction conditions described in Examples 1 and 2b.
The invention is now illustrated by the accompanying working examples, which are not meant to limit the scope of the present invention.
Examples
Example 1 : Synthesis of N-(5-bromo-3-methyl-pyridin-2-yl)-NN-dimethyl-formamidine
Figure imgf000006_0001
(2) (4)
A mixture of 37.4 g (0.20 mol) of 2-amino-5-bromo-3-methylpyridine and 33 mL (0.25 mol) of N,N-dimethylformamide dimethyl acetal (3) was heated to reflux temperature for about 15 h (until the disappearance of the starting material was indicated by HPLC analysis). The reaction mixture was cooled and then concentrated under vacuum (35-40 mmHg) at 55°C to constant weight. Heptane (45 mL) was added in one portion and the mixture stirred for 30 min. The mixture was cooled to -20°C and then kept at this temperature for 5 h for crystallization. The crystals were filtered, washed with 30 g of cold heptane and dried under vacuum at room temperature to afford 44.55 g (92%) of compound 4 with a purity of >99 area% (HPLC).
Example 2a: Synthesis of 5-bromo-7-azaindole (1):
Figure imgf000006_0002
(4) (1 )
A four-necked flask fitted with a thermometer, adding funnel, and mechanical stirring was flushed with nitrogen for 3 times before use. To this flask, 75 mL of LDA (2.0 M in THF, 0.15 mol) was added and then cooled to -30 ± 2°C. In a separate vessel, 24.2 g (0.10 mol) of compound 4 was dissolved in 121 mL of dry THF and then the solution was injected into the adding funnel. This solution was added slowly within about 2 h. The reaction mixture was then kept at the same temperature for 5-6 h until the disappearance of the compound 4 was shown by HPLC analysis. A mixture of 20 ml (0.35 mol) of acetic acid and THF (50 mL) was then added drop wise with further vigorous stirring for 10 min. Then 150 mL of water was injected until two clear phases appeared. The organic layer was separated and the aqueous phase was extracted with 4x 100 mL of hot toluene (40°C). The organic layers were combined and THF was removed under vacuum at 45°C. The residual toluene solution was washed with 3 x 150 mL of water and 2 150 mL of saturated sodium chloride solution, and dried over 8 g MgSC>4 for 1 h. After filtration, the mixture was concentrated under vacuum to furnish 20.5 g of a black, sticky oil. This oil was heated in 40 mL of toluene until complete dissolution, and was subsequently cooled to room temperature (rt). The mixture was kept at this temperature for 10 h, then cooled and kept at 0°C for 2 h for crystallization. After filtration, the solid was washed by a small amount of toluene and dried at 50°C for 6 h. The dried solid was dissolved in 15 mL toluene and refluxed with charcoal for 1 h. After filtration, charcoal was washed with toluene. The solutions were combined, cooled to 0°C and kept at this temperature for 2 h for crystallization. The crystals were isolated by filtration, washed with cold toluene and dried at 50°C for 8 h under vacuum to afford 2.1 g of the title compound (1) with a purity of >99 % (HPLC). All filtrates were combined and concentrated. The residue was purified by column chromatography on silica gel using hexanes/ethyl acetate 10: 1 as eluent to afford additional 1.4 g of the title compound (1) with a purity of >98.9 % (HPLC). In total 3.5 g (18%) of 5-bromo-7-azaindole (1) were obtained. HPLC retention time of compound 1 : 12.307 min.
Conditions:
Column: Zorbax Eclipse Plus C18, 150 mm*4.6 mm, particle size 3.5 μπι
Column Temperature: 50°C
Mobile Phase:
Phase A: 10 m KH2P03, which was adjusted to pH 2.5 with H3P04
Phase B: Acetonitrile
Gradient:
Figure imgf000007_0001
Flow rate: 2.0 mL/min
Wavelength: UV 230 nm
Injection volume: 5 μΐ
Preparation of sample solution: A suitable amount of compound 1, about 5.4-6.2 mg, was accurately weighed and dissolved in a 25 rtiL volumetric flask with solvent by ultrasound.
Solvent: Acetonitrile/H^O 20: 80 (v/v)
Example 2b: Synthesis of 5-bromo-7-azaindole (1): 150 mL of LDA (2.0 M in THF, 0.30 mol) was added into a flask and cooled to -30°C. Then 24.2 g (0. 10 mol) of the compound of formula (4) was dissolved in 121 mL of dry THF and the solution was slowly added (within about 2 h) to keep the reaction at constant temperature for 5-6 h until the disappearance of the compound 4 was shown by HPLC analysis. Then, 37.2 mL (0.65 mol) of acetic acid in 90 mL of THF was slowly added and the resulting solution was further vigorously stirred for 10 min. Then, 150 mL of water was injected until two clear phases appeared. The organic layer was separated and the aqueous phase was extracted with 4x 100 mL of hot toluene (40°C). The organic phases were combined and THF was removed under vacuum at 45°C. The residual toluene solution was washed with 3 x 150 mL of water and 2x 150 mL of saturated sodium chloride solution, and then dried over 8 g magnesium sulfate for 1 h. After filtration, the mixture was concentrated under vacuum to furnish 22 g of a black, sticky oil. This oil was heated in 40 mL toluene until complete dissolution, and was then cooled to room temperature. The mixture was kept at this temperature for 10 h and then cooled and kept at 0°C for 2 h for crystallization. After filtration, the solid was washed by a small amount of toluene and dried at 50°C for 8 h to furnish 2.8 g of the title compound (1) with a HPLC purity of >99 %. All filtrates were combined and concentrated. The residue was purified by column chromatography on silica gel using hexanes/ethyl acetate 10: 1 as eluent to afford additional 2.2 g of the title compound (1) with a purity of >98.9 % (HPLC). In total 5.0 g (26%) of 5-bromo-7-azaindole (1) were obtained.

Claims

Claims
1. A process for the manufacture of the compound of formula (I)
Figure imgf000009_0001
wherein,
(a) the compound of formula (II)
Figure imgf000009_0002
is reacted in the presence of the compound of formula (III)
—0
^NRR'
— 0 (HI), the compound of formula (IV)
Figure imgf000009_0003
(b) said compound of formula (IV) is further reacted in the presence of a strong base to give the compound of formula (I), and wherein R and R' are independently selected from CI -4 alkyl; and X is -CI or -Br.
2. The process according to claim 1, wherein X is -Br.
3. The process according to claim 1, wherein X is -CI.
4. The process according to claim 2 or 3, wherein
R and R' are both methyl; and
the strong base used in reaction step (b) is lithium diisopropylamide (LDA).
5. The novel process substantially as described herein before.
PCT/CN2010/070925 2010-03-09 2010-03-09 Novel process for the manufacture of 5-halogenated-7-azaindoles Ceased WO2011109932A1 (en)

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US13/039,383 US20110224438A1 (en) 2010-03-09 2011-03-03 Novel process for the manufacture of 5-halogenated-7-azaindoles
PCT/EP2011/053252 WO2011110479A1 (en) 2010-03-09 2011-03-04 Process for the manufacture of 5-halogenated-7-azaindoles

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KR20160144402A (en) * 2014-04-22 2016-12-16 우니페르시테트 바젤 Novel manufacturing process for triazine, pyrimidine and pyridine derivatives
CN109053727A (en) * 2018-09-29 2018-12-21 山东轩德医药科技有限公司 A kind of preparation method of ABT-199 intermediate
CN110128421A (en) * 2018-02-09 2019-08-16 新发药业有限公司 A kind of simple and convenient process for preparing of the halogenated -7- azaindole of 5-

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CN104557917A (en) * 2014-12-12 2015-04-29 重庆博腾制药科技股份有限公司 Preparation method of 5-halogenated azacycloindole
CN108752341A (en) * 2018-08-03 2018-11-06 南京杰运医药科技有限公司 A kind of preparation method of bromo- 7 azaindoles of 5-
CN108976228A (en) * 2018-09-21 2018-12-11 华东师范大学 A kind of preparation method of 7- azaindole
CN110128422B (en) * 2019-01-04 2022-03-18 金凯(辽宁)生命科技股份有限公司 Synthesis method of 5-methoxy-7-azaindole
CN115521307B (en) * 2022-09-30 2023-09-22 甘肃皓天医药科技有限责任公司 A kind of preparation method of 5-halo-7-azaindole

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KR20160144402A (en) * 2014-04-22 2016-12-16 우니페르시테트 바젤 Novel manufacturing process for triazine, pyrimidine and pyridine derivatives
JP2017513888A (en) * 2014-04-22 2017-06-01 ウニヴェルズィテート バーゼル Novel process for producing triazine, pyrimidine and pyridine derivatives
US10100031B2 (en) 2014-04-22 2018-10-16 Universitaet Basel Manufacturing process for triazine, pyrimidine and pyridine derivatives
US10766874B2 (en) 2014-04-22 2020-09-08 Universitaet Basel Manufacturing process for triazine, pyrimidine and pyridine derivatives
KR102472711B1 (en) * 2014-04-22 2022-12-01 우니페르시테트 바젤 Novel manufacturing process for triazine, pyrimidine and pyridine derivatives
CN110128421A (en) * 2018-02-09 2019-08-16 新发药业有限公司 A kind of simple and convenient process for preparing of the halogenated -7- azaindole of 5-
CN110128421B (en) * 2018-02-09 2020-08-11 新发药业有限公司 Simple preparation method of 5-halogenated-7-azaindole
CN109053727A (en) * 2018-09-29 2018-12-21 山东轩德医药科技有限公司 A kind of preparation method of ABT-199 intermediate
CN109053727B (en) * 2018-09-29 2021-01-26 山东轩德医药科技有限公司 Preparation method of ABT-199 intermediate

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