Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
  • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
  • C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
• • 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
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B61/00—Other general methods

Definitions

• the present invention provides a method for producing a tetrahydronaphthyl urea derivative having a tropomyosin receptor kinase A (TrkA) inhibitory activity represented by the following formula (I) of Scheme 7 and a compound represented by formula (I): And a process for producing a compound represented by the formula (AM-X).
• TrkA tropomyosin receptor kinase A
• a tetrahydronaphthyl urea derivative represented by the formula (I) is produced by a urea reaction using an amino compound represented by the formula (AM-1) and an amine salt represented by the formula (AM-2-RRS). (Scheme 1) (Patent Document 1).
• the amine salt represented by the formula (AM-2-RRS) is a compound (RAM-2) obtained through two steps using a compound represented by the formula (TH-1) as a starting material. ) Can be produced by fractional recrystallization after conversion to the salt represented by the formula (RAM-2-S) with D-tartaric acid.
• the production method using fractional recrystallization is excellent in that the formula (AM-2-RRS) is obtained as a compound having high optical purity, but other isomers after the resolution (for example, (1S, 2S) isomers , Etc.) is difficult to reuse, and in the mass synthesis or industrial production of the compound represented by formula (I), an improved production method is required. That is, when mass synthesis or industrial production of the compound represented by the formula (I) is considered, a novel production method different from the production method using the amine salt represented by the formula (AM-2-RRS) is found.
• the synthesis method of the compound represented by Formula (EP-1), which can be a synthetic intermediate of the compound represented by Formula (AM-X), is Chemistry® Letters, (11), P2231-4, 1992 (Non-patent document 1), or Bulletin of the Chemical Society of Japan, 67 (8), p2248-56, 1994 (Non-patent document 2).
• the synthesis method is an oxidation reaction using oxygen gas and a manganese catalyst and is not suitable for mass synthesis.
• the chemical yield is as low as 35% and the optical purity is as low as 63% for use as a pharmaceutical raw material. Therefore, this reaction condition is not used in mass synthesis or industrial production of the compound represented by the formula (AM-X).
• P 0, 1,2-dihydronaphthalene ring
• the compound from which the dimethyl group at the 1-position was removed was oxidized using hydrogen peroxide and a titanium catalyst in Synlett, 20, p3545-3547, 2006 (Non-patent Document 3), or Synlett, 15, p2445 -2447, 2007 (Non-patent Document 4) (Scheme 6).
• the production method of the compound represented by the formula (I) through the fractional recrystallization method of the represented compound that is, using the compound represented by the formula (AM-X), represented by the formula (I)
• the present inventors have conducted intensive research to solve the above problems. As a result, in the following (Scheme 7), by performing an asymmetric epoxidation reaction using a titanium catalyst using a compound represented by the formula (TH-1) as a starting material and hydrogen peroxide as an oxygen source.
• the present inventors have found that an epoxy compound having a desired configuration represented by the formula (EP-1) can be obtained with high chemical yield and high optical purity. Further, it has been found that the compound represented by the formula (AM-X) can be obtained with high chemical yield and high optical purity by the subsequent aminohydroxylation reaction.
• the present inventors have found a process for producing a compound of formula (AM-X), which can suppress the formation of an isomer of the compound of formula (AM-X) by these successive reactions.
• ring A is the following formula: 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group.
• the present invention relates to a method for producing a tetrahydronaphthylurea derivative having a tropomyosin receptor kinase A (TrkA) inhibitory activity represented by formula (I), and (1R, 2R) -1 represented by formula (AM-X)
• the present invention relates to a production method for synthesizing a large amount of amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ol derivative with high yield and high optical purity.
• the present invention provides an intermediate used for the production of a tetrahydronaphthylurea derivative having a tropomyosin receptor kinase A (TrkA) inhibitory activity represented by the following formula (I) with a good chemical yield and high optical activity purity. It is possible to provide a novel method for producing by a short process, an easy and industrially advantageous method, and the industrial utility is high.
• TrkA tropomyosin receptor kinase A
• the present invention relates to a tetrahydronaphthyl urea derivative represented by the following formula (I) shown in the following embodiment, (1R, 2R) -1-amino-4,4-dimethyl-
• the present invention relates to a method for producing a 1,2,3,4-tetrahydronaphthalen-2-ol derivative and an epoxy derivative represented by the formula (EP-1). More specifically, exemplary embodiments of the present invention can be as described in [1] to [5] below.
• a first aspect of the present invention is the following formula (I):
• p is an integer selected from 0, 1, and 2;
• R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a hydroxy group;
• ring A is 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridine- Which is a 3-yl group], comprising the following steps: (1) The following formula (TH-1):
• p and R 1 are as defined in the formula (I)] and a titanium catalyst (for example, titanium tetrachloride, titanium tetrabromide, titanium Alkoxide (titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide (Ti (OCH 2 CH 2 CH 3 ) 4 ), titanium tetraisopropoxide (Ti (OCH (CH 3 ) 2 ) 4 ), titanium tetra Normal butoxide (Ti (OCH 2 CH 2 CH 2 CH 3 ) 4 ), titanium tetratertiary butoxide (Ti (OC (CH 3 ) 3 ) 4 , etc.) and the following formula (LG-1) as a ligand ):
• a titanium catalyst for example, titanium tetrachloride, titanium tetrabromide, titanium Alkoxide (titanium tetramethoxide, titanium tetraethoxide,
• a solvent for example, a solvent not involved in the reaction, preferably an organic solvent, more preferably a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, chlorobenzene, fluorobenzene, etc.
• a basic solvent an aromatic hydrocarbon solvent such as benzene and toluene, an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran, and a nitrile solvent such as acetonitrile
• the mixed solution (1) is reacted at a reaction temperature (external temperature) in the range of 30 ° C. to 50 ° C., preferably in the range of 35 to 45 ° C., and the following formula (EP-1):
• ring A is a 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group
• triphosgene Phosgene
• trichloromethyl chloroformate 2,2,2-trichloroethyl chloroformate
• phenyl chloroformate p-nitrophenyl chloroformate
• p-tolyl chloroformate N, N′-carbonyldiimidazole, and N, N ′
• the reaction is carried out at any temperature up to the temperature at which (5) refluxes, and the following formula (CB-1):
• Ring A is a 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group; Y is a trichloromethoxy group, chlorine Atom, 2,2,2-trichloroethoxy group, phenoxy group, p-nitrophenoxy group, p-methylphenoxy group, imidazol-1-yl group, (2,5-dioxopyrrolidin-1-yl) oxy group, (7) a compound represented by the formula (AM-X) obtained in the step (4), and a compound represented by the formula (CB-1).
• the mixed solution (7) is any one of from 0 ° C. to a temperature at which the mixed solution (7) is refluxed.
• the reaction is carried out at a temperature of To obtain a compound, a production method including a.
• the formula (AM-1) is 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-amine shown below.
• the amount of the hydrogen peroxide solution is preferably 1.5 to 10 equivalents relative to 1 equivalent of the formula (TH-1). More preferably 1.5 to 5 equivalents; particularly preferably 1.5 or 5.0 equivalents.
• “equivalent” means that the molar ratio is 1: 1. That is, when the amount of the hydrogen peroxide solution is 1.5 to 10 equivalents relative to 1 equivalent of the formula (TH-1), the amount of the hydrogen peroxide solution is 1: 1.5 to 1 in molar ratio. It means 1:10.
• the titanium catalyst is preferably titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide, titanium tetraisopropoxide, titanium tetra Normal butoxide or titanium tetratertiary butoxide; more preferably titanium tetraisopropoxide.
• the amount of the titanium catalyst is preferably in the range of 0.1 to 10 mol% based on the formula (TH-1); more preferably It is in the range of 1.0 to 5.0 mol%; particularly preferably 1.0, 3.0, or 5.0 mol%.
• the ligand is preferably in the range of 0.1 to 12 mol% with respect to the formula (TH-1); more preferably 1 In the range of 2 to 6.0 mol%; particularly preferably 1.2, 3.6, or 6.0 mol%.
• the solvent is preferably a solvent that does not participate in the reaction, more preferably an organic solvent, and further preferably dichloromethane, 1,2-dichloroethane.
• a halogenated hydrocarbon solvent such as chlorobenzene and fluorobenzene, an aromatic hydrocarbon solvent such as toluene, an ester solvent such as ethyl acetate, and an ether solvent such as tetrahydrofuran; more preferably dichloromethane.
• the amount of the solvent is preferably 1 to 20 times the mass of the formula (TH-1). More preferred is a range of 5 to 20 times the amount; particularly preferred is 5 or 20 times the amount.
• the buffer is preferably a citrate / NaOH buffer, a citrate / sodium citrate buffer, a borate / NaOH buffer, phosphorus An acid buffer, KH 2 PO 4 / NaOH buffer; more preferably a phosphate buffer, KH 2 PO 4 / NaOH buffer; particularly preferably a phosphate buffer.
• the pH of the reaction solution can be adjusted with the buffer solution.
• the reaction time is preferably 20 hours or less; more preferably 4.0 hours or less.
• the reaction in the step (4) of the embodiment [1] is preferably a sealed tube reaction using a sealed tube reaction bottle.
• the reaction temperature of the sealed tube reaction of the embodiment [1-8-1] is preferably 100 ° C.
• the urea agent is preferably phenyl chloroformate, p-tolyl chloroformate, or 2,2,2-trichloroethyl chloroformate; More preferred is 2,2,2-trichloroethyl chloroformate.
• the base is preferably pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-.
• Organic bases such as undecene (DBU), inorganic bases such as sodium bicarbonate, sodium carbonate, or potassium carbonate, metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, or hydrogen
• a metal hydride compound such as calcium hydroxide, an alkyl lithium such as methyl lithium or butyl lithium, a lithium amide such as lithium hexamethyldisilazide, or lithium diisopropylamide, or a mixture thereof; more preferably, pyridine It is.
• the solvent is preferably an aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile, diethyl ether Ether solvents such as tetrahydrofuran, dimethoxyethane, or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, chlorine solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, or the like A mixed solvent or the like; 1,2-dichloroethane is more preferable.
• aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile
• diethyl ether Ether solvents such as tetrahydrofuran, dimethoxyethane, or 1,4-dioxane
• ester solvents
• Y in the formula (CB-1) is preferably a phenoxy group, a p-methylphenoxy group, or a 2,2,2-trichloroethoxy group. More preferably a 2,2,2-trichloroethoxy group.
• the base is preferably pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-.
• Organic bases such as undecene (DBU), inorganic bases such as sodium bicarbonate, sodium carbonate, or potassium carbonate, metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, or hydrogen
• a metal hydride compound such as calcium hydroxide, an alkyl lithium such as methyl lithium or butyl lithium, a lithium amide such as lithium hexamethyldisilazide, or lithium diisopropylamide, or a mixture thereof; more preferably triethylamine And 1,8-diazabicyclo 5.4.0] -7-undecene (DBU).
• p is preferably an integer of 0 or 1, more preferably an integer of 0.
• R 1 is preferably a halogen atom, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 A substituent selected from an alkyl group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; more preferably a halogen atom or a C 1-6 alkoxy C 1-6 alkyl group; and still more preferably a hydrogen atom , A fluorine atom, a bromine atom or a methoxymethyl group may be substituted by 1 to 2 substituents; particularly preferably, it is unsubstituted.
• the amount of the hydrogen peroxide solution is preferably in the range of 1.5 to 5 equivalents with respect to 1 equivalent of the formula (TH-1).
• the amount of the titanium catalyst is in the range of 1.0 to 5.0 mol% with respect to the formula (TH-1); the ligand is 1.2 with respect to the formula (TH-1).
• the titanium catalyst is titanium tetraisopropoxide;
• the buffer is a phosphate buffer;
• the solvent (a solvent not involved in the reaction) is dichloromethane;
• the amount of the solvent not involved in the formula is in the range of 5 to 20 times the mass of the formula (TH-1);
• the amount of the hydrogen peroxide solution is 1.5 or 5.0 equivalents relative to 1 equivalent of the formula (TH-1).
• the amount of titanium catalyst is 1.0 or 3.0 mol% relative to formula (TH-1); the ligand is 1.2 or 3.6 mol relative to formula (TH-1)
• the titanium catalyst is titanium tetraisopropoxide; the buffer is a phosphate buffer; the solvent (the solvent that does not participate in the reaction) is dichloromethane; and the solvent (the solvent that does not participate in the reaction).
• a second aspect of the present invention is the following formula (AM-X):
• p is an integer selected from 0, 1, and 2;
• R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, or a halogenated C 1-6 alkyl group.
• Hydroxy C 1-6 alkyl group, cyanated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, mono / di-C 2-7 alkanoylamino group, carboxamide group, and C 1-6 alkoxycarbonyl group is a method for producing a compound represented by the following steps: (1) The following formula (TH-1):
• p and R 1 are as defined in the formula (AM-X)] and a titanium catalyst (for example, titanium tetrachloride, titanium tetrabromide) , Titanium alkoxide (titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide (Ti (OCH 2 CH 2 CH 3 ) 4 ), titanium tetraisopropoxide (Ti (OCH (CH 3 ) 2 ) 4 ), Titanium tetranormal butoxide (Ti (OCH 2 CH 2 CH 2 CH 3 ) 4 ), titanium tetratertiary butoxide (Ti (OC (CH 3 ) 3 ) 4 ), etc.) and the following formula (LG) -1):
• a solvent for example, a solvent not involved in the reaction, preferably an organic solvent, more preferably a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, chlorobenzene, fluorobenzene, etc.
• a basic solvent an aromatic hydrocarbon solvent such as benzene and toluene, an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran, and a nitrile solvent such as acetonitrile
• the mixed solution (1) is reacted at a reaction temperature (external temperature) in the range of 30 ° C. to 50 ° C., preferably in the range of 35 to 45 ° C., and the following formula (EP-1):
• the amount of the hydrogen peroxide solution is preferably 1.5 to 10 equivalents relative to 1 equivalent of the formula (TH-1). More preferably 1.5 to 5 equivalents; particularly preferably 1.5 or 5.0 equivalents.
• step (1) of the embodiment [2] it is preferable to use a hydrogen peroxide solution having a concentration of about 30%.
• the titanium catalyst is preferably titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide, titanium tetraisopropoxide, titanium tetra Normal butoxide or titanium tetratertiary butoxide; more preferably titanium tetraisopropoxide.
• the amount of the titanium catalyst is preferably in the range of 0.1 to 10 mol% with respect to the formula (TH-1); more preferably It is in the range of 1.0 to 5.0 mol%; particularly preferably 1.0, 3.0, or 5.0 mol%.
• the ligand is preferably in the range of 0.1 to 12 mol% with respect to the formula (TH-1); more preferably 1 In the range of 2 to 6.0 mol%; particularly preferably 1.2, 3.6, or 6.0 mol%.
• the solvent is preferably a solvent that does not participate in the reaction, more preferably an organic solvent, and further preferably dichloromethane, 1,2-dichloroethane.
• a halogenated hydrocarbon solvent such as chlorobenzene and fluorobenzene, an aromatic hydrocarbon solvent such as toluene, an ester solvent such as ethyl acetate, and an ether solvent such as tetrahydrofuran; more preferably dichloromethane.
• the amount of the solvent is preferably 1 to 20 times the mass of the formula (TH-1). More preferred is a range of 5 to 20 times the amount; particularly preferred is 5 or 20 times the amount.
• the buffer is preferably a citrate / NaOH buffer, a citrate / sodium citrate buffer, a borate / NaOH buffer, phosphorus
• the pH of the reaction solution can be adjusted with the buffer solution.
• the reaction time is preferably 20 hours or less; more preferably 4.0 hours or less.
• the reaction in the step (2) of the embodiment [2] is preferably a sealed tube reaction using a sealed tube reaction bottle.
• the reaction temperature of the sealed tube reaction in the above embodiment [2-8-1] is preferably 100 ° C.
• p is preferably an integer of 0 or 1, more preferably an integer of 0.
• R 1 is preferably a halogen atom, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 A substituent selected from an alkyl group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; more preferably a halogen atom or a C 1-6 alkoxy C 1-6 alkyl group; and still more preferably a hydrogen atom , A fluorine atom, a bromine atom or a methoxymethyl group may be substituted by 1 to 2 substituents; particularly preferably, it is unsubstituted.
• R 1 The partial structural formula in the case where two substituents are substituted by R 1 takes a substitution pattern represented by the following partial structural formula (PH-5) to (PH-10));
• the amount of the hydrogen peroxide solution is preferably in the range of 1.5 to 5 equivalents with respect to 1 equivalent of the formula (TH-1).
• the amount of the titanium catalyst is in the range of 1.0 to 5.0 mol% with respect to the formula (TH-1); the ligand is 1.2 with respect to the formula (TH-1).
• the titanium catalyst is titanium tetraisopropoxide;
• the buffer is a phosphate buffer;
• the solvent (a solvent not involved in the reaction) is dichloromethane;
• the amount of the solvent not involved in the formula is in the range of 5 to 20 times the mass of the formula (TH-1);
• the amount of the hydrogen peroxide solution is 1.5 or 5.0 equivalents relative to 1 equivalent of the formula (TH-1).
• the amount of titanium catalyst is 1.0 or 3.0 mol% relative to formula (TH-1); the ligand is 1.2 or 3.6 mol relative to formula (TH-1)
• the titanium catalyst is titanium tetraisopropoxide; the buffer is a phosphate buffer; the solvent (the solvent that does not participate in the reaction) is dichloromethane; and the solvent (the solvent that does not participate in the reaction).
• a third aspect of the present invention is the following formula (EP-1):
• p is an integer selected from 0, 1, and 2;
• R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, or a halogenated C 1-6 alkyl group.
• Hydroxy C 1-6 alkyl group, cyanated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, mono / di-C 2-7 alkanoylamino group, carboxamide group, and C 1-6 alkoxycarbonyl group is a method for producing a compound represented by the following steps: (1) The following formula (TH-1):
• p and R 1 are as defined in the formula (AM-X)] and a titanium catalyst (for example, titanium tetrachloride, titanium tetrabromide) , Titanium alkoxide (titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide (Ti (OCH 2 CH 2 CH 3 ) 4 ), titanium tetraisopropoxide (Ti (OCH (CH 3 ) 2 ) 4 ), Titanium tetranormal butoxide (Ti (OCH 2 CH 2 CH 2 CH 3 ) 4 ), titanium tetratertiary butoxide (Ti (OC (CH 3 ) 3 ) 4 ), etc.) and the following formula (LG) -1):
• a solvent for example, a solvent not involved in the reaction, preferably an organic solvent, more preferably a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, chlorobenzene, fluorobenzene, etc.
• a basic solvent an aromatic hydrocarbon solvent such as benzene and toluene, an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran, and a nitrile solvent such as acetonitrile
• the mixed solution (1) is reacted at a reaction temperature (external temperature) in the range of 30 ° C. to 50 ° C., preferably in the range of 35 to 45 ° C., and represented by the formula (EP-1)
• a production method comprising a step of obtaining a compound.
• the amount of the hydrogen peroxide solution is preferably 1.5 to 10 equivalents relative to 1 equivalent of the formula (TH-1). More preferably 1.5 to 5 equivalents; particularly preferably 1.5 or 5.0 equivalents.
• the titanium catalyst is preferably titanium tetramethoxide, titanium tetraethoxide, titanium tetranormal propoxide, titanium tetraisopropoxide, titanium tetra Normal butoxide or titanium tetratertiary butoxide; more preferably titanium tetraisopropoxide.
• the amount of the titanium catalyst is preferably in the range of 0.1 to 10 mol% based on the formula (TH-1); more preferably It is in the range of 1.0 to 5.0 mol%; particularly preferably 1.0, 3.0, or 5.0 mol%.
• the ligand is preferably in the range of 0.1 to 12 mol% with respect to the formula (TH-1); more preferably 1 In the range of 2 to 6.0 mol%; particularly preferably 1.2, 3.6, or 6.0 mol%.
• the solvent is preferably a solvent that does not participate in the reaction, more preferably an organic solvent, and still more preferably dichloromethane, 1,2-dichloroethane.
• a halogenated hydrocarbon solvent such as chlorobenzene and fluorobenzene, an aromatic hydrocarbon solvent such as toluene, an ester solvent such as ethyl acetate, and an ether solvent such as tetrahydrofuran; more preferably dichloromethane.
• the amount of the solvent is preferably 1 to 20 times the mass of the formula (TH-1). More preferred is a range of 5 to 20 times the amount; particularly preferred is 5 or 20 times the amount.
• the buffer is preferably a citrate / NaOH buffer, a citrate / sodium citrate buffer, a borate / NaOH buffer, phosphorus
• the pH of the reaction solution can be adjusted with the buffer solution.
• the reaction time is preferably 20 hours or less; more preferably 4.0 hours or less.
• p is preferably an integer of 0 or 1, more preferably an integer of 0.
• R 1 is preferably a halogen atom, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 A substituent selected from an alkyl group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; more preferably a halogen atom or a C 1-6 alkoxy C 1-6 alkyl group; and still more preferably a hydrogen atom , A fluorine atom, a bromine atom or a methoxymethyl group may be substituted by 1 to 2 substituents; particularly preferably, it is unsubstituted.
• R 1 The partial structural formula in the case where two substituents are substituted by R 1 takes a substitution pattern represented by the following partial structural formula (PH-5) to (PH-10));
• the amount of the hydrogen peroxide solution is preferably in the range of 1.5 to 5 equivalents with respect to 1 equivalent of the formula (TH-1).
• the amount of the titanium catalyst is in the range of 1.0 to 5.0 mol% with respect to the formula (TH-1); the ligand is 1.2 with respect to the formula (TH-1).
• the titanium catalyst is titanium tetraisopropoxide;
• the buffer is a phosphate buffer;
• the solvent (a solvent not involved in the reaction) is dichloromethane;
• the amount of the solvent not involved in the formula is in the range of 5 to 20 times the mass of the formula (TH-1);
• the amount of the hydrogen peroxide solution is 1.5 or 5.0 equivalents relative to 1 equivalent of the formula (TH-1).
• the amount of titanium catalyst is 1.0 or 3.0 mol% relative to formula (TH-1); the ligand is 1.2 or 3.6 mol relative to formula (TH-1)
• the titanium catalyst is titanium tetraisopropoxide; the buffer is a phosphate buffer; the solvent (the solvent that does not participate in the reaction) is dichloromethane; and the solvent (the solvent that does not participate in the reaction).
• a fourth aspect of the present invention is the following formula (AM-X):
• p is an integer selected from 0, 1, and 2;
• R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, or a halogenated C 1-6 alkyl group.
• Hydroxy C 1-6 alkyl group, cyanated C 1-6 alkyl group, C 1-6 alkoxy group, halogenated C 1-6 alkoxy group, C 1-6 alkoxy C 1-6 alkyl group, mono / di-C 2-7 alkanoylamino group, carboxamide group, and C 1-6 alkoxycarbonyl group is a method for producing a compound represented by the following steps: (3) The following formula (EP-1):
• the reaction in the step (4) of the embodiment [4] is preferably a sealed tube reaction using a sealed tube reaction bottle.
• a preferred reaction temperature for the sealed tube reaction of the embodiment [4-1-1] is 100 ° C.
• the preferred reaction time for the sealed tube reaction of the embodiment [4-1-1] is 2 hours.
• p is preferably an integer of 0 or 1, more preferably an integer of 0.
• R 1 is preferably a halogen atom, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 A substituent selected from an alkyl group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; more preferably a halogen atom or a C 1-6 alkoxy C 1-6 alkyl group; and still more preferably a hydrogen atom , A fluorine atom, a bromine atom or a methoxymethyl group may be substituted by 1 to 2 substituents; particularly preferably, it is unsubstituted.
• a fifth aspect of the present invention is the following formula (I):
• p is an integer selected from 0, 1, and 2;
• R 1 is a halogen atom, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a hydroxy group;
• ring A is 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridine- Which is a 3-yl group], comprising the following steps: (5)
• ring A is a 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group
• triphosgene Phosgene
• trichloromethyl chloroformate 2,2,2-trichloroethyl chloroformate
• phenyl chloroformate p-nitrophenyl chloroformate
• p-tolyl chloroformate N, N′-carbonyldiimidazole, and N, N ′
• the reaction is carried out at any temperature up to the temperature at which (5) refluxes, and the following formula (CB-1):
• Ring A is a 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-yl group; Y is a trichloromethoxy group, chlorine Atom, 2,2,2-trichloroethoxy group, phenoxy group, p-nitrophenoxy group, p-methylphenoxy group, imidazol-1-yl group, (2,5-dioxopyrrolidin-1-yl) oxy group, A step of obtaining a compound represented by the formula: A compound represented by the formula (CB-1); The following formula (AM-X):
• the urea agent is preferably phenyl chloroformate, p-tolyl chloroformate, or 2,2,2-trichloroethyl chloroformate; More preferred is 2,2,2-trichloroethyl chloroformate.
• the base is preferably pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-.
• Organic bases such as undecene (DBU), inorganic bases such as sodium bicarbonate, sodium carbonate, or potassium carbonate, metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, or hydrogen
• a metal hydride compound such as calcium hydroxide, an alkyl lithium such as methyl lithium or butyl lithium, a lithium amide such as lithium hexamethyldisilazide, or lithium diisopropylamide, or a mixture thereof; more preferably, pyridine It is.
• the solvent is preferably an aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile, diethyl ether Ether solvents such as tetrahydrofuran, dimethoxyethane, or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, chlorine solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, or the like A mixed solvent or the like; more preferably tetrahydrofuran.
• aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile
• diethyl ether Ether solvents such as tetrahydrofuran, dimethoxyethane, or 1,4-dioxane
• ester solvents such as
• Y in the formula (CB-1) is preferably a phenoxy group, a p-methylphenoxy group, or a 2,2,2-trichloroethoxy group. More preferably a 2,2,2-trichloroethoxy group.
• the solvent is preferably an aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile, diethyl ether Ether solvents such as tetrahydrofuran, dimethoxyethane, or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, chlorine solvents such as dichloromethane, chloroform, or 1,2-dichloroethane, or the like A mixed solvent or the like; more preferably N-methylpyrrolidone.
• aprotic polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, or acetonitrile
• diethyl ether Ether solvents such as tetrahydrofuran, dimethoxyethane, or 1,4-dioxane
• ester solvents such as
• the base is preferably pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene.
• DBU organic bases such as sodium bicarbonate, sodium carbonate, or potassium carbonate
• metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, sodium hydride, potassium hydride, or hydrogenated
• a metal hydride compound such as calcium, an alkyl lithium such as methyl lithium or butyl lithium, a lithium amide such as lithium hexamethyldisilazide, or lithium diisopropylamide, or a mixture thereof; more preferably, triethylamine is there.
• p is preferably an integer of 0 or 1, more preferably an integer of 0.
• R 1 is preferably a halogen atom, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 A substituent selected from an alkyl group, a carboxamide group, and a C 1-6 alkoxycarbonyl group; more preferably a halogen atom or a C 1-6 alkoxy C 1-6 alkyl group; and still more preferably a hydrogen atom , A fluorine atom, a bromine atom or a methoxymethyl group may be substituted by 1 to 2 substituents; particularly preferably, it is unsubstituted.
• R 1 The partial structural formula in the case where two substituents are substituted by R 1 takes a substitution pattern represented by the following partial structural formula (PH-5) to (PH-10));
• C 1-6 means that the number of carbon atoms constituting the compound is 1 to 6, and unless otherwise specified, the total carbon of a linear, branched or cyclic group Represents the number of atoms. For a group containing a chain group and a cyclic group, it means “total number of carbon atoms in the chain and ring”.
• halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
• the “halogenation” in the “halogenated C 1-6 alkyl group” and the like refers to several, preferably 1 to 5, of the above “halogen atoms” as substituents. It means that you may have.
• “cyanation” in “cyanated C 1-6 alkyl” and the like has several, preferably 1 to 5 “cyano groups” as substituents. It means that it may be.
• C 1-6 alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, Or groups, such as hexyl, are mentioned.
• halogenated C 1-6 alkyl group means that the “C 1-6 alkyl” is optionally substituted with several, preferably 1 to 5 halogen atoms.
• a group such as fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, or pentafluoroethyl. Can be mentioned.
• the “cyanated C 1-6 alkyl group” means that the “C 1-6 alkyl” is optionally substituted with several, preferably 1-5 cyano. Groups such as cyanomethyl, 1-cyanoethyl, 2-cyanoethyl and the like.
• the “C 1-6 alkoxy group” means alkoxy in which the above-mentioned “C 1-6 alkyl” is bonded to an oxygen atom, and includes, for example, methoxy, ethoxy, propoxy, iso Examples include groups such as propoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, or hexyloxy.
• the “halogenated C 1-6 alkoxy group” represents a halogenated alkoxy in which the above-mentioned “halogenated C 1-6 alkyl” is bonded to an oxygen atom. Examples include methoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy and the like.
• the “C 1-6 alkoxy C 1-6 alkyl group” means a group in which the “C 1-6 alkoxy” is substituted with the “C 1-6 alkyl”. To do. Unless otherwise specified, in this specification, examples of the “C 1-6 alkoxy C 1-6 alkyl” include methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, 1,1-dimethoxymethyl, or 1, Examples include groups such as 1-diethoxyethyl.
• the “mono / di C 2-7 alkanoylamino group” means that one or two hydrogen atoms on the nitrogen atom of the “amino group” are described later in “C 2 ⁇ ⁇ 7 alkanoyl group '' means an amino group substituted with, for example, acetamide, propionamide, butyramide, isobutyramide, valeramide, isovaleramide, pivalamide, hexaneamide, heptanamide, cyclopropanecarboxamide, cyclobutanecarboxamide, cyclopentanecarboxamide, Examples include cyclohexanecarboxamide, 2-methylcyclopropanecarboxamide, or diacetamide.
• the “C 2-7 alkanoyl group” means a “C 1-6 alkylcarbonyl group” in which a carbonyl group is bonded to the “C 1-6 alkyl group”.
• a group such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cyclopropylmethylcarbonyl, or 2-methylcyclopropylcarbonyl Is mentioned.
• C 1-6 alkoxycarbonyl group means a group in which a hydrogen atom of a “carboxy group (—COOH)” is substituted with the above “C 1-6 alkyl group”.
• “Ester group” means a group such as methoxycarbonyl (methyl ester), ethoxycarbonyl (ethyl ester), or tert-butoxycarbonyl (tert-butyl ester).
• urea agent includes triphosgene, phosgene, trichloromethyl chloroformate, 2,2,2-trichloroethyl chloroformate, phenyl chloroformate, chloroformate p- Examples thereof include nitrophenyl, p-tolyl chloroformate, N, N′-carbonyldiimidazole, and N, N′-disuccinimidyl carbonate. However, it is not necessarily limited to the urea agent described above.
• examples of the “base” include pyridine, triethylamine, or N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
• solvent or “solvent not involved in the reaction” refers to, for example, water, cyclohexane, hexane, benzene, chlorobenzene, toluene, xylene, methanol, ethanol, 1-propanol, 2-propanol, tert- Butyl alcohol, N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone (NMP), hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide ( DMSO), acetonitrile, propionitrile, diethyl ether, diisopropyl ether, diphenyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2 Dimethoxyethanethane, N, N-di
• an R or S symbol indicating a configuration may be added in the vicinity of the asymmetric carbon.
• the 1-position and the 2-position are asymmetric carbons, and the symbol of R or S is attached in the vicinity of the asymmetric carbon in each formula. .
• the compounds herein may form a salt with an inorganic or organic acid (acid addition salt) or a salt with an inorganic or organic base depending on the type of substituent.
• a salt is not particularly limited as long as it is a pharmaceutically acceptable salt.
• metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basicity, Or the salt with an acidic amino acid etc. are mentioned.
• the metal salt include alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt, and aluminum salt.
• alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt
• alkaline earth metal salts such as calcium salt, magnesium salt and barium salt
• aluminum salt for example, besides a mono salt, a disodium salt and a dipotassium salt are also included.
• the salt with an organic base include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, triamine.
• the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
• the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarbox
• Salt with organic carboxylic acid salt with organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, gluta Acid addition salts with acidic amino acids such as phosphate and the like.
• salts with basic amino acids include, for example, salts with arginine, lysine, ornithine
• salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
• an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt)
• an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
• examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
• the salt is formed by, for example, mixing the compound in the present specification with a solution containing an appropriate amount of acid or base to form a desired salt, and then fractionally filtering or removing the mixed solvent. It can be obtained by leaving.
• the compound in this specification or its salt can form solvates with solvents, such as water, ethanol, and glycerol.
• solvents such as water, ethanol, and glycerol.
• solvate means a molecular complex comprising a compound herein and one or more pharmaceutically acceptable solvent molecules (eg, water, ethanol, etc.). When the solvent molecule is water, it is specifically called “hydrate”.
• the compounds in the present specification are represented by geometric isomers (geometric isomers), configurational isomers (configurational isomers), tautomers (tortomeric isomers), optical isomers (optical isomers), stereoisomers (diastereomers). Isomers), positional isomers (regioisomers), rotational isomers (rotational isomers) and the like.
• each isomer is simply separated by a synthesis method or separation method known per se. It can be obtained as a single compound.
• the optical resolution method include methods known per se, such as (1) fractional recrystallization method, (2) diastereomer method, (3) chiral column method and the like.
• Fractionation recrystallization method After obtaining a crystalline diastereomer by ion-bonding an optical resolving agent to a racemate, it is separated by a fractional recrystallization method and, if desired, a neutralization step is performed. This is a method for obtaining a free optically pure compound.
• the optical resolution agent include (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, ( ⁇ )-1-phenethylamine, Examples include cinchonine, ( ⁇ )-cinchonidine, brucine and the like.
• Diastereomer method An optical resolution agent is covalently bonded (reacted) to a racemic mixture to obtain a mixture of diastereomers, which is then subjected to usual separation means (eg, fractional recrystallization, silica gel column chromatography). , HPLC (High Performance Liquid Chromatography, etc.) etc., and then optically pure by removing the optical resolving agent by chemical treatment such as hydrolysis reaction. This is a method for obtaining an optical isomer.
• separation means eg, fractional recrystallization, silica gel column chromatography).
• HPLC High Performance Liquid Chromatography, etc.
• the compound of the present invention when the compound of the present invention has an intramolecular hydroxyl group or a primary or secondary amino group, the compound and an optically active organic acid (eg, MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid], (-)-Menthoxyacetic acid and the like) are subjected to a condensation reaction to obtain ester or amide diastereomers, respectively.
• an amide or ester diastereomer can be obtained by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction. Each of the separated diastereomers is converted to an optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.
• Chiral column method This is a method in which a racemate or a salt thereof is subjected to direct optical resolution by subjecting it to chromatography on a chiral column (optical isomer separation column).
• a racemate or a salt thereof is subjected to direct optical resolution by subjecting it to chromatography on a chiral column (optical isomer separation column).
• HPLC high performance liquid chromatography
• a mixture of optical isomers is added to a chiral column such as Daicel's CHIRAL series, water, various buffers (eg, phosphate buffer)
• Optical isomers can be separated by developing using an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine) alone or as a mixed solution.
• separation can be performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).
• the compound in the present specification may be a crystal.
• the crystal form may be single or a crystal form mixture.
• the compound herein may be a pharmaceutically acceptable cocrystal or cocrystal salt.
• co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a simple solid.
• the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
• the compounds herein include isotopes (eg, hydrogen isotopes: 2 H and 3 H, carbon isotopes: 11 C, 13 C, and 14 C, chlorine isotopes: 36 Cl, etc. , Fluorine isotopes: 18 F, iodine isotopes: 123 I and 125 I, nitrogen isotopes: 13 N and 15 N, oxygen isotopes: 15 O, 17 O, and 18 O, etc. Also included are compounds labeled or substituted with phosphorus isotopes: 32 P, etc., and sulfur isotopes: 35 S, etc.
• isotopes eg, hydrogen isotopes: 2 H and 3 H, carbon isotopes: 11 C, 13 C, and 14 C, chlorine isotopes: 36 Cl, etc.
• Fluorine isotopes: 18 F Fluorine isotopes: 18 F, iodine isotopes: 123 I and
• Compounds of the invention labeled or substituted with certain isotopes can be synthesized, for example, by Positron Emission Tomography; PET ) Can be used as a tracer (PET tracer) for use in medical diagnosis and the like.
• Compounds of the invention labeled or substituted with certain isotopic labels are useful in drug and / or substrate tissue distribution studies.
• 3 H and 14 C are useful for this research purpose because they are easy to label or displace and easy to detect.
• the isotope-labeled compound of the present invention can be obtained by a common technique known to those skilled in the art or by a method similar to the synthesis method described in the Examples below.
• the obtained isotope-labeled compound can be used for pharmacological experiments instead of the unlabeled compound.
• any temperature between 0 ° C. and the temperature at which the mixed solution is refluxed “from 0 ° C. to the temperature at which the solvent is refluxed”
• the phrase “any temperature in between” means any temperature (constant temperature) within a range from 0 ° C. to the temperature at which each mixed solution (solvent) is refluxed.
• room temperature means a temperature in a laboratory, laboratory, etc., and is usually about 1 ° C. to about 30 ° C., preferably usually about 5 ° C. to about 30 ° C. More preferably, it usually exhibits a temperature of about 15 ° C. to about 25 ° C., more preferably 20 ⁇ 3 ° C.
• the solvent to be used one kind of solvent may be used alone, or two or more kinds of solvents may be mixed and used at an appropriate ratio as appropriate depending on the reaction conditions.
• steps such as compound extraction, drying, and purification can be appropriately performed by a known method.
• the reaction time in each step may be appropriately selected as long as the reaction proceeds sufficiently unless otherwise specified.
• a method for producing a compound represented by the formula (TH-1) in the present invention A method for producing a compound represented by the formula (TH-1) in the present invention:
• the formula (TH-1) [the definitions of p and R 1 in the formula (TH-1) are the same as the definitions of the formula (I) in the embodiment [1]]
• the method for producing the compound will be described in detail.
• the compound represented by the formula (TH-1) and a solvate thereof are commercially available compounds or compounds that can be easily obtained from commercially available compounds by known production methods in the literature as starting materials or synthetic intermediates. It can be easily manufactured by combining chemical manufacturing methods. For example, it can be manufactured according to the following representative manufacturing methods.
• R A is a C 1-6 alkyl group such as a methyl group, an ethyl group, a propyl group, or a tert-butyl group, a phenyl group, or a benzyl group unless otherwise specified.
• SM-1 a compound represented by the formula (SM-1)
• the compound of formula (SM-1) is a commercially available compound or a compound that can be produced from a commercially available compound by a production method known in the literature
• a known method such as “Experimental Chemistry Course 4th edition 22 Organic Synthesis IV Acid / Amino Acid / Peptide, 1-82, 1992, Maruzen”, etc., hydrochloric acid, sulfuric acid, thionyl chloride,
• an acidic reagent such as acetyl chloride, the reaction is performed at a temperature between 0 ° C.
• an alkyl halide agent for example, methyl iodide, ethyl iodide, etc.
• a base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, N, N-dimethylformamide, dimethyl sulfoxide
• a polar solvent such as N-methylpyrrolidone to produce a compound represented by the formula (IM-1) by carrying out the reaction at any temperature between 0 ° C. and the temperature at which the solvent is refluxed. it can.
• SM-1 a compound represented by the formula (SM-1), for example, “Chemical & Pharmaceutical Bulletin, 29 (5), pp. 1475-1478, 1981”
• the reaction is carried out from 0 ° C. to room temperature in a methylating agent such as diazomethane or trimethylsilyldiazomethane, a solvent that does not participate in the reaction such as ether or methanol, or a mixed solvent thereof.
• a methylating agent such as diazomethane or trimethylsilyldiazomethane
• a solvent that does not participate in the reaction such as ether or methanol, or a mixed solvent thereof.
• the compound represented by -1) can be produced.
• the compound represented by the formula (SM-1) is converted into a method known in the literature, for example, “Journal of the American Chemical Society”, 109 (24), p7488-7494.
• a base such as triethylamine, N, N-diisopropylethylamine, N, N-dimethylaminopyridine, thionyl chloride, oxalyl chloride, phosphoryl chloride, chloride
• Halogenating agents such as sulfuryl, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, 1,4-dioxane, tetrahydrofuran, 1,2-dimethoxyethane, benzene, toluene, dichloromethane, 1,2-dichloroethane, chloroform, etc.
• reaction is carried out at any temperature between 0 ° C. and the temperature at which the solvent is refluxed, and then converted to an acid halide, followed by alcohol (eg, methanol, ethanol, benzyl alcohol). Etc.) according to methods known in the literature, for example, the method described in “Experimental Chemistry Course, 4th Edition, 22.
• ⁇ Step 2> [Production Method A] Using the compound represented by the formula (IM-1) obtained in ⁇ Step 1>, a method known in the literature, for example, “Experimental Chemistry Course 4th Edition 25, Organic Synthesis VII” In accordance with the method described in "Synthesis with organometallic reagents, pages 13-19, 59-72, 1992, Maruzen", etc., Grignard reagent (eg, methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium bromide, etc.
• Grignard reagent eg, methylmagnesium chloride, methylmagnesium bromide, ethylmagnesium bromide, etc.
• ⁇ Step 3> [Production Method A] Using the compound represented by the formula (IM-2) obtained in ⁇ Step 2>, a method known in the literature, for example, “Tetrahedron Letters, 54 (32), p4330-4332.
• an acid reagent such as trifluoromethanesulfonic acid, diphosphorus pentoxide, phosphorous pentachloride, sulfuric acid, phosphoric acid, bismuth (III) trifluoromethanesulfonate
• a solvent inert to the reaction such as dichloromethane, chloroform, cyclohexane, benzene, toluene, xylene, diethyl ether, 2-propanol, water, or a mixed solvent thereof, the temperature between 0 ° C. and the temperature at which the solvent is refluxed.
• the reaction can be carried out at any temperature to produce the compound represented by the formula (IM-3).
• ⁇ Step 4> [Production Method A] Using the compound represented by the formula (IM-3) obtained in ⁇ Step 3>, a method known in the literature, for example, “Chemistry Letters, 70 (10), p1042-1043. In the presence of an oxidizing agent such as Oxone (registered trademark) (DuPont), tert-butyl hydroperoxide (TBHP), potassium permanganate, manganese dioxide, chromic acid, and the like. , Chloroform, carbon tetrachloride, benzene, acetonitrile, tert-butyl alcohol, water, or a solvent inert to the reaction, or a mixed solvent thereof. By reacting at a temperature, a compound represented by the formula (IM-4) can be produced.
• Oxone registered trademark
• TBHP tert-butyl hydroperoxide
• ⁇ Step 6> [Production Method A] Using a compound represented by the formula (IM-5) obtained in ⁇ Step 5>, a method known in the literature, for example, described in “International Publication No. 2014/078454 Pamphlet”, etc. Inactive in the reaction of dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, xylene, 1,2-dimethoxyethane, etc. in the presence of an acid reagent such as p-toluenesulfonic acid, etc.
• a compound represented by the formula (TH-1) can be produced by performing a reaction at any temperature between 0 ° C. and the temperature at which the solvent is refluxed using a suitable solvent or a mixed solvent thereof. .
• [Production Method B] A method for producing a compound represented by the formula (AM-1) in the present invention: Hereinafter, the method for producing the compound represented by the formula (AM-1) in the present invention will be described in detail.
• the compound represented by the formula (AM-1) and a solvate thereof are known compounds that are commercially available compounds or compounds that can be easily obtained from commercially available compounds by known production methods in the literature as starting materials or synthetic intermediates. It can be easily manufactured by combining chemical manufacturing methods. For example, it can be manufactured according to the following representative manufacturing methods. In the following production method, [B] is boronic acid, boronic acid ester, boronic acid N-methyliminodiacetic acid (MIDA) ester or the like.
• MIDA boronic acid N-methyliminodiacetic acid
• Formula (SM-2) and Formula (RG-1) are commercially available compounds or can be produced from commercially available compounds by known production methods in the literature. Using a compound represented by the above formula, a method known in the literature, for example, “Experimental Chemistry Course 5th edition 18 Synthesis of organic compounds VI —Organic synthesis using metals—327-352, 2004, Maruzen” And palladium (II) acetate (Pd (OAc) 2 ), tetrakistriphenylphosphinepalladium (Pd (Pd (OAc) 2 )), and the method described in “Journal of Medicinal Chemistry, 48 (20), p6326-6339, 2005”.
• ⁇ Step 2> [Production Method B] Using the compound of formula (IM-6) obtained in ⁇ Step 1> and N-bromosuccinimide (NBS), methods known in the literature, for example, “International Publication 2009/088103” N-methylpyrrolidone, dimethylformamide, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile and other solvents (solvents not involved in the reaction), or a mixture thereof.
• the compound represented by the formula (IM-7) can be produced by performing the reaction at any temperature between 0 ° C. and the temperature at which the solvent is refluxed using a solvent.
• the compounds of formula (IM-4), formula (IM-5), formula (IM-6), and formula (IM-7) may form a salt, and as such a salt, pharmaceutically
• examples thereof include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic salts, and salts with acidic amino acids. It is done.
• the metal salt include alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt, and aluminum salt.
• alkali metal salts such as lithium salt, sodium salt, potassium salt and cesium salt
• alkaline earth metal salts such as calcium salt, magnesium salt and barium salt
• aluminum salt for example, besides a mono salt, a disodium salt and a dipotassium salt are also included.
• the salt with an organic base include, for example, methylamine, ethylamine, t-butylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine, diethanolamine, triamine.
• the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
• the salt with an organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, Salts with aliphatic monocarboxylic acids such as mandelic acid, salts with aliphatic dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, and aliphatic tricarboxylic acids such as citric acid Salts with acids, salts with aromatic monocarboxylic acids such as benzoic acid and salicylic acid, salts of aromatic dicarboxylic acids such as phthalic acid, cinnamic acid, glycolic acid, pyruvic acid, oxylic acid, salicylic acid, N-acetylcysteine, etc.
• Salt with organic carboxylic acid salt with organic sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, gluta Acid addition salts with acidic amino acids such as phosphate and the like.
• Preferable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine
• preferable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
• an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt)
• an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
• examples thereof include salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and p-toluenesulfonic acid.
• the formula (IM-6), and the compound of the formula (IM-7) can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method. It can be easily purified by means known per se, for example, separation means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography and the like.
• reaction conditions in the production method are as follows unless otherwise specified.
• the reaction temperature is not limited as long as it is in the range from ⁇ 78 ° C. to the temperature at which the solvent is refluxed.
• the reaction time is not limited as long as the reaction is sufficiently advanced unless otherwise specified.
• range of the temperature at which the solvent refluxes from ⁇ 78 ° C.” in the reaction temperature means a temperature within the range from ⁇ 78 ° C. to the temperature at which the solvent (or mixed solvent) used in the reaction refluxes. .
• “at a temperature at which the solvent is refluxed from ⁇ 78 ° C.” means a temperature within a range from ⁇ 78 ° C. to a temperature at which the methanol is refluxed.
• “at a temperature at which the reaction solution is refluxed from ⁇ 78 ° C.” means any temperature within a range from ⁇ 78 ° C. to a temperature at which the reaction solution is refluxed.
• Each step of [Production Method A] or [Production Method B] can be performed without solvent or by dissolving or suspending the raw material compound in an appropriate solvent before the reaction.
• the solvent is preferably a solvent that does not participate in the reaction.
• the solvent is preferably a solvent that does not participate in the reaction.
• solvents can be used alone, or can be appropriately selected depending on the reaction conditions, and two or more solvents can be mixed and used at an appropriate ratio. These solvents are appropriately selected according to the reaction conditions. Unless otherwise specified, in the production method of the present specification, when “solvent”, “solvent not involved in the reaction” or “solvent inert to the reaction” is described, the solvent to be used is a single solvent. Alternatively, it may be selected as appropriate depending on the reaction conditions, and two or more solvents may be mixed and used at an appropriate ratio.
• Examples of the base (or deoxidizing agent) used in each step of [Production Method A] or [Production Method B] include lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium carbonate, Sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium bicarbonate, tripotassium phosphate, sodium acetate, cesium fluoride, triethylamine, N, N-diisopropylethylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, 4- Dimethylaminopyridine (DMAP), N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,4- Diazabicyclo [2.2.2] octane, 1,8-dia Zabicyclo [5.4.0] -7-undecene (
• Examples of the acid or acid catalyst used in each step of [Production Method A] or [Production Method B] include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid, Phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, boron trifluoride ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous chloride Examples include zinc and anhydrous iron chloride. However, it is not necessarily limited to those described above. These acids or acid catalysts are appropriately selected according to the reaction conditions.
• JEOL JNM-ECX400 FT-NMR or JEOL JNM-ECX300 FT-NMR (JEOL) was used.
• 1 H-NMR (#) is described in the 1 H-NMR data in the examples, it means that measurement was performed using JEOL JNM-ECX300 FT-NMR (JEOL).
• the liquid chromatography-mass spectrometry spectrum (LC-Mass) was measured by the following method.
• SFC supercritical fluid liquid chromatography
• room temperature in the reference examples and examples usually indicates a temperature of about 20 to 25 ° C.
• DCM in the column of solvent in the table of (Example 2) means dichloromethane
• DCE means 1,2-dichloroethane.
• ⁇ Step 2> Synthesis of 1,1-dimethyl-1,2-dihydronaphthalene: (Reference Example 1) A toluene (10 mL) solution of the compound (1.0 g) obtained in ⁇ Step 1> and p-toluenesulfonic acid monohydrate (0.05 g) was stirred at 90 ° C. for 1.5 hours. did. After cooling to room temperature, ethyl acetate (40 mL) and saturated aqueous sodium hydrogencarbonate (30 mL) were added and partitioned.
• ⁇ Step 2> Synthesis of 6-bromo-5-methyl-2-phenylpyridin-3-amine: (Reference Example 2) N-bromosuccinimide (0.21 g) was added to a solution of the compound (0.19 g) obtained in ⁇ Step 1> in N-methylpyrrolidone (2.0 mL), and the mixture was stirred at room temperature for 2 hours. Water (2.0 mL) was added to the reaction solution, extracted twice with tert-butyl methyl ether, and the organic layer was washed with water.
• ⁇ Step 3> Synthesis of 5-methyl-6- (2-methylpyrimidin-5-yl) -2-phenylpyridin-3-amine: Reference Example 2 To a mixed solution of the compound obtained in ⁇ Step 2> (0.40 g) in 1,2-dimethoxyethane (10 mL) and water (2.0 mL) was added 2-methyl-5- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine (0.44 g), cesium carbonate (1.5 g) and dichloro [1,1′bis (diphenylphosphino) ferrocene] Palladium dichloromethane adduct (0.12 g) was added and stirred at 80 ° C.
• the conversion rate in the above table means the ratio to the supply amount of the reaction material (starting material) disappeared by the reaction. That is, it can be understood that the higher the conversion rate, the more the reaction material (starting material) disappears and the reaction proceeds.
• the pass-through rate was calculated from the UPLC 220 nm UV spectrum intensity. The measurement yield was calculated by comparison with an internal standard substance (dimethyl terephthalate) from NMR.
• Diazabicycloundecene (0.59 mL) was added to a solution of the compound (0.75 g) obtained in (Example 3) and the compound (1.77 g) obtained in (Example 1) in dimethyl sulfoxide (10 mL). And stirred at room temperature overnight. Water (10 mL) and ethanol (10 mL) were added to the reaction solution obtained by stirring, and the mixture was stirred at 55 ° C. for 1 hour. The reaction mixture obtained by stirring was cooled and stirred at room temperature for 3 hours.
• a production method suitable for industrial production of the compound represented by formula (I) in a short process in a short process.
• a useful process for producing a compound represented by the formula (AM-X), which is an intermediate for the production of the compound represented by the formula (I) is provided.

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