WO2014189238A1 - Process for the preparation of pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof - Google Patents

Process for the preparation of pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof Download PDF

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WO2014189238A1
WO2014189238A1 PCT/KR2014/004440 KR2014004440W WO2014189238A1 WO 2014189238 A1 WO2014189238 A1 WO 2014189238A1 KR 2014004440 W KR2014004440 W KR 2014004440W WO 2014189238 A1 WO2014189238 A1 WO 2014189238A1
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formula
compound
group
mmol
optionally substituted
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PCT/KR2014/004440
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French (fr)
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Jae-Gyu Kim
Ja-Heouk Khoo
Jun-Sup Lee
Woo-Seob Shin
Su-Bin CHOI
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Yuhan Corporation
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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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C07D213/77—Hydrazine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to an improved process for preparing pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof. And also, the present invention relates to a novel intermediate useful for the process and a process for preparing the same.
  • WO2006/025716 has disclosed pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof having excellent and reversible proton pump inhibitory activity.
  • the pharmaceutically acceptable salts include an acid addition salt, such as hydrochloride.
  • WO2006/025716 has also disclosed processes for preparing the pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof, for example a process according to the following reaction scheme 1.
  • the pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof are prepared according to a process which comprises (a) adding sodium nitrite to a compound of Formula (V), followed by reducing the product with tin chloride to obtain a compound of Formula (VI); (b) reacting the compound of Formula (VI) with a compound of Formula (VII) to obtain a compound of Formula (VIII); (c) cyclizing the compound of Formula (VIII) to obtain a compound of Formula (Ib); (d) reacting the compound of Formula (Ib) with R 5 -Q to obtain a compound of Formula (Ia); and (e) reacting the compound of Formula (Ia) with R 1 -X to obtain a compound of Formula (I).
  • Said process includes reducing with tin chloride for obtaining the compound of Formula (VI).
  • lots of by-products are produced in the reducing step, which requires performing one or more unit processes for removing the by-products.
  • the by-products which are very toxic materials, may result in additional problems of environmental contamination.
  • the compound of Formula (VIII) obtained as an intermediate in said process is easily decomposed due to its unstable property to temperature and/or moisture, which leads to formation of unwanted impurities in high amounts in the subsequent reaction, thereby reducing the yield of the product.
  • the present inventors have carried out various researches in order to develop improved processes for preparing pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof, the processes of which are suitable for industrial mass production. Especially, the present inventors have carried out various researches for developing a process having new synthetic route, which can avoid both using tin chloride and preparing the unstable intermediate, i.e., the compound of Formula (VIII). As a result thereof, we have found that the preparation of pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof via a novel intermediate (hereinafter, defined as a compound of Formula 2) not only can solve said problems in the known processes but also is suitable for industrial mass production.
  • a novel intermediate hereinafter, defined as a compound of Formula 2
  • the present invention provides an improved process for preparing pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof using the novel intermediate.
  • the present invention provides said intermediate and a process for preparing the same.
  • a process for preparing a compound of Formula 1a or its salt which comprises reacting a compound of Formula 2 with a compound of Formula 3:
  • R 2 is a straight or branched C 1 ⁇ C 5 alkyl group
  • R 3 is a straight or branched C 1 ⁇ C 5 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy and cyano,
  • R 4 is hydrogen
  • R 5 is a 1,2,3,4-tetrahydroisoquinolinyl group optionally substituted with one or more substituents selected from the group consisting of C 1 ⁇ C 3 alkyl and halogen, and
  • R 6 and R 7 are, independently each other, a C 6 ⁇ C 12 aryl group optionally substituted with one or more substituents selected from the group consisting of halogen and C 1 ⁇ C 3 alkyl.
  • a process for preparing a compound of Formula 1 or its pharmaceutically acceptable salt which comprises preparing a compound of Formula 1a or its salt according to said process; and reacting the compound of Formula 1a or its salt with R 1 -X (wherein X is halogen):
  • R 1 is a straight or branched C 1 ⁇ C 5 alkyl group optionally substituted with one or more substituents selected from the group consisting of C 1 ⁇ C 3 alkoxy and pyridyl; a straight or branched C 2 ⁇ C 5 alkenyl group; or a -(CH 2 ) p -phenyl group (wherein p is 1, 2, or 3; and the phenyl ring is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, and C 1 ⁇ C 3 alkyl), and
  • R 2 , R 3 , R 4 , and R 5 are the same as defined in the above.
  • R 4 , R 5 , R 6 , and R 7 are the same as defined in the above.
  • R 4 , R 5 , R 6 , and R 7 are the same as defined in the above; and X is halogen.
  • the pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof are prepared via a novel intermediate, i.e., a compound of Formula 2.
  • the compound of Formula 2 which contains a C 6 ⁇ C 12 aryl group having abundant electron density as the R 6 and R 7 substituents, shows better stability in comparison with a corresponding compound containing alkyl groups.
  • the compound of Formula 2 contains an electron-donating group such as 1,2,3,4-tetrahydroisoquinolinyl group as the R 5 substituent, thereby increasing the reactivity for cyclization, which makes it possible to prepare the compound of Formula 1a under mild condition, leading to high yield. Therefore, the process of the present invention can solve the problems in the known processes which involve both using tin chloride and preparing the unstable intermediate, i.e., the compound of Formula (VIII). In addition, the process of the present invention is suitable for industrial mass production.
  • the present invention provides a process for preparing a compound of Formula 1a or its salt, which comprises reacting a compound of Formula 2 with a compound of Formula 3:
  • R 2 is a straight or branched C 1 ⁇ C 5 alkyl group
  • R 3 is a straight or branched C 1 ⁇ C 5 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy and cyano,
  • R 4 is hydrogen
  • R 5 is a 1,2,3,4-tetrahydroisoquinolinyl group optionally substituted with one or more substituents selected from the group consisting of C 1 ⁇ C 3 alkyl and halogen, and
  • R 6 and R 7 are, independently each other, a C 6 ⁇ C 12 aryl group optionally substituted with one or more substituents selected from the group consisting of halogen and C 1 ⁇ C 3 alkyl.
  • R 2 may be a straight or branched C 1 ⁇ C 3 alkyl group; and R 3 may be a straight or branched C 1 ⁇ C 3 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy and cyano.
  • R 2 may be methyl; and R 3 may be methyl, ethyl, propyl, hydroxyethyl, or cyanoethyl.
  • R 6 and R 7 may be, independently each other, a phenyl or naphthyl group optionally substituted with one or more substituents selected from the group consisting of halogen and C 1 ⁇ C 3 alkyl.
  • the reaction between the compound of Formula 2 and the compound of Formula 3 may be carried out preferably in the presence of an acid.
  • the acid may be is one or more selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, formic acid, sulfonic acid, and p -toluenesulfonic acid.
  • the acid may be p -toluenesulfonic acid or hydrochloric acid.
  • the acid may be used e.g., in an amount of 1 to 5 equivalents based on the compound of Formula 2, but not limited thereto.
  • reaction between the compound of Formula 2 and the compound of Formula 3 may be carried out in one or more solvents selected from the group consisting of dichloromethane, dichloroethane, N,N -dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, C 1 ⁇ C 5 alcohol, ethyl acetate, and toluene.
  • the solvent may be preferably C 1 ⁇ C 5 alcohol, such as methanol, ethanol, isopropyl alcohol, butanol, etc, more preferably ethanol.
  • the reaction between the compound of Formula 2 and the compound of Formula 3 may be carried out at 40°C to 150°C, preferably at 60°C to 85°C.
  • the compound of Formula 1a obtained from the reaction of the compound of Formula 2 and the compound of Formula 3 may be isolated in a free base form, or in a salt form with an organic acid or inorganic acid (for example, in a hydrochloride form) according to conventional methods.
  • the present invention also provides a process for preparing a compound of Formula 1 or its pharmaceutically acceptable salt, which comprises preparing a compound of Formula 1a or its salt according to said process; and reacting the compound of Formula 1a or its salt with R 1 -X (wherein X is halogen):
  • R 1 is a straight or branched C 1 ⁇ C 5 alkyl group optionally substituted with one or more substituents selected from the group consisting of C 1 ⁇ C 3 alkoxy and pyridyl; a straight or branched C 2 ⁇ C 5 alkenyl group; or a -(CH 2 ) p -phenyl group (wherein p is 1, 2, or 3; and the phenyl ring is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, and C 1 ⁇ C 3 alkyl), and
  • R 2 , R 3 , R 4 , and R 5 are the same as defined in the above.
  • R 1 may be allyl; R 2 may be a straight or branched C 1 ⁇ C 3 alkyl group; and R 3 may be a straight or branched C 1 ⁇ C 3 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy and cyano.
  • R 1 may be allyl; R 2 may be methyl; and R 3 may be methyl, ethyl, propyl, hydroxyethyl, or cyanoethyl.
  • the step for preparing the compound of Formula 1a or its salt is carried out according to the process described in the above.
  • the reaction between the compound of Formula 1a or its salt and R 1 -X may be carried out according to the process disclosed in WO2006/025716.
  • the process may further comprise a step for obtaining the compound of Formula 1 as an acid addition salt with an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, formic acid, sulfonic acid, etc.
  • the present invention provides a novel intermediate useful for preparing the compound of Formula 1a or its salt, i.e., the compound of Formula 2:
  • R 4 , R 5 , R 6 , and R 7 are the same as defined in the above.
  • R 6 and R 7 may be, independently each other, a phenyl or naphthyl group optionally substituted with one or more substituents selected from the group consisting of halogen and C 1 ⁇ C 3 alkyl.
  • the present invention also provides a process for preparing the compound of Formula 2. That is, the present invention provides a process for preparing a compound of Formula 2, which comprises reacting a compound of Formula 4 with a compound of Formula 5:
  • R 4 , R 5 , R 6 , and R 7 are the same as defined in the above; and X is halogen.
  • the reaction between the compound of Formula 4 and the compound of Formula 5 may be carried out in the presences of a metal catalyst, a ligand, and a base.
  • the metal catalyst may be one or more selected from the group consisting of palladium, copper, iron, cadmium, zinc, and nickel.
  • the metal catalyst may be palladium acetate, palladium acetylacetonate, bis(dibenzylideneacetone)palladium, or tris(dibenzylideneacetone)dipalladium.
  • the ligand may be one or more selected from the group consisting of 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP), 1,1'-bis(diphenylphosphino)ferrocene (DPPF), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), preferably 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP).
  • BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene
  • DPPF 1,1'-bis(diphenylphosphino)ferrocene
  • Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
  • BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene
  • the base which functions as an acid acceptor, may be one or more selected from the group consisting of potassium tert -butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, potassium phosphate (including potassium phosphate monobasic, potassium phosphate dibasic, and potassium phosphate tribasic), sodium phosphate (including sodium phosphate monobasic, sodium phosphate dibasic, and sodium phosphate tribasic), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, triethylamine, diisopropylamine, and diisopropylethylamine.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DABCO 1,4-diazabic
  • reaction between the compound of Formula 4 and the compound of Formula 5 may be carried out in one or more solvents selected from the group consisting of dichloromethane, dichloroethane, N,N -dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, C 1 ⁇ C 5 alcohol, ethyl acetate, and toluene.
  • the solvent may be preferably C 1 ⁇ C 5 alcohol, such as methanol, ethanol, isopropyl alcohol, butanol, etc, more preferably tert -butanol.
  • the reaction between the compound of Formula 4 and the compound of Formula 5 may be carried out at 40°C to 150°C, preferably at 70°C to 90°C.
  • the compound of Formula 4 and the compound of Formula 5, which are known compounds, are commercially available or may be prepared according to conventional methods.
  • the compound of Formula 4 may be prepared by reacting a compound of Formula 6 having 2 halogen groups with R 5 H:
  • R 4 is the same as defined in the above; and X and X' are, independently each other, halogen.
  • the reaction between the compound of Formula 6 and R 5 H may be carried out in the presence of one or more bases selected from the group consisting of potassium tert -butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, potassium phosphate (including potassium phosphate monobasic, potassium phosphate dibasic, and potassium phosphate tribasic), sodium phosphate (including sodium phosphate monobasic, sodium phosphate dibasic, and sodium phosphate tribasic), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, triethylamine, diisopropylamine, and diisopropylethylamine, preferably in the presence of diisopropylamine.
  • bases selected from the group consisting of potassium ter
  • the reaction between the compound of Formula 6 and R 5 H may be in the presence of or in the absence of a solvent. If the reaction is carried out in the presence of a solvent, the solvent may be one or more selected from the group consisting of dichloromethane, dichloroethane, N,N -dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, C 1 ⁇ C 5 alcohol, ethyl acetate, and toluene. And also, the reaction between the compound of Formula 6 and R 5 H may be carried out at 40°C to 150°C.
  • Step 2 N-benzhydrylidene-N'-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-hydrazine
  • the reaction mixture was sequentially washed with purified water, a 1N aqueous solution of hydrochloric acid, a 9% aqueous solution of sodium bicarbonate, and purified water.
  • the reaction mixture was concentrated under reduced pressure to give 2.8 g of the titled compound. (Yield: 83.9%)
  • the reaction mixture was sequentially washed with purified water, a 1N aqueous solution of hydrochloric acid, a 9% aqueous solution of sodium bicarbonate, and purified water.
  • the reaction mixture was concentrated under reduced pressure to give 2.4 g of the titled compound. (Yield: 83.1%)
  • the reaction mixture was sequentially washed with purified water, a 1N aqueous solution of hydrochloric acid, a 9% aqueous solution of sodium bicarbonate, and purified water.
  • the reaction mixture was concentrated under reduced pressure to give 3.0 g of the titled compound. (Yield: 86.2%)
  • Step 1 7-bromo-2-(3-bromo-pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline
  • Step 2 N-benzhydrylidene-N'-[2-(7-bromo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-hydrazine
  • the reaction mixture was sequentially washed with purified water, a 1N aqueous solution of hydrochloric acid, a 9% aqueous solution of sodium bicarbonate, and purified water.
  • the reaction mixture was concentrated under reduced pressure to give 1.4 g of the titled compound. (Yield: 53.6%)
  • Step 2 N-benzhydrylidene-N'-[2-(7-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-hydrazine
  • the reaction mixture was sequentially washed with purified water, a 1N aqueous solution of hydrochloric acid, a 9% aqueous solution of sodium bicarbonate, and purified water.
  • the reaction mixture was concentrated under reduced pressure to give 1.4 g of the titled compound. (Yield: 50.7%)
  • Step 1 2-(2-methyl-3-propyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
  • Step 1 2-[7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl]-ethanol
  • Step 2 2-[1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl]-ethanol
  • Step 1 3-[7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl]-propionitrile
  • Step 2 3-[1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl]-propionitrile hydrochloride
  • Step 1 7-bromo-2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
  • Step 2 2-(1-allyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-7-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride
  • Step 1 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-7-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride

Abstract

The present invention provides an improved process for preparing pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof having excellent and reversible proton pump inhibitory activity. And also, the present invention provides a novel intermediate useful for the process and a process for preparing the same.

Description

PROCESS FOR THE PREPARATION OF PYRROLO[2,3-C]PYRIDINE DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
The present invention relates to an improved process for preparing pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof. And also, the present invention relates to a novel intermediate useful for the process and a process for preparing the same.
WO2006/025716 has disclosed pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof having excellent and reversible proton pump inhibitory activity. The pharmaceutically acceptable salts include an acid addition salt, such as hydrochloride. WO2006/025716 has also disclosed processes for preparing the pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof, for example a process according to the following reaction scheme 1.
<Reaction scheme 1>
Figure PCTKR2014004440-appb-I000001
Specifically, the pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof are prepared according to a process which comprises (a) adding sodium nitrite to a compound of Formula (V), followed by reducing the product with tin chloride to obtain a compound of Formula (VI); (b) reacting the compound of Formula (VI) with a compound of Formula (VII) to obtain a compound of Formula (VIII); (c) cyclizing the compound of Formula (VIII) to obtain a compound of Formula (Ib); (d) reacting the compound of Formula (Ib) with R5-Q to obtain a compound of Formula (Ia); and (e) reacting the compound of Formula (Ia) with R1-X to obtain a compound of Formula (I).
Said process includes reducing with tin chloride for obtaining the compound of Formula (VI). However, lots of by-products are produced in the reducing step, which requires performing one or more unit processes for removing the by-products. The by-products, which are very toxic materials, may result in additional problems of environmental contamination. And also, the compound of Formula (VIII) obtained as an intermediate in said process is easily decomposed due to its unstable property to temperature and/or moisture, which leads to formation of unwanted impurities in high amounts in the subsequent reaction, thereby reducing the yield of the product.
The present inventors have carried out various researches in order to develop improved processes for preparing pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof, the processes of which are suitable for industrial mass production. Especially, the present inventors have carried out various researches for developing a process having new synthetic route, which can avoid both using tin chloride and preparing the unstable intermediate, i.e., the compound of Formula (VIII). As a result thereof, we have found that the preparation of pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof via a novel intermediate (hereinafter, defined as a compound of Formula 2) not only can solve said problems in the known processes but also is suitable for industrial mass production.
Therefore, the present invention provides an improved process for preparing pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof using the novel intermediate.
And also, the present invention provides said intermediate and a process for preparing the same.
In accordance with an aspect of the present invention, there is provided a process for preparing a compound of Formula 1a or its salt, which comprises reacting a compound of Formula 2 with a compound of Formula 3:
<Formula 1a>
Figure PCTKR2014004440-appb-I000002
<Formula 2>
Figure PCTKR2014004440-appb-I000003
<Formula 3>
Figure PCTKR2014004440-appb-I000004
wherein,
R2 is a straight or branched C1∼C5 alkyl group,
R3 is a straight or branched C1∼C5 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy and cyano,
R4 is hydrogen,
R5 is a 1,2,3,4-tetrahydroisoquinolinyl group optionally substituted with one or more substituents selected from the group consisting of C1∼C3 alkyl and halogen, and
R6 and R7 are, independently each other, a C6∼C12 aryl group optionally substituted with one or more substituents selected from the group consisting of halogen and C1∼C3 alkyl.
According to another aspect of the present invention, there is provided a process for preparing a compound of Formula 1 or its pharmaceutically acceptable salt, which comprises preparing a compound of Formula 1a or its salt according to said process; and reacting the compound of Formula 1a or its salt with R1-X (wherein X is halogen):
<Formula 1>
Figure PCTKR2014004440-appb-I000005
<Formula 1a>
Figure PCTKR2014004440-appb-I000006
wherein,
R1 is a straight or branched C1∼C5 alkyl group optionally substituted with one or more substituents selected from the group consisting of C1∼C3 alkoxy and pyridyl; a straight or branched C2∼C5 alkenyl group; or a -(CH2)p-phenyl group (wherein p is 1, 2, or 3; and the phenyl ring is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, and C1∼C3 alkyl), and
R2, R3, R4, and R5 are the same as defined in the above.
According to still another aspect of the present invention, there is provided a compound of Formula 2:
<Formula 2>
Figure PCTKR2014004440-appb-I000007
wherein, R4, R5, R6, and R7 are the same as defined in the above.
According to still another aspect of the present invention, there is provided a process for preparing a compound of Formula 2, which comprises reacting a compound of Formula 4 with a compound of Formula 5:
<Formula 2>
Figure PCTKR2014004440-appb-I000008
<Formula 4>
Figure PCTKR2014004440-appb-I000009
<Formula 5>
Figure PCTKR2014004440-appb-I000010
wherein, R4, R5, R6, and R7 are the same as defined in the above; and X is halogen.
In the process of the present invention, the pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof are prepared via a novel intermediate, i.e., a compound of Formula 2. The compound of Formula 2, which contains a C6∼C12 aryl group having abundant electron density as the R6 and R7 substituents, shows better stability in comparison with a corresponding compound containing alkyl groups. And also, the compound of Formula 2 contains an electron-donating group such as 1,2,3,4-tetrahydroisoquinolinyl group as the R5 substituent, thereby increasing the reactivity for cyclization, which makes it possible to prepare the compound of Formula 1a under mild condition, leading to high yield. Therefore, the process of the present invention can solve the problems in the known processes which involve both using tin chloride and preparing the unstable intermediate, i.e., the compound of Formula (VIII). In addition, the process of the present invention is suitable for industrial mass production.
The present invention provides a process for preparing a compound of Formula 1a or its salt, which comprises reacting a compound of Formula 2 with a compound of Formula 3:
<Formula 1a>
Figure PCTKR2014004440-appb-I000011
<Formula 2>
Figure PCTKR2014004440-appb-I000012
<Formula 3>
Figure PCTKR2014004440-appb-I000013
wherein,
R2 is a straight or branched C1∼C5 alkyl group,
R3 is a straight or branched C1∼C5 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy and cyano,
R4 is hydrogen,
R5 is a 1,2,3,4-tetrahydroisoquinolinyl group optionally substituted with one or more substituents selected from the group consisting of C1∼C3 alkyl and halogen, and
R6 and R7 are, independently each other, a C6∼C12 aryl group optionally substituted with one or more substituents selected from the group consisting of halogen and C1∼C3 alkyl.
In an embodiment, R2 may be a straight or branched C1∼C3 alkyl group; and R3 may be a straight or branched C1∼C3 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy and cyano. In another embodiment, R2 may be methyl; and R3 may be methyl, ethyl, propyl, hydroxyethyl, or cyanoethyl. In still another embodiment, R6 and R7 may be, independently each other, a phenyl or naphthyl group optionally substituted with one or more substituents selected from the group consisting of halogen and C1∼C3 alkyl.
The reaction between the compound of Formula 2 and the compound of Formula 3 may be carried out preferably in the presence of an acid. The acid may be is one or more selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, formic acid, sulfonic acid, and p-toluenesulfonic acid. Preferably, the acid may be p-toluenesulfonic acid or hydrochloric acid. The acid may be used e.g., in an amount of 1 to 5 equivalents based on the compound of Formula 2, but not limited thereto. And also, the reaction between the compound of Formula 2 and the compound of Formula 3 may be carried out in one or more solvents selected from the group consisting of dichloromethane, dichloroethane, N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, C1∼C5 alcohol, ethyl acetate, and toluene. The solvent may be preferably C1∼C5 alcohol, such as methanol, ethanol, isopropyl alcohol, butanol, etc, more preferably ethanol. The reaction between the compound of Formula 2 and the compound of Formula 3 may be carried out at 40℃ to 150℃, preferably at 60℃ to 85℃. The compound of Formula 1a obtained from the reaction of the compound of Formula 2 and the compound of Formula 3 may be isolated in a free base form, or in a salt form with an organic acid or inorganic acid (for example, in a hydrochloride form) according to conventional methods.
The present invention also provides a process for preparing a compound of Formula 1 or its pharmaceutically acceptable salt, which comprises preparing a compound of Formula 1a or its salt according to said process; and reacting the compound of Formula 1a or its salt with R1-X (wherein X is halogen):
<Formula 1>
Figure PCTKR2014004440-appb-I000014
<Formula 1a>
Figure PCTKR2014004440-appb-I000015
wherein,
R1 is a straight or branched C1∼C5 alkyl group optionally substituted with one or more substituents selected from the group consisting of C1∼C3 alkoxy and pyridyl; a straight or branched C2∼C5 alkenyl group; or a -(CH2)p-phenyl group (wherein p is 1, 2, or 3; and the phenyl ring is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, and C1∼C3 alkyl), and
R2, R3, R4, and R5 are the same as defined in the above.
In an embodiment, R1 may be allyl; R2 may be a straight or branched C1∼C3 alkyl group; and R3 may be a straight or branched C1∼C3 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy and cyano. In another embodiment, R1 may be allyl; R2 may be methyl; and R3 may be methyl, ethyl, propyl, hydroxyethyl, or cyanoethyl.
In the process for preparing a compound of Formula 1 or its pharmaceutically acceptable salt, the step for preparing the compound of Formula 1a or its salt is carried out according to the process described in the above. The reaction between the compound of Formula 1a or its salt and R1-X may be carried out according to the process disclosed in WO2006/025716. If necessary, the process may further comprise a step for obtaining the compound of Formula 1 as an acid addition salt with an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, formic acid, sulfonic acid, etc.
The present invention provides a novel intermediate useful for preparing the compound of Formula 1a or its salt, i.e., the compound of Formula 2:
<Formula 2>
Figure PCTKR2014004440-appb-I000016
wherein, R4, R5, R6, and R7 are the same as defined in the above.
In an embodiment, R6 and R7 may be, independently each other, a phenyl or naphthyl group optionally substituted with one or more substituents selected from the group consisting of halogen and C1∼C3 alkyl.
The present invention also provides a process for preparing the compound of Formula 2. That is, the present invention provides a process for preparing a compound of Formula 2, which comprises reacting a compound of Formula 4 with a compound of Formula 5:
<Formula 2>
Figure PCTKR2014004440-appb-I000017
<Formula 4>
Figure PCTKR2014004440-appb-I000018
<Formula 5>
Figure PCTKR2014004440-appb-I000019
wherein, R4, R5, R6, and R7 are the same as defined in the above; and X is halogen.
The reaction between the compound of Formula 4 and the compound of Formula 5 may be carried out in the presences of a metal catalyst, a ligand, and a base. The metal catalyst may be one or more selected from the group consisting of palladium, copper, iron, cadmium, zinc, and nickel. Preferably, the metal catalyst may be palladium acetate, palladium acetylacetonate, bis(dibenzylideneacetone)palladium, or tris(dibenzylideneacetone)dipalladium. The ligand may be one or more selected from the group consisting of 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP), 1,1'-bis(diphenylphosphino)ferrocene (DPPF), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), preferably 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP). The metal catalyst and ligand may be used e.g., in an amount of 1.0 to 0.005 equivalents based on the compound of Formula 4, although the amount depends on the kinds thereof. The base, which functions as an acid acceptor, may be one or more selected from the group consisting of potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, potassium phosphate (including potassium phosphate monobasic, potassium phosphate dibasic, and potassium phosphate tribasic), sodium phosphate (including sodium phosphate monobasic, sodium phosphate dibasic, and sodium phosphate tribasic), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, triethylamine, diisopropylamine, and diisopropylethylamine. And also, the reaction between the compound of Formula 4 and the compound of Formula 5 may be carried out in one or more solvents selected from the group consisting of dichloromethane, dichloroethane, N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, C1∼C5 alcohol, ethyl acetate, and toluene. The solvent may be preferably C1∼C5 alcohol, such as methanol, ethanol, isopropyl alcohol, butanol, etc, more preferably tert-butanol. The reaction between the compound of Formula 4 and the compound of Formula 5 may be carried out at 40℃ to 150℃, preferably at 70℃ to 90℃.
The compound of Formula 4 and the compound of Formula 5, which are known compounds, are commercially available or may be prepared according to conventional methods.
For example, the compound of Formula 4 may be prepared by reacting a compound of Formula 6 having 2 halogen groups with R5H:
<Formula 6>
Figure PCTKR2014004440-appb-I000020
wherein, R4 is the same as defined in the above; and X and X' are, independently each other, halogen.
The reaction between the compound of Formula 6 and R5H may be carried out in the presence of one or more bases selected from the group consisting of potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, potassium phosphate (including potassium phosphate monobasic, potassium phosphate dibasic, and potassium phosphate tribasic), sodium phosphate (including sodium phosphate monobasic, sodium phosphate dibasic, and sodium phosphate tribasic), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, triethylamine, diisopropylamine, and diisopropylethylamine, preferably in the presence of diisopropylamine. The reaction between the compound of Formula 6 and R5H may be in the presence of or in the absence of a solvent. If the reaction is carried out in the presence of a solvent, the solvent may be one or more selected from the group consisting of dichloromethane, dichloroethane, N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, C1∼C5 alcohol, ethyl acetate, and toluene. And also, the reaction between the compound of Formula 6 and R5H may be carried out at 40℃ to 150℃.
The following examples and experimental examples are provided for illustration purposes only, and are not intended to limit the scope of the invention.
Preparation 1. N-benzhydrylidene-N'-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-hydrazine
Step 1: 2-(3-bromo-pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline
A mixture of n-butanol (25.0 mL), 3-bromo-2-chloropyridine (50.0 g, 259.8 mmol), diisopropylethylamine (40.3 g, 311.8 mmol), and 1,2,3,4-tetrahydroisoquinoline (51.9 g, 389.7 mmol) was refluxed for 24 hours and then toluene (250.0 mL) was added thereto. The reaction mixture was sequentially washed with purified water, a 1N aqueous solution of hydrochloric acid, a 9% aqueous solution of sodium bicarbonate, and purified water. The reaction mixture was concentrated under reduced pressure. To the resulting residue, was added isopropyl alcohol (150.0 mL). The mixture was stirred for 1 hour, cooled to cooled to 0∼5℃, stirred for 1 hour, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 67.6 g of the titled compound. (Yield: 90%)
1H-NMR(400MHz, DMSO) δ 8.28(d, 1H), 7.99(d, 1H), 7.15(m, 4H), 6.94(q, 1H), 4.44(s, 2H), 3.53(t, 2H), 2.99(t, 2H)
Step 2: N-benzhydrylidene-N'-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-hydrazine
A mixture of 2-(3-bromo-pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (50.0 g, 172.9 mmol) prepared in Step 1, tert-butanol (250.0 mL), palladium acetate (0.2 g, 0.9 mmol), BINAP (1.1 g, 1.7 mmol), benzophenone hydrazone (37.3 g, 190.2 mmol), and sodium hydroxide (13.8 g, 345.8 mmol) was refluxed for 24 hours and then toluene (350.0 mL) was added thereto. The reaction mixture was sequentially washed with purified water, a 1N aqueous solution of hydrochloric acid, a 9% aqueous solution of sodium bicarbonate, and purified water. The reaction mixture was concentrated under reduced pressure to give the titled compound. (Yield: 94%)
1H-NMR(400MHz, DMSO) δ 7.85(m, 2H), 7.82(d, 1H), 7.55(m, 2H), 7.35(m, 8H), 7.10(m, 5H), 4.08(s, 2H), 2.96(t, 2H), 2.32(t, 2H)
Preparation 2. N-[(4-bromo-phenyl)-phenyl-methylene]-N'-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-hydrazine
A mixture of 2-(3-bromo-pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (2.0 g, 6.9 mmol) prepared in Step 1 of Preparation 1, tert-butanol (10.0 mL), palladium acetate (0.2 g, 0.7 mmol), BINAP (0.9 g, 1.4 mmol), [(4-bromophenyl)-phenyl-methylene]-hydrazine (2.1 g, 7.6 mmol), and sodium hydroxide (0.6 g, 13.8 mmol) was refluxed for 24 hours and then toluene (10.0 mL) was added thereto. The reaction mixture was sequentially washed with purified water, a 1N aqueous solution of hydrochloric acid, a 9% aqueous solution of sodium bicarbonate, and purified water. The reaction mixture was concentrated under reduced pressure to give 2.8 g of the titled compound. (Yield: 83.9%)
1H-NMR(400MHz, CDCl3) δ 8.02(d, 1H), 7.87-7.91(m, 2H), 7.56-7.58(m, 1H), 7.40-7.48(m, 3H), 7.23-7.34(m, 4H), 7.10-7.21(m, 4H), 7.00-7.07(m, 2H), 4.11(s, 2H), 3.10(t, 2H), 2.41(t, 2H)
Preparation 3. N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-N'-(phenyl-m-tolyl-methylene)-hydrazine
A mixture of 2-(3-bromo-pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (2.0 g, 6.9 mmol) prepared in Step 1 of Preparation 1, tert-butanol (10.0 mL), palladium acetate (0.2 g, 0.7 mmol), BINAP (0.9 g, 1.4 mmol), (phenyl-m-tolyl-methylene)-hydrazine (1.6 g, 7.6 mmol), and sodium hydroxide (0.6 g, 13.8 mmol) was refluxed for 24 hours and then toluene (10.0 mL) was added thereto. The reaction mixture was sequentially washed with purified water, a 1N aqueous solution of hydrochloric acid, a 9% aqueous solution of sodium bicarbonate, and purified water. The reaction mixture was concentrated under reduced pressure to give 2.4 g of the titled compound. (Yield: 83.1%)
1H-NMR(400MHz, CDCl3) δ 8.03(d, 1H), 7.87-7.93(m, 2H), 7.62(d, 1H), 7.11-7.38(m, 8H), 7.00-7.08(m, 4H), 4.13(d, 2H), 3.09(s, 2H), 2.39(t, 2H), 2.30(d, 3H)
Preparation 4. N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-N'-(di-naphthalen-2-yl-methylene)-hydrazine
A mixture of 2-(3-bromo-pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (2.0 g, 6.9 mmol) prepared in Step 1 of Preparation 1, tert-butanol (10.0 mL), palladium acetate (0.2 g, 0.7 mmol), BINAP (0.9 g, 1.4 mmol), (di-naphthalen-2-yl-methylene)-hydrazine (2.3 g, 7.6 mmol), and sodium hydroxide (0.6 g, 13.8 mmol) was refluxed for 24 hours and then toluene (10.0 mL) was added thereto. The reaction mixture was sequentially washed with purified water, a 1N aqueous solution of hydrochloric acid, a 9% aqueous solution of sodium bicarbonate, and purified water. The reaction mixture was concentrated under reduced pressure to give 3.0 g of the titled compound. (Yield: 86.2%)
1H-NMR(400MHz, CDCl3) δ 8.29(d, 1H), 8.13(s, 1H), 7.90(d, 1H), 7.85(t, 3H), 7.80(d, 1H), 7.74(d, 1H), 7.58-7.64(m, 3H), 7.52(t, 1H), 7.35-7.47(m, 3H), 7.00-7.11(m, 3H), 6.95(d, 1H), 6.51(d, 1H), 4.13(s, 2H), 2.98(t, 2H), 1.88(t, 2H)
Preparation 5. N-benzhydrylidene-N'-[2-(7-bromo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-hydrazine
Step 1: 7-bromo-2-(3-bromo-pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline
A mixture of 3-bromo-2-chloro-pyridine (3.0 g, 15.6 mmol), diisopropylethylamine (2.4 g, 18.7 mmol), and 7-bromo-1,2,3,4-tetrahydroisoquinoline (5.0 g, 23.4 mmol) was refluxed for 24 hours and then toluene (15.0 mL) was added thereto. The reaction mixture was sequentially washed with purified water, a 1N aqueous solution of hydrochloric acid, a 9% aqueous solution of sodium bicarbonate, and purified water. The reaction mixture was concentrated under reduced pressure to discard the solvent. The resulting residue was purified with chromatography (hexane : ethyl acetate = 8 : 1, v/v) to give 2.4 g of the titled compound. (Yield: 41.8%)
1H-NMR(400MHz, CDCl3) δ 8.17(d, 1H), 7.73(d,1H), 7.18-7.30(m, 2H), 6.97(d, 1H), 6.71(d, 1H), 4.42(s, 2H), 3.53(t, 2H), 2.95(t, 2H)
Step 2: N-benzhydrylidene-N'-[2-(7-bromo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-hydrazine
A mixture of 7-bromo-2-(3-bromo-pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (2.0 g, 5.4 mmol) prepared in Step 1, tert-butanol (10.0 mL), palladium acetate (0.1 g, 0.5 mmol), BINAP (0.7 g, 1.1 mmol), benzophenone hydrazone (1.2 g, 5.9 mmol), and sodium hydroxide (0.4 g, 10.8 mmol) was refluxed for 24 hours and then toluene (10.0 mL) was added thereto. The reaction mixture was sequentially washed with purified water, a 1N aqueous solution of hydrochloric acid, a 9% aqueous solution of sodium bicarbonate, and purified water. The reaction mixture was concentrated under reduced pressure to give 1.4 g of the titled compound. (Yield: 53.6%)
1H-NMR(400MHz, CDCl3) δ 8.03(s, 1H), 7.91(d, 1H), 7.88(d, 1H), 7.61(d, 2H), 7.23-7.36(m, 7H), 7.05(q, 1H), 6.85-6.92(m, 2H), 6.81(s, 1H), 4.09(s, 2H), 3.08(t, 2H), 2.31(t, 2H)
Preparation 6. N-benzhydrylidene-N'-[2-(7-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-hydrazine
Step 1: 2-(3-bromo-pyridin-2-yl)-7-methyl-1,2,3,4-tetrahydroisoquinoline
A mixture of 3-bromo-2-chloro-pyridine (3.0 g, 15.6 mmol), diisopropylethylamine (2.4 g, 18.7 mmol), and 7-methyl-1,2,3,4-tetrahydroisoquinoline (3.4 g, 23.4 mmol) was refluxed for 24 hours and then toluene (15.0 mL) was added thereto. The reaction mixture was sequentially washed with purified water, a 1N aqueous solution of hydrochloric acid, a 9% aqueous solution of sodium bicarbonate, and purified water. The reaction mixture was concentrated under reduced pressure to discard the solvent. The resulting residue was purified with chromatography (hexane : ethyl acetate = 8 : 1, v/v) to give 2.1 g of the titled compound. (Yield: 44.4%)
1H-NMR(400MHz, CDCl3) δ 8.28(d, 1H), 7.83(d, 1H), 7.00-7.11(m, 3H), 6.79(q, 1H), 4.54(s, 2H), 3.65(t, 2H), 3.09(t, 2H), 2.35(s, 3H)
Step 2: N-benzhydrylidene-N'-[2-(7-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-hydrazine
A mixture of 2-(3-bromo-pyridin-2-yl)-7-methyl-1,2,3,4-tetrahydroisoquinoline (2.0 g, 6.6 mmol) prepared in Step 1, tert-butanol (10.0 mL), palladium acetate (0.2 g, 0.7 mmol), BINAP (0.8 g, 1.3 mmol), benzophenone hydrazone (1.4 g, 7.3 mmol), and sodium hydroxide (0.5 g, 13.2 mmol) was refluxed for 24 hours and then toluene (10.0 mL) was added thereto. The reaction mixture was sequentially washed with purified water, a 1N aqueous solution of hydrochloric acid, a 9% aqueous solution of sodium bicarbonate, and purified water. The reaction mixture was concentrated under reduced pressure to give 1.4 g of the titled compound. (Yield: 50.7%)
1H-NMR(400MHz, CDCl3) δ 8.00(s, 1H), 7.91(d, 1H), 7.89(d, 1H), 7.61(d, 2H), 7.22-7.34(m, 7H), 7.05(q, 1H), 6.98(d, 1H), 6.92(d, 1H), 6.82(s, 1H), 4.09(s, 2H), 3.08(t, 2H), 2.35(t, 2H), 2.32(s, 3H)
Example 1. 2-(1-allyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
Step 1: 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
A mixture of N-benzhydrylidene-N'-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-hydrazine (80.0 g, 197.8 mmol) prepared in Preparation 1, p-toluenesulfonic acid (112.9 g, 593.3 mmol), methyl ethyl ketone (28.5 g, 395.6 mmol), and ethanol (240 mL) was refluxed for 3 hours. The reaction mixture was concentrated and then sequentially washed with methylene chloride, purified water, a 9% aqueous solution of sodium bicarbonate, and purified water. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in acetone (720.0 mL) and then hydrochloric acid (20.6 g) was added thereto. The reaction mixture was stirred at room temperature for 1 hour, cooled to 0∼5℃, stirred for 1 hour, and then filtered under reduced pressure. The resulting solid was dried under reduced pressure to give 59.0 g of the titled compound. (Yield: 95%)
1H-NMR(400MHz, DMSO) δ 13.14(s, 1H), 12.08(s, 1H), 7.53(d, 1H), 7.29(m, 4H), 7.19(d, 1H), 5.02(s, 2H), 4.00(t, 2H), 3.12(t, 2H), 2.05(s, 3H), 2.18(s, 3H)
Step 2: 2-(1-allyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
A mixture of 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (10.0 g, 31.9 mmol) prepared in Step 1 and N,N-dimethylformamide (50.0 mL) was cooled to -10℃ and then sodium tert-butoxide (6.4 g, 66.9 mmol) and allyl chloride (2.9 g, 38.2 mmol) were added thereto. While maintaining the temperature of the reaction mixture at less than 30℃, the reaction mixture was stirred for 3 hours. Toluene (100.0 mL) and purified water (100.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was concentrated under reduced pressure to discard the solvent. To the resulting residue, was added N,N-dimethylformamide (20.0 mL). Hydrochloric acid (3.3 g, 31.9 mmol) was dropwise added thereto. The reaction mixture was stirred at 20∼30℃ for 30 minutes, cooled to 0∼5℃, stirred for 1 hour, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 8.6 g of the titled compound. (Yield: 76.3%)
1H-NMR(400 MHz, CDCl3) δ 8.14(d, 1H), 7.46(d, 1H), 7.16-7.23(m, 3H), 7.03(d, 1H), 5.81(m, 1H), 5.14(d, 1H), 5.05(s, 2H), 4.55(brs, 2H), 4.51(d, 1H), 3.91(t, 2H), 3.12(t, 2H), 2.42(s, 3H), 2.30(s, 3H)
Example 2. 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
A mixture of N-[(4-bromo-phenyl)-phenyl-methylene]-N'-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-hydrazine (2.0 g, 4.1 mmol) prepared in Preparation 2, hydrochloric acid (1.3 g, 12.4 mmol), methyl ethyl ketone (0.6 g, 8.2 mmol), and ethanol (6.0 mL) was stirred at 78∼85℃ for 4 hours. The reaction mixture was cooled to 20∼30℃ and then concentrated under reduced pressure to discard the solvent. Dichloromethane (10.0 mL) and purified water (10.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was washed with a sodium hydrogen carbonate solution (10.0 mL) and then concentrated under reduced pressure to discard the solvent. To the resulting residue, was added acetone (18.0 mL). Hydrochloric acid (0.4 g, 4.1 mmol) was dropwise added to the mixture, which was then stirred at 20∼30℃ for 1 hour. The reaction mixture was cooled to 0∼5℃, stirred for 2 hours, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 0.9 g of the titled compound. (Yield: 69.9%)
1H-NMR(400MHz, DMSO) δ 7.54(d, 1H), 7.32-7.26(m, 4H), 7.21(d, 1H), 4.99(s, 2H), 3.98(t, 2H), 3.12(t, 2H), 2.49(s, 3H), 2.19(s, 3H)
Example 3. 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
A mixture of N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-N'-(phenyl-m-tolyl-methylene)-hydrazine (2.0 g, 4.8 mmol) prepared in Preparation 3, hydrochloric acid (1.5 g, 14.4 mmol), methyl ethyl ketone (0.7 g, 9.6 mmol), and ethanol (6.0 mL) was stirred at 78∼85℃ for 4 hours. The reaction mixture was cooled to 20∼30℃ and then concentrated under reduced pressure to discard the solvent. Dichloromethane (10.0 mL) and purified water (10.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was washed with a sodium hydrogen carbonate solution (10.0 mL) and then concentrated under reduced pressure to discard the solvent. To the resulting residue, was added acetone (18.0 mL). Hydrochloric acid (0.5 g, 4.8 mmol) was dropwise added to the mixture, which was then stirred at 20∼30℃ for 1 hour. The reaction mixture was cooled to 0∼5℃, stirred for 2 hours, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 1.0 g of the titled compound. (Yield: 66.4%)
1H-NMR(400MHz, DMSO) δ 7.54(d, 1H), 7.32-7.26(m, 4H), 7.21(d, 1H), 4.99(s, 2H), 3.98(t, 2H), 3.12(t, 2H), 2.49(s, 3H), 2.19(s, 3H)
Example 4. 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
A mixture of N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-N'-(di-naphthalen-2-yl-methylene)-hydrazine (2.0 g, 4.0 mmol) prepared in Preparation 4, hydrochloric acid (1.3 g, 12.0 mmol), methyl ethyl ketone (0.6 g, 8.0 mmol), and ethanol (6.0 mL) was stirred at 78∼85℃ for 4 hours. The reaction mixture was cooled to 20∼30℃ and then concentrated under reduced pressure to discard the solvent. Dichloromethane (10.0 mL) and purified water (10.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was washed with a sodium hydrogen carbonate solution (10.0 mL) and then concentrated under reduced pressure to discard the solvent. To the resulting residue, was added acetone (18.0 mL). Hydrochloric acid (0.4 g, 4.0 mmol) was dropwise added to the mixture, which was then stirred at 20∼30℃ for 1 hour. The reaction mixture was cooled to 0∼5℃, stirred for 2 hours, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 0.9 g of the titled compound. (Yield: 71.7%)
1H-NMR(400MHz, DMSO) δ 7.54(d, 1H), 7.32-7.26(m, 4H), 7.21(d, 1H), 4.99(s, 2H), 3.98(t, 2H), 3.12(t, 2H), 2.49(s, 3H), 2.19(s, 3H)
Example 5. 2-[1-(3-methoxy-propyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline hydrochloride
A mixture of 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (5.0 g, 15.9 mmol) prepared in Step 1 of Example 1 and N,N-dimethylformamide (25.0 mL) was cooled to -10℃ and then sodium tert-butoxide (3.2 g, 33.4 mmol) and 1-chloro-3-methoxypropane (2.6 g, 23.9 mmol) were added thereto. While maintaining the temperature of the reaction mixture at less than 30℃, the reaction mixture was stirred for 6 hours. Toluene (50.0 mL) and purified water (50.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was concentrated under reduced pressure to discard the solvent. To the resulting residue, was added N,N-dimethylformamide (10.0 mL). Hydrochloric acid (1.7 g, 15.9 mmol) was dropwise added thereto. The reaction mixture was stirred at 20∼30℃ for 1 hour, cooled to 0∼5℃, stirred for 2 hours, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 3.4 g of the titled compound. (Yield: 60.4%)
1H-NMR(400MHz, DMSO) δ 7.96(d, 1H), 7.73(d, 1H), 7.19-7.29(m, 3H), 7.16(d, 1H), 4.52(s, 2H), 4.36(t, 2H), 3.72(t, 2H), 3.47(s, 2H), 3.15(s, 2H), 2.95(s, 3H), 2.93(t, 2H), 2.50-2.51(m, 2H), 2.49(s, 3H), 2.28(s, 3H), 1.71(q, 2H)
Example 6. 2-(2,3-dimethyl-1-pyridin-3-ylmethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
A mixture of 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (4.0 g, 12.7 mmol) prepared in Step 1 of Example 1 and N,N-dimethylformamide (20.0 mL) was cooled to -10℃ and then sodium tert-butoxide (3.8 g, 39.5 mmol) and 3-chloromethylpyridine hydrochloride (3.1 g, 19.1 mmol) were added thereto. While maintaining the temperature of the reaction mixture at less than 30℃, the reaction mixture was stirred for 5 hours. Toluene (40.0 mL) and purified water (40.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was concentrated under reduced pressure to discard the solvent. To the resulting residue, was added N,N-dimethylformamide (8.0 mL). Hydrochloric acid (1.3 g, 12.7 mmol) was dropwise added thereto. The reaction mixture was stirred at 20∼30℃ for 1 hour, cooled to 0∼5℃, stirred for 2 hours, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 3.3 g of the titled compound. (Yield: 63.5%)
1H-NMR(400MHz, DMSO) δ 8.43(d, 1H), 8.04(s, 1H), 8.00(d, 1H), 7.73(d, 1H), 7.28(q, 1H), 7.14-7.21(m, 4H), 6.97(d, 1H), 5.72(s, 2H), 4.39(s, 2H), 3.55(s, 2H), 2.84(t, 2H), 2.35(s, 3H), 2.28(s, 3H)
Example 7. 2-(2,3-dimethyl-1-pentyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
A mixture of 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (4.0 g, 12.7 mmol) prepared in Step 1 of Example 1 and N,N-dimethylformamide (20.0 mL) was cooled to -10℃ and then sodium tert-butoxide (3.8 g, 39.5 mmol) and 1-bromopentane (2.9 g, 19.1 mmol) were added thereto. While maintaining the temperature of the reaction mixture at less than 30℃, the reaction mixture was stirred for 3 hours. Toluene (40.0 mL) and purified water (40.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was concentrated under reduced pressure to discard the solvent. To the resulting residue, was added N,N-dimethylformamide (8.0 mL). Hydrochloric acid (1.3 g, 12.7 mmol) was dropwise added thereto. The reaction mixture was stirred at 20∼30℃ for 1 hour, cooled to 0∼5℃, stirred for 2 hours, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 3.4 g of the titled compound. (Yield: 70.5%)
1H-NMR(400MHz, DMSO) δ 7.96(d, 1H), 7.70(d, 1H), 7.15-7.26(m, 4H), 4.49(s, 2H), 4.27(t, 2H), 3.70(t, 3H), 3.09(s, 2H), 2.48(s, 3H), 2.27(s, 3H), 1.45(s, 2H), 1.00-1.05(m, 2H), 0.84-0.90(m, 2H), 0.63(t, 3H)
Example 8. 2-[7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-pyrrolo[2,3-c]pyridin-1-ylmethyl]-benzonitrile hydrochloride
A mixture of 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (5.0 g, 15.9 mmol) prepared in Step 1 of Example 1 and N,N-dimethylformamide (25.0 mL) was cooled to -10℃ and then sodium tert-butoxide (3.2 g, 33.4 mmol) and 2-cyanobenzyl bromide (4.7 g, 23.9 mmol) were added thereto. While maintaining the temperature of the reaction mixture at less than 30℃, the reaction mixture was stirred for 5 hours. Toluene (50.0 mL) and purified water (50.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was concentrated under reduced pressure to discard the solvent. To the resulting residue, was added N,N-dimethylformamide (10.0 mL). Hydrochloric acid (1.7 g, 15.9 mmol) was dropwise added thereto. The reaction mixture was stirred at 20∼30℃ for 1 hour, cooled to 0∼5℃, stirred for 2 hours, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 3.4 g of the titled compound. (Yield: 44.0%)
1H-NMR(400MHz, DMSO) δ 8.06(d, 1H), 7.87(d, 1H), 7.59(d, 1H), 7.53(t, 1H), 7.39(t, 1H), 7.13-7.21(m, 2H), 7.05(t, 1H), 6.61(d, 1H), 6.42(d, 1H), 5.90(s, 2H), 3.87(s, 2H), 3.54(t, 2H), 2.82(t, 2H), 2.38(s, 3H), 2.34(s, 3H)
Example 9. 2-[2,3-dimethyl-1-(4-methyl-benzyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline hydrochloride
A mixture of 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (5.7 g, 18.2 mmol) prepared in Step 1 of Example 1 and N,N-dimethylformamide (34.0 mL) was cooled to -10℃ and then sodium tert-butoxide (3.8 g, 40.0 mmol) and 4-methylbenzyl bromide (5.0 g, 27.2 mmol) were added thereto. While maintaining the temperature of the reaction mixture at less than 30℃, the reaction mixture was stirred for 5 hours. Toluene (50.0 mL) and purified water (50.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was concentrated under reduced pressure to discard the solvent. To the resulting residue, was added N,N-dimethylformamide (11.0 mL). Hydrochloric acid (1.9 g, 18.2 mmol) was dropwise added thereto. The reaction mixture was stirred at 20∼30℃ for 1 hour, cooled to 0∼5℃, stirred for 2 hours, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 4.3 g of the titled compound. (Yield: 57.1%)
1H-NMR(400MHz, DMSO) δ 8.00(d, 1H), 7.79(d, 1H), 7.14-7.23(m, 3H), 7.01(d, 2H), 6.94(d, 1H), 6.62(d, 2H), 5.65(s, 2H), 4.45(s, 2H), 3.61(t, 2H), 2.83(t, 2H), 2.34(s, 3H), 2.29(s, 3H), 2.22(s, 3H)
Example 10. 2-[1-(4-bromo-benzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline hydrochloride
A mixture of 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (4.5 g, 14.3 mmol) prepared in Step 1 of Example 1 and N,N-dimethylformamide (23.0 mL) was cooled to -10℃ and then sodium tert-butoxide (3.0 g, 31.5 mmol) and 4-bromobenzyl bromide (5.4 g, 21.5 mmol) were added thereto. While maintaining the temperature of the reaction mixture at less than 30℃, the reaction mixture was stirred for 3 hours. Toluene (40.0 mL) and purified water (40.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was concentrated under reduced pressure to discard the solvent. To the resulting residue, was added N,N-dimethylformamide (9.0 mL). Hydrochloric acid (1.5 g, 14.3 mmol) was dropwise added thereto. The reaction mixture was stirred at 20∼30℃ for 1 hour, cooled to 0∼5℃, stirred for 2 hours, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 4.1 g of the titled compound. (Yield: 59.0%)
1H-NMR(400MHz, DMSO) δ 8.01(d, 1H), 7.79(d, 1H), 7.38(d, 2H), 7.13-7.21(m, 3H), 6.92(d, 1H), 6.68(d, 2H), 5.66(s, 2H), 4.39(s, 2H), 3.58(t, 2H), 2.84(t, 2H), 2.34(s, 3H), 2.30(s, 3H)
Example 11. 2-(1-benzyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
A mixture of 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (5.7 g, 18.2 mmol) prepared in Step 1 of Example 1 and N,N-dimethylformamide (34.0 mL) was cooled to -10℃ and then sodium tert-butoxide (3.8 g, 40.0 mmol) and benzyl bromide (4.7 g, 27.2 mmol) were added thereto. While maintaining the temperature of the reaction mixture at less than 30℃, the reaction mixture was stirred for 6 hours. Toluene (50.0 mL) and purified water (50.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was concentrated under reduced pressure to discard the solvent. To the resulting residue, was added N,N-dimethylformamide (11.0 mL). Hydrochloric acid (1.9 g, 18.2 mmol) was dropwise added thereto. The reaction mixture was stirred at 20∼30℃ for 1 hour, cooled to 0∼5℃, stirred for 2 hours, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 4.8 g of the titled compound. (Yield: 65.9%)
1H-NMR(400MHz, DMSO) δ 8.01(d, 1H), 7.82(d, 1H), 7.15-7.22(m, 6H), 6.92(d, 1H), 6.71-6.73(m, 2H), 5.71(s, 2H), 4.45(s, 2H), 3.61(t, 2H), 2.80(t, 2H), 2.35(s, 3H), 2.31(s, 3H)
Example 12. 2-(1-allyl-2-methyl-3-propyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
Step 1: 2-(2-methyl-3-propyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
A mixture of N-benzhydrylidene-N'-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-hydrazine (20.0 g, 49.4 mmol) prepared in Preparation 1, p-toluenesulfonic acid monohydrate (28.2 g, 148.3 mmol), 2-hexanone (9.9 g, 98.8 mmol), and ethanol (60.0 mL) was stirred at 80∼85℃ for 4 hours. The reaction mixture was cooled to 20∼30℃ and then concentrated under reduced pressure to discard the solvent. Dichloromethane (100.0 mL) and purified water (100.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was washed with a sodium hydrogen carbonate solution (100.0 mL) and then concentrated under reduced pressure to discard the solvent. To the resulting residue, was added acetone (180.0 mL). Hydrochloric acid (5.1 g, 49.4 mmol) was dropwise added to the mixture, which was then stirred at 20∼30℃ for 1 hour. The reaction mixture was cooled to 0∼5℃, stirred for 3 hours, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 11.9 g of the titled compound. (Yield: 70.5%)
1H-NMR(400MHz, MeOD) δ 7.48(d, 1H), 7.31(s, 4H), 7.24(d, 1H), 4.97(s, 2H), 4.01(s, 2H), 3.19(s, 2H), 2.73(t, 2H), 2.38(s, 3H), 1.68-1.62(m, 2H), 0.97(t, 3H)
Step 2: 2-(1-allyl-2-methyl-3-propyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
A mixture of (2-(2-methyl-3-propyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride(10.0 g, 29.2 mmol) prepared in Step 1 and N,N-dimethylformamide (50.0 mL) was cooled to -10℃ and then sodium tert-butoxide (5.9 g, 61.4 mmol) and allyl chloride (2.7 g, 35.0 mmol) were added thereto. While maintaining the temperature of the reaction mixture at less than 30℃, the reaction mixture was stirred for 4 hours. Toluene (100.0 mL) and purified water (100.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was concentrated under reduced pressure to discard the solvent. To the resulting residue, was added N,N-dimethylformamide (20.0 mL). Hydrochloric acid (3.0 g, 29.2 mmol) was dropwise added thereto. The reaction mixture was stirred at 20∼30℃ for 1 hour, cooled to 0∼5℃, stirred for 2 hours, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 7.7 g of the titled compound. (Yield: 69.0 %)
1H-NMR(400MHz, CDCl3) δ 8.13(t, 1H), 7.49(d, 1H), 7.18-7.24(m, 3H), 7.04(d, 1H), 5.82(m, 1H), 5.14(d, 1H), 5.06(s, 2H), 4.59(brs, 2H), 4.49(d, 1H), 3.91(t, 2H), 3.12(t, 2H), 2.72(t, 2H), 2.43(s, 3H), 1.62-1.64(m, 2H), 0.96(s, 3H)
Example 13. 2-[1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl]-ethanol
Step 1: 2-[7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl]-ethanol
A mixture of N-benzhydrylidene-N'-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-hydrazine (10.0 g, 24.7 mmol) prepared in Preparation 1, hydrochloric acid (7.7 g, 74.2 mmol), 5-hydroxy-2-pentanone (5.0 g, 49.4 mmol), and ethanol (30.0 mL) was stirred at 78∼85℃ for 4 hours. The reaction mixture was cooled to 20∼30℃ and then concentrated under reduced pressure to discard the solvent. Dichloromethane (50.0 mL) and purified water (50.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was washed with a sodium hydrogen carbonate solution (50.0 mL) and then concentrated under reduced pressure to discard the solvent. The resulting residue was purified with chromatography (hexane : ethyl acetate = 5 : 1, v/v) to give 4.1 g of the titled compound. (Yield: 54.0%)
1H-NMR(400MHz, CDCl3) δ 8.18(s, 1H), 7.93(d, 1H), 7.15-7.19(m, 4H), 7.09(d, 1H), 4.59(s, 2H), 3.83(t, 2H), 3.70(t, 2H), 3.10(t, 2H), 2.93(t, 2H), 2.44(s, 3H)
Step 2: 2-[1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl]-ethanol
A mixture of 2-[7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl]-ethanol (4.0 g, 13.0 mmol) prepared in Step 1 and N,N-dimethylformamide (20.0 mL) was cooled to -10℃ and then sodium tert-butoxide (1.6 g, 16.9 mmol) and allyl chloride(1.5 g, 19.5 mmol) were added thereto. While maintaining the temperature of the reaction mixture at less than 30℃, the reaction mixture was stirred for 3 hours. Toluene (40.0 mL) and purified water (40.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was concentrated under reduced pressure to discard the solvent. The resulting residue was purified with chromatography (hexane : ethyl acetate = 6 : 1, v/v) to give 3.1 g of the titled compound. (Yield: 68.6%)
1H-NMR(400MHz, DMSO) δ 8.00(d, 1H), 7.26(d, 1H), 7.16-7.20(m, 3H), 7.09(d, 1H), 5.82-8.90(m, 1H), 5.13(d, 2H), 5.05(d, 1H), 4.59(d, 1H), 4.34(d, 2H), 4.21(t, 2H), 3.44(d, 2H), 3.08(d, 2H), 3.03(t, 2H), 2.34(s, 3H)
Example 14. 3-[1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl]-propionitrile hydrochloride
Step 1: 3-[7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl]-propionitrile
A mixture of N-benzhydrylidene-N'-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-hydrazine (10.0 g, 24.7 mmol) prepared in Preparation 1, hydrochloric acid (7.7 g, 74.2 mmol), 5-ketohexanenitrile (5.5 g, 49.4 mmol), and ethanol (30.0 mL) was stirred at 78∼85℃ for 4 hours. The reaction mixture was cooled to 20∼30℃ and then concentrated under reduced pressure to discard the solvent. Dichloromethane (50.0 mL) and purified water (50.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was washed with a sodium hydrogen carbonate solution (50.0 mL) and then concentrated under reduced pressure to give 4.4 g of the titled compound. (Yield: 56.3%)
1H-NMR(400MHz, CDCl3) δ 8.24(s, 1H), 7.95(d, 1H), 7.16-7.20(m, 4H), 7.01(d, 1H), 4.60(s, 2H), 3.72(t, 2H), 3.10(t, 2H), 3.04(t, 2H), 2.62(t, 2H), 2.48(s, 3H)
Step 2: 3-[1-allyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl]-propionitrile hydrochloride
A mixture of 3-[7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl]-propionitrile (4.0 g, 12.6 mmol) prepared in Step 1 and N,N-dimethylformamide (20.0 mL) was cooled to -10℃ and then sodium tert-butoxide (1.6 g, 16.4 mmol) and allyl chloride (1.5 g, 19.0 mmol) were added thereto. While maintaining the temperature of the reaction mixture at less than 30℃, the reaction mixture was stirred for 4 hours. Toluene (40.0 mL) and purified water (40.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was concentrated under reduced pressure to discard the solvent. To the resulting residue, was added N,N-dimethylformamide (8.0 mL). Hydrochloric acid (1.3 g, 12.6 mmol) was dropwise added thereto. The reaction mixture was stirred at 20∼30℃ for 1 hour, cooled to 0∼5℃, stirred for 2 hours, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 3.1 g of the titled compound. (Yield: 62.6%)
1H-NMR(400MHz, DMSO) δ 8.01(d, 1H), 7.89(d, 1H), 7.20-7.27(m, 3H), 7.13(d, 1H), 5.87-5.96(m, 1H), 5.10(s, 2H), 5.08(d, 1H), 4.55(d, 1H), 4.52(s, 2H), 3.65(t, 2H), 3.14(t, 2H), 3.06(s, 2H), 2.78(t, 2H), 2.49(s, 3H)
Example 15. 2-(1-allyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-7-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride
Step 1: 7-bromo-2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
A mixture of N-benzhydrylidene-N'-[2-(7-bromo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-hydrazine (1.2 g, 2.5 mmol) prepared in Preparation 5, hydrochloric acid (0.8 g, 7.5 mmol), methyl ethyl ketone (0.4 g, 5.0 mmol), and ethanol (5.0 mL) was stirred at 78∼85℃ for 4 hours. The reaction mixture was cooled to 20∼30℃ and then concentrated under reduced pressure to discard the solvent. Dichloromethane (10.0 mL) and purified water (10.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was washed with a sodium hydrogen carbonate solution (6.0 mL) and then concentrated under reduced pressure to discard the solvent. To the resulting residue, was added acetone (11.0 mL). Hydrochloric acid (0.3 g, 2.5 mmol) was dropwise added to the mixture, which was then stirred at 20∼30℃ for 1 hour. The reaction mixture was cooled to 0∼5℃, stirred for 2 hours, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 0.6 g of the titled compound. (Yield: 61.1%)
1H-NMR(400MHz, DMSO) δ 7.55(d, 1H), 7.50(s, 2H), 7.47(d, 1H), 7.29(d, 1H), 7.24(d, 1H), 5.00 (s, 2H), 3.96(t, 2H), 3.08(t, 2H), 2.49(s, 3H), 2.19(s, 3H)
Step 2: 2-(1-allyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-7-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride
A mixture of 7-bromo-2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.5 g, 1.3 mmol) prepared in Step 1 and N,N-dimethylformamide (3.0 mL) was cooled to -10℃ and then sodium tert-butoxide (0.3 g, 2.7 mmol) and allyl chloride (0.2 g, 2.0 mmol) were added thereto. While maintaining the temperature of the reaction mixture at less than 30℃, the reaction mixture was stirred for 3 hours. Toluene (5.0 mL) and purified water (5.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was concentrated under reduced pressure to discard the solvent. To the resulting residue, was added N,N-dimethylformamide (1.0 mL). Hydrochloric acid (0.1 g, 1.3 mmol) was dropwise added thereto. The reaction mixture was stirred at 20∼30℃ for 1 hour, cooled to 0∼5℃, stirred for 2 hours, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 0.4 g of the titled compound. (Yield: 71.1%)
1H-NMR(400MHz, DMSO) δ 7.98(d, 1H), 7.79(d, 1H), 7.43(d, 1H), 7.37(s, 1H), 7.24(d, 1H), 5.87-5.92(m, 1H), 5.08(d, 1H), 5.06(s, 2H), 4.55(d, 1H), 4.53(s, 2H), 3.65(t, 2H), 3.01(t, 2H), 2.44(s, 3H), 2.30(s, 3H)
Example 16. 2-(1-allyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-7-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride
Step 1: 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-7-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride
A mixture of N-benzhydrylidene-N'-[2-(7-methyl-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-hydrazine (1.2 g, 2.9 mmol) prepared in Preparation 6, hydrochloric acid (0.9 g, 8.7 mmol), methyl ethyl ketone (0.4 g, 5.8 mmol), and ethanol (5.0 mL) was stirred at 78∼85℃ for 4 hours. The reaction mixture was cooled to 20∼30℃ and then concentrated under reduced pressure to discard the solvent. Dichloromethane (6.0 mL) and purified water (6.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was washed with a sodium hydrogen carbonate solution (6.0 mL) and then concentrated under reduced pressure to discard the solvent. To the resulting residue, was added acetone (11.0 mL). Hydrochloric acid (0.3 g, 2.9 mmol) was dropwise added to the mixture, which was then stirred at 20∼30℃ for 1 hour. The reaction mixture was cooled to 0∼5℃, stirred for 2 hours, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 0.7 g of the titled compound. (Yield: 73.6%)
1H-NMR(400MHz, DMSO) δ 7.53(d, 1H), 7.42(s, 1H), 7.20(d, 1H), 7.17(d, 1H), 7.08(d, 1H), 4.95(s, 2H), 3.97(t, 2H), 3.06(t, 2H), 2.49(s, 3H), 2.30(s, 3H), 2.19(s, 3H)
Step 2: 2-(1-allyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-7-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride
A mixture of 2-(2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-7-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.6 g, 1.8 mmol) prepared in Step 1 and N,N-dimethylformamide (3.0 mL) was cooled to -10℃ and then sodium tert-butoxide (0.4 g, 3.8 mmol) and allyl chloride (0.2 g, 2.7 mmol) were added thereto. While maintaining the temperature of the reaction mixture at less than 30℃, the reaction mixture was stirred for 4 hours. Toluene (6.0 mL) and purified water (6.0 mL) were added to the reaction mixture, which was then stirred for 30 minutes. The separated organic layer was concentrated under reduced pressure to discard the solvent. To the resulting residue, was added N,N-dimethylformamide (1.2 mL). Hydrochloric acid (0.2 g, 1.8 mmol) was dropwise added thereto. The reaction mixture was stirred at 20∼30℃ for 1 hour, cooled to 0∼5℃, stirred for 2 hours, and then filtered under reduced pressure. The resulting solid was dried in vacuo to give 0.4 g of the titled compound. (Yield: 60.4%)
1H-NMR(400MHz, DMSO) δ 7.96(d, 1H), 7.76(d, 1H), 7.15(d, 1H), 7.06(d, 1H), 5.86-5.95(m, 1H), 5.08(d, 1H), 5.07(s, 2H), 4.57(d, 1H), 4.48(s, 2H), 3.64(t, 2H), 3.00(t, 2H), 2.43(s, 3H), 2.29(s, 3H), 2.28(s, 3H)

Claims (15)

  1. A process for preparing a compound of Formula 1a or its salt, which comprises reacting a compound of Formula 2 with a compound of Formula 3:
    <Formula 1a>
    Figure PCTKR2014004440-appb-I000021
    <Formula 2>
    Figure PCTKR2014004440-appb-I000022
    <Formula 3>
    Figure PCTKR2014004440-appb-I000023
    wherein,
    R2 is a straight or branched C1~C5 alkyl group,
    R3 is a straight or branched C1~C5 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy and cyano,
    R4 is hydrogen,
    R5 is a 1,2,3,4-tetrahydroisoquinolinyl group optionally substituted with one or more substituents selected from the group consisting of C1~C3 alkyl and halogen, and
    R6 and R7 are, independently each other, a C6~C12 aryl group optionally substituted with one or more substituents selected from the group consisting of halogen and C1~C3 alkyl.
  2. The process according to claim 1, wherein R2 is a straight or branched C1~C3 alkyl group; and R3 is a straight or branched C1~C3 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy and cyano.
  3. The process according to claim 1, wherein R6 and R7 are, independently each other, a phenyl or naphthyl group optionally substituted with one or more substituents selected from the group consisting of halogen and C1~C3 alkyl.
  4. The process according to claim 1, wherein the reacting is carried out in the presence of an acid.
  5. The process according to claim 4, wherein the acid is one or more selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, formic acid, sulfonic acid, and p-toluenesulfonic acid
  6. A process for preparing a compound of Formula 1 or its pharmaceutically acceptable salt, which comprises preparing a compound of Formula 1a or its salt according to any one of claims 1 to 5; and reacting the compound of Formula 1a or its salt with R1-X (wherein X is halogen):
    <Formula 1>
    Figure PCTKR2014004440-appb-I000024
    <Formula 1a>
    Figure PCTKR2014004440-appb-I000025
    wherein,
    R1 is a straight or branched C1~C5 alkyl group optionally substituted with one or more substituents selected from the group consisting of C1~C3 alkoxy and pyridyl; a straight or branched C2~C5 alkenyl group; or a -(CH2)p-phenyl group (wherein p is 1, 2, or 3; and the phenyl ring is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, and C1~C3 alkyl), and
    R2, R3, R4, and R5 are the same as defined in claim 1.
  7. The process according to claim 6, wherein R1 is allyl; R2 is a straight or branched C1~C3 alkyl group; and R3 is a straight or branched C1~C3 alkyl group optionally substituted with one or more substituents selected from the group consisting of hydroxy and cyano.
  8. The process according to any one of claims 1 to 5, wherein the compound of Formula 2 is obtained by a process comprising reacting a compound of Formula 4 with a compound of Formula 5:
    <Formula 4>
    Figure PCTKR2014004440-appb-I000026
    <Formula 5>
    Figure PCTKR2014004440-appb-I000027
    wherein, R4, R5, R6, and R7 are the same as defined in claim 1; and X is halogen.
  9. A compound of Formula 2:
    <Formula 2>
    Figure PCTKR2014004440-appb-I000028
    wherein,
    R4 is hydrogen,
    R5 is a 1,2,3,4-tetrahydroisoquinolinyl group optionally substituted with one or more substituents selected from the group consisting of C1~C3 alkyl and halogen, and
    R6 and R7 are, independently each other, a C6~C12 aryl group optionally substituted with one or more substituents selected from the group consisting of halogen and C1~C3 alkyl.
  10. The compound of Formula 2 according to claim 9, wherein R6 and R7 are, independently each other, a phenyl or naphthyl group optionally substituted with one or more substituents selected from the group consisting of halogen and C1~C3 alkyl.
  11. A process for preparing a compound of Formula 2, which comprises reacting a compound of Formula 4 with a compound of Formula 5:
    <Formula 2>
    Figure PCTKR2014004440-appb-I000029
    <Formula 4>
    Figure PCTKR2014004440-appb-I000030
    <Formula 5>
    Figure PCTKR2014004440-appb-I000031
    wherein, R4, R5, R6, and R7 are the same as defined in claim 1; and X is halogen.
  12. The process according to claim 11, wherein comprises the reaction between the compound of Formula 4 and the compound of Formula 5 is carried out in the presence of one or more metal catalysts selected from the group consisting of palladium, copper, iron, cadmium, zinc, and nickel.
  13. The process according to claim 11, wherein comprises the reaction between the compound of Formula 4 and the compound of Formula 5 is carried out in the presence of one or more ligands selected from the group consisting of 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene, 1,1'-bis(diphenylphosphino)ferrocene, and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
  14. The process according to claim 11, wherein comprises the reaction between the compound of Formula 4 and the compound of Formula 5 is carried out in the presence of one or more bases selected from the group consisting of potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, potassium phosphate, sodium phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, triethylamine, diisopropylamine, and diisopropylethylamine.
  15. The process according to claim 11, wherein comprises the reaction between the compound of Formula 4 and the compound of Formula 5 is carried out in one or more solvents selected from the group consisting of dichloromethane, dichloroethane, N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, C1∼C5 alcohol, ethyl acetate, and toluene.
PCT/KR2014/004440 2013-05-20 2014-05-19 Process for the preparation of pyrrolo[2,3-c]pyridine derivatives or pharmaceutically acceptable salts thereof WO2014189238A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5604240A (en) * 1994-11-21 1997-02-18 Merck, Sharp & Dohme, Ltd. Pyrrolo-pyridine derivatives
WO2005061498A1 (en) * 2003-12-11 2005-07-07 Aventis Pharmaceuticals Inc. Substituted 1h-pyrrolo[3,2-b, 3,2-c, and 2,3-c]pyridine-2-carboxamides and related analogs as inhibitors of casein kinase i epsilon
WO2006011670A1 (en) * 2004-07-28 2006-02-02 Takeda Pharmaceutical Company Limited PYRROLO[2,3-c]PYRIDINE COMPOUND, PROCESS FOR PRODUCING THE SAME, AND USE
WO2006025717A1 (en) * 2004-09-03 2006-03-09 Yuhan Corporation PYRROLO[2,3-c]PYRIDINE DERIVATIVES AND PROCESSES FOR THE PREPARATION THEREOF

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101142363B1 (en) * 2005-06-27 2012-05-21 주식회사유한양행 A composition for treating a cancer comprising pyrrolopyridine derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5604240A (en) * 1994-11-21 1997-02-18 Merck, Sharp & Dohme, Ltd. Pyrrolo-pyridine derivatives
WO2005061498A1 (en) * 2003-12-11 2005-07-07 Aventis Pharmaceuticals Inc. Substituted 1h-pyrrolo[3,2-b, 3,2-c, and 2,3-c]pyridine-2-carboxamides and related analogs as inhibitors of casein kinase i epsilon
WO2006011670A1 (en) * 2004-07-28 2006-02-02 Takeda Pharmaceutical Company Limited PYRROLO[2,3-c]PYRIDINE COMPOUND, PROCESS FOR PRODUCING THE SAME, AND USE
WO2006025717A1 (en) * 2004-09-03 2006-03-09 Yuhan Corporation PYRROLO[2,3-c]PYRIDINE DERIVATIVES AND PROCESSES FOR THE PREPARATION THEREOF

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