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. 10-2019-0073020 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 method for preparing 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 activity 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 novel manufacturing method for synthesizing an indole or indazole compound that exhibits preventive or therapeutic and ameliorating effects on cell necrosis and related diseases.
[8]
Conventionally, borane dimethyl sulfide (BH 3 SMe 2 ) was used in the process of synthesizing an indole or indazole compound . Since borane dimethyl sulfide (BH 3 SMe 2 ) is a toxic substance, there was a safety problem, and the process Since this process is complicated through many steps, there is a problem in that the yield is not good.
[9]
In addition, conventionally, a method for reducing the indole or indazole compound containing a nitro group to an indole or indazole compound containing an amine group using an iron (Fe) catalyst has been used. However, in this case, problems such as poor reproducibility due to various particle sizes of iron (Fe), poor stirring during the reaction, or a decrease in yield due to impurities generated in the reaction when the reaction time is prolonged has occurred. In addition, the reactor was coated with iron oxide produced after the reaction, and there was a difficulty due to the cost and time required to wash it.
[10]
Accordingly, there is a need to develop a new manufacturing method that solves problems occurring in the conventional manufacturing process and improves the yield and the like.
[11]
[Prior art literature]
[12]
[Patent Literature]
[13]
International Publication WO2006/112549 (2006.10.26)
[14]
International Publication WO1995/007276 (1995.03.16)
[15]
International Publication WO2004/018428 (2004.03.04)
[16]
International Publication WO2009/025478 (2009.02.26)
DETAILED DESCRIPTION OF THE INVENTION
technical challenge
[17]
The present invention provides a method for preparing a pharmaceutically useful indole or indazole compound, ensuring safety, improving the yield through simplification of the process, and using a conventional iron (Fe) catalyst An object of the present invention is to provide a novel method for preparing an indole or indazole compound that can solve the
means of solving the problem
[18]
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:
[19]
[Formula 1]
[20]

[21]
[Formula 2]
[22]

[23]
In the above formula,
[24]
n is an integer from 1 to 3,
[25]
m is 0 or 1,
[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 ) p CO 2 R 8 , —(CH 2 ) p OR 8 , —(CH 2 ) p 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 ) p -heterocycle- R 10 , wherein p is an integer from 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 ) s — heterocycle, wherein s 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 ) g -, where g is an integer from 0 to 3, R 8 and R 9 are as defined above, 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 an integer from 0 to 3, and B is 1 selected from N, O and S atoms or represents a 5-6 membered heterocycle containing 2 heteroatoms or C 6 -C 10 -aryl, R 13 is hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy or carboxy-C 1-C 6 -alkyl, with the proviso that when X is N then R 4 represents hydrogen or C 1 -C 6 -alkyl,
[32]
R 5 represents -Y'R 11 , wherein Y' is a direct bond or represents -(CR 8 R 9 ) h Y"-, where h is an integer from 0 to 3, R 8 , R 9 , R 11 is as defined above,
[33]
Y" is selected from the group consisting of -O-, -C(O)- and -C(O)O-, with the proviso that when X is N then R 5 represents hydrogen or C 1 -C 6 -alkyl;
[34]
R 6 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 6 is hydrogen,
[35]
R 7 represents -(CR 8 R 9 ) u -ZDWR 14 , where u is an integer from 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 7 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,
[36]
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
[37]
According to the present invention, safety (safety) can be secured due to the non-use of borane dimethyl sulfide (BH 3 SMe 2 ), the yield is improved through the simplification of the process, and the problems with the conventional iron (Fe) catalyst It is possible to produce an indole or indazole compound with reproducibility and excellent yield by solving the problem, and it is possible to reduce the cost and time required for cleaning by solving the iron oxide coating problem of the reactor.
Modes for carrying out the invention
[38]
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.
[39]
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.
[40]
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
[41]
The term 'alkoxy', unless otherwise defined, means alkyloxy having 1 to 10 carbon atoms.
[42]
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.
[43]
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, unless otherwise defined, in the present specification, aryl means a 4-10 membered, preferably 6-10 membered aromatic monocyclic or multicyclic ring including phenyl, naphthyl, and the like.
[44]
The term 'heteroaryl', unless otherwise defined, includes an aromatic 3-10 membered ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, which may 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.
[45]
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.
[46]
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.
[47]
[48]
The present invention relates to a method for preparing a pharmaceutically useful indole or indazole compound, and 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:
[49]
[Formula 1]
[50]

[51]
In Formula 1,
[52]
n is an integer from 1 to 3,
[53]
m is 0 or 1,
[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 ) p CO 2 R 8 , —(CH 2 ) p OR 8 , —(CH 2 ) p 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 ) p -heterocycle- R 10 , wherein p is an integer from 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 ) s — heterocycle, wherein s is an integer from 1 to 3, with the proviso that when X is N then R 3 is hydrogen or phenyl,
[59]
R 4 represents -YR 11 , wherein Y is a direct bond or represents -(CR 8 R 9 ) g -, where g is an integer from 0 to 3, R 8 and R 9 are as defined above, 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 an integer from 0 to 3, and B is 1 selected from N, O and S atoms or represents a 5-6 membered heterocycle containing 2 heteroatoms or C 6 -C 10 -aryl, R 13 is hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy or carboxy-C 1-C 6 -alkyl, with the proviso that when X is N, R 4 represents hydrogen or C 1 -C 6 -alkyl.
[60]
[61]
[Formula 2]
[62]

[63]
In Formula 2, n, m, X, A, R 1 , R 2 , R 3 are as defined above,
[64]
R 5 represents -Y'R 11 , wherein Y' is a direct bond or represents -(CR 8 R 9 ) h Y"-, where h is an integer from 0 to 3, R 8 , R 9 , R 11 is as defined above,
[65]
Y" is selected from the group consisting of -O-, -C(O)- and -C(O)O-, with the proviso that when X is N then R 5 represents hydrogen or C 1 -C 6 -alkyl;
[66]
R 6 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 6 is hydrogen,
[67]
R 7 represents -(CR 8 R 9 ) u -ZDWR 14 , where u is an integer from 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 7 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,
[68]
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.
[69]
[70]
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.
[71]
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 ) p NR 8 R 9 , -NHR 10 , -N(H)S ( O) 2 R 10 or -NHC(O) 2It may represent R 10 or -(CH 2 ) p -heterocycle-R 10 , wherein heterocycle, p, R 8 , R 9 and R 10 are as described above.
[72]
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.
[73]
In addition, Y is a direct bond, Y' is a direct bond, or -O-, -C(O)- and -CH 2 C(O)- It may be selected from the group consisting of.
[74]
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), -CH 2 -(2-oxopiperazin-4-yl), -1,1-dioxo-thi It may be selected from the group consisting of omopolin-4-yl and -2-oxopiperazin-4-yl.
[75]
In addition, in Formula 2, R 6 may be hydrogen, methyl, or isobutyl.
[76]
R 7 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.
[77]
As an embodiment of the present invention, the compound represented by Formula 1 may be (1,1-dioxidothiomorpholino)(7-nitro-2-phenyl-1H-indol-5-yl)methanone, The compound represented by Formula 2 is 4-((2-phenyl-7-((tetrahydro-2H-pyran-4-yl)amino)-1H-indol-5-yl)methyl)thiomorpholine 1,1 - It may be a dioxide.
[78]
[79]
The compound represented by Formula 1 may be prepared by an amidation reaction of a compound represented by Formula 3 below.
[80]
[Formula 3]
[81]

[82]
In Formula 3, n, m, X, A, R 1 , R 2 , and R 3 are as defined above.
[83]
The amidation step is not particularly limited and may be carried out in a conventional manner.
[84]
Conventionally, a process for reducing the compound represented by Formula 3 using borane dimethylsulfide (BH 3 SMe 2 ) was performed. Borane dimethylsulfide (BH 3 SMe 2 ) used in this process was a toxic substance, so safety was a problem. However, in the present invention, the compound represented by Chemical Formula 3 is amidated to produce the intermediate represented by Chemical Formula 1, thereby securing safety due to non-use of borane dimethyl sulfide (BH 3 SMe 2 ). can do.
[85]
[86]
Next, the present invention may include the step of preparing a compound represented by the following formula (4) by primary reduction and secondary reduction of the compound represented by the formula (1).
[87]
[Formula 4]
[88]

[89]
In Formula 4, n, m, X, A, R 1 , R 2 , R 3 , and R 4 are the same as defined above.
[90]
In this case, the primary reduction is at least one selected from the group consisting of sodium borohydride (NaBH 4 ), boron trifluoride etherate (BF 3 OEt 2 , Boron trifluoride etherate), and lithium aluminum hydride (LAH, lithium aluminum hydride). The above may be used as a reducing agent, more preferably sodium borohydride (NaBH 4 ) and boron trifluoride etherate (BF 3 OEt 2 , Boron trifluoride etherate) may be used together. The carbonyl group (C=O) of the compound represented by Formula 1 may be reduced through the primary reduction to produce a compound represented by Formula 5 below.
[91]
[Formula 5]
[92]

[93]
In Formula 5, n, m, X, A, R 1 , R 2 , R 3 , and R 4 are the same as defined above.
[94]
[95]
The secondary reduction is Pd/C, NiBr 2 , NiCl 2 , ZnCl 2 , ZrCl 4 , I 2 , BiCl 3 , Cu, FeCl 3 .6H 2 O, In(OTf 3 ), Ni, NiCl 2 .6H 2 O , SnCl 2 , LiBH 4 , LiCl, NaBF 4 and CoCl 2 ·6H 2 O may be used as a reducing agent, and more preferably Pd/C may be used. The nitro group (-NO 2 ) of the compound represented by Formula 5 through the secondary reduction is an amine group (-NH 2 ) of the compound represented by Formula 4) can be reduced to
[96]
Conventionally, when synthesizing an indole or indazole compound , iron (Fe) in the process of reducing from a compound represented by Formula 5 having a nitro group (-NO 2 ) to a compound represented by Formula 4 having an amine group (-NH 2 ) A catalyst was used. However, in this case, problems such as poor reproducibility due to various particle sizes of iron (Fe), poor stirring during the reaction, or a decrease in yield due to impurities generated in the reaction when the reaction time is prolonged has occurred. In addition, the reactor was coated with iron oxide produced after the reaction, and there was a difficulty due to the cost and time required to wash it. However, the present invention solves the problems of the conventional iron (Fe) catalyst by performing primary and secondary reduction in the same manner as above without using an iron (Fe) catalyst, thereby providing indole or indole in excellent yield with reproducibility. The indazole compound can be prepared, and the cost and time required for cleaning can be reduced by solving the iron oxide coating problem of the reactor.
[97]
[98]
In addition, conventionally, when synthesizing an indole or indazole compound, when preparing the compound represented by Formula 5 from the compound represented by Formula 3, borane dimethylsulfide (BH 3 SMe 2 ) from the compound represented by Formula 3 After reduction (step 1), halogenation (step 2) and amine substitution (step 3) were performed again. However, in the present invention, when the compound represented by Formula 5 is prepared from the compound represented by Formula 3, an amidation reaction of the compound represented by Formula 3 is performed (Step 1), and then carbohydrate through primary reduction. It can be carried out through a total of two steps, which is a step (2 steps) of reducing the nyl group (C=O). As such, the present invention improved synthesis efficiency and improved yield through process simplification.
[99]
[100]
Next, the preparation method of the present invention can be prepared including the step of preparing the compound represented by the formula (2) by reacting the compound represented by the formula (4) with a ketone or an aldehyde.
[101]
[102]
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.
[103]
[104]
Example
[105]
Step a) Synthesis of (1,1-dioxidothiomorpholino)(7-nitro-2-phenyl-1H-indol-5-yl)methanone
[106]
7-Nitro-2-phenyl-1H-indole-5-carboxylic acid (250 g) with HOBt·H 2 O [C 6 H 5 N 3 O·H 2 O] (54.25 g), 1-(3-dimethylaminopropyl) )-3-ethylcarbodiimide hydrochloride (EDC HCl) (186.78 g), 1,1-dioxothiomorpholine hydrochloride (151.98 g), diisopropylethylamine (DIPEA) (154.27 mL), N ,N-dimethylformamide (DMF) (1.37 L) was added to the reactor at room temperature and stirred. After heating the reaction mixture to 75-80°C, the reaction was terminated when the result of sampling and analysis after 1 hour showed that the peak of 7-nitro-2-phenyl-1H-indole-5-carboxylic acid was 1.0% or less. .
[107]
After confirming the completion of the reaction, the reaction mixture was cooled to 35-40 °C, H 2 O (3.75 L) was slowly added dropwise, and then stirred at room temperature for 1 hour. After stirring, the mixture was filtered, washed with H 2 O (0.75 L), and washed once again with ethanol/H 2 O (1/2, 0.75 L). Crude (1,1-dioxidothiomorpholino) (7-nitro-2-phenyl-1H-indol-5-yl) methanone (336.09 g, Purity: 93.43%) was synthesized by drying under N 2 pressure. . At room temperature, crude (1,1-dioxidothiomorpholino)(7-nitro-2-phenyl-1H-indol-5-yl)methanone (336.09 g) and tetrahydrofuran (THF) (2.69 L) were prepared After the addition, the temperature was raised and the mixture was stirred under reflux for 1 hour. After the reaction mixture was cooled to 35-40 °C, H 2 O (4.03 L) was added dropwise, stirred at room temperature for 1 hour, and then washed with THF/H 2 O (1 L). Drying under N 2 pressure (1,1-dioxidothiomorpholino)(7-nitro-2-phenyl-1H-indol-5-yl)methanone (314.1 g, Yield: 88.78%, purity (Purity): 95.87%) was synthesized.
[108]
1 H NMR (400 MHz, DMSO-d 6 ) δ 11.87 (s, 1H), 8.25 (s, 1H), 8.19 (s, 1H), 8.02 (m, 2H), 7.52 (t, J= 7.6 Hz, 2H ) 7.43 (dd, J = 6.8, 7.2 Hz, 1H), 7.23 (s, 1H), 3.93 (m, 4H), 3.30 (m, 4H).
[109]
[110]
Step b) Synthesis of 4-((7-amino-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide
[111]
NaBH 4 (1.137 g) and THF (30 ml) were added to the reactor, and the reactor temperature was cooled to 10° C. or less, and then boron trifluoride etherate (BF 3 Et 2 O) (3.71 mL) was slowly added. (1,1-dioxidothiomorpholino)(7-nitro-2-phenyl-1H-indol-5-yl)methanone (4 g) was added, heated to 40 ℃, and then sampled from 1 hour after As a result of the analysis, when the peak of (1,1-dioxidothiomorpholino)(7-nitro-2-phenyl-1H-indol-5-yl)methanone was 1.0% or less, the reaction was terminated.
[112]
After the reactor temperature was cooled to 10 °C, 10 wt% Pd/C (53 mg) and NaBH 4 (1.137 g) were added, and then ethanol (40 ml) was added dropwise at the same temperature. When the result of sampling and analysis after 0.5 hour is less than 1.0% of the peak of 4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide The reaction was terminated. The reaction solution was heated to 25 ~ 30 ℃, then H 2 O (20 ml) was added, stirred for 30 minutes, and then concentrated under reduced pressure. H 2 O (80 ml) was added, heated to 80 ~ 90 °C, stirred for 1 hour, and filtered. First washed with H 2 O (20ml), then washed with ethanol/H 2 O= 1/2, (20ml), and dried under N 2 pressure to crude 4-((7-amino-2-phenyl- 1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide (3.51 g, Purity: 98.42%) was synthesized.
[113]
Crude 4-((7-amino-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide (3.51 g) and H 2 O (52 mL) were put into a reactor, and 10° C. After cooling to below, methanesulfonic acid (1.8 mL) was added dropwise while maintaining 25° C. or less to adjust the pH to 3-4. After stirring at room temperature for 30 minutes, it was filtered through celite and washed with H 2 O (11 mL). 6N NaOH (5 mL) was added to the filtrate to adjust the pH to 9, followed by stirring at room temperature for 30 minutes, followed by filtration. First washed with H 2 O (11 mL), then washed with ethanol/H 2 O= 1/2, 11 mL), and then dried under N 2 pressure to 4-((7-amino-2-phenyl-1H) -Indol-5-yl)methyl)thiomorpholine 1,1-dioxide (3.13 g (Yield): 87.92%, Purity: 91.31%) was synthesized.
[114]
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).
[115]
[116]
Step c) Synthesis of 4-((2-phenyl-7-((tetrahydro-2H-pyran-4-yl)amino)-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide
[117]
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.
[118]
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.
[119]
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).
[120]
[121]
comparative example
[122]
[123]
Step a) Synthesis of 7-nitro-2-phenyl-1H-indol-5-yl methanol
[124]
7-Nitro-2-phenyl-1H-indole-5-carboxylic acid (5.8 kg) and THF (61L) were put into a reactor at room temperature, stirred, and the reaction mixture was cooled to 10-15 °C, and then 5M borane Dimethyl sulfide (BH 3 SMe 2 ) (12.3 L) was slowly added dropwise so that the internal temperature did not exceed 40°C. After the dropwise addition was completed and the temperature of the reactor was heated to 40°C, the reaction mixture was stirred for 2 hours, and as a result of HPLC analysis, the peak of 7-nitro-2-phenyl-1H-indole-5-carboxylic acid was 1.0%. The reaction was terminated in the following cases.
[125]
After confirming the completion of the reaction, H 2 O (55L) was slowly added dropwise to the reaction mixture, the layers were separated to store the organic layer, and the water layer was extracted with ethyl acetate, EtOAc (29L) and mixed with the stored organic layer. It was distilled under reduced pressure. EtOH/H 2 O (6.1 L/12.2 L) was added to the obtained concentrate, stirred for 2 hours or more, and then filtered. After washing with a washing solution (EtOH/H 2 O= 1/3, 9.0 L), and then drying under N 2 pressure for 16 hours, 7-nitro-2-phenyl-1H-indol-5-yl methanol (4.6 kg, yield) (Yield): 83.5%, Purity: 98.4%) was synthesized.
[126]
1 H NMR (500 MHz, DMSO-d 6 ) δ 11.6 (s, 1H), 8.07 (s, 1H), 8.00 (m, 3H), 7.49 (t, J= 7.7 Hz, 2H) 7.40 (d, J= 7.3 Hz, 1H), 7.14 (s, 1H), 5.42 (t, J= 6.7 Hz, 1H), 4.66 (d, J= 6.7 Hz, 2H).
[127]
[128]
Step b) Synthesis of 4-((7-nitro-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide
[129]
At room temperature, 7-nitro-2-phenyl-1H-indol-5-yl_methanol (4.6 kg) and THF (46L) were added to the reactor and stirred, and then 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.
[130]
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. .
[131]
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, and the organic solvent was distilled under reduced pressure again to 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.
[132]
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.
[133]
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).
[134]
[135]
Step c) Synthesis of 4-((7-amino-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1-dioxide
[136]
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.
[137]
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.
[138]
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).
[139]
[140]
Next, in the same manner as in step c) of Example 1, 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 prepared.
[141]
[142]
Referring to the above Examples and Comparative Examples, 4-((7-amino-2-phenyl-1H-indol-5-yl)methyl) from 7-nitro-2-phenyl-1H-indole-5-carboxylic acid An example in which thiomorpholine 1,1-dioxide was synthesized in two steps according to the present invention is 4-((7-amino-2-phenyl-1H-indol-5-yl)methyl)thiomorpholine 1,1- The total yield of dioxide is 78.06% (step a) 88.78%, step b) 87.92% multiplied value), and in the case of a comparative example synthesized through three steps, 4-((7-amino-2-phenyl-1H-indole-5) The total yield of -yl)methyl)thiomorpholine 1,1-dioxide is calculated to be 52.27% (step a) multiplied by 83.5%, step b)77.0%, step c) 81.3%). That is, it can be confirmed that the present invention significantly improves the yield through the simplification of the process.
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, , 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 , represents 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 when X is C m is 1, 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 then R 1 is hydrogen and R 2 represents hydrogen, halogen or C 1 -C 6 -alkoxy, or —(CH 2 ) p CO 2 R 8 , — (CH 2 ) p OR 8 , -(CH 2 ) p NR 8 R 9 , -NHR 10 ,-N(H)S(O) 2 R 8 or -NHC(O)R 10or -(CH 2 ) p -heterocycle- R 10 , wherein the heterocycle moiety is a 5 to 6 membered ring containing 1 or 2 heteroatoms selected from N, O and S atoms , wherein p 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 s -heterocycle, wherein s is an integer from 1 to 3, provided 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 ) g -, wherein g is an integer from 0 to 3, R 8 and R 9 are as defined above, R 11 is hydrogen, halogen, C 1 -C 6 -alkyl and -(CH 2 ) t is selected from the group consisting of B-R 13 , t is an integer from 0 to 3, B is a 5 to 6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O and S atoms represents 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 -Y'R 11 , where Y' is a direct bond or represents -(CR 8 R 9 ) h Y"-, where h is an integer from 0 to 3 and R 8 , R 9 , R 11 are as defined above, and Y" is selected from the group consisting of -O-, -C(O)- and -C(O)O-, provided that X is N when R 5 is hydrogen or C 1 -C 6-alkyl, R 6 represents hydrogen, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, heterocycle or heterocyclyl-C 1 -C 6 -alkyl, wherein heterocycle is N and a 3 to 8 membered ring including 1 to 3 heteroatoms selected from O atoms, with the proviso that when X is N, R 6 is hydrogen and R 7 is -(CR 8 R 9 ) 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-, D represents a direct bond, or C 4 -C 6- represents cycloalkyl or 5 to 6 membered heteroaryl comprising 1 or 2 N atoms, or 5 to 6 membered heterocycle comprising 1 or 2 heteroatoms selected from N, O and S atoms and W represents a direct bond or represents -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, N, O and 5 to 6 membered heterocycle comprising 1 to 3 heteroatoms selected from S atoms, or C 6 -C 10 -ar-C 1 -C 6-alkyl, provided that when X is N, R 7 represents C 4 -C 6 -cycloalkyl or 5 to 6 membered heteroatom including 1 or 2 heteroatoms selected from N, O and S atoms cycle, 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, carboxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, carboxy-C 1 -C 6 -alkyl and oxo.
[Claim 2]
The method according to claim 1, wherein the compound represented by Formula 1 is prepared by amidation reaction of the compound represented by Formula 3: [Formula 3] Wherein , n, m, X, A, R 1 , R 2 , R 3 are as defined in claim 1.
[Claim 3]
The method according to claim 1, comprising the step of preparing a compound represented by the following formula (4) by primary reduction and secondary reduction of the compound represented by the formula (1): [Formula 4] In the formula, n, m, X, A, R 1 , R 2 , R 3 , R 4 are as defined in claim 1.
[Claim 4]
4. The group of claim 3, wherein the primary reduction is sodium borohydride (NaBH 4 ), boron trifluoride etherate (BF 3 OEt 2 , Boron trifluoride etherate), and lithium aluminum hydride (LAH, Lithium aluminum hydride). A method of manufacturing that uses at least one or more selected from the reducing agent.
[Claim 5]
According to claim 3, wherein the secondary reduction is Pd/C, NiBr 2 , NiCl 2 , ZnCl 2 , ZrCl 4 , I 2 , BiCl 3 , Cu, FeCl 3 · 6H 2 O, In(OTf 3 ), Ni, NiCl 2 · 6H 2 O, SnCl 2 , LiBH 4 , LiCl, NaBF 4 and CoCl 2 · 6H 2 O Manufacturing method that uses at least one or more selected from the group consisting of a reducing agent.
[Claim 6]
The method according to claim 3, comprising the step of preparing the compound represented by Formula 2 by reacting the compound represented by Formula 4 with a ketone or an aldehyde.