Title of Invention: Method for preparing indole or indazole compound
technical field
[One]
Cross Citation with Related Applications
[2]
This application claims the benefit of priority based on Korean Patent Application No. 10-2019-0073018 dated June 19, 2019, and all contents disclosed in the literature of the Korean patent application are incorporated as a part of this specification.
[3]
technical field
[4]
The present invention relates to a novel preparation method incorporating a stable intermediate in the preparation of a pharmaceutically useful indole or indazole compound.
background
[5]
Diseases caused by cell necrosis include ischemic (eg, myocardial infarction, stroke, neurological color), neurodegenerative, and inflammatory diseases. Cell necrosis is an uncontrolled accidental death in a pathological situation, and it is a discovery and development of anti-cell necrosis inhibitors to treat ischemic, neurodegenerative, and inflammatory diseases that cause necrosis and to elucidate the biological and pathological causes of necrosis. Research is ongoing.
[6]
Indole derivatives are pharmaceutically useful structures for inhibiting cell necrosis, and many studies on these structures have been reported. For example, patent WO2006/112549, which reports that it is active against glucokinase, patent WO95/07276, which reports that it is useful as an antitumor and cardiovascular production inhibitor, and patent WO2004/018428, which reports that it can be used as an antibiotic, are representative. . In addition, there is WO2009/025478 reporting a novel structure of indole or indazole derivatives useful for preventing or treating and ameliorating apoptosis and related diseases.
[7]
Among them, the present invention relates to a manufacturing method introducing a novel intermediate in synthesizing an indole or indazole compound exhibiting a preventive or therapeutic and ameliorating effect on cell necrosis and related diseases.
[8]
Conventionally, intermediates generated during the synthesis of indole or indazole compounds are unstable, so that a lot of impurities are generated, the yield is low, and it is difficult to stably scale-up.
[9]
Accordingly, there is a need to develop a new manufacturing method that solves problems caused by conventional unstable intermediates and introduces more stable intermediates.
[10]
[Prior art literature]
[11]
[Patent Literature]
[12]
International Publication WO2006/112549 (2006.10.26)
[13]
International Publication WO1995/007276 (1995.03.16)
[14]
International Publication WO2004/018428 (2004.03.04)
[15]
International Publication WO2009/025478 (2009.02.26)
DETAILED DESCRIPTION OF THE INVENTION
technical challenge
[16]
The present invention relates to a method for preparing a pharmaceutically useful indole or indazole compound, which reduces the generation of impurities, improves yield, and introduces a more stable novel intermediate in order to be stably applied to scale up. An object of the present invention is to provide a method for preparing an indole or indazole compound.
means of solving the problem
[17]
The present invention provides a method for preparing a compound represented by the following formula (2) comprising the compound represented by the following formula (1) as a reaction intermediate:
[18]
[Formula 1]
[19]

[20]
[Formula 2]
[21]

[22]
In the above formula,
[23]
n is an integer from 1 to 3,
[24]
m is 0 or 1,
[25]
p is an integer from 1 to 3,
[26]
A represents phenyl or 5 membered heteroaryl or heterocycle each containing 1 to 3 heteroatoms selected from N, O and S atoms and optionally substituted by R, wherein R represents hydrogen, C 1 -C 4 -alkyl optionally substituted by hydroxy or amino ,
[27]
X represents C or N, with the proviso that when X is N, m is 0 and when X is C, m is 1,
[28]
R 1 represents hydrogen, C 1 -C 6 -alkyl or —(CH 2 ) r NR 8 R 9 , wherein r is an integer from 2 to 5, and R 8 and R 9 are each independently hydrogen or C 1 -C 3 -alkyl, with the proviso that when X is N R 1 is hydrogen,
[29]
R 2 represents hydrogen, halogen or C 1 -C 6 -alkoxy, or -(CH 2 ) s CO 2 R 8 , -(CH 2 ) s OR 8 , -(CH 2 ) s NR 8 R 9 , - 5 to NHR 10 , —N(H)S(O) 2 R 8 or —NHC(O)R 10 , or the heterocycle moiety contains 1 or 2 heteroatoms selected from N, O and S atoms 6-membered ring -(CH 2 ) s -heterocycle- R 10 , wherein s is an integer of 0 to 3, R 8 and R 9 are as defined above, and R 10 is hydrogen, oxo, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxy or C 1 -C 6 -alkyl or 5 to 6 membered heterocycle comprising 1 or 2 nitrogen atoms as heteroatoms,
[30]
R 3 represents hydrogen, halogen, C 1 -C 6 -alkyl or phenyl, or the heterocycle contains 1 or 2 heteroatoms selected from N and O atoms and is a 5 to 6 membered ring -(CH 2 ) g - heterocycle, wherein g is an integer from 1 to 3 with the proviso that when X is N then R 3 is hydrogen or phenyl;
[31]
R 4 represents -YR 11 , wherein Y is a direct bond or represents -(CR 8 R 9 ) e Y'-, where e is an integer from 0 to 3, and R 8 and R 9 are as defined above and
[32]
Y' is selected from the group consisting of -O-, -C(O)- and -C(O)O-, R 11 is hydrogen, halogen, C 1 -C 6 -alkyl and -(CH 2 ) t B-R is selected from the group consisting of 13 , t is an integer of 0 to 3, B is a 5 to 6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O and S atoms, or C 6 -C 10 -aryl, R 13 represents hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy or carboxy -C 1 -C 6 -alkyl, with the proviso that when X is N, R 4 is hydrogen or C 1 -C 6 -alkyl,
[33]
R 5 represents hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, heterocycle or heterocyclyl-C 1 -C 6 -alkyl, wherein the heterocycle is selected from N and O atoms It is a 3 to 8 membered ring containing 1 to 3 heteroatoms, with the proviso that when X is N, R 5 is hydrogen,
[34]
R 6 represents -(CR 8 R 9 ) u -ZDWR 14 , where u is an integer of 0 to 3, and Z represents a direct bond or -C(O)- and -C(O)O- selected from the group consisting of, D represents a direct bond, C 4 -C 6 -cycloalkyl, 5 to 6 membered heteroaryl comprising 1 or 2 N atoms, or N, O and S Represents a 5 to 6 membered heterocycle containing 1 or 2 heteroatoms selected from atoms, W represents a direct bond or -NR 8 -, -C(O)-, -C(O)O-, -C (O)NR 12 - or -S(O) y -, R 12 is hydrogen, C 1 -C 3 -alkyl or C 6 -C 10-aryl, y is an integer of 1 or 2, R 14 is hydrogen, hydroxy, C 1 -C 6 -alkyl, 5 to 6 containing 1 to 3 heteroatoms selected from N, O and S atoms membered heterocycle, or C 6 -C 10 -ar-C 1 -C 6 -alkyl with the proviso that when X is N then R 6 represents C 4 -C 6 -cycloalkyl or N, O and Represents a 5-6 membered heterocycle comprising 1 or 2 heteroatoms selected from S atoms,
[35]
wherein alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl may be optionally substituted, the substituents being hydroxy, C 1 -C 6 -alkylamino, di(C 1 -C 6 -alkyl)amino, at least one selected from the group consisting of carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, carboxy-C 1 -C 6 -alkyl and oxo.
Effects of the Invention
[36]
According to the present invention, it is possible to reduce the generation of impurities by solving the problems caused by the conventional unstable intermediate, to prepare an indole or indazole compound in excellent yield, and to stably apply to scale up.
Modes for carrying out the invention
[37]
Hereinafter, the present invention will be described in more detail to help the understanding of the present invention. At this time, the terms or words used in the present specification and claims should not be construed as being limited to conventional or dictionary meanings, and the inventor appropriately defines the concept of the term to describe his invention in the best way. It should be interpreted as meaning and concept consistent with the technical idea of ​​the present invention based on the principle that it can be done.
[38]
In the definition of the substituents of the formulas according to the invention, the term 'alkyl' means an aliphatic hydrocarbon radical. Alkyl may be "saturated alkyl" containing no alkenyl or alkynyl moieties, or "unsaturated alkyl" containing at least one alkenyl or alkynyl moiety. "Alkenyl" means a group comprising at least one carbon-carbon double bond, and "alkynyl" means a group comprising at least one carbon-carbon triple bond. Alkyl, when used alone or in combination with alkoxy, may be branched or straight-chain, respectively.
[39]
Alkyl groups may have from 1 to 20 carbon atoms unless otherwise defined. The alkyl group may be a medium sized alkyl having from 1 to 10 carbon atoms. The alkyl group may be a lower alkyl having 1 to 6 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like. For example, C 1 -C 4 -alkyl has 1 to 4 carbon atoms in the alkyl chain and is in the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl is chosen
[40]
The term 'alkoxy', unless otherwise defined, means alkyloxy having 1 to 10 carbon atoms.
[41]
The term 'cycloalkyl' means a saturated aliphatic 3-10 membered ring, unless otherwise defined. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
[42]
The term 'aryl' includes at least one ring having a shared pi electron system, for example monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups. . That is, in the present specification, unless otherwise defined, aryl means a 4-10 membered, preferably 6-10 membered aromatic monocyclic or multicyclic ring including phenyl, naphthyl, and the like.
[43]
The term 'heteroaryl', unless otherwise defined, contains 1 to 3 heteroatoms selected from the group consisting of N, O and S, and an aromatic 3-10 membered ring that can be fused with benzo or C3-C8 cycloalkyl; Preferably it means a 4-8 membered ring, More preferably, it means a 5-6 membered ring. Examples of monocyclic heteroaryl include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, isothiazole, pyrazole, triazole, triazine, thiadiazole, tetrazole, oxadia sol, pyridine, pyridazine, pyrimidine, pyrazine and the like. Examples of bicyclic heteroaryls include indole, indoline, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine. , puropyridine and a group similar thereto, but are not limited thereto.
[44]
The term 'heterocycle', unless otherwise defined, contains 1 to 3 heteroatoms selected from the group consisting of N, O and S, may be fused with benzo or C3-C8 cycloalkyl, may be saturated or may contain 1 or 2 It means a 3-10 membered ring containing a double bond, preferably a 4-8 membered ring, more preferably a 5-6 membered ring. Examples of heterocycles include pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, morpholine, thiomorpholine, piperazine, hydrofuran, and the like. However, it is not limited only to these.
[45]
Other terms and abbreviations used in this specification may be interpreted as meanings commonly understood by those skilled in the art to which the present invention belongs, unless otherwise defined.
[46]
[47]
The present invention relates to a method for preparing a pharmaceutically useful indole or indazole compound, and the compound represented by the following formula (2) is prepared by including the compound represented by the following formula (1) as a reaction intermediate.
[48]
[Formula 1]
[49]

[50]
In Formula 1,
[51]
n is an integer from 1 to 3,
[52]
m is 0 or 1,
[53]
p is an integer from 1 to 3,
[54]
A represents phenyl or 5 membered heteroaryl or heterocycle each containing 1 to 3 heteroatoms selected from N, O and S atoms and optionally substituted by R, wherein R represents hydrogen, C 1 -C 4 -alkyl optionally substituted by hydroxy or amino ,
[55]
X represents C or N, with the proviso that when X is N, m is 0 and when X is C, m is 1,
[56]
R 1 represents hydrogen, C 1 -C 6 -alkyl or —(CH 2 ) r NR 8 R 9 , wherein r is an integer from 2 to 5, and R 8 and R 9 are each independently hydrogen or C 1 -C 3 -alkyl, with the proviso that when X is N R 1 is hydrogen,
[57]
R 2 represents hydrogen, halogen or C 1 -C 6 -alkoxy, or -(CH 2 ) s CO 2 R 8 , -(CH 2 ) s OR 8 , -(CH 2 ) s NR 8 R 9 , - 5 to NHR 10 , —N(H)S(O) 2 R 8 or —NHC(O)R 10 , or the heterocycle moiety contains 1 or 2 heteroatoms selected from N, O and S atoms 6-membered ring -(CH 2 ) s -heterocycle- R 10 , wherein s is an integer of 0 to 3, R 8 and R 9 are as defined above, and R 10 is hydrogen, oxo, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxy or C 1 -C 6 -alkyl or 5 to 6 membered heterocycle comprising 1 or 2 nitrogen atoms as heteroatoms,
[58]
R 3 represents hydrogen, halogen, C 1 -C 6 -alkyl or phenyl, or the heterocycle contains 1 or 2 heteroatoms selected from N and O atoms and is a 5 to 6 membered ring -(CH 2 ) g - heterocycle, wherein g is an integer from 1 to 3 with the proviso that when X is N then R 3 is hydrogen or phenyl.
[59]
[60]
[Formula 2]
[61]

[62]
In Formula 2, n, m, X, A, R 1 , R 2 , R 3 are as defined above,
[63]
R 4 represents -YR 11 , wherein Y is a direct bond or represents -(CR 8 R 9 ) e Y'-, where e is an integer from 0 to 3, and R 8 and R 9 are as defined above and
[64]
Y' is selected from the group consisting of -O-, -C(O)- and -C(O)O-, R 11 is hydrogen, halogen, C 1 -C 6 -alkyl and -(CH 2 ) t B-R is selected from the group consisting of 13 , t is an integer of 0 to 3, B is a 5 to 6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O and S atoms, or C 6 -C 10 -aryl, R 13 represents hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy or carboxy -C 1 -C 6 -alkyl, with the proviso that when X is N, R 4 is hydrogen or C 1 -C 6 -alkyl,
[65]
R 5 represents hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, heterocycle or heterocyclyl-C 1 -C 6 -alkyl, wherein the heterocycle is selected from N and O atoms It is a 3 to 8 membered ring containing 1 to 3 heteroatoms, with the proviso that when X is N, R 5 is hydrogen,
[66]
R 6 represents -(CR 8 R 9 ) u -ZDWR 14 , where u is an integer of 0 to 3, and Z represents a direct bond or -C(O)- and -C(O)O- selected from the group consisting of, D represents a direct bond, C 4 -C 6 -cycloalkyl, 5 to 6 membered heteroaryl comprising 1 or 2 N atoms, or N, O and S Represents a 5 to 6 membered heterocycle containing 1 or 2 heteroatoms selected from atoms, W represents a direct bond or -NR 8 -, -C(O)-, -C(O)O-, -C (O)NR 12 - or -S(O) y -, R 12 is hydrogen, C 1 -C 3 -alkyl or C 6 -C 10-aryl, y is an integer of 1 or 2, R 14 is hydrogen, hydroxy, C 1 -C 6 -alkyl, 5 to 6 containing 1 to 3 heteroatoms selected from N, O and S atoms membered heterocycle, or C 6 -C 10 -ar-C 1 -C 6 -alkyl with the proviso that when X is N then R 6 represents C 4 -C 6 -cycloalkyl or N, O and Represents a 5-6 membered heterocycle comprising 1 or 2 heteroatoms selected from S atoms,
[67]
wherein alkyl, alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl may be optionally substituted, the substituents being hydroxy, C 1 -C 6 -alkylamino, di(C 1 -C 6 -alkyl)amino, at least one selected from the group consisting of carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, carboxy-C 1 -C 6 -alkyl and oxo.
[68]
[69]
Specifically, in Formulas 1 and 2, R 1 may be hydrogen, C 1 -C 6 -alkyl, or di(C 1 -C 3 -alkyl)amino-C 2 -C 3 -alkyl.
[70]
In addition, the R 2 is hydrogen, halogen, carboxy, carboxy -C 1 -C 3 -alkyl, C 1 -C 3 -alkoxycarbonyl, C 1 -C 3 -alkoxycarbonyl-C 1 -C 3 -alkyl, hydroxy-C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, -(CH 2 ) s NR 8 R 9 , -NHR 10 , -N(H)S( O) 2 R 10 or -NHC(O) 2It may represent R 10 or -(CH 2 ) s -heterocycle-R 10 , wherein heterocycle, s, R 8 , R 9 and R 10 are as described above.
[71]
Furthermore, R 3 represents hydrogen, methyl or halogen, or represents phenyl optionally substituted by C 1 -C 3 -alkoxy, or the heterocycle comprises 1 or 2 heteroatoms selected from N and O atoms and 1 or heterocyclyl-C 1 -C 3 -alkylene, which is a 5 to 6 membered ring optionally substituted by two oxo groups.
[72]
In addition, Y may be selected from the group consisting of a direct bond, -O-, -C(O)-, and -CH 2 C(O)-.
[73]
In addition, R 11 is hydrogen, methyl, ethyl, phenyl, fluoro, chloro, 2-carboxy-pyrrolidin-1-yl, pyrrolidin-1-yl, 4-acetic acid-1,3-thiazoline- 2-yl, -CH 2 -(1,1-dioxo-thiomorpholin-4-yl) and -CH 2 -(2-oxopiperazin-4-yl).
[74]
In addition, in Formula 2, R 5 may be hydrogen, methyl, or isobutyl.
[75]
R 6 may be selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, 4-methyl-cyclopentyl, 4,4-difluorocyclohexyl, or D is cyclopentyl, cyclohexyl, pyrrolidine , tetrahydropyran, tetrahydrofuran and piperidine may be selected from the group consisting of, W represents a direct bond or -SO 2 -, -CO-, -C(O)O- or -CONR 12 - may be represented, wherein R 12 is as described above.
[76]
As an embodiment of the present invention, the compound represented by Formula 1 may be 5-(bromomethyl)-7-nitro-2-phenyl-1H-indole, and the compound represented by Formula 2 may be 4-( (2-phenyl-7-((tetrahydro-2H-pyran-4-yl)amino)-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide.
[77]
[78]
The compound represented by Formula 1 may be prepared by brominating the compound represented by Formula 3 below.
[79]
[Formula 3]
[80]

[81]
In Formula 3, n, m, p, X, A, R 1 , R 2 , and R 3 are as defined above.
[82]
The step of brominating is not particularly limited and may be performed in a conventional manner.
[83]
By brominating the compound represented by Formula 3 to produce a more stable intermediate represented by Formula 1, it is possible to reduce the generation of impurities, improve the reaction yield, and stably scale up.
[84]
The compound represented by Formula 1 may be prepared by reacting the compound represented by Formula 3 in the presence of at least one compound selected from the group consisting of PBr 3 , SOBr 2 , HBr and LiBr, more preferably PBr 3 can be used
[85]
[86]
The preparation method of the present invention comprises the steps of forming the intermediate of Chemical Formula 1, then substituting the compound represented by Chemical Formula 1 to prepare a compound represented by Chemical Formula 4; Preparing a compound represented by; and reacting the compound represented by the formula (5) with a ketone or an aldehyde to prepare a compound represented by the formula (2).
[87]
[Formula 4]
[88]

[89]
[Formula 5]
[90]

[91]
In Formulas 4 and 5, n, m, X, A, R 1 , R 2 , R 3 , R 4 are the same as defined above.
[92]
[93]
Hereinafter, embodiments of the present invention will be described in detail so that those of ordinary skill in the art can easily carry out the present invention. However, the present invention may be embodied in several different forms and is not limited to the embodiments described herein.
[94]
[95]
Example
[96]
Step a) Synthesis of 4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide
[97]
At room temperature, 5-(hydroxymethyl)-7-nitro-2-phenyl-1H-indole (4.6 kg) and THF (46 L) were added to the reactor and stirred, and the temperature of the reactor was cooled to 0° C. and then PBr 3 (2.8 kg) was added while the internal temperature of the reaction did not exceed 20 °C. After completion of the input, the temperature of the reactor was raised to 25° C., stirred for 1 hour, and sampled and analyzed showed that the peak of 5-(hydroxymethyl)-7-nitro-2-phenyl-1H-indole was 1.0% or less. In this case, the reaction was terminated.
[98]
After confirming the completion of the reaction, the reaction mixture was cooled to 0 °C, and 1,1-dioxothiomorpholine hydrochloride (4.4 kg) and N,N-diisopropylethylamine (DIPEA) (8.0 kg) were added to the reaction internal temperature. It was added while not exceeding 20 °C. After completion of the input, the temperature of the reactor was raised to 50° C., stirred for 4 hours, and sampled. When the peak of 5-(bromomethyl)-7-nitro-2-phenyl-1H-indole was 1.0% or less, the reaction was terminated. .
[99]
After confirming the completion of the reaction, the temperature of the reactor was cooled to 0° C., water (46.0 L) was added, followed by stirring, and the organic solvent was distilled under reduced pressure. After distillation under reduced pressure, ethyl acetate (EtOAc) (48.0 L) was further added, the organic solvent was distilled again under reduced pressure, and 4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1, 1-dioxide was obtained as a solid and then filtered. After washing with water (26.0 L) and ethanol (26.0 L), the crude 4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomo was dried under N 2 pressure for 16 hours. Pauline 1,1-dioxide (6.4 kg, Purity: 92.9%) was synthesized.
[100]
For purification, the above crude 4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide was mixed with DMF (6.0 L) and toluene (60.0 L). ), added to the mixture, stirred, heated to 120° C., stirred for 2 hours, then lowered to room temperature and stirred for an additional 2 hours. Toluene (60.0 L) was additionally added and stirred for 2 hours, then the solid in the solution was filtered, washed with toluene (20.0 L), and 4-((7-nitro-2-phenyl-1H- Indol-5-yl)methyl)thiomorpholine 1,1-dioxide (5.1 kg, Yield: 77.0% overall, Purity: 98.4%) was synthesized.
[101]
1 H NMR (500 MHz, DMSO-d 6 ) δ 11.63 (s, 1H), 8.07 (s, 1H), 8.04 (m, 3H), 7.49 (t, J= 7.7 Hz, 2H) 7.38 (d, J= 7.3 Hz, 1H), 7.14 (s, 1H), 3.79 (s, 2H), 3.12 (m, 4H), 2.84 (m, 4H).
[102]
[103]
Step b) Synthesis of 4-((7-amino-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide
[104]
4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide (0.60 kg), THF/methanol/H 2 O (1:1:1, 3.0 L) and NH 4 Cl (124 g) were added to the reactor at room temperature, and after stirring, Fe (480 g) was added. After heating the temperature of the reactor to 60 °C and stirring for at least 1 hour, the analysis result was 4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide The reaction was terminated when the peak of 0.5% or less.
[105]
After confirming the completion of the reaction, THF (3.0 L) was added to the reaction mixture, and the mixture was stirred for 10 minutes, filtered through Celite, and washed with THF/H 2 O (1:1, 3.0 L). The filtrate was reduced pressure, and THF and methanol were distilled to form a solid, and then the reaction mixture was stirred at room temperature for 2 hours or more. It was filtered and washed with a washing solution [1st H 2 O: 500 mL, 2nd ethanol/H 2 O= 1/3, 1.0 L], and then dried under N 2 pressure for 16 hours to 4-((7-amino-2- Phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide [0.45 kg (Yield: 81.3%, Purity: 97.2%)] was synthesized.
[106]
1 H NMR (500 MHz, DMSO-d 6 ) δ 10.89 (s, 1H), 7.80 (m, 2H), 7.48 (t, J= 7.7 Hz, 2H) 7.30 (d, J= 7.3 Hz, 1H), 6.74 (m, 2H), 6.34 (s, 1H), 5.15 (s, 2H), 3.07 (m, 4H), 2.87 (m, 4H).
[107]
[108]
Step c) Synthesis of 4-((2-phenyl-7-((tetrahydro-2H-pyran-4-yl)amino)-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide
[109]
4-((7-amino-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide (3.8 kg), tetrahydro-4H-pyran-4-one (1.3 kg), After adding acetic acid (AcOH) (4.6 kg) and isopropyl acetate (23.2 L) to the reactor and stirring, NaBH(OAc) 3 (4.6 kg) was added, followed by stirring at room temperature for at least 1 hour before analysis As a result, when the peak of 4-((7-amino-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide was 0.5% or less, the reaction was terminated.
[110]
After confirming the completion of the reaction, 1N aqueous NaOH solution (23.2 L) was added to the reaction mixture, followed by stirring for an additional 1 hour or more, and then the organic solvent was distilled off under reduced pressure. After filtering the solid present in the remaining aqueous solution, it was washed with water (38.7 L) and t-butylmethyl ether (38.7 L), and then dried under N 2 pressure for 16 hours to 4-((2-phenyl-7-(( Tetrahydro-2H-pyran-4-yl)amino)-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide (3.9 kg, Yield: 82.4%, Purity: 98.5 %) was synthesized.
[111]
1 H NMR (500 MHz, DMSO-d 6 ) δ 10.96 (s, 1H), 7.80 (m, 2H), 7.48 (t, J= 7.7 Hz, 2H) 7.30 (d, J= 7.3 Hz, 1H), 6.74 (s, 2H), 6.30 (s, 1H), 5.36 (m, 1H), 3.95 (m, 2H), 3.62 (s, 2H), 3.50 (m, 2H), 3.09 (m, 4H), 2.87 ( m, 4H), 2.05 (m, 2H), 1.45 (m, 2H).
[112]
[113]
comparative example
[114]
Step a) Synthesis of 4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide
[115]
Dissolve 5-(hydroxymethyl)-7-nitro-2-phenyl-1H-indole (804 mg, 3 mmol) in THF (10 mL) at room temperature, imidazole (408 mg, 6 mmol) and triphenylphos Pin (1.52 g, 6 mmol) was added. Iodine (453 mg, 3.9 mmol) was added and stirred for 2 hours. Upon completion of the reaction, it was filtered through celite and used in the next reaction without further purification.
[116]
5-iodomethyl-2-phenyl-7-nitro-1H-indole (850 mg, 2.5 mmol) obtained above was dissolved in THF (10 mL), and 1,1-dioxo-thiomorpholine (405 mg) , 2.25 mmol) was added and stirred for 2 hours. Upon completion of the reaction, the mixture was diluted with water, and the organic material was extracted with ethyl acetate (EtOAc), dried over anhydrous magnesium sulfate, and filtered. The residue was recrystallized from DCM and hexane to 4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide (625 mg, Yield: 65% , Purity: 97.2%) was obtained.
[117]
[118]
Next, in the same manner as in step b) and step c) of Example 1, 4-((2-phenyl-7-((tetrahydro-2H-pyran-4-yl)amino)-1H-indole-5 -yl)methyl)thiomorpholine 1,1-dioxide was prepared.
[119]
[120]
Referring to the above examples and comparative examples, 5-(hydroxymethyl)-7-nitro-2-phenyl-1H-indole from 4-((7-nitro-2-phenyl-1H-indol-5-yl) The yield of step a) of Example in which methyl)thiomorpholine 1,1-dioxide was synthesized through 5-(bromomethyl)-7-nitro-2-phenyl-1H-indole intermediate according to the present invention was 77.0% , it can be seen that compared to step a) of Comparative Example, the yield is significantly improved compared to 65%.
Claims
[Claim 1]
A method for producing a compound represented by the following formula (2) comprising a compound represented by the following formula (1) as a reaction intermediate: [Formula 1] [Formula 2] In the formula, n is an integer of 1 to 3, m is 0 or 1, , p is an integer from 1 to 3, A represents phenyl or 5 membered heteroaryl or heterocycle each containing 1 to 3 heteroatoms selected from N, O and S atoms and optionally substituted by R , wherein R represents hydrogen or C 1 -C 4 -alkyl optionally substituted by hydroxy or amino , X represents C or N, with the proviso that when X is N, m is 0 and X is C When m is 1, R 1 represents hydrogen, C 1 -C 6 -alkyl or —(CH 2 ) r NR 8 R 9 , where r is an integer of 2 to 5, R 8 and R 9 are each independently hydrogen or C 1-C 3 -alkyl, with the proviso that when X is N then R 1 is hydrogen and R 2 represents hydrogen, halogen or C 1 -C 6 -alkoxy, or —(CH 2 ) s CO 2 R 8 , — (CH 2 ) s OR 8 , -(CH 2 ) s NR 8 R 9 , -NHR 10 ,-N(H)S(O) 2 R 8 or -NHC(O)R 10or -(CH 2 ) s -heterocycle- R 10 , wherein the heterocycle moiety is a 5 to 6 membered ring comprising 1 or 2 heteroatoms selected from N, O and S atoms , wherein s is 0 to 3, R 8 and R 9 are as defined above, and R 10 is hydrogen, oxo, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxy or C 1 -C 6 -alkyl. represents or represents a 5 to 6 membered heterocycle comprising 1 or 2 nitrogen atoms as heteroatoms, R 3 represents hydrogen, halogen, C 1 -C 6 -alkyl or phenyl, or the heterocycle is N and O atoms -(CH) which contains 1 or 2 heteroatoms selected from and is a 5 to 6 membered ring 2 ) represents g -heterocycle, wherein g is an integer from 1 to 3, with the proviso that when X is N, R 3 is hydrogen or phenyl, R 4 represents -YR 11 , wherein Y is a direct bond or -(CR 8 R 9 ) represents Y'-, wherein e is an integer of 0 to 3, R 8 and R 9 are as defined above, and Y' is -O-, -C(O)- and -C(O)O-, R 11 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 -alkyl and -(CH 2 ) t B-R 13 , t is 0 to 3 is an integer of, B represents a 5 to 6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O and S atoms, or C 6 -C 10 -aryl, R 13 represents hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy or carboxy -C 1 -C 6 -alkyl, with the proviso that when X is N, R 4 is hydrogen or C 1 -C 6 -alkyl, R 5 represents hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, heterocycle or heterocyclyl-C 1 -C 6 -alkyl , wherein heterocycle is a 3 to 8 membered ring comprising 1 to 3 heteroatoms selected from N and O atoms, with the proviso that when X is N, R 5 is hydrogen and R 6 is -(CR 8 R 9 ) represents u -ZDWR 14 , wherein u is an integer from 0 to 3, Z represents a direct bond or is selected from the group consisting of -C(O)- and -C(O)O-, and D is represents a direct bond, represents C 4 -C 6 -cycloalkyl, represents 5 to 6 membered heteroaryl containing 1 or 2 N atoms, or 1 or 2 heteroaryls selected from N, O and S atoms represents a 5 to 6 membered heterocycle containing an atom, W represents a direct bond or -NR 8 -, -C(O)-, -C(O)O-, -C(O)NR 12 - or - S(O) y -, R 12 represents hydrogen, C 1 -C 3 -alkyl or C 6 -C 10 -aryl, y is an integer of 1 or 2, R 14 is hydrogen, hydroxy, C 1 -C 6 -alkyl, 5 to 6 membered heterocycle comprising 1 to 3 heteroatoms selected from N, O and S atoms, or C 6 -C 10 -ar-C 1 -C 6 -alkyl, provided that When X is N, R 6 represents C 4 -C 6 -cycloalkyl or a 5 to 6 membered heterocycle comprising 1 or 2 heteroatoms selected from N, O and S atoms, in which alkyl , alkoxy, aryl, cycloalkyl, heterocycle and heteroaryl can be optionally substituted, the substituents being hydroxy, C 1 -C 6 -alkylamino, di(C 1 -C 6 -alkyl)amino, carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, carboxy-C 1-C 6 -Alkyl and at least one selected from the group consisting of oxo.
[Claim 2]
The method according to claim 1, wherein the compound represented by Formula 1 is prepared by brominating the compound represented by Formula 3: [Formula 3] Wherein , n, m, p, X, A, R 1 , R 2 , R 3 are as defined in claim 1.
[Claim 3]
The method according to claim 2, wherein the compound represented by Formula 1 is prepared by reacting the compound represented by Formula 3 in the presence of at least one compound selected from the group consisting of PBr3, SOBr 2 , HBr and LiBr. .
[Claim 4]
The method of claim 1, further comprising: preparing a compound represented by the following formula (4) by substituting the compound represented by the formula (1); preparing a compound represented by Formula 5 by reducing the compound represented by Formula 4; and preparing a compound represented by Formula 2 by reacting the compound represented by Formula 5 with a ketone or aldehyde: [Formula 4] [Formula 5] In the formula, n, m, X, A, R 1 , R 2 , R 3 , and R 4 are as defined in claim 1.