WO2021166934A1 - Production method for pyrrolidine compound - Google Patents

Production method for pyrrolidine compound Download PDF

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WO2021166934A1
WO2021166934A1 PCT/JP2021/005848 JP2021005848W WO2021166934A1 WO 2021166934 A1 WO2021166934 A1 WO 2021166934A1 JP 2021005848 W JP2021005848 W JP 2021005848W WO 2021166934 A1 WO2021166934 A1 WO 2021166934A1
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compound
methyl
pyrrolidine
mixture
added
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PCT/JP2021/005848
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French (fr)
Japanese (ja)
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雄一 梶田
享史 阿部
敬規 山下
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武田薬品工業株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical

Definitions

  • the present invention relates to a method for producing a pyrrolidine compound.
  • Pyrrolidine compounds such as N- ⁇ (2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] -1- (2-hydroxy-2-methylpropanol) pyrrolidine-3- Il) ethanesulfonamide, N- ⁇ (2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl ] Pyrrolidine-3-yl ⁇ methanesulfoneamide, and N- ⁇ (2S, 3S) -1- (2-hydroxy-2-methylpropanol) -2-[(2,3', 5'-trifluorobiphenyl) -3-Il) Methyl] pyrrolidine-3-yl ⁇ ethanesulfonamide is useful as a pharmaceutical, and a production method suitable for industrial production is desired.
  • Patent Document 1 describes N- ⁇ (2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] -1- (2-hydroxy-2-methylpropanol) pyrrolidine-3. -Il) Ethane sulfonamide and N- ⁇ (2S, 3S) -1- (2-hydroxy-2-methylpropanol) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) It is described that each of methyl] pyrrolidine-3-yl ⁇ ethanesulfonamide is produced using a free sulfonamide raw material compound.
  • Patent Document 1 describes N- ⁇ (2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl ⁇ methanesulfonamide hydrochloride. Is reacted with 1-chloro-2-methyl-1-oxopropan-2-yl acetate, and then N- ⁇ (2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2. It is also described to produce-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl ⁇ methanesulfonamide. In the manufacturing process of each of the above compounds disclosed in Patent Document 1, a column operation is performed after the post-treatment of the reaction mixture.
  • the present invention relates to N- ⁇ (2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] -1- (2-hydroxy-2-methylpropanol) pyrrolidine-3-yl.
  • Ethan sulfonamide hydrochloride N- ⁇ (2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl ⁇ methanesulfonamide hydrochloride, or N- ⁇ (2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl ⁇ ethanesulfoneamide hydrochloride, 2-hydroxy-2- High-purity N- ⁇ (2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] -1- (2-hydroxy-2-methyl) by condensing with methylpropanoic acid Propanoyl) pyrrolidine-3-yl) ethanesulfoneamide, N- ⁇ (2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2-[(2,
  • the present invention is as follows.
  • N- ⁇ (2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl ⁇ ethanesulfoneamide hydrochloride (hereinafter abbreviated as compound a1) N- ⁇ (2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl), which comprises the step of subjecting 2-hydroxy-2-methylpropanoic acid to a condensation reaction.
  • ] -1- (2-Hydroxy-2-methylpropanol) pyrrolidine-3-yl)
  • a method for producing ethanesulfoneamide (hereinafter, may be abbreviated as Compound A).
  • N- ⁇ (2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl ⁇ methanesulfonamide hydrochloride (hereinafter, compound b1) N- ⁇ (2S, 3S) -1- (2-hydroxy-2-methylpropanoyl), which comprises a step of subjecting 2-hydroxy-2-methylpropanoic acid to a condensation reaction.
  • a method for producing -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl ⁇ methanesulfonamide hereinafter, may be abbreviated as Compound B).
  • N- ⁇ (2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl ⁇ ethanesulfoneamide hydrochloride (hereinafter, compound c1) N- ⁇ (2S, 3S) -1- (2-hydroxy-2-methylpropanoyl), which comprises a step of subjecting 2-hydroxy-2-methylpropanoic acid to a condensation reaction.
  • a method for producing -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl ⁇ ethanesulfoneamide (hereinafter, may be abbreviated as Compound C).
  • compound A, compound B and compound C can be obtained with high purity, so that the production method of the present invention is suitable for industrial production.
  • the production method of the present invention will be described below.
  • the compound obtained in each step can be used as a reaction solution or as a crude product and then used in the next reaction, or the compound obtained in each step is concentrated from the reaction mixture according to a conventional method.
  • the commercially available product can be used as it is.
  • these reactions are carried out without solvent or by dissolving or suspending in a suitable solvent.
  • the solvent include the solvents described in Examples described later, or the following.
  • Alcohols Methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, 1-propanol, 2-propanol, etc .
  • Ethers diethyl ether, diisopropyl ether, cyclopentyl methyl ether (CPME), diphenyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane, 1,4-dioxane, cyclopentyl methyl ether, etc.
  • Aromatic hydrocarbons chlorobenzene, toluene, xylene, etc .
  • Saturated hydrocarbons cyclohexane, hexane, etc .
  • Amides N, N-dimethylformamide, N, N-dimethylacetamide,
  • Inorganic bases sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium acetate, lithium hydroxide, tripotassium phosphate, etc .
  • Organic bases triethylamine, diethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.
  • Metal alkoxides sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, lithium ethoxide, etc .
  • Alkali metal hydrides sodium hydride, etc .
  • Metal amides sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc .
  • Organolithium n-butyllithium, etc.
  • the method for producing compound A, compound B and compound C in the present invention includes a step of subjecting compound a1, compound b1 or compound c1 and 2-hydroxy-2-methylpropanoic acid to a condensation reaction.
  • the condensation reaction is carried out by reacting compound a1, compound b1 or compound c1 with 2-hydroxy-2-methylpropanoic acid in the presence of a condensing agent and a base.
  • Compound a1, compound b1 and compound c1 can be produced by a method known per se or a method similar thereto. For example, it can be produced by the method described in Patent Document 1 or a method similar thereto, for example, a method described later.
  • 2-hydroxy-2-methylpropanoic acid The amount of 2-hydroxy-2-methylpropanoic acid used is usually 2.4 to 2.6 mol, preferably 2.45 to 2.55 mol, or 2.45 to 2.55 mol, based on 1 mol of compound a1, compound b1 or compound c1. It is 1.0 to 1.2 mol, preferably 1.05 to 1.15 mol.
  • bases examples include organic bases and inorganic bases.
  • the base is preferably triethylamine.
  • the amount of the base used is usually 3.55 to 3.85 mol, preferably 3.65 to 3.75 mol, or 1.35 to 1.65 mol, relative to 1 mol of compound a1, compound b1 or compound c1. , Preferably 1.45 to 1.55 mol.
  • a carbodiimide-based condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD); 4- (4,6-dimethoxy-1,3,5-triazine-2- Il) Triazine-based condensing agents such as 4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate ester-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoryl azide (diphenylphosphoryl azide) DPPA); benzotriazole-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukoyama reagent); thionyl chloride; lower alkyl halogitate such as ethyl chlorophosphate; O -(7-azabenzotriazole-1
  • the condensing agent is preferably CDI or WSCD.
  • the condensing agent is particularly preferably CDI.
  • the additive is preferably HOBt or HONB.
  • the additive is particularly preferably HONB.
  • the amount of the condensing agent used is usually 2.40 to 2.60 mol, preferably 2.45 to 2.55 mol, or 1.20 to 1.40 mol, relative to 1 mol of compound a1, compound b1 or compound c1. It is mol, preferably 1.25 to 1.35 mol.
  • the amount of the additive used is usually 2.20 to 3.40 mol, preferably 2.25 to 2.35 mol, or 1.20 to 1.40 mol, relative to 1 mol of compound a1, compound b1 or compound c1. It is mol, preferably 1.25 to 1.35 mol.
  • the reaction is usually carried out in a solvent.
  • the solvent include amides and the like.
  • the solvent is preferably amides, more preferably dimethylacetamide.
  • the reaction is usually carried out at 20-40 ° C, preferably 35-39 ° C.
  • the reaction time is usually about 5 minutes to about 7 hours, preferably about 5 hours to about 6 hours.
  • compound a1, compound b1 and compound c1 used as raw materials can be produced by steps 1 and 2 of the following method.
  • N- (2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidine-3-yl) ethanesulfonamide having a protecting group at the 1-position is reacted with (3-fluorophenyl) boronic acid.
  • N- (2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidine-3-yl) methanesulfonamide having the above is reacted with (3,5-difluorophenyl) boronic acid to the 1-position.
  • N- (2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidine-3-yl) ethanesulfonamide is reacted with (3,5-difluorophenyl) boronic acid to 1 N- (2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) pyrrolidine-3-yl] ethanesulfonamide having a protecting group at the position is obtained.
  • Examples of the protecting group include a tert-butoxycarbonyl group, a benzyloxycarbonyl group, an acetyl group, a trityl group, a benzyl group, a 9-fluorenylmethyloxycarbonyl group (Fmoc group), and a 2,2,2-trichloroethoxycarbonyl group.
  • Troc group methoxymethyl group (MOM group) and the like can be mentioned, and among them, the tert-butoxycarbonyl group is preferable from the viewpoint of easy deprotection.
  • the N- (2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidine-3-yl) ethanesulfonamide having a protecting group at the 1-position is preferably tert-butyl (2S, 3S) -2.
  • -(3-Bromo-2-fluorobenzyl) -3-[(ethylsulfonyl) amino] pyrrolidine-1-carboxylate hereinafter, may be abbreviated as Compound X).
  • the N- (2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidine-3-yl) methanesulfonamide having a protecting group at the 1-position is preferably tert-butyl (2S, 3S) -2.
  • -(3-Bromo-2-fluorobenzyl) -3-[(methylsulfonyl) amino] pyrrolidine-1-carboxylate hereinafter, may be abbreviated as compound Y).
  • a preferred embodiment of the process is tert-Butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3-[(ethylsulfonyl) amino] pyrrolidine-1-carboxylate (Compound X) to (3-fluorophenyl) boric acid Reacts with tert-butyl (2S, 3S) -3-[(ethylsulfonyl) amino] -2-[(2,3'-difluorobiphenyl-3-yl) methyl] pyrrolidine-1-carboxylate (compound) Obtain a2); or tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3-[(methylsulfonyl) amino] pyrrolidine-1-carboxylate (Compound Y) (3).
  • the step is usually carried out in a solvent in the presence of a palladium catalyst, a phosphine ligand and a base.
  • a palladium catalyst a phosphine ligand and a base.
  • the (3-fluorophenyl) boronic acid or the (3,5-difluorophenyl) boronic acid a commercially available product can be used.
  • the amount of (3-fluorophenyl) boronic acid or (3,5-difluorophenyl) boronic acid used is usually 1.10 to 1.30 mol, preferably 1.15 to 1 mol, relative to 1 mol of compound X or compound Y. It is 1.25 mol.
  • the palladium catalyst examples include Pd carbon powder, di-tert-butyl (3-methyl-2-butenyl) phosphine (Pd (m-Crophos) Cl 2 ), palladium (II) acetate, and tetrakis (triphenylphosphine) palladium (0). ), Dichlorobis (triphenylphosphine) palladium (II), dichlorobis (triethylphosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), 1,1'-bis (diphenylphosphino) ferrocene palladium ( II) and the like.
  • Pd carbon powder di-tert-butyl (3-methyl-2-butenyl) phosphine (Pd (m-Crophos) Cl 2 ), palladium (II) acetate, and tetrakis (triphenylphosphine) palladium (0)
  • the palladium catalyst is preferably di-tert-butyl (3-methyl-2-butenyl) phosphine (Pd (m-Crophos) Cl 2 ) or Pd carbon powder, particularly preferably 10% Pd carbon powder (PE-TYPE). , NE CHEMCAT).
  • the amount of the palladium catalyst used is the amount of the catalyst. Specifically, it is usually 0.08 to 0.12 mol%, preferably 0.09 to 0.11 mol%, or 0.09 to 0.11 mol%, or 0.09 to 0.11 mol%, or 0.09 to 0.11 mol%, or 0.09 to 0.11 mol%, based on 1 mol of the compound X or the compound Y. It is 0.018 to 0.022 mol%, preferably 0.019 to 0.021 mol%.
  • Examples of the phosphine ligand include XPhos (2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl), Xantphos (4,5-bis (diphenylphosphino) -9,9-dimethylxanthene) and the like. Can be given.
  • the phosphine ligand is preferably XPhos (2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl).
  • the amount of the phosphine ligand used is a catalytic amount, specifically, 0.16 to 0.24 mol%, preferably 0.18 to 0.22 mol%, based on 1 mol of compound X or compound Y. Is.
  • bases examples include organic bases and inorganic bases.
  • the base is preferably N, N-diisopropylethylamine, sodium hydroxide, and particularly preferably sodium hydroxide.
  • the amount of the base used is usually 1.35 to 1.65 mol, preferably 1.45 to 1.55 mol, based on 1 mol of compound X or compound Y.
  • the solvent is preferably ethers, more preferably 1,2-dimethoxyethane.
  • the reaction is usually carried out at 73-83 ° C, preferably 78-81 ° C.
  • the reaction time is usually about 3 hours to about 5 hours, preferably about 3 hours to about 4 hours.
  • ethyl acetate and water are added to the reaction mixture, and then the insoluble material is filtered off. Further, the mixture is treated with N-acetylcysteine and NaCl, water is added at 60 to 70 ° C., and the mixture is cooled to 20 to 30 ° C. to precipitate crystals of compound a2, compound b2 or compound c2. Crystals of compound a2, compound b2 or compound c2 can be obtained by washing the precipitated crystals with ethanol-water and drying them.
  • Step 2 N- (2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) pyrrolidine-3-yl] ethanesulfonamide having a protecting group at the 1-position is deprotected to N- ⁇ ((2,3'-difluorobiphenyl-3-yl) pyrrolidine-3-yl] 2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl ⁇ ethanesulfonamide hydrochloride (Compound a1) is obtained; or N having a protecting group at the 1-position.
  • the protecting groups are as described above.
  • a preferred embodiment of the process is tert-butyl (2S, 3S) -3-[(ethylsulfonyl) amino] -2-[(2,3'-difluorobiphenyl-3-yl) methyl] pyrrolidine-1-carboxylate (compound a2) is deprotected.
  • the step is carried out by treating with an acid in a solvent.
  • the acid include hydrogen chloride.
  • Hydrogen chloride is preferably used as a solution of an organic solvent, particularly preferably as a 2-propanol or ethyl acetate solution of hydrogen chloride, and particularly preferably as a 2-propanol solution of hydrogen chloride.
  • the solvent include alcohols, esters, water and the like.
  • the solvent is preferably alcohols, esters or a mixed solvent thereof, more preferably ethanol, ethyl acetate, 2-propanol or a mixed solvent thereof, and particularly preferably 2-propanol.
  • the reaction is usually carried out at 65-75 ° C, preferably 67-73 ° C.
  • the reaction time is usually about 1 hour to about 4 hours, preferably about 2 hours to about 3 hours.
  • n-heptane is added at 65 to 75 ° C. for crystallization, and after cooling to 0 to 10 ° C. over 1 hour or more, 2-propanol / n-heptane or ethanol / n-heptane is preferable.
  • the elution in the column chromatography of the example was carried out under observation by TLC (Thin Layer Chromatography, thin layer chromatography).
  • TLC Thin Layer Chromatography, thin layer chromatography
  • 60 F 254 manufactured by Merck Group was used as the TLC plate
  • the solvent used as the elution solvent in the column chromatography was used as the developing solvent.
  • a UV detector was used for detection.
  • silica gel column chromatography aminopropylsilane-bonded silica gel was used when it was described as NH, and 3- (2,3-dihydroxypropoxy) propylsilane-bonded silica gel was used when it was described as Diol.
  • Ethylenediamine and Ecosorb C-947 were added to the organic layer at 25 ° C., and the mixture was stirred for 2 hours or more in the same manner as described above, filtered, and the insoluble matter was washed with ethyl acetate.
  • 50 ml of ethanol was added to the filtrate, and the mixture was concentrated under reduced pressure to about 75 ml at an outside temperature of 60 ° C. or lower.
  • 50 ml of ethanol was added with stirring at 40 ° C. or lower, and the step of concentrating under reduced pressure to about 75 ml at an external temperature of 60 ° C. or lower was repeated twice.
  • Reference example 2 N- ⁇ (2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl ⁇ methanesulfonamide hydrochloride (Compound b1) 32 ml of ethanol was added to 2.90 g of the crystal of compound b2, and 4.6 ml of a 4M hydrogen chloride / ethyl acetate solution was added dropwise with stirring at 25 ° C. The temperature of this mixed solution was gradually raised to 50 ° C., the mixture was stirred for 4 hours or more, and then 48 ml of n-heptane was added dropwise.
  • Compound b1 32 ml of ethanol was added to 2.90 g of the crystal of compound b2, and 4.6 ml of a 4M hydrogen chloride / ethyl acetate solution was added dropwise with stirring at 25 ° C. The temperature of this mixed solution was gradually raised to 50 ° C.,
  • Reference example 2-1 N- ⁇ (2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl ⁇ methanesulfonamide hydrochloride (Compound b1) 55 ml of 2-propanol was added to 5.00 g of crystals of compound b2, and 6.2 ml of a 5-6 M hydrogen chloride / 2-propanol solution was added dropwise with stirring at 25 ° C. The temperature of this mixed solution was gradually raised to 70 ° C., the mixture was stirred for 2 hours or more, and then 82.5 ml of n-heptane was added dropwise.
  • Compound b1 55 ml of 2-propanol was added to 5.00 g of crystals of compound b2, and 6.2 ml of a 5-6 M hydrogen chloride / 2-propanol solution was added dropwise with stirring at 25 ° C. The temperature of this mixed solution was gradually raised to 70
  • Reference example 3 N- ⁇ (2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl ⁇ ethanesulfonamide hydrochloride (Compound a1) 146 kg of ethanol, 185 kg of water and tert-butyl (2S, 3S) -3-[(ethylsulfonyl) amino] -2-[(2,3'-difluorobiphenyl-3-yl) methyl] pyrrolidine-1-carboxylate ( 61.57 kg of crystals of compound a2) were added, and a mixed solution of 50.7 kg of water and 66.7 kg of hydrochloric acid was added dropwise with stirring at 59 to 62 ° C.
  • Compound a1 146 kg of ethanol, 185 kg of water and tert-butyl (2S, 3S) -3-[(ethylsulfonyl) amino] -2-[
  • Example 1 N- ⁇ (2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] -1- (2-hydroxy-2-methylpropanol) pyrrolidine-3-yl ⁇ ethanesulfonamide (Compound A) Under a nitrogen atmosphere, 50.0 g of crystals of compound a1 were added to 375 ml of dimethylacetamide. At 20-30 ° C., 13.7 g of 2-hydroxy-2-methylpropanoic acid was added and washed with 50 ml of dimethylacetamide. Further, 20.2 g of 1-hydroxybenzotriazole hydrate was added and washed with 25 ml of dimethylacetamide.
  • the obtained aqueous layer was re-extracted twice with 400 ml of ethyl acetate. 600 ml of a 5 v / w% citric acid aqueous solution was added to the combined organic layers to separate the liquids. The obtained organic layer was washed successively with 600 ml of a 5 v / w% citric acid aqueous solution, 600 ml of a 5 v / w% sodium hydrogen carbonate aqueous solution and 600 ml of water, 2.5 g of activated carbon Shirasagi A was added, and the mixture was stirred at room temperature for 30 minutes.
  • the insoluble material was removed by filtration, washed with 100 ml of ethyl acetate, and then concentrated under reduced pressure to 150 ml. After adding 350 ml of ethanol to this concentrated solution, the operation of concentrating under reduced pressure to 150 ml was repeated twice. 300 ml of ethanol was added, and 350 ml of water was added dropwise at 19-25 ° C. The mixture was cooled to 2-8 ° C., 50 mg of compound A hydrate seed crystals were added at the same temperature, and the mixture was stirred for about 16 hours. 450 ml of water was added dropwise to the obtained crystal slurry at 2 to 8 ° C., and the mixture was stirred at the same temperature for 3 hours.
  • the crystals were separated and washed with 150 ml of a 1: 2 volume ratio mixture of ethanol and water previously cooled to 10 ° C. or lower. After draining the liquid, the mixture was dried under reduced pressure at an outside temperature of 35 to 45 ° C. and allowed to stand at room temperature for 21 hours in an open system to obtain 53.3 g of crude crystals of compound A hydrate. 40 ml of ethanol was added to 5 g of the crude crystals of the compound A hydrate thus obtained to obtain a solution. After dropping 35 ml of water at 19 to 25 ° C., the mixture was cooled to 2 to 8 ° C., 5 mg of a seed crystal of Compound A hydrate was added, and the mixture was stirred at the same temperature for 4 hours.
  • Example 2 N- ⁇ (2S, 3S) -1- (2-Hydroxy-2-methylpropanol) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl ⁇ Methanesulfonamide (Compound B) Sesquihydrate 30 ml of dimethylacetamide was added under a nitrogen atmosphere. At ⁇ 10 to 0 ° C., 3.09 g of 2-hydroxy-2-methylpropanoic acid and 4.82 g of 1,1-carbonyldiimidazole (CDI) were added, and the mixture was washed with 1.35 ml of dimethylacetamide.
  • CDI 1,1-carbonyldiimidazole
  • Example 2-1 N- ⁇ (2S, 3S) -1- (2-Hydroxy-2-methylpropanol) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl ⁇ Methanesulfonamide (Compound B) Sesquihydrate Under a nitrogen atmosphere, 90 ml of dimethylacetamide was added to 15 g of crystals of compound b1. Add 4.08 g of 2-hydroxy-2-methylpropanoic acid, 7.10 g of 1-hydroxybenzotriazole aqueous solution, and 8.88 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride at 20 to 30 ° C.
  • N- ⁇ (2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] -1- (2-hydroxy-2-methylpropanol) Pyrrolidine-3-yl) ethanesulfonamide (Compound A)
  • N- ⁇ (2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2-[(2,3', 5'-tri" Fluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl ⁇ methanesulfoneamide Compound B
  • N- ⁇ (2S, 3S) -1- (2-hydroxy-2-methylpropanol) -2-[ (2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl ⁇ ethanesulfoneamide (Compound C) can be obtained with high purity, so that the production method of the present invention can be used. Suitable for

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  • Plural Heterocyclic Compounds (AREA)

Abstract

Provided is a production method suitable for the industrial production of N-{(2S,3S)-2-[(2,3'-difluorobiphenyl-3-yl)methyl]-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl}ethane sulfonamide, N-{(2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluorobiphenyl-3-yl)methyl]pyrrolidin-3-yl}methane sulfonamide, and N-{(2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluorobiphenyl-3-yl)methyl]pyrrolidin-3-yl}ethane sulfonamide.　The present invention pertains to a method for producing N-{(2S,3S)-2-[(2,3'-difluorobiphenyl-3-yl)methyl]-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl}ethane sulfonamide, N-{(2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluorobiphenyl-3-yl)methyl]pyrrolidin-3-yl}methane sulfonamide, or N-{(2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluorobiphenyl-3-yl)methyl]pyrrolidin-3-yl}ethane sulfonamide, the method comprising a step for subjecting 2-hydroxy-2-methylpropanoic acid, and N-{(2S,3S)-2-[(2,3'-difluorobiphenyl-3-yl)methyl]pyrrolidin-3-yl}ethane sulfonamide hydrochloride, N-{(2S,3S)-2-[(2,3',5'-trifluorobiphenyl-3-yl)methyl]pyrrolidin-3-yl}methane sulfonamide hydrochloride, or N-{(2S,3S)-2-[(2,3',5'-trifluorobiphenyl-3-yl)methyl]pyrrolidin-3-yl}ethane sulfonamide hydrochloride to a condensation reaction.

Description

ピロリジン化合物の製造方法Method for producing pyrrolidine compound
　本発明は、ピロリジン化合物の製造方法に関する。 The present invention relates to a method for producing a pyrrolidine compound.
（発明の背景）
　ピロリジン化合物、例えば、Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］－１－（２－ヒドロキシ－２－メチルプロパノイル）ピロリジン－３－イル）エタンスルホンアミド、Ｎ－｛（２Ｓ，３Ｓ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミド、およびＮ－｛（２Ｓ，３Ｓ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミドは医薬品として有用であり、工業的製造に適した製造法が望まれている。 (Background of invention)
Pyrrolidine compounds, such as N-{(2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] -1- (2-hydroxy-2-methylpropanol) pyrrolidine-3- Il) ethanesulfonamide, N-{(2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl ] Pyrrolidine-3-yl} methanesulfoneamide, and N-{(2S, 3S) -1- (2-hydroxy-2-methylpropanol) -2-[(2,3', 5'-trifluorobiphenyl) -3-Il) Methyl] pyrrolidine-3-yl} ethanesulfonamide is useful as a pharmaceutical, and a production method suitable for industrial production is desired.
　特許文献１には、Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］－１－（２－ヒドロキシ－２－メチルプロパノイル）ピロリジン－３－イル）エタンスルホンアミドおよびＮ－｛（２Ｓ，３Ｓ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミドを、それぞれフリー体スルホンアミド原料化合物を用いて製造することが記載されている。
　また、特許文献１には、Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミド　塩酸塩を、１－クロロ－２－メチル－１－オキソプロパン－２－イル　アセテートと反応させる工程を経て、Ｎ－｛（２Ｓ，３Ｓ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミドを製造することも記載されている。
　特許文献１で開示されている上記各化合物の製造工程では、反応混合物の後処理後にカラム操作を行っている。 Patent Document 1 describes N-{(2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] -1- (2-hydroxy-2-methylpropanol) pyrrolidine-3. -Il) Ethane sulfonamide and N-{(2S, 3S) -1- (2-hydroxy-2-methylpropanol) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) It is described that each of methyl] pyrrolidine-3-yl} ethanesulfonamide is produced using a free sulfonamide raw material compound.
Further, Patent Document 1 describes N-{(2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} methanesulfonamide hydrochloride. Is reacted with 1-chloro-2-methyl-1-oxopropan-2-yl acetate, and then N-{(2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2. It is also described to produce-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} methanesulfonamide.
In the manufacturing process of each of the above compounds disclosed in Patent Document 1, a column operation is performed after the post-treatment of the reaction mixture.
ＷＯ２０１９／０２７０５８WO2019 / 027058
　本発明は、Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］－１－（２－ヒドロキシ－２－メチルプロパノイル）ピロリジン－３－イル）エタンスルホンアミド、Ｎ－｛（２Ｓ，３Ｓ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミド、およびＮ－｛（２Ｓ，３Ｓ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミドの工業的製造に適した製造方法を提供することを目的とする。 The present invention relates to N-{(2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] -1- (2-hydroxy-2-methylpropanol) pyrrolidine-3-yl. ) Ethanesulfonamide, N-{(2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] Pyrrolidine-3-yl} methanesulfoneamide, and N-{(2S, 3S) -1- (2-hydroxy-2-methylpropanol) -2-[(2,3', 5'-trifluorobiphenyl-" It is an object of the present invention to provide a production method suitable for industrial production of 3-yl) methyl] pyrrolidine-3-yl} ethanesulfoneamide.
　本発明者らは、上記課題を解決すべく鋭意検討した結果、Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミド　塩酸塩、Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミド　塩酸塩、またはＮ－｛（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミド　塩酸塩を、２－ヒドロキシ－２－メチルプロパン酸と縮合させることにより、高純度のＮ－｛（２Ｓ，３Ｓ）－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］－１－（２－ヒドロキシ－２－メチルプロパノイル）ピロリジン－３－イル）エタンスルホンアミド、Ｎ－｛（２Ｓ，３Ｓ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミド、またはＮ－｛（２Ｓ，３Ｓ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミドを取得できることを見出し、本発明を完成するに至った。 As a result of diligent studies to solve the above problems, the present inventors have conducted N-{(2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl}. Ethan sulfonamide hydrochloride, N-{(2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} methanesulfonamide hydrochloride, or N-{(2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} ethanesulfoneamide hydrochloride, 2-hydroxy-2- High-purity N-{(2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] -1- (2-hydroxy-2-methyl) by condensing with methylpropanoic acid Propanoyl) pyrrolidine-3-yl) ethanesulfoneamide, N-{(2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2-[(2,3', 5'-trifluoro) Biphenyl-3-yl) methyl] pyrrolidine-3-yl} methanesulfoneamide, or N-{(2S, 3S) -1- (2-hydroxy-2-methylpropanol) -2-[(2,3') , 5'-Trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} ethanesulfonamide was found to be obtained, and the present invention was completed.
　即ち、本発明は、以下の通りである。 That is, the present invention is as follows.
［１］　Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミド　塩酸塩（以下、化合物ａ１と略称することもある）と、２－ヒドロキシ－２－メチルプロパン酸とを縮合反応に付す工程を含む、Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］－１－（２－ヒドロキシ－２－メチルプロパノイル）ピロリジン－３－イル）エタンスルホンアミド（以下、化合物Ａと略称することもある）の製造方法。 [1] N-{(2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} ethanesulfoneamide hydrochloride (hereinafter abbreviated as compound a1) N-{(2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl), which comprises the step of subjecting 2-hydroxy-2-methylpropanoic acid to a condensation reaction. ] -1- (2-Hydroxy-2-methylpropanol) pyrrolidine-3-yl) A method for producing ethanesulfoneamide (hereinafter, may be abbreviated as Compound A).
［２］　ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－３－［（エチルスルホニル）アミノ］－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］ピロリジン－１－カルボキシラート（以下、化合物ａ２と略称することもある）を、酸の存在下で脱保護して、Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミド　塩酸塩（化合物ａ１）を得る工程を前工程としてさらに含む、前記［１］の方法。 [2] tert-butyl (2S, 3S) -3-[(ethylsulfonyl) amino] -2-[(2,3'-difluorobiphenyl-3-yl) methyl] pyrrolidine-1-carboxylate (hereinafter, compound) (Sometimes abbreviated as a2) is deprotected in the presence of acid to N-{(2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] pyrrolidine-3. -Il} The method of [1] above, further comprising a step of obtaining an ethanesulfone amide hydrochloride (compound a1) as a pre-step.
［３］　Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミド　塩酸塩（以下、化合物ｂ１と略称することもある）と、２－ヒドロキシ－２－メチルプロパン酸とを縮合反応に付す工程を含む、Ｎ－｛（２Ｓ，３Ｓ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミド（以下、化合物Ｂと略称することもある）の製造方法。 [3] N-{(2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} methanesulfonamide hydrochloride (hereinafter, compound b1) N-{(2S, 3S) -1- (2-hydroxy-2-methylpropanoyl), which comprises a step of subjecting 2-hydroxy-2-methylpropanoic acid to a condensation reaction. A method for producing -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} methanesulfonamide (hereinafter, may be abbreviated as Compound B).
［４］　ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－３－［（メチルスルホニル）アミノ］－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－１－カルボキシラート（以下、化合物ｂ２と略称することもある）を、酸の存在下で脱保護して、Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミド　塩酸塩（化合物ｂ１）を得る工程を前工程としてさらに含む、前記［３］の方法。 [4] tert-Butyl (2S, 3S) -3-[(methylsulfonyl) amino] -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-1-carboxylate (Hereinafter, sometimes abbreviated as compound b2) is deprotected in the presence of an acid to N-{(2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3). -Il) Methyl] pyrrolidine-3-yl} methanesulfonamide The method of [3] above, further comprising a step of obtaining a hydrochloride (compound b1) as a pre-step.
［５］　Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミド　塩酸塩（以下、化合物ｃ１と略称することもある）と、２－ヒドロキシ－２－メチルプロパン酸とを縮合反応に付す工程を含む、Ｎ－｛（２Ｓ，３Ｓ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミド（以下、化合物Ｃと略称することもある）の製造方法。 [5] N-{(2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} ethanesulfoneamide hydrochloride (hereinafter, compound c1) N-{(2S, 3S) -1- (2-hydroxy-2-methylpropanoyl), which comprises a step of subjecting 2-hydroxy-2-methylpropanoic acid to a condensation reaction. A method for producing -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} ethanesulfoneamide (hereinafter, may be abbreviated as Compound C).
［６］　ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－３－［（エチルスルホニル）アミノ］－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－１－カルボキシラート（以下、化合物ｃ２と略称することもある）を、酸の存在下で脱保護して、Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミド　塩酸塩（化合物ｃ１）を得る工程を前工程としてさらに含む、前記［５］の方法。 [6] tert-butyl (2S, 3S) -3-[(ethylsulfonyl) amino] -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-1-carboxylate (Hereinafter, sometimes abbreviated as compound c2) is deprotected in the presence of an acid to N-{(2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3). -Il) Methyl] pyrrolidine-3-yl} ethanesulfoneamide The method of [5] above, further comprising a step of obtaining a hydrochloride (compound c1) as a pre-step.
　本発明の製造方法によれば、化合物Ａ、化合物Ｂおよび化合物Ｃを、高純度で取得することができるので、本発明の製造方法は工業的製造に適している。 According to the production method of the present invention, compound A, compound B and compound C can be obtained with high purity, so that the production method of the present invention is suitable for industrial production.
（発明の詳細な説明）
　本発明の製造法について以下に説明する。
　各工程で得られた化合物は反応液のままか、または粗生成物として得た後に、次反応に用いることもできる、あるいは、各工程で得られた化合物を、常法に従って、反応混合物から濃縮、晶出、再結晶、蒸留、溶媒抽出、分溜、クロマトグラフィーなどの分離手段により単離および／または精製することができる。 (Detailed description of the invention)
The production method of the present invention will be described below.
The compound obtained in each step can be used as a reaction solution or as a crude product and then used in the next reaction, or the compound obtained in each step is concentrated from the reaction mixture according to a conventional method. Can be isolated and / or purified by separation means such as crystallization, recrystallization, distillation, solvent extraction, fractionation, chromatography and the like.
　各工程の原料や試薬の化合物が市販されている場合には、市販品をそのまま用いることができる。 If the raw material or reagent compound for each process is commercially available, the commercially available product can be used as it is.
　各工程の反応において、特に記載が無い場合、これらの反応は、無溶媒、あるいは適当な溶媒に溶解または懸濁して行われる。溶媒の具体例としては、後述の実施例に記載されている溶媒、あるいは以下が挙げられる。
アルコール類：メタノール、エタノール、ｔｅｒｔ－ブチルアルコール、２－メトキシエタノール、１－プロパノール、２－プロパノールなど；
エーテル類：ジエチルエーテル、ジイソプロピルエーテル、シクロペンチルメチルエーテル（ＣＰＭＥ）、ジフェニルエーテル、テトラヒドロフラン（ＴＨＦ）、１，２－ジメトキシエタン、１，４－ジオキサン、シクロペンチルメチルエーテルなど；
芳香族炭化水素類：クロロベンゼン、トルエン、キシレンなど；
飽和炭化水素類：シクロヘキサン、ヘキサンなど；
アミド類：Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドンなど；
ハロゲン化炭化水素類：ジクロロメタン、四塩化炭素など；
ニトリル類：アセトニトリルなど；
スルホキシド類：ジメチルスルホキシドなど；
有機塩基類：ピリジン、トリエチルアミンなど；
酸無水物類：無水酢酸など；
有機酸類：ギ酸、酢酸、トリフルオロ酢酸など；
無機酸類：塩酸、硫酸など；
エステル類：酢酸エチル、酢酸イソプロピルなど；
ケトン類：アセトン、メチルエチルケトンなど；
水。
　上記溶媒は、二種以上を適宜の割合で混合して用いてもよい。 Unless otherwise specified, in the reaction of each step, these reactions are carried out without solvent or by dissolving or suspending in a suitable solvent. Specific examples of the solvent include the solvents described in Examples described later, or the following.
Alcohols: Methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, 1-propanol, 2-propanol, etc .;
Ethers: diethyl ether, diisopropyl ether, cyclopentyl methyl ether (CPME), diphenyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane, 1,4-dioxane, cyclopentyl methyl ether, etc.;
Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc .;
Saturated hydrocarbons: cyclohexane, hexane, etc .;
Amides: N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc .;
Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc .;
Nitriles: acetonitrile, etc .;
Sulfoxides: Dimethyl sulfoxide, etc .;
Organic bases: pyridine, triethylamine, etc .;
Acid anhydrides: acetic anhydride, etc .;
Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc .;
Inorganic acids: hydrochloric acid, sulfuric acid, etc .;
Esters: ethyl acetate, isopropyl acetate, etc .;
Ketones: acetone, methyl ethyl ketone, etc .;
water.
As the above solvent, two or more kinds may be mixed and used in an appropriate ratio.
　各工程の反応において塩基を用いる場合、例えば、以下に示す塩基、あるいは後述の実施例に記載されている塩基が用いられる。
無機塩基類：水酸化ナトリウム、水酸化マグネシウム、炭酸ナトリウム、炭酸カルシウム、炭酸水素ナトリウム、炭酸カリウム、酢酸ナトリウム、水酸化リチウム、リン酸三カリウムなど；
有機塩基類：トリエチルアミン、ジエチルアミン、ジイソプロピルエチルアミン、ピリジン、４－ジメチルアミノピリジン、Ｎ，Ｎ－ジメチルアニリン、１，４－ジアザビシクロ［２．２．２］オクタン、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン、イミダゾール、ピペリジンなど；　
金属アルコキシド類：ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、リチウムエトキシドなど；
アルカリ金属水素化物類：水素化ナトリウムなど；
金属アミド類：ナトリウムアミド、リチウムジイソプロピルアミド、リチウムヘキサメチルジシラジドなど；
有機リチウム類：ｎ－ブチルリチウムなど。 When a base is used in the reaction of each step, for example, the base shown below or the base described in Examples described later is used.
Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium acetate, lithium hydroxide, tripotassium phosphate, etc .;
Organic bases: triethylamine, diethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4. 0] -7-undecene, imidazole, piperidine, etc .;
Metal alkoxides: sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, lithium ethoxide, etc .;
Alkali metal hydrides: sodium hydride, etc .;
Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc .;
Organolithium: n-butyllithium, etc.
　本発明における、化合物Ａ、化合物Ｂおよび化合物Ｃの製造方法は、化合物ａ１、化合物ｂ１または化合物ｃ１と、２－ヒドロキシ－２－メチルプロパン酸とを縮合反応に付す工程を含む。 The method for producing compound A, compound B and compound C in the present invention includes a step of subjecting compound a1, compound b1 or compound c1 and 2-hydroxy-2-methylpropanoic acid to a condensation reaction.
　当該縮合反応は、縮合剤および塩基の存在下、化合物ａ１、化合物ｂ１または化合物ｃ１を、２－ヒドロキシ－２－メチルプロパン酸と反応させることにより行われる。 The condensation reaction is carried out by reacting compound a1, compound b1 or compound c1 with 2-hydroxy-2-methylpropanoic acid in the presence of a condensing agent and a base.
　化合物ａ１、化合物ｂ１および化合物ｃ１は、自体公知の方法またはこれに準ずる方法により製造することができる。例えば、特許文献１に記載の方法またはこれに準ずる方法、例えば、後述する方法により製造することができる。 Compound a1, compound b1 and compound c1 can be produced by a method known per se or a method similar thereto. For example, it can be produced by the method described in Patent Document 1 or a method similar thereto, for example, a method described later.
　２－ヒドロキシ－２－メチルプロパン酸は、市販品を使用することができる。２－ヒドロキシ－２－メチルプロパン酸の使用量は、化合物ａ１、化合物ｂ１または化合物ｃ１の１モルに対し、通常２．４～２．６モル、好ましくは２．４５～２．５５モル、あるいは１．０～１．２モル、好ましくは１．０５～１．１５モルである。 Commercially available products can be used for 2-hydroxy-2-methylpropanoic acid. The amount of 2-hydroxy-2-methylpropanoic acid used is usually 2.4 to 2.6 mol, preferably 2.45 to 2.55 mol, or 2.45 to 2.55 mol, based on 1 mol of compound a1, compound b1 or compound c1. It is 1.0 to 1.2 mol, preferably 1.05 to 1.15 mol.
　塩基としては、有機塩基、無機塩基が挙げられる。塩基は、好ましくはトリエチルアミンである。塩基の使用量は、化合物ａ１、化合物ｂ１または化合物ｃ１の１モルに対し、通常３．５５～３．８５モル、好ましくは３．６５～３．７５モル、あるいは１．３５～１．６５モル、好ましくは１．４５～１．５５モルである。 Examples of bases include organic bases and inorganic bases. The base is preferably triethylamine. The amount of the base used is usually 3.55 to 3.85 mol, preferably 3.65 to 3.75 mol, or 1.35 to 1.65 mol, relative to 1 mol of compound a1, compound b1 or compound c1. , Preferably 1.45 to 1.55 mol.
　縮合剤としては、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（ＷＳＣＤ）などのカルボジイミド系縮合剤；４－（４，６－ジメトキシ－１，３，５－トリアジン－２－イル）－４－メチルモルホリニウムクロライド－ｎ－ハイドレート（ＤＭＴ－ＭＭ）などのトリアジン系縮合剤；１，１－カルボニルジイミダゾール（ＣＤＩ）などの炭酸エステル系縮合剤；ジフェニルリン酸アジド（ＤＰＰＡ）；ベンゾトリアゾール－１－イルオキシ－トリスジメチルアミノホスホニウム塩（ＢＯＰ試薬）；ヨウ化２－クロロ－１－メチル－ピリジニウム（向山試薬）；塩化チオニル；クロロギ酸エチルなどのハロギ酸低級アルキル；Ｏ－（７－アザベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム　ヘキサフルオロリン酸塩（ＨＡＴＵ）；硫酸；あるいはこれらの組み合わせなどが挙げられる。カルボジイミド系縮合剤を用いる場合、１－ヒドロキシベンゾトリアゾール（ＨＯＢｔ）、Ｎ－ヒドロキシコハク酸イミド（ＨＯＳｕ）、Ｎ－ヒドロキシ－５－ノルボルネン－２，３－ジカルボキシイミド（ＨＯＮＢ）、ジメチルアミノピリジン（ＤＭＡＰ）などの添加剤をさらに反応に加えてもよい。縮合剤は、好ましくはＣＤＩまたはＷＳＣＤである。縮合剤は、特に好ましくはＣＤＩである。添加剤は、好ましくはＨＯＢｔまたはＨＯＮＢである。添加剤は、特に好ましくはＨＯＮＢである。縮合剤の使用量は、化合物ａ１、化合物ｂ１または化合物ｃ１の１モルに対し、通常２．４０～２．６０モル、好ましくは２．４５～２．５５モル、あるいは１．２０～１．４０モル、好ましくは１．２５～１．３５モルである。添加剤の使用量は、化合物ａ１、化合物ｂ１または化合物ｃ１の１モルに対し、通常２．２０～３．４０モル、好ましくは２．２５～２．３５モル、あるいは１．２０～１．４０モル、好ましくは１．２５～１．３５モルである。 As the condensing agent, a carbodiimide-based condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD); 4- (4,6-dimethoxy-1,3,5-triazine-2- Il) Triazine-based condensing agents such as 4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate ester-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoryl azide (diphenylphosphoryl azide) DPPA); benzotriazole-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukoyama reagent); thionyl chloride; lower alkyl halogitate such as ethyl chlorophosphate; O -(7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; or a combination thereof. When a carbodiimide-based condensing agent is used, 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-2,3-dicarboxyimide (HONB), dimethylaminopyridine (HOB) Additives such as DMAP) may be further added to the reaction. The condensing agent is preferably CDI or WSCD. The condensing agent is particularly preferably CDI. The additive is preferably HOBt or HONB. The additive is particularly preferably HONB. The amount of the condensing agent used is usually 2.40 to 2.60 mol, preferably 2.45 to 2.55 mol, or 1.20 to 1.40 mol, relative to 1 mol of compound a1, compound b1 or compound c1. It is mol, preferably 1.25 to 1.35 mol. The amount of the additive used is usually 2.20 to 3.40 mol, preferably 2.25 to 2.35 mol, or 1.20 to 1.40 mol, relative to 1 mol of compound a1, compound b1 or compound c1. It is mol, preferably 1.25 to 1.35 mol.
　当該反応は、通常、溶媒下で行われる。溶媒としては、アミド類などが挙げられる。溶媒は、好ましくはアミド類であり、より好ましくはジメチルアセトアミドである。
　当該反応は、通常２０～４０℃、好ましくは３５～３９℃で行われる。反応時間は、通常約５分～約７時間、好ましくは約５時間～約６時間である。 The reaction is usually carried out in a solvent. Examples of the solvent include amides and the like. The solvent is preferably amides, more preferably dimethylacetamide.
The reaction is usually carried out at 20-40 ° C, preferably 35-39 ° C. The reaction time is usually about 5 minutes to about 7 hours, preferably about 5 hours to about 6 hours.
　反応終了後、反応混合物に水を添加し、水酸化ナトリウムにてｐＨをアルカリ性に調整後、加熱撹拌し、続いて室温で塩酸を用いてｐＨを中性に調整後、水を添加することで、化合物Ａ、化合物Ｂまたは化合物Ｃの結晶を析出させる。必要により、種晶（例えばセスキ水和物の種晶）を添加してもよい。例えば、１５～４５℃で水を添加後、水酸化ナトリウムでｐＨを１３．４～１３．８に調整し５０℃で撹拌する。次いで、３０℃に冷却後、塩酸でｐＨを７．５～８．５に調整する。続いて、５５～６５℃で水を滴下し、種晶を添加して５５～６５℃で攪拌したのち、５５～６５℃で水を滴下し、次いで、０．５時間以上かけて４５～５５℃に冷却後、１．５時間以上かけて３０℃以下に冷却することにより、化合物Ａ、化合物Ｂまたは化合物Ｃの結晶を析出させる。析出した結晶をエタノール－水で洗浄して、化合物Ａ、化合物Ｂまたは化合物Ｃの結晶を水和物（例えばセスキ水和物）として取得することができる。必要により、エタノール－水－トリエチルアミン中での懸濁撹拌やエタノール－水で再結晶を行ってもよい。
　このようにして得られた化合物Ａ、化合物Ｂおよび化合物Ｃの結晶は９９％以上の純度を有する。 After completion of the reaction, water is added to the reaction mixture, the pH is adjusted to alkaline with sodium hydroxide, heated and stirred, and then the pH is adjusted to neutral with hydrochloric acid at room temperature, and then water is added. , Compound A, Compound B or Compound C crystals are precipitated. If necessary, a seed crystal (for example, a seed crystal of sesquihydrate) may be added. For example, after adding water at 15 to 45 ° C, the pH is adjusted to 13.4 to 13.8 with sodium hydroxide and stirred at 50 ° C. Then, after cooling to 30 ° C., the pH is adjusted to 7.5 to 8.5 with hydrochloric acid. Subsequently, water was added dropwise at 55 to 65 ° C., seed crystals were added, the mixture was stirred at 55 to 65 ° C., water was added dropwise at 55 to 65 ° C., and then 45 to 55 was added over 0.5 hours or more. After cooling to ° C., the crystals of compound A, compound B or compound C are precipitated by cooling to 30 ° C. or lower over 1.5 hours. The precipitated crystals can be washed with ethanol-water to obtain crystals of compound A, compound B or compound C as a hydrate (eg, sesquihydrate). If necessary, suspension stirring in ethanol-water-triethylamine or recrystallization in ethanol-water may be performed.
The crystals of Compound A, Compound B and Compound C thus obtained have a purity of 99% or more.
　上記縮合反応において、原料として使用する化合物ａ１、化合物ｂ１および化合物ｃ１は、以下の方法の工程１および２により製造することができる。 In the above condensation reaction, compound a1, compound b1 and compound c1 used as raw materials can be produced by steps 1 and 2 of the following method.
工程１
１位に保護基を有するＮ－（２Ｓ，３Ｓ）－２－（３－ブロモ－２－フルオロベンジル）ピロリジン－３－イル）エタンスルホンアミドを、（３－フルオロフェニル）ボロン酸と反応させて、１位に保護基を有するＮ－（２Ｓ，３Ｓ）－２－［（２，３’－ジフルオロビフェニル－３－イル）ピロリジン－３－イル］エタンスルホンアミドを得る；または
１位に保護基を有するＮ－（２Ｓ，３Ｓ）－２－（３－ブロモ－２－フルオロベンジル）ピロリジン－３－イル）メタンスルホンアミドを、（３，５－ジフルオロフェニル）ボロン酸と反応させて、１位に保護基を有するＮ－（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）ピロリジン－３－イル］メタンスルホンアミドを得る；または
１位に保護基を有するＮ－（２Ｓ，３Ｓ）－２－（３－ブロモ－２－フルオロベンジル）ピロリジン－３－イル）エタンスルホンアミドを、（３，５－ジフルオロフェニル）ボロン酸と反応させて、１位に保護基を有するＮ－（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）ピロリジン－３－イル］エタンスルホンアミドを得る。 Process 1
N- (2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidine-3-yl) ethanesulfonamide having a protecting group at the 1-position is reacted with (3-fluorophenyl) boronic acid. Obtain N- (2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) pyrrolidine-3-yl] ethanesulfonamide having a protecting group at the 1-position; or a protecting group at the 1-position. N- (2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidine-3-yl) methanesulfonamide having the above is reacted with (3,5-difluorophenyl) boronic acid to the 1-position. Obtains N- (2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) pyrrolidine-3-yl] methanesulfonamide having a protecting group on; or protected at the 1-position. The group-bearing N- (2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidine-3-yl) ethanesulfonamide is reacted with (3,5-difluorophenyl) boronic acid to 1 N- (2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) pyrrolidine-3-yl] ethanesulfonamide having a protecting group at the position is obtained.
　上記保護基としては、ｔｅｒｔ－ブトキシカルボニル基、ベンジルオキシカルボニル基、アセチル基、トリチル基、ベンジル基、９－フルオレニルメチルオキシカルボニル基（Ｆｍｏｃ基）、２，２，２－トリクロロエトキシカルボニル基（Ｔｒｏｃ基）、メトキシメチル基（ＭＯＭ基）等が挙げられ、中でも、脱保護が容易である点から、ｔｅｒｔ－ブトキシカルボニル基が好ましい。
　１位に保護基を有するＮ－（２Ｓ，３Ｓ）－２－（３－ブロモ－２－フルオロベンジル）ピロリジン－３－イル）エタンスルホンアミドは、好ましくはｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－２－（３－ブロモ－２－フルオロベンジル）－３－［（エチルスルホニル）アミノ］ピロリジン－１－カルボキシラート（以下、化合物Ｘと略称することもある）である。
　１位に保護基を有するＮ－（２Ｓ，３Ｓ）－２－（３－ブロモ－２－フルオロベンジル）ピロリジン－３－イル）メタンスルホンアミドは、好ましくはｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－２－（３－ブロモ－２－フルオロベンジル）－３－［（メチルスルホニル）アミノ］ピロリジン－１－カルボキシラート（以下、化合物Ｙと略称することもある）である。
　当該工程の好ましい態様としては、
ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－２－（３－ブロモ－２－フルオロベンジル）－３－［（エチルスルホニル）アミノ］ピロリジン－１－カルボキシラート（化合物Ｘ）を（３－フルオロフェニル）ボロン酸と反応させて、ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－３－［（エチルスルホニル）アミノ］－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］ピロリジン－１－カルボキシラート（化合物ａ２）を得る；または
ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－２－（３－ブロモ－２－フルオロベンジル）－３－［（メチルスルホニル）アミノ］ピロリジン－１－カルボキシラート（化合物Ｙ）を（３，５－ジフルオロフェニル）ボロン酸と反応させて、ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－３－［（メチルスルホニル）アミノ］－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－１－カルボキシラート（化合物ｂ２）を得る；または
ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－２－（３－ブロモ－２－フルオロベンジル）－３－［（エチルスルホニル）アミノ］ピロリジン－１－カルボキシラート（化合物Ｘ）を（３，５－ジフルオロフェニル）ボロン酸と反応させて、ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－３－［（エチルスルホニル）アミノ］－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－１－カルボキシラート（化合物ｃ２）を得る。 Examples of the protecting group include a tert-butoxycarbonyl group, a benzyloxycarbonyl group, an acetyl group, a trityl group, a benzyl group, a 9-fluorenylmethyloxycarbonyl group (Fmoc group), and a 2,2,2-trichloroethoxycarbonyl group. (Troc group), methoxymethyl group (MOM group) and the like can be mentioned, and among them, the tert-butoxycarbonyl group is preferable from the viewpoint of easy deprotection.
The N- (2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidine-3-yl) ethanesulfonamide having a protecting group at the 1-position is preferably tert-butyl (2S, 3S) -2. -(3-Bromo-2-fluorobenzyl) -3-[(ethylsulfonyl) amino] pyrrolidine-1-carboxylate (hereinafter, may be abbreviated as Compound X).
The N- (2S, 3S) -2- (3-bromo-2-fluorobenzyl) pyrrolidine-3-yl) methanesulfonamide having a protecting group at the 1-position is preferably tert-butyl (2S, 3S) -2. -(3-Bromo-2-fluorobenzyl) -3-[(methylsulfonyl) amino] pyrrolidine-1-carboxylate (hereinafter, may be abbreviated as compound Y).
A preferred embodiment of the process is
tert-Butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3-[(ethylsulfonyl) amino] pyrrolidine-1-carboxylate (Compound X) to (3-fluorophenyl) boric acid Reacts with tert-butyl (2S, 3S) -3-[(ethylsulfonyl) amino] -2-[(2,3'-difluorobiphenyl-3-yl) methyl] pyrrolidine-1-carboxylate (compound) Obtain a2); or tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3-[(methylsulfonyl) amino] pyrrolidine-1-carboxylate (Compound Y) (3). , 5-Difluorophenyl) React with boronic acid to tert-butyl (2S, 3S) -3-[(methylsulfonyl) amino] -2-[(2,3', 5'-trifluorobiphenyl-3-3' Il) methyl] pyrrolidine-1-carboxylate (Compound b2); or tert-butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3-[(ethylsulfonyl) amino] pyrrolidine Reacting -1-carboxylate (Compound X) with (3,5-difluorophenyl) boronic acid, tert-butyl (2S, 3S) -3-[(ethylsulfonyl) amino] -2-[(2, 3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-1-carboxylate (Compound c2) is obtained.
　当該工程は、通常、溶媒中、パラジウム触媒、ホスフィン配位子および塩基の存在下で行われる。
　（３－フルオロフェニル）ボロン酸または（３，５－ジフルオロフェニル）ボロン酸は、市販品を使用することができる。（３－フルオロフェニル）ボロン酸または（３，５－ジフルオロフェニル）ボロン酸の使用量は、化合物Ｘまたは化合物Ｙ１モルに対して、通常１．１０～１．３０モル、好ましくは１．１５～１．２５モルである。 The step is usually carried out in a solvent in the presence of a palladium catalyst, a phosphine ligand and a base.
As the (3-fluorophenyl) boronic acid or the (3,5-difluorophenyl) boronic acid, a commercially available product can be used. The amount of (3-fluorophenyl) boronic acid or (3,5-difluorophenyl) boronic acid used is usually 1.10 to 1.30 mol, preferably 1.15 to 1 mol, relative to 1 mol of compound X or compound Y. It is 1.25 mol.
　パラジウム触媒としては、Ｐｄカーボン粉末、ジ－ｔｅｒｔ－ブチル（３－メチル－２－ブテニル）ホスフィン（Ｐｄ（ｍ－Ｃｒｏｐｈｏｓ）Ｃｌ２）、酢酸パラジウム（ＩＩ）、テトラキス（トリフェニルホスフィン）パラジウム（０）、ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）、ジクロロビス（トリエチルホスフィン）パラジウム（ＩＩ）、トリス（ジベンジリデンアセトン）ジパラジウム（０）、塩化１，１’－ビス（ジフェニルホスフィノ）フェロセンパラジウム（ＩＩ）などが挙げられる。パラジウム触媒は、好ましくはジ－ｔｅｒｔ－ブチル（３－メチル－２－ブテニル）ホスフィン（Ｐｄ（ｍ－Ｃｒｏｐｈｏｓ）Ｃｌ２）またはＰｄカーボン粉末であり、特に好ましくは１０％Ｐｄカーボン粉末（ＰＥ－ＴＹＰＥ、Ｎ．Ｅ．ＣＨＥＭＣＡＴ製）である。パラジウム触媒の使用量は触媒量であり、具体的には、化合物Ｘまたは化合物Ｙ１モルに対して、通常０．０８～０．１２モル％、好ましくは０．０９～０．１１モル％、あるいは０．０１８～０．０２２モル％、好ましくは０．０１９～０．０２１モル％である。 Examples of the palladium catalyst include Pd carbon powder, di-tert-butyl (3-methyl-2-butenyl) phosphine (Pd (m-Crophos) Cl 2 ), palladium (II) acetate, and tetrakis (triphenylphosphine) palladium (0). ), Dichlorobis (triphenylphosphine) palladium (II), dichlorobis (triethylphosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), 1,1'-bis (diphenylphosphino) ferrocene palladium ( II) and the like. The palladium catalyst is preferably di-tert-butyl (3-methyl-2-butenyl) phosphine (Pd (m-Crophos) Cl 2 ) or Pd carbon powder, particularly preferably 10% Pd carbon powder (PE-TYPE). , NE CHEMCAT). The amount of the palladium catalyst used is the amount of the catalyst. Specifically, it is usually 0.08 to 0.12 mol%, preferably 0.09 to 0.11 mol%, or 0.09 to 0.11 mol%, or 0.09 to 0.11 mol%, or 0.09 to 0.11 mol%, based on 1 mol of the compound X or the compound Y. It is 0.018 to 0.022 mol%, preferably 0.019 to 0.021 mol%.
　ホスフィン配位子としては、ＸＰｈｏｓ（２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピルビフェニル）、Ｘａｎｔｐｈｏｓ（４，５－ビス（ジフェニルホスフィノ）－９，９－ジメチルキサンテン）などがあげられる。ホスフィン配位子は、好ましくはＸＰｈｏｓ（２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピルビフェニル）である。ホスフィン配位子の使用量は触媒量であり、具体的には、化合物Ｘまたは化合物Ｙ１モルに対して、通常０．１６～０．２４モル％、好ましくは０．１８～０．２２モル％である。 Examples of the phosphine ligand include XPhos (2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl), Xantphos (4,5-bis (diphenylphosphino) -9,9-dimethylxanthene) and the like. Can be given. The phosphine ligand is preferably XPhos (2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl). The amount of the phosphine ligand used is a catalytic amount, specifically, 0.16 to 0.24 mol%, preferably 0.18 to 0.22 mol%, based on 1 mol of compound X or compound Y. Is.
　塩基としては、有機塩基、無機塩基が挙げられる。塩基は、好ましくはＮ，Ｎ－ジイソプロピルエチルアミン、水酸化ナトリウムであり、特に好ましくは水酸化ナトリウムである。塩基の使用量は、化合物Ｘまたは化合物Ｙ１モルに対して、通常１．３５～１．６５モル、好ましくは１．４５～１．５５モルである。 Examples of bases include organic bases and inorganic bases. The base is preferably N, N-diisopropylethylamine, sodium hydroxide, and particularly preferably sodium hydroxide. The amount of the base used is usually 1.35 to 1.65 mol, preferably 1.45 to 1.55 mol, based on 1 mol of compound X or compound Y.
　溶媒は、好ましくはエーテル類であり、より好ましくは１，２－ジメトキシエタンである。
　当該反応は、通常７３～８３℃、好ましくは７８～８１℃で行われる。反応時間は、通常約３時間～約５時間、好ましくは約３時間～約４時間である。
　反応終了後、反応混合物に酢酸エチルおよび水を添加し、続いて不溶物を濾別する。さらにＮ－アセチルシステインおよびＮａＣｌで処理し、６０～７０℃で水を添加し、２０～３０℃に冷却することにより、化合物ａ２、化合物ｂ２または化合物ｃ２の結晶を析出させる。析出した結晶をエタノール－水で洗浄して乾燥させることにより、化合物ａ２、化合物ｂ２または化合物ｃ２の結晶を取得することができる。 The solvent is preferably ethers, more preferably 1,2-dimethoxyethane.
The reaction is usually carried out at 73-83 ° C, preferably 78-81 ° C. The reaction time is usually about 3 hours to about 5 hours, preferably about 3 hours to about 4 hours.
After completion of the reaction, ethyl acetate and water are added to the reaction mixture, and then the insoluble material is filtered off. Further, the mixture is treated with N-acetylcysteine and NaCl, water is added at 60 to 70 ° C., and the mixture is cooled to 20 to 30 ° C. to precipitate crystals of compound a2, compound b2 or compound c2. Crystals of compound a2, compound b2 or compound c2 can be obtained by washing the precipitated crystals with ethanol-water and drying them.
工程２
１位に保護基を有するＮ－（２Ｓ，３Ｓ）－２－［（２，３’－ジフルオロビフェニル－３－イル）ピロリジン－３－イル］エタンスルホンアミドを脱保護して、Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミド　塩酸塩（化合物ａ１）を得る；または
１位に保護基を有するＮ－（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）ピロリジン－３－イル］メタンスルホンアミドを脱保護して、Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミド　塩酸塩（化合物ｂ１）を得る；または
１位に保護基を有するＮ－（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）ピロリジン－３－イル］エタンスルホンアミドを脱保護して、Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミド　塩酸塩（化合物ｃ１）を得る。 Step 2
N- (2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) pyrrolidine-3-yl] ethanesulfonamide having a protecting group at the 1-position is deprotected to N-{((2,3'-difluorobiphenyl-3-yl) pyrrolidine-3-yl] 2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} ethanesulfonamide hydrochloride (Compound a1) is obtained; or N having a protecting group at the 1-position. -(2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) pyrrolidine-3-yl] Deprotects methanesulfonamide and N-{(2S, 3S) -(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} methanesulfonamide hydrochloride (Compound b1) is obtained; or N having a protecting group at the 1-position. -(2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) pyrrolidine-3-yl] Etan sulfonamide is deprotected and N-{(2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} ethanesulfonamide hydrochloride (Compound c1) is obtained.
　上記保護基は、前述のとおりである。
　当該工程の好ましい態様としては、
ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－３－［（エチルスルホニル）アミノ］－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］ピロリジン－１－カルボキシラート（化合物ａ２）を脱保護して、Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミド　塩酸塩（化合物ａ１）を得る；または
ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－３－［（メチルスルホニル）アミノ］－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－１－カルボキシラート（化合物ｂ２）を脱保護して、Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミド　塩酸塩（化合物ｂ１）を得る；または
ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－３－［（エチルスルホニル）アミノ］－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－１－カルボキシラート（化合物ｃ２）を脱保護して、Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミド　塩酸塩（化合物ｃ１）を得る。 The protecting groups are as described above.
A preferred embodiment of the process is
tert-butyl (2S, 3S) -3-[(ethylsulfonyl) amino] -2-[(2,3'-difluorobiphenyl-3-yl) methyl] pyrrolidine-1-carboxylate (compound a2) is deprotected. To obtain N-{(2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} ethanesulfonamide hydrochloride (Compound a1); or tert -Butyl (2S, 3S) -3-[(Methylsulfonyl) amino] -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-1-carboxylate (Compound b2) N-{(2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} methanesulfonamide hydrochloride (compound) b1) is obtained; or tert-butyl (2S, 3S) -3-[(ethylsulfonyl) amino] -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-1 -Deprotecting carboxylate (Compound c2), N-{(2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} Etan sulfonamide hydrochloride (Compound c1) is obtained.
　当該工程は、溶媒中、酸で処理することにより行われる。
　酸としては、塩化水素などが挙げられる。塩化水素は、有機溶媒の溶液として使用することが好ましく、特に塩化水素の２－プロパノールまたは酢酸エチル溶液として使用することが好ましく、塩化水素の２－プロパノール溶液として使用することが特に好ましい。
　溶媒としては、アルコール類、エステル類、水などが挙げられる。溶媒は、好ましくはアルコール類、エステル類またはそれらの混合溶媒であり、より好ましくはエタノール、酢酸エチル、２－プロパノールまたはそれらの混合溶媒であり、特に好ましくは２－プロパノールである。
　当該反応は、通常６５～７５℃、好ましくは６７～７３℃で行われる。反応時間は、通常約１時間～約４時間、好ましくは約２時間～約３時間である。
　反応終了後、６５～７５℃でｎ－へプタンを加えて晶析させ、１時間以上かけて０～１０℃に冷却後、２－プロパノール／ｎ－へプタンまたはエタノール／ｎ－へプタン、好ましくは２－プロパノール／ｎ－へプタンで洗浄することにより、化合物ａ１、化合物ｂ１または化合物ｃ１を取得することができる。 The step is carried out by treating with an acid in a solvent.
Examples of the acid include hydrogen chloride. Hydrogen chloride is preferably used as a solution of an organic solvent, particularly preferably as a 2-propanol or ethyl acetate solution of hydrogen chloride, and particularly preferably as a 2-propanol solution of hydrogen chloride.
Examples of the solvent include alcohols, esters, water and the like. The solvent is preferably alcohols, esters or a mixed solvent thereof, more preferably ethanol, ethyl acetate, 2-propanol or a mixed solvent thereof, and particularly preferably 2-propanol.
The reaction is usually carried out at 65-75 ° C, preferably 67-73 ° C. The reaction time is usually about 1 hour to about 4 hours, preferably about 2 hours to about 3 hours.
After completion of the reaction, n-heptane is added at 65 to 75 ° C. for crystallization, and after cooling to 0 to 10 ° C. over 1 hour or more, 2-propanol / n-heptane or ethanol / n-heptane is preferable. Can be obtained from compound a1, compound b1 or compound c1 by washing with 2-propanol / n-heptane.
　本発明は、更に以下の実施例により詳しく説明されるが、これらは本発明を限定するものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。
　以下の実施例中の「室温」は通常約１０℃ないし約３５℃を示す。混合溶媒において示した比は、特に断らない限り容量比を示す。％は、特に断らない限り重量％を示す。 The present invention will be further described in detail with reference to the following examples, but these are not limited to the present invention and may be changed without departing from the scope of the present invention.
"Room temperature" in the following examples usually indicates about 10 ° C to about 35 ° C. The ratio shown in the mixed solvent indicates the volume ratio unless otherwise specified. % Indicates% by weight unless otherwise specified.
　実施例のカラムクロマトグラフィーにおける溶出は、特に言及しない限り、ＴＬＣ（Ｔｈｉｎ　Ｌａｙｅｒ　Ｃｈｒｏｍａｔｏｇｒａｐｈｙ，薄層クロマトグラフィー）による観察下に行った。ＴＬＣ観察においては、ＴＬＣプレートとしてメルク（Ｍｅｒｃｋ）社製の６０　Ｆ２５４を用い、展開溶媒として、カラムクロマトグラフィーで溶出溶媒として用いた溶媒を用いた。また、検出にはＵＶ検出器を採用した。シリカゲルカラムクロマトグラフィーにおいて、ＮＨと記載した場合はアミノプロピルシラン結合シリカゲルを、Ｄｉｏｌと記載した場合は３－（２，３－ジヒドロキシプロポキシ）プロピルシラン結合シリカゲルを用いた。分取ＨＰＬＣ（高速液体クロマトグラフィー）において、Ｃ１８と記載した場合はオクタデシル結合シリカゲルを用いた。溶出溶媒において示した比は、特に断らない限り容量比を示す。なお、参考例および実施例に記載の反応操作および処理操作における温度は、±５℃の範囲の変動を含んでいる。
　１Ｈ　ＮＭＲはフーリエ変換型ＮＭＲで測定した。１Ｈ　ＮＭＲの解析にはＡＣＤ／ＳｐｅｃＭａｎａｇｅｒ（商品名）ソフトウエアなどを用いた。水酸基やアミノ基などのプロトンピークが非常に緩やかなピークについては記載していないことがある。 Unless otherwise specified, the elution in the column chromatography of the example was carried out under observation by TLC (Thin Layer Chromatography, thin layer chromatography). In the TLC observation, 60 F 254 manufactured by Merck Group was used as the TLC plate, and the solvent used as the elution solvent in the column chromatography was used as the developing solvent. In addition, a UV detector was used for detection. In silica gel column chromatography, aminopropylsilane-bonded silica gel was used when it was described as NH, and 3- (2,3-dihydroxypropoxy) propylsilane-bonded silica gel was used when it was described as Diol. In preparative HPLC (high performance liquid chromatography), when described as C18, octadecyl-bonded silica gel was used. The ratio shown in the elution solvent indicates the volume ratio unless otherwise specified. The temperature in the reaction operation and the processing operation described in the reference example and the example includes a variation in the range of ± 5 ° C.
1 1 H NMR was measured by Fourier transform type NMR. 1 ACD / SpecManager (trade name) software or the like was used for the 1 H NMR analysis. Peaks with very gentle proton peaks such as hydroxyl groups and amino groups may not be described.
　以下の実施例においては下記の略号を使用する。
M：モル濃度
N：規定度
HPLC：high performance liquid chromatography The following abbreviations are used in the following examples.
M: Molarity
N: Equivalent concentration
HPLC: high performance liquid chromatography
参考例１
ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－３－［（メチルスルホニル）アミノ］－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－１－カルボキシラート（化合物ｂ２）
　１，２－ジメトキシエタン２５ｍｌに、２５℃で、ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－２－（３－ブロモ－２－フルオロベンジル）－３－［（メチルスルホニル）アミノ］ピロリジン－１－カルボキシラート（化合物Ｙ）の結晶５ｇ、Ｎ，Ｎ－ジイソプロピルエチルアミン２．１５ｇ、（３，５－ジフルオロフェニル）ボロン酸２．１ｇを添加した。ここにＰｄ（ｍ－Ｃｒｏｐｈｏｓ）Ｃｌ２（ＮＥＣＯ－２９６、ＮＥケムキャット社製）１３４．５ｍｇを添加して、反応容器内を窒素置換したのち、４５℃で別途調整した脱気水３．０ｍｌを添加し、４５℃で窒素ガスフロー下で滴下した。得られた混合液を７８℃で７時間以上攪拌したのち、５０℃で酢酸エチル５５ｍｌ、水３０ｍｌを添加しここに２５℃で１０％アンモニア水２５ｍｌを滴下し、１０分以上攪拌した。この混合物を３５℃で静置し、水層を分液して残った有機層にエチレンジアミン２．５０ｇ、Ｅｃｏｓｏｒｂ　Ｃ－９４７（富士フイルム和光純薬社製、活性炭）２．５０ｇを添加し、２時間以上攪拌した。攪拌液をろ過し、不溶物を酢酸エチル１５ｍｌで洗浄した。２５℃で有機層にエチレンジアミンとＥｃｏｓｏｒｂ　Ｃ－９４７を加え、前記と同様にして、２時間以上攪拌後、ろ過し、不溶物を酢酸エチルで洗浄した。２５℃で、ろ液にエタノール５０ｍｌを添加し、外温６０℃以下で約７５ｍｌになるまで減圧濃縮した。続いて、４０℃以下で攪拌しながらエタノール５０ｍｌを添加し、外温６０℃以下で約７５ｍｌになるまで減圧濃縮する工程を２回繰り返した。得られた濃縮液に、４０℃以下で１Ｍ　水酸化ナトリウム溶液２５ｍｌを添加し、６５℃で６時間以上攪拌した。攪拌液に、２５℃でエタノール溶液２５ｍｌを添加し、さらに６Ｍ塩酸を滴下してｐＨ７．０（ｐＨ６．０～８．０の範囲の変動を含む）になるように調整した。この混合液を６５℃に加温し、３０分以上攪拌し、ｐＨ調整の過程で生じてきた結晶をほぼ溶解させた。ここに、水を６３ｍｌ滴下し、３０分以上攪拌した。その後２５℃での攪拌を１時間以上行ない、結晶を析出させた。析出した結晶を分離し、エタノール／水（１：１）混合液２５ｍｌで洗浄した。これを外温４０℃で減圧乾燥し、標題の化合物ｂ２の結晶４．７０ｇを得た。
（化合物ＮＭＲデータ）
1H NMR (300 MHz, DMSO-d6) δ 0.96 （9H, s), 1.91-2.05 (1H, m), 2.14-2.22 (1H, m), 2.44-2.50 (1H, m), 2.97-3.03 (1H, m), 3.01 (3H, s), 3.27-3.35 (2H, m), 3.85-3.95 (1H, m), 4.10-4.16 (1H, m), 7.20-7.33 (5H, m), 7.45-7.50 (1H, m), 7.59-7.61 (1H, m). Reference example 1
tert-butyl (2S, 3S) -3-[(methylsulfonyl) amino] -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-1-carboxylate (Compound b2) )
Tert-Butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3-[(methylsulfonyl) amino] pyrrolidine-1-carboxylate in 25 ml of 1,2-dimethoxyethane at 25 ° C. 5 g of crystals of (Compound Y), 2.15 g of N, N-diisopropylethylamine, and 2.1 g of (3,5-difluorophenyl) boronic acid were added. To this, 134.5 mg of Pd (m-Crophos) Cl 2 (NECO-296, manufactured by NE Chemcat) was added, the inside of the reaction vessel was replaced with nitrogen, and then 3.0 ml of degassed water separately adjusted at 45 ° C. was added. It was added and added dropwise at 45 ° C. under a nitrogen gas flow. The obtained mixed solution was stirred at 78 ° C. for 7 hours or more, 55 ml of ethyl acetate and 30 ml of water were added at 50 ° C., 25 ml of 10% ammonia water was added dropwise at 25 ° C., and the mixture was stirred for 10 minutes or more. This mixture was allowed to stand at 35 ° C., and 2.50 g of ethylenediamine and 2.50 g of Ecosorb C-947 (activated carbon manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were added to the remaining organic layer after separating the aqueous layer, and 2 Stirred for more than an hour. The stirrer was filtered and the insoluble material was washed with 15 ml of ethyl acetate. Ethylenediamine and Ecosorb C-947 were added to the organic layer at 25 ° C., and the mixture was stirred for 2 hours or more in the same manner as described above, filtered, and the insoluble matter was washed with ethyl acetate. At 25 ° C., 50 ml of ethanol was added to the filtrate, and the mixture was concentrated under reduced pressure to about 75 ml at an outside temperature of 60 ° C. or lower. Subsequently, 50 ml of ethanol was added with stirring at 40 ° C. or lower, and the step of concentrating under reduced pressure to about 75 ml at an external temperature of 60 ° C. or lower was repeated twice. To the obtained concentrate, 25 ml of 1 M sodium hydroxide solution was added at 40 ° C. or lower, and the mixture was stirred at 65 ° C. for 6 hours or longer. To the stirring solution, 25 ml of an ethanol solution was added at 25 ° C., and 6M hydrochloric acid was further added dropwise to adjust the pH to 7.0 (including fluctuations in the range of pH 6.0 to 8.0). This mixed solution was heated to 65 ° C. and stirred for 30 minutes or more to substantially dissolve the crystals generated in the process of pH adjustment. 63 ml of water was added dropwise thereto, and the mixture was stirred for 30 minutes or longer. After that, stirring at 25 ° C. was carried out for 1 hour or more to precipitate crystals. The precipitated crystals were separated and washed with 25 ml of an ethanol / water (1: 1) mixture. This was dried under reduced pressure at an outside temperature of 40 ° C. to obtain 4.70 g of crystals of the title compound b2.
(Compound NMR data)
1 1 H NMR (300 MHz, DMSO-d 6 ) δ 0.96 (9H, s), 1.91-2.05 (1H, m), 2.14-2.22 (1H, m), 2.44-2.50 (1H, m), 2.97-3.03 (1H, m), 3.01 (3H, s), 3.27-3.35 (2H, m), 3.85-3.95 (1H, m), 4.10-4.16 (1H, m), 7.20-7.33 (5H, m), 7.45 -7.50 (1H, m), 7.59-7.61 (1H, m).
（ＨＰＬＣ分析条件）
カラム：ＩｎｅｒｔＳｕｓｔａｉｎＳｗｉｆｔ　Ｃ８　ＨＰシリーズ（ジーエルサイエンス株式会社製、型番５０２０－８８５２５）、カラムサイズ４．６ｘ１５０ｍｍ、粒子径３μｍ
カラム温度：２５℃付近の一定温度
移動相：Ａ液）０．１％リン酸水素水溶液
　　　　Ｂ液）ＭｅＣＮ
グラジエントプログラム (HPLC analysis conditions)
Column: InertSsteinSwift C8 HP series (manufactured by GL Sciences Co., Ltd., model number 5020-88525), column size 4.6x150 mm, particle size 3 μm
Column temperature: Constant temperature around 25 ° C Mobile phase: Liquid A) 0.1% aqueous hydrogen phosphate solution Liquid B) MeCN
Gradient program
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
流量：１．０ｍｌ／ｍｉｎ
保持時間：化合物ｂ２　約１４分、化合物Ｙ　約１０分 Flow rate: 1.0 ml / min
Retention time: Compound b2 approx. 14 minutes, Compound Y approx. 10 minutes
参考例１－２
ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－３－［（メチルスルホニル）アミノ］－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－１－カルボキシラート（化合物ｂ２）
　１，２－ジメトキシエタン２２５ｍｌ、水１３５ｍｌ、水酸化ナトリウム３．９９ｇに、２５℃で、ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－２－（３－ブロモ－２－フルオロベンジル）－３－［（メチルスルホニル）アミノ］ピロリジン－１－カルボキシラート（化合物Ｙ）の結晶３０ｇ、（３，５－ジフルオロフェニル）ボロン酸１２．６ｇを添加した。ここに１０％Ｐｄカーボン粉末（ＰＥ－ＴＹＰＥ、Ｎ．Ｅ．ＣＨＥＭＣＡＴ製）１７９．３ｍｇ、ＸＰｈｏｓ６３．４ｍｇを添加して、反応容器内を窒素置換したのち、得られた混合液を７８℃で３時間以上攪拌し、５０℃で酢酸エチル３３０ｍｌ、水２７０ｍｌを添加し２５℃で、不溶物を濾別し酢酸エチル６０ｍｌ、続いて水６０ｍｌで洗浄した。２５℃でろ過液にＮ－アセチルシステイン５．４２ｇ、ＮａＣｌ１９．５ｇを添加し、２５℃で３０分以上攪拌後、分液した。有機層に２５℃でエタノール３００ｍｌを添加し、外温６０℃以下で約４５０ｍｌになるまで減圧濃縮した。続いて、４０℃以下で攪拌しながらエタノール３００ｍｌを添加し、外温６０℃以下で約４５０ｍｌになるまで減圧濃縮する工程を２回繰り返した。得られた濃縮液に、４０℃以下でエタノール１５０ｍｌを添加し６５℃に加温して３０分以上攪拌し、ここに、水を６００ｍｌ滴下し、３０分以上攪拌した。その後２５℃での攪拌を１時間以上行ない、結晶を析出させた。析出した結晶を分離し、エタノール／水（１：１）混合液１５０ｍｌで洗浄した。これを外温６０℃で減圧乾燥し、標題の化合物ｂ２の結晶３１．４０ｇを得た。
（化合物ＮＭＲデータ）
1H NMR (300 MHz, DMSO-d6) δ 0.96 （9H, s), 1.91-2.05 (1H, m), 2.14-2.22 (1H, m), 2.44-2.50 (1H, m), 2.97-3.03 (1H, m), 3.01 (3H, s), 3.27-3.35 (2H, m), 3.85-3.95 (1H, m), 4.10-4.16 (1H, m), 7.20-7.33 (5H, m), 7.45-7.50 (1H, m), 7.59-7.61 (1H, m). Reference example 1-2
tert-butyl (2S, 3S) -3-[(methylsulfonyl) amino] -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-1-carboxylate (Compound b2) )
Tert-Butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3-[(methyl) in 225 ml of 1,2-dimethoxyethane, 135 ml of water, and 3.99 g of sodium hydroxide at 25 ° C. 30 g of crystals of sulfonyl) amino] pyrrolidine-1-carboxylate (Compound Y) and 12.6 g of (3,5-difluorophenyl) boronic acid were added. 179.3 mg of 10% Pd carbon powder (PE-TYPE, manufactured by NE CHEMCAT) and 63.4 mg of XPhos were added thereto to replace the inside of the reaction vessel with nitrogen, and then the obtained mixed solution was prepared at 78 ° C. for 3 After stirring for more than an hour, 330 ml of ethyl acetate and 270 ml of water were added at 50 ° C., and the insoluble material was filtered off at 25 ° C. and washed with 60 ml of ethyl acetate and then 60 ml of water. 5.42 g of N-acetylcysteine and 19.5 g of NaCl were added to the filtrate at 25 ° C., and the mixture was stirred at 25 ° C. for 30 minutes or more and then separated. 300 ml of ethanol was added to the organic layer at 25 ° C., and the mixture was concentrated under reduced pressure to about 450 ml at an outside temperature of 60 ° C. or lower. Subsequently, 300 ml of ethanol was added with stirring at 40 ° C. or lower, and the step of concentrating under reduced pressure to about 450 ml at an outside temperature of 60 ° C. or lower was repeated twice. To the obtained concentrate, 150 ml of ethanol was added at 40 ° C. or lower, the mixture was heated to 65 ° C. and stirred for 30 minutes or longer, and 600 ml of water was added dropwise thereto and the mixture was stirred for 30 minutes or longer. After that, stirring at 25 ° C. was carried out for 1 hour or more to precipitate crystals. The precipitated crystals were separated and washed with 150 ml of an ethanol / water (1: 1) mixture. This was dried under reduced pressure at an outside temperature of 60 ° C. to obtain 31.40 g of crystals of the title compound b2.
(Compound NMR data)
1 1 H NMR (300 MHz, DMSO-d 6 ) δ 0.96 (9H, s), 1.91-2.05 (1H, m), 2.14-2.22 (1H, m), 2.44-2.50 (1H, m), 2.97-3.03 (1H, m), 3.01 (3H, s), 3.27-3.35 (2H, m), 3.85-3.95 (1H, m), 4.10-4.16 (1H, m), 7.20-7.33 (5H, m), 7.45 -7.50 (1H, m), 7.59-7.61 (1H, m).
（ＨＰＬＣ分析条件）
カラム：Ｌ－ｃｏｌｕｍｎ２　ＯＤＳ（ＣＥＲＩ，Ｊａｐａｎ)、カラムサイズ４．６ｘ１００ｍｍ、粒子径３μｍ
カラム温度：２５℃付近の一定温度
移動相：Ａ液）０．１％リン酸水素水溶液
　　　　Ｂ液）ＭｅＣＮ
グラジエントプログラム (HPLC analysis conditions)
Column: L-column2 ODS (CERI, Japan), column size 4.6x100 mm, particle size 3 μm
Column temperature: Constant temperature around 25 ° C Mobile phase: Liquid A) 0.1% aqueous hydrogen phosphate solution Liquid B) MeCN
Gradient program
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
流量：１．０ｍｌ／ｍｉｎ
保持時間：化合物ｂ２　約１０分、化合物Ｙ　約９分 Flow rate: 1.0 ml / min
Retention time: Compound b2 approx. 10 minutes, Compound Y approx. 9 minutes
参考例２
Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミド　塩酸塩（化合物ｂ１）
　化合物ｂ２の結晶２．９０ｇにエタノール３２ｍｌを添加し、２５℃で攪拌しながら４Ｍ塩化水素／酢酸エチル溶液４．６ｍｌを滴下した。この混合液を徐々に５０℃まで昇温し、４時間以上攪拌したのち、ｎ－ヘプタン４８ｍｌを滴下した。徐々に５℃まで冷却したのち、２時間以上攪拌した。析出した結晶を分離し、エタノール／ｎ－ヘプタン（１：２）の混合液８．６ｍｌで洗浄した。これを外温５０℃で減圧乾燥し、表題の化合物ｂ１の結晶２．３０ｇを得た。
（化合物ＮＭＲデータ）
1H NMR (300 MHz, DMSO-d6) δ 2.00-2.10 (1H, m), 2.25-2.38 (1H, m), 3.01 (3H, s), 3.09-3.24 (3H, m), 3.37-3.47 (1H, m), 3.83-3.89 (1H, m), 4.11-4.19 (1H, m), 7.27-7.36 (4H, m), 7.49-7.60 (3H, m), 9.38 (2H, brs). Reference example 2
N-{(2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} methanesulfonamide hydrochloride (Compound b1)
32 ml of ethanol was added to 2.90 g of the crystal of compound b2, and 4.6 ml of a 4M hydrogen chloride / ethyl acetate solution was added dropwise with stirring at 25 ° C. The temperature of this mixed solution was gradually raised to 50 ° C., the mixture was stirred for 4 hours or more, and then 48 ml of n-heptane was added dropwise. After gradually cooling to 5 ° C., the mixture was stirred for 2 hours or more. The precipitated crystals were separated and washed with 8.6 ml of a mixed solution of ethanol / n-heptane (1: 2). This was dried under reduced pressure at an outside temperature of 50 ° C. to obtain 2.30 g of the title compound b1 crystal.
(Compound NMR data)
1 1 H NMR (300 MHz, DMSO-d 6 ) δ 2.00-2.10 (1H, m), 2.25-2.38 (1H, m), 3.01 (3H, s), 3.09-3.24 (3H, m), 3.37-3.47 (1H, m), 3.83-3.89 (1H, m), 4.11-4.19 (1H, m), 7.27-7.36 (4H, m), 7.49-7.60 (3H, m), 9.38 (2H, brs).
（ＨＰＬＣ分析条件）
カラム：ＩｎｅｒｔＳｕｓｔａｉｎＳｗｉｆｔ　Ｃ８　ＨＰシリーズ（ジーエルサイエンス株式会社製、型番５０２０－８８５２５）、カラムサイズ４．６ｘ１５０ｍｍ、粒子径３μｍ
カラム温度：２５℃付近の一定温度
移動相：Ａ液）　０．１％リン酸水素水溶液
　　　　Ｂ液）　ＭｅＣＮ
グラジエントプログラム (HPLC analysis conditions)
Column: InertSsteinSwift C8 HP series (manufactured by GL Sciences Co., Ltd., model number 5020-88525), column size 4.6x150 mm, particle size 3 μm
Column temperature: Constant temperature mobile phase around 25 ° C: Liquid A) 0.1% aqueous hydrogen phosphate solution Liquid B) MeCN
Gradient program
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
流量：１．０ｍｌ／ｍｉｎ
保持時間：化合物ｂ１　約６分、化合物ｂ２　約１４分 Flow rate: 1.0 ml / min
Retention time: Compound b1 about 6 minutes, Compound b2 about 14 minutes
参考例２－１
Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミド　塩酸塩（化合物ｂ１）
　化合物ｂ２の結晶５．００ｇに２－プロパノール５５ｍｌを添加し、２５℃で攪拌しながら５－６Ｍ塩化水素／２－プロパノール溶液６．２ｍｌを滴下した。この混合液を徐々に７０℃まで昇温し、２時間以上攪拌したのち、ｎ－ヘプタン８２．５ｍｌを滴下した。徐々に５℃まで冷却したのち、２時間以上攪拌した。析出した結晶を分離し、２－プロパノール／ｎ－ヘプタン（１：２）の混合液１５ｍｌで洗浄した。これを外温５０℃で減圧乾燥し、表題の化合物ｂ１の結晶４．１５ｇを得た。
（化合物ＮＭＲデータ）
1H NMR (300 MHz, DMSO-d6) δ 2.00-2.10 (1H, m), 2.25-2.38 (1H, m), 3.01 (3H, s), 3.09-3.24 (3H, m), 3.37-3.47 (1H, m), 3.83-3.89 (1H, m), 4.11-4.19 (1H, m), 7.27-7.36 (4H, m), 7.49-7.60 (3H, m), 9.38 (2H, brs). Reference example 2-1
N-{(2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} methanesulfonamide hydrochloride (Compound b1)
55 ml of 2-propanol was added to 5.00 g of crystals of compound b2, and 6.2 ml of a 5-6 M hydrogen chloride / 2-propanol solution was added dropwise with stirring at 25 ° C. The temperature of this mixed solution was gradually raised to 70 ° C., the mixture was stirred for 2 hours or more, and then 82.5 ml of n-heptane was added dropwise. After gradually cooling to 5 ° C., the mixture was stirred for 2 hours or more. The precipitated crystals were separated and washed with 15 ml of a mixed solution of 2-propanol / n-heptane (1: 2). This was dried under reduced pressure at an outside temperature of 50 ° C. to obtain 4.15 g of the title compound b1 crystal.
(Compound NMR data)
1 1 H NMR (300 MHz, DMSO-d 6 ) δ 2.00-2.10 (1H, m), 2.25-2.38 (1H, m), 3.01 (3H, s), 3.09-3.24 (3H, m), 3.37-3.47 (1H, m), 3.83-3.89 (1H, m), 4.11-4.19 (1H, m), 7.27-7.36 (4H, m), 7.49-7.60 (3H, m), 9.38 (2H, brs).
（ＨＰＬＣ分析条件）
カラム：Ｌ－ｃｏｌｕｍｎ２　ＯＤＳ（ＣＥＲＩ，Ｊａｐａｎ)、カラムサイズ４．６ｘ１００ｍｍ、粒子径３μｍ
カラム温度：２５℃付近の一定温度
移動相：Ａ液）０．１％リン酸水素水溶液
　　　　Ｂ液）ＭｅＣＮ
グラジエントプログラム (HPLC analysis conditions)
Column: L-column2 ODS (CERI, Japan), column size 4.6x100 mm, particle size 3 μm
Column temperature: Constant temperature around 25 ° C Mobile phase: Liquid A) 0.1% aqueous hydrogen phosphate solution Liquid B) MeCN
Gradient program
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
流量：１．０ｍｌ／ｍｉｎ
保持時間：化合物ｂ１　約５分、化合物ｂ２　約１０分 Flow rate: 1.0 ml / min
Retention time: Compound b1 about 5 minutes, Compound b2 about 10 minutes
（ＨＰＬＣ分析条件）
カラム：ＹＭＣ―Ｐａｃｋ　Ｐｒｏ　Ｃｌ８　ＲＳ（ＹＭＣ，Ｊａｐａｎ)、カラムサイズ４．６ｘ２５０ｍｍ、粒子径５μｍ
カラム温度：２５℃付近の一定温度
移動相：Ａ液）０．１％リン酸水素水溶液
　　　　Ｂ液）ＭｅＣＮ
グラジエントプログラム (HPLC analysis conditions)
Column: YMC-Pack Pro Cl8 RS (YMC, Japan), column size 4.6x250 mm, particle size 5 μm
Column temperature: Constant temperature around 25 ° C Mobile phase: Liquid A) 0.1% aqueous hydrogen phosphate solution Liquid B) MeCN
Gradient program
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
流量：１．０ｍｌ／ｍｉｎ
保持時間：化合物ｂ１　約１７分 Flow rate: 1.0 ml / min
Retention time: Compound b1 Approximately 17 minutes
参考例３
Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミド　塩酸塩（化合物ａ１）
　エタノール１４６ｋｇに水１８５ｋｇとｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－３－［（エチルスルホニル）アミノ］－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］ピロリジン－１－カルボキシラート（化合物ａ２）の結晶６１．５７ｋｇを添加し、さらに５９～６２℃で攪拌しながら水５０．７ｋｇと塩酸６６．７ｋｇの混合液を滴下した。同温度で４時間攪拌したのち、５６～５９℃で水２６３ｋｇを滴下して１時間撹拌した。徐々に２０～３０℃まで冷却したのち、１時間攪拌した。析出した結晶を分離し、エタノール１６．１ｋｇと水１０３ｋｇの混合液で洗浄した。これを外温６０℃で減圧乾燥し、表題の化合物ａ１の結晶４９．１８ｋｇを得た。
（化合物ＮＭＲデータ）
1H NMR (400MHz, DMSO-d6) δ 1.19-1.28 (3H,m), 1.91-2.08 (1H,m), 2.25-2.38 (1H,m), 3.01-3.16 (4H,m), 3.17-3.26 (1H,m), 3.36-3.50 (1H,m), 3.77-3.93 (1H,m), 4.08-4.21 (1H,m), 7.22-7.34 (2H,m), 7.42 (2H,d,J=7.3Hz), 7.46-7.59 (4H,m), 8.51-9.61 (2H,m). Reference example 3
N-{(2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} ethanesulfonamide hydrochloride (Compound a1)
146 kg of ethanol, 185 kg of water and tert-butyl (2S, 3S) -3-[(ethylsulfonyl) amino] -2-[(2,3'-difluorobiphenyl-3-yl) methyl] pyrrolidine-1-carboxylate ( 61.57 kg of crystals of compound a2) were added, and a mixed solution of 50.7 kg of water and 66.7 kg of hydrochloric acid was added dropwise with stirring at 59 to 62 ° C. After stirring at the same temperature for 4 hours, 263 kg of water was added dropwise at 56 to 59 ° C. and the mixture was stirred for 1 hour. After gradually cooling to 20 to 30 ° C., the mixture was stirred for 1 hour. The precipitated crystals were separated and washed with a mixed solution of 16.1 kg of ethanol and 103 kg of water. This was dried under reduced pressure at an outside temperature of 60 ° C. to obtain 49.18 kg of crystals of the title compound a1.
(Compound NMR data)
1 1 H NMR (400MHz, DMSO-d 6 ) δ 1.19-1.28 (3H, m), 1.91-2.08 (1H, m), 2.25-2.38 (1H, m), 3.01-3.16 (4H, m), 3.17- 3.26 (1H, m), 3.36-3.50 (1H, m), 3.77-3.93 (1H, m), 4.08-4.21 (1H, m), 7.22-7.34 (2H, m), 7.42 (2H, d, J) = 7.3Hz), 7.46-7.59 (4H, m), 8.51-9.61 (2H, m).
（ＨＰＬＣ分析条件）
カラム：ＩｎｅｒｔＳｕｓｔａｉｎＳｗｉｆｔ　Ｃ８　ＨＰシリーズ（ジーエルサイエンス株式会社）、カラムサイズ４．６ｘ１５０ｍｍ、粒子径３μｍ
カラム温度：２５℃付近の一定温度
移動相：Ａ液）０．０２ｍｏｌ／Ｌリン酸水素二カリウムバッファー（ｐＨ７．０）：ＭｅＣＮ＝７：３
　　　　Ｂ液）ＭｅＣＮ：０．０１ｍｏｌ／Ｌリン酸水素二カリウムバッファー（ｐＨ７．０）＝３：７
グラジエントプログラム (HPLC analysis conditions)
Column: InertSsteinSwift C8 HP series (GL Sciences Co., Ltd.), column size 4.6x150 mm, particle size 3 μm
Column temperature: Constant temperature around 25 ° C. Mobile phase: Liquid A) 0.02 mol / L Dipotassium hydrogen phosphate buffer (pH 7.0): MeCN = 7: 3
Liquid B) MeCN: 0.01 mol / L Dipotassium hydrogen phosphate buffer (pH 7.0) = 3: 7
Gradient program
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
流量：１．０ｍｌ／ｍｉｎ
保持時間：化合物ａ１　約８分 Flow rate: 1.0 ml / min
Retention time: Compound a1 Approximately 8 minutes
参考例４
Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミド　塩酸塩（化合物ｃ１）
　ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－３－［（エチルスルホニル）アミノ］－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－１－カルボキシラート（化合物ｃ２）の結晶０．６６３ｇにエタノール７．３ｍｌを添加し、２５℃で攪拌しながら４Ｍ塩化水素／酢酸エチル溶液１．０ｍｌを滴下した。この混合液を徐々に５０℃まで昇温し、４時間以上攪拌したのち、ｎ－ヘプタン１１ｍｌを滴下した。徐々に５℃まで冷却したのち、１時間攪拌した。析出した結晶を分離し、エタノールとｎ－ヘプタンの容量比１：２混合液を少量使用して洗浄した。これを外温５０℃で減圧乾燥し、表題の化合物ｃ１の結晶０．５６０ｇを得た。
（化合物ＮＭＲデータ）
1H NMR (300MHz, DMSO-d6) δ 1.18-1.27 (3H,m), 1.93-2.06 (1H,m), 2.24-2.39 (1H, m), 3.04-3.26 (5H,m), 3.35-3.50 (1H,m), 3.78-3.92 (1H,m), 4.14 (1H,dtd,J=8.8,6.0,3.0Hz), 7.26-7.39 (4H,m), 7.48-7.60 (3H,m), 9.04 (1H,brs), 9.45(1H,brs). Reference example 4
N-{(2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} ethanesulfonamide hydrochloride (Compound c1)
tert-butyl (2S, 3S) -3-[(ethylsulfonyl) amino] -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-1-carboxylate (compound c2) 7.3 ml of ethanol was added to 0.663 g of the crystals of), and 1.0 ml of a 4M hydrogen chloride / ethyl acetate solution was added dropwise at 25 ° C. with stirring. The temperature of this mixed solution was gradually raised to 50 ° C., the mixture was stirred for 4 hours or more, and then 11 ml of n-heptane was added dropwise. After gradually cooling to 5 ° C., the mixture was stirred for 1 hour. The precipitated crystals were separated and washed with a small amount of a 1: 2 volume ratio mixture of ethanol and n-heptane. This was dried under reduced pressure at an outside temperature of 50 ° C. to obtain 0.560 g of crystals of the title compound c1.
(Compound NMR data)
1 1 H NMR (300MHz, DMSO-d 6 ) δ 1.18-1.27 (3H, m), 1.93-2.06 (1H, m), 2.24-2.39 (1H, m), 3.04-3.26 (5H, m), 3.35- 3.50 (1H, m), 3.78-3.92 (1H, m), 4.14 (1H, dtd, J = 8.8,6.0,3.0Hz), 7.26-7.39 (4H, m), 7.48-7.60 (3H, m), 9.04 (1H, brs), 9.45 (1H, brs).
（ＨＰＬＣ分析条件）
カラム：ＩｎｅｒｔＳｕｓｔａｉｎＳｗｉｆｔ　Ｃ８　ＨＰシリーズ（ジーエルサイエンス株式会社）、カラムサイズ４．６ｘ１５０ｍｍ、粒子径３μｍ
カラム温度：２５℃付近の一定温度
移動相：Ａ液）０．１％リン酸水溶液
　　　　Ｂ液）ＭｅＣＮ
グラジエントプログラム (HPLC analysis conditions)
Column: InertSsteinSwift C8 HP series (GL Sciences Co., Ltd.), column size 4.6x150 mm, particle size 3 μm
Column temperature: Constant temperature around 25 ° C Mobile phase: Liquid A) 0.1% aqueous phosphoric acid solution Liquid B) MeCN
Gradient program
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
流量：１．０ｍｌ／ｍｉｎ
保持時間：化合物ｃ１　約６分 Flow rate: 1.0 ml / min
Retention time: Compound c1 Approximately 6 minutes
参考例５
ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－３－［（エチルスルホニル）アミノ］－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－１－カルボキシラート（化合物ｃ２）
　１，２－ジメトキシエタン４ｍｌに、２５℃で、ｔｅｒｔ－ブチル　（２Ｓ，３Ｓ）－２－（３－ブロモ－２－フルオロベンジル）－３－［（エチルスルホニル）アミノ］ピロリジン－１－カルボキシラート（化合物Ｘ）の結晶０．７４５ｇ、Ｎ，Ｎ－ジイソプロピルエチルアミン０．３１ｇ、（３，５－ジフルオロフェニル）ボロン酸０．３０３ｇを添加した。ここにＰｄ（ｍ－Ｃｒｏｐｈｏｓ）Ｃｌ２（ＮＥＣＯ－２９６、ＮＥケムキャット社製）１９．４ｍｇを添加して、反応容器内を窒素置換したのち、別途調整した脱気水０．５ｍｌを４５℃で窒素ガスフロー下で滴下した。得られた混合液を７３℃で１０時間以上攪拌したのち、室温で酢酸エチル８．２ｍｌ、水４．５ｍｌ、１０％アンモニア水３．７ｍｌを添加した。分液して残った有機層にエチレンジアミン０．１８ｇ、Ｅｃｏｓｏｒｂ　Ｃ－９４７（富士フィルム和光純薬社製、活性炭）０．１８ｇを添加し、２時間以上攪拌した。攪拌液をろ過し、不溶物を酢酸エチル２．２ｍｌで洗浄してろ液と合わせた。約３．７ｍｌ以下になるまで減圧濃縮し、エタノール７．４ｍｌを添加する工程を３回繰り返した。約５．２ｍｌになるまで減圧濃縮し、撹拌しながら水１．１ｍｌを滴下したところ結晶化し、そのまま３０分間撹拌してスラリー溶液となった。室温で撹拌しながら水５．０ｍｌを滴下し、そのまま1時間撹拌したうえで結晶を分離し、エタノール／水（１：３）混合液３．７ｍｌで洗浄した。これを外温５０℃で減圧乾燥し、標題の化合物ｃ２の結晶０．７１２ｇを得た。
（化合物ＮＭＲデータ）
1H NMR (300MHz, CDCl3) δ 1.11-1.48 (12H,m), 1.69-1.89 (1H,m), 2.19-2.37(1H,m), 2.58-3.14 (4H,m), 3.36 (2H,brs), 3.92-4.07 (1H,m), 4.27-4.39 (1H,m), 4.48 (1H,dd,J=9.1,2.6Hz), 6.82 (1H,tt,J=8.9,2.3 Hz), 7.00-7.11 (2H,m), 7.13-7.20 (1H,m), 7.21-7.33 (2H,m). Reference example 5
tert-butyl (2S, 3S) -3-[(ethylsulfonyl) amino] -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-1-carboxylate (compound c2) )
Tert-Butyl (2S, 3S) -2- (3-bromo-2-fluorobenzyl) -3-[(ethylsulfonyl) amino] pyrrolidine-1-carboxylate in 4 ml of 1,2-dimethoxyethane at 25 ° C. 0.745 g of crystals of (Compound X), 0.31 g of N, N-diisopropylethylamine, and 0.303 g of (3,5-difluorophenyl) boronic acid were added. To this, 19.4 mg of Pd (m-Crophos) Cl 2 (NECO-296, manufactured by NE Chemcat) was added, the inside of the reaction vessel was replaced with nitrogen, and then 0.5 ml of separately adjusted degassed water was added at 45 ° C. It was added dropwise under a nitrogen gas flow. The obtained mixed solution was stirred at 73 ° C. for 10 hours or more, and then 8.2 ml of ethyl acetate, 4.5 ml of water and 3.7 ml of 10% aqueous ammonia were added at room temperature. 0.18 g of ethylenediamine and 0.18 g of Ecosorb C-947 (activated carbon manufactured by Fuji Film Wako Pure Chemical Industries, Ltd.) were added to the organic layer remaining after the liquid separation, and the mixture was stirred for 2 hours or more. The stirrer was filtered and the insoluble material was washed with 2.2 ml of ethyl acetate and combined with the filtrate. The step of concentrating under reduced pressure until the amount became about 3.7 ml or less and adding 7.4 ml of ethanol was repeated 3 times. The mixture was concentrated under reduced pressure until it reached about 5.2 ml, and 1.1 ml of water was added dropwise with stirring to crystallize the mixture, and the mixture was stirred as it was for 30 minutes to obtain a slurry solution. 5.0 ml of water was added dropwise with stirring at room temperature, and the crystals were separated after stirring for 1 hour as it was, and washed with 3.7 ml of an ethanol / water (1: 3) mixture. This was dried under reduced pressure at an outside temperature of 50 ° C. to obtain 0.712 g of crystals of the title compound c2.
(Compound NMR data)
1 1 H NMR (300MHz, CDCl 3 ) δ 1.11-1.48 (12H, m), 1.69-1.89 (1H, m), 2.19-2.37 (1H, m), 2.58-3.14 (4H, m), 3.36 (2H, brs), 3.92-4.07 (1H, m), 4.27-4.39 (1H, m), 4.48 (1H, dd, J = 9.1, 2.6Hz), 6.82 (1H, tt, J = 8.9, 2.3 Hz), 7.00 -7.11 (2H, m), 7.13-7.20 (1H, m), 7.21-7.33 (2H, m).
（ＨＰＬＣ分析条件）
カラム：ＩｎｅｒｔＳｕｓｔａｉｎＳｗｉｆｔ　Ｃ８　ＨＰシリーズ（ジーエルサイエンス株式会社）、カラムサイズ４．６ｘ１５０ｍｍ、粒子径３μｍ
カラム温度：２５℃付近の一定温度
移動相：Ａ液）０．１％リン酸水溶液
　　　　Ｂ液）ＭｅＣＮ
グラジエントプログラム (HPLC analysis conditions)
Column: InertSsteinSwift C8 HP series (GL Sciences Co., Ltd.), column size 4.6x150 mm, particle size 3 μm
Column temperature: Constant temperature around 25 ° C Mobile phase: Liquid A) 0.1% aqueous phosphoric acid solution Liquid B) MeCN
Gradient program
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
流量：１．０ｍｌ／ｍｉｎ
保持時間：化合物ｃ２　約１６分 Flow rate: 1.0 ml / min
Retention time: Compound c2 Approximately 16 minutes
実施例１
Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］－１－（２－ヒドロキシ－２－メチルプロパノイル）ピロリジン－３－イル｝エタンスルホンアミド（化合物Ａ）
　窒素雰囲気下で、ジメチルアセトアミド３７５ｍｌに化合物ａ１の結晶５０．０ｇを添加した。２０～３０℃で２－ヒドロキシ－２－メチルプロパン酸１３．７ｇを添加し、ジメチルアセトアミド５０ｍｌで洗い込んだ。さらに１－ヒドロキシベンゾトリアゾール水和物２０．２ｇを添加し、ジメチルアセトアミド２５ｍｌで洗い込んだ。さらに１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩４１．４ｇを添加して、ジメチルアセトアミド２５ｍｌで洗い込んだ。この混合液を１９～２５℃で３０分以上攪拌したのち、２０～３０℃でトリエチルアミン３６．４ｇを滴下し、ジメチルアセトアミド２５ｍｌで洗い込んだ。この混合物を２５℃で２時間以上攪拌したものに、２０～３０℃で１０ｖ／ｗ％食塩水４００ｍｌと酢酸エチル７５０ｍｌを添加し分液した。得られた水層から酢酸エチル４００ｍｌで2回再抽出した。合わせた有機層に５ｖ／ｗ％クエン酸水溶液６００ｍｌを加えて分液した。得られた有機層を５ｖ／ｗ％クエン酸水溶液６００ｍｌ、５ｖ／ｗ％炭酸水素ナトリウム水溶液６００ｍｌ、水６００ｍｌで順に洗浄したのち、活性炭白鷺Ａ　２．５ｇを加え、室温で３０分撹拌した。濾過により不溶物を除去し、酢酸エチル１００ｍｌで洗い込んだのちに合わせて１５０ｍｌになるまで減圧濃縮した。この濃縮液にエタノール３５０ｍｌを加えた後、１５０ｍｌになるまで減圧濃縮する操作を２回繰り返した。エタノール ３００ｍｌを加えて、１９～２５℃で水３５０ｍｌを滴下した。この混合物を２～８℃へ冷却し、同温度にて化合物Ａ水和物の種結晶５０ｍｇを添加し約１６時間撹拌した。得られた結晶スラリーに対して２～８℃で水４５０ｍｌを滴下し、同温度にて３時間撹拌した。結晶を分離し、あらかじめ１０℃以下に冷却したエタノールと水の容量比１：２混合液１５０ｍｌで洗浄した。液切りをしたのち外温３５～４５℃で減圧乾燥し、室温、開放系において２１時間静置して化合物Ａ水和物の粗結晶５３．３ｇを得た。
　このようにして得られる化合物Ａ水和物の粗結晶５ｇにエタノール４０ｍｌを添加し溶解液を得た。１９～２５℃で水３５ｍｌを滴下してから２～８℃へ冷却し、化合物Ａ水和物の種結晶５ｍｇを添加し同温度にて４時間撹拌した。得られた結晶スラリー液に対して２～８℃で水４５ｍｌを滴下し、同温度にて２時間撹拌した。あらかじめ１０℃以下に冷却したエタノールと水の容量比１：２混合液１５ｍｌで洗浄した。液切りをしたのち外温３５～４５℃で減圧乾燥し、化合物Ａ水和物の結晶４．５４ｇを得た。
　このようにして得られる化合物Ａ水和物の結晶５ｇに酢酸エチル２５ｍｌを添加し溶解液を得た。溶解液を１０ｍｌになるまで減圧濃縮したのち、濾過して酢酸エチル５ｍｌで洗い込んだ。濾液を２１℃に温度調整したのち、撹拌しながらジイソプロピルエーテル１２．５ｍｌを滴下した。２１℃に温度調整したのち、化合物Ａの種結晶５ｍｇを添加し２．５時間撹拌した。３２℃に温度調整したのち、同温度付近で１時間撹拌した。さらに２１℃まで徐々に冷却したのち、同温度付近で３０分間撹拌した。約２１℃で撹拌しながらジイソプロピルエーテル１７．５ｍｌを滴下し、３０分間撹拌した。約２１℃で撹拌しながらｎ－ヘプタン２０ｍｌを滴下し、１時間撹拌した。結晶を分離し、酢酸エチルとｎ－ヘプタンの容量比１：３混合液１０ｍｌで洗浄した。これを外温６０℃で減圧乾燥し、標題の化合物Ａの結晶４．４９ｇを得た。
（化合物ＮＭＲデータ）
1H NMR (400MHz, CDCl3) δ 1.22 (3H,brt,J=7.2Hz), 1.36-1.46 (6H,m), 1.80-2.03 (1H,m), 2.28-2.43 (1H,m), 2.76-2.91 (2H,m), 2.96 (1H,dd,J=14.5,4.6Hz), 3.13 (1H,dd,J=14.4,7.2Hz), 3.66 (2H,brs), 3.89 (1H,brs), 3.94-4.05 (1H,m), 4.54 (1H,brs), 4.73 (1H,brs), 7.04-7.11 (1H,m), 7.16-7.21 (1H,m), 7.21-7.25 (1H,m), 7.27-7.33 (2H,m), 7.35-7.45 (2H,m). Example 1
N-{(2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] -1- (2-hydroxy-2-methylpropanol) pyrrolidine-3-yl} ethanesulfonamide (Compound A)
Under a nitrogen atmosphere, 50.0 g of crystals of compound a1 were added to 375 ml of dimethylacetamide. At 20-30 ° C., 13.7 g of 2-hydroxy-2-methylpropanoic acid was added and washed with 50 ml of dimethylacetamide. Further, 20.2 g of 1-hydroxybenzotriazole hydrate was added and washed with 25 ml of dimethylacetamide. Further, 41.4 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was washed with 25 ml of dimethylacetamide. After stirring this mixed solution at 19 to 25 ° C. for 30 minutes or more, 36.4 g of triethylamine was added dropwise at 20 to 30 ° C., and the mixture was washed with 25 ml of dimethylacetamide. This mixture was stirred at 25 ° C. for 2 hours or more, and 400 ml of 10 v / w% saline solution and 750 ml of ethyl acetate were added at 20 to 30 ° C. to separate the solutions. The obtained aqueous layer was re-extracted twice with 400 ml of ethyl acetate. 600 ml of a 5 v / w% citric acid aqueous solution was added to the combined organic layers to separate the liquids. The obtained organic layer was washed successively with 600 ml of a 5 v / w% citric acid aqueous solution, 600 ml of a 5 v / w% sodium hydrogen carbonate aqueous solution and 600 ml of water, 2.5 g of activated carbon Shirasagi A was added, and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, washed with 100 ml of ethyl acetate, and then concentrated under reduced pressure to 150 ml. After adding 350 ml of ethanol to this concentrated solution, the operation of concentrating under reduced pressure to 150 ml was repeated twice. 300 ml of ethanol was added, and 350 ml of water was added dropwise at 19-25 ° C. The mixture was cooled to 2-8 ° C., 50 mg of compound A hydrate seed crystals were added at the same temperature, and the mixture was stirred for about 16 hours. 450 ml of water was added dropwise to the obtained crystal slurry at 2 to 8 ° C., and the mixture was stirred at the same temperature for 3 hours. The crystals were separated and washed with 150 ml of a 1: 2 volume ratio mixture of ethanol and water previously cooled to 10 ° C. or lower. After draining the liquid, the mixture was dried under reduced pressure at an outside temperature of 35 to 45 ° C. and allowed to stand at room temperature for 21 hours in an open system to obtain 53.3 g of crude crystals of compound A hydrate.
40 ml of ethanol was added to 5 g of the crude crystals of the compound A hydrate thus obtained to obtain a solution. After dropping 35 ml of water at 19 to 25 ° C., the mixture was cooled to 2 to 8 ° C., 5 mg of a seed crystal of Compound A hydrate was added, and the mixture was stirred at the same temperature for 4 hours. 45 ml of water was added dropwise to the obtained crystalline slurry liquid at 2 to 8 ° C., and the mixture was stirred at the same temperature for 2 hours. The mixture was washed with 15 ml of a 1: 2 volume ratio mixture of ethanol and water previously cooled to 10 ° C. or lower. After draining the liquid, the mixture was dried under reduced pressure at an outside temperature of 35 to 45 ° C. to obtain 4.54 g of crystals of compound A hydrate.
25 ml of ethyl acetate was added to 5 g of crystals of the compound A hydrate thus obtained to obtain a solution. The solution was concentrated under reduced pressure to 10 ml, filtered and washed with 5 ml of ethyl acetate. After adjusting the temperature of the filtrate to 21 ° C., 12.5 ml of diisopropyl ether was added dropwise with stirring. After adjusting the temperature to 21 ° C., 5 mg of a seed crystal of Compound A was added, and the mixture was stirred for 2.5 hours. After adjusting the temperature to 32 ° C., the mixture was stirred at around the same temperature for 1 hour. After gradually cooling to 21 ° C., the mixture was stirred at the same temperature for 30 minutes. 17.5 ml of diisopropyl ether was added dropwise with stirring at about 21 ° C., and the mixture was stirred for 30 minutes. 20 ml of n-heptane was added dropwise with stirring at about 21 ° C., and the mixture was stirred for 1 hour. The crystals were separated and washed with 10 ml of a 1: 3 volume ratio mixture of ethyl acetate and n-heptane. This was dried under reduced pressure at an outside temperature of 60 ° C. to obtain 4.49 g of the title compound A crystal.
(Compound NMR data)
1 1 H NMR (400MHz, CDCl 3 ) δ 1.22 (3H, brt, J = 7.2Hz), 1.36-1.46 (6H, m), 1.80-2.03 (1H, m), 2.28-2.43 (1H, m), 2.76 -2.91 (2H, m), 2.96 (1H, dd, J = 14.5, 4.6Hz), 3.13 (1H, dd, J = 14.4, 7.2Hz), 3.66 (2H, brs), 3.89 (1H, brs), 3.94-4.05 (1H, m), 4.54 (1H, brs), 4.73 (1H, brs), 7.04-7.11 (1H, m), 7.16-7.21 (1H, m), 7.21-7.25 (1H, m), 7.27-7.33 (2H, m), 7.35-7.45 (2H, m).
（ＨＰＬＣ分析条件）
カラム：ＹＭＣ－Ｐａｃｋ　Ｐｒｏ Ｃ１８（株式会社ワイエムシィ）、カラムサイズ４．６ｘ１５０ｍｍ、粒子径５μｍ
カラム温度：２５℃付近の一定温度
移動相：Ａ液）０．０１ｍｏｌ／Ｌリン酸２水素カリウムバッファー（ｐＨ３．０）：ＭｅＣＮ＝７：３
　　　　Ｂ液）ＭｅＣＮ：０．０１ｍｏｌ／Ｌリン酸２水素カリウムバッファー（ｐＨ３．０）＝４：１
グラジエントプログラム (HPLC analysis conditions)
Column: YMC-Pack Pro C18 (YMC Co., Ltd.), column size 4.6x150 mm, particle size 5 μm
Column temperature: Constant temperature mobile phase around 25 ° C.: Liquid A) 0.01 mol / L Potassium dihydrogen phosphate buffer (pH 3.0): MeCN = 7: 3
Liquid B) MeCN: 0.01 mol / L Potassium dihydrogen phosphate buffer (pH 3.0) = 4: 1
Gradient program
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
流量：１．０ｍｌ／ｍｉｎ
保持時間：化合物Ａ　約１７分 Flow rate: 1.0 ml / min
Retention time: Compound A Approximately 17 minutes
実施例２
Ｎ－｛（２Ｓ，３Ｓ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミド（化合物Ｂ）セスキ水和物
　窒素雰囲気下、ジメチルアセトアミド３０ｍｌを添加した。－１０～０℃で２－ヒドロキシ－２－メチルプロパン酸３．０９ｇ、１，１－カルボニルジイミダゾール（ＣＤＩ）４．８２ｇを添加し、ジメチルアセトアミド１．３５ｍｌで洗浄した。続いて－１０～０℃でＮ－ヒドロキシ－５－ノルボルネン－２，３－ジカルボキシイミド４．９０ｇを添加して、ジメチルアセトアミド１．３５ｍｌで洗浄した。減圧脱気操作を２回繰り返した後、混合液に－１０～０℃で化合物ｂ１の結晶５．００ｇを添加し、ジメチルアセトアミド１．３５ｍｌで洗浄した。－１０～０℃でトリエチルアミン４．４５ｇを滴下したのち、ジメチルアセトアミド０．９５ｍｌで洗浄した。この混合物を３０～４０（目標約３７℃）℃で４時間以上攪拌したものに、１５～４５℃で水３５ｍｌを滴下した。１５～４５℃でｐＨが１３．４～１３．８になるまで水酸化ナトリウムを添加した。４０～６０℃で１時間以上撹拌した。２０～４０℃で６規定塩酸を加えてｐＨ７．５～８．５に調整した。６０℃に加温してから水（化合物ｂ１に対して６．５ｖ／ｗ－６規定塩酸量）を滴下した。ここに化合物Ｂセスキ水和物の種結晶２．５ｍｇを添加し、５５～６５℃で１時間以上攪拌した。５５～６５℃で水１０ｍｌを滴下し、混合液を３０分以上かけて徐々に４５～５５℃まで冷却してから１時間以上攪拌し、その後１．５時間以上かけて２０～３０℃まで冷却してから１時間以上攪拌した。析出した結晶を分離し、エタノール１０ｍｌと水３０ｍｌの混合液で２回洗浄して、粗製の化合物Ｂセスキ水和物のｐｒｅ－ｒｅｓｌｕｒｒｙ－ｆｏｒｍを得た。エタノール１２．５ｍｌ、水１２．５ｍｌ、トリエチルアミン０．３０ｇを仕込んだ後に、得られた粗製の化合物Ｂセスキ水和物のｐｒｅ－ｒｅｓｌｕｒｒｙ－ｆｏｒｍを添加した。４０～５０℃で３０分以上撹拌し、４０～５０℃で水２５ｍｌを２０分以上かけて滴下した。続いて４０～５０℃で１時間以上撹拌し、２０～３０℃まで１時間以上かけて冷却し１時間以上撹拌した。エタノール１０ｍｌと水３０ｍｌの混合液で２回洗浄して液切りをしたのち、外温５０℃で減圧乾燥し、化合物Ｂセスキ水和物の粗結晶５．３９ｇを得た。
　このようにして得られた化合物Ｂセスキ水和物の粗結晶５ｇとエタノール４０ｍｌ、精製水５．０ｍｌを反応器に添加し、４０℃で攪拌し溶解液を得た。溶解液を除塵ろ過し、エタノール５．０ｍｌで洗浄した。ろ過液に対して４３～５３℃で精製水４０ｍｌを滴下し、化合物Ｂセスキ水和物の種結晶２．５ｍｇを加えた。晶析を確認してから４８～５３℃で精製水５４ｍｌを２時間以上かけて滴下したのち、４３～５３℃で１時間以上撹拌し、さらに６０～６５℃へ昇温し１時間以上撹拌した。２５℃まで２時間以上かけて冷却し、さらに１時間以上攪拌した。結晶を分離し、エタノール１０ｍｌと精製水３０ｍｌの混合液で洗浄した。これを外温５０℃で減圧乾燥および調湿を行い、標題の化合物Ｂセスキ水和物の結晶４．９０ｇ（純度９９．８％）を得た。
（化合物ＮＭＲデータ）
1H NMR (400 MHz, DMSO-d6) δ 1.04-1.19 (6H, m), 1.90-2.07 (1H, m), 2.11-2.23 (1H, m), 2.59-2.70 (1H, m), 2.85-2.95 (3H, m), 2.95-3.10 (1H, m), 3.69-3.99 (3H, m), 4.50-4.68 (1H, m), 5.00 (1H, s), 7.08-7.18 (1H, m), 7.21-7.51 (6H, m). Example 2
N-{(2S, 3S) -1- (2-Hydroxy-2-methylpropanol) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl } Methanesulfonamide (Compound B) Sesquihydrate 30 ml of dimethylacetamide was added under a nitrogen atmosphere. At −10 to 0 ° C., 3.09 g of 2-hydroxy-2-methylpropanoic acid and 4.82 g of 1,1-carbonyldiimidazole (CDI) were added, and the mixture was washed with 1.35 ml of dimethylacetamide. Subsequently, 4.90 g of N-hydroxy-5-norbornene-2,3-dicarboxyimide was added at −10 to 0 ° C., and the mixture was washed with 1.35 ml of dimethylacetamide. After repeating the degassing operation under reduced pressure twice, 5.00 g of crystals of compound b1 was added to the mixed solution at −10 to 0 ° C., and the mixture was washed with 1.35 ml of dimethylacetamide. After adding 4.45 g of triethylamine at −10 to 0 ° C., the mixture was washed with 0.95 ml of dimethylacetamide. The mixture was stirred at 30-40 ° C. (target about 37 ° C.) for 4 hours or more, and 35 ml of water was added dropwise at 15-45 ° C. Sodium hydroxide was added at 15-45 ° C. until the pH reached 13.4-13.8. The mixture was stirred at 40 to 60 ° C. for 1 hour or longer. The pH was adjusted to 7.5 to 8.5 by adding 6N hydrochloric acid at 20 to 40 ° C. After heating to 60 ° C., water (6.5 v / w-6 specified amount of hydrochloric acid with respect to compound b1) was added dropwise. 2.5 mg of a seed crystal of compound B sesquihydrate was added thereto, and the mixture was stirred at 55 to 65 ° C. for 1 hour or more. 10 ml of water is added dropwise at 55 to 65 ° C., the mixture is gradually cooled to 45 to 55 ° C. over 30 minutes, stirred for 1 hour or longer, and then cooled to 20 to 30 ° C. over 1.5 hours. Then, the mixture was stirred for 1 hour or more. The precipitated crystals were separated and washed twice with a mixed solution of 10 ml of ethanol and 30 ml of water to obtain a pre-resurry-form of crude compound B sesquihydrate. After charging 12.5 ml of ethanol, 12.5 ml of water and 0.30 g of triethylamine, the obtained crude compound B sesquihydrate pre-resurry-form was added. The mixture was stirred at 40 to 50 ° C. for 30 minutes or more, and 25 ml of water was added dropwise at 40 to 50 ° C. over 20 minutes. Subsequently, the mixture was stirred at 40 to 50 ° C. for 1 hour or longer, cooled to 20 to 30 ° C. over 1 hour or longer, and stirred for 1 hour or longer. The mixture was washed twice with a mixed solution of 10 ml of ethanol and 30 ml of water to drain the liquid, and then dried under reduced pressure at an outside temperature of 50 ° C. to obtain 5.39 g of crude crystals of compound B sesquihydrate.
5 g of crude crystals of compound B sesquihydrate thus obtained, 40 ml of ethanol, and 5.0 ml of purified water were added to the reactor, and the mixture was stirred at 40 ° C. to obtain a solution. The lysate was dust-removed and filtered, and washed with 5.0 ml of ethanol. 40 ml of purified water was added dropwise to the filtrate at 43 to 53 ° C., and 2.5 mg of seed crystals of compound B sesquihydrate was added. After confirming crystallization, 54 ml of purified water was added dropwise at 48 to 53 ° C. over 2 hours, then the mixture was stirred at 43 to 53 ° C. for 1 hour or longer, further heated to 60 to 65 ° C. and stirred for 1 hour or longer. .. It was cooled to 25 ° C. for 2 hours or more, and further stirred for 1 hour or more. The crystals were separated and washed with a mixed solution of 10 ml of ethanol and 30 ml of purified water. This was dried under reduced pressure and humidity control at an outside temperature of 50 ° C. to obtain 4.90 g (purity 99.8%) of crystals of the title compound B sesquihydrate.
(Compound NMR data)
1 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.04-1.19 (6H, m), 1.90-2.07 (1H, m), 2.11-2.23 (1H, m), 2.59-2.70 (1H, m), 2.85 -2.95 (3H, m), 2.95-3.10 (1H, m), 3.69-3.99 (3H, m), 4.50-4.68 (1H, m), 5.00 (1H, s), 7.08-7.18 (1H, m) , 7.21-7.51 (6H, m).
（ＨＰＬＣ分析条件）
カラム：ＹＭＣ－Ｐａｃｋ　Ｐｒｏ Ｃ１８（株式会社ワイエムシィ）、カラムサイズ４．６ｘ１５０ｍｍ、粒子径５μｍ
カラム温度：２５℃付近の一定温度
移動相：Ａ液）０．０１ｍｏｌ／Ｌリン酸バッファー（ｐＨ３．０）：ＭｅＣＮ＝７：３
　　　　Ｂ液）ＭｅＣＮ：０．０１ｍｏｌ／Ｌリン酸バッファー（ｐＨ３．０）＝４：１グラジエントプログラム (HPLC analysis conditions)
Column: YMC-Pack Pro C18 (YMC Co., Ltd.), column size 4.6x150 mm, particle size 5 μm
Column temperature: Constant temperature around 25 ° C. Mobile phase: Solution A) 0.01 mol / L Phosphate buffer (pH 3.0): MeCN = 7: 3
Liquid B) MeCN: 0.01 mol / L phosphate buffer (pH 3.0) = 4: 1 gradient program
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
流量：１．０ｍｌ／ｍｉｎ
保持時間：化合物Ｂセスキ水和物　約１７分 Flow rate: 1.0 ml / min
Retention time: Compound B sesquihydrate about 17 minutes
カラム：ＣＨＩＲＡＬＰＡＫ　ＩＥ－３（ＤＡＩＣＥＬ）、カラムサイズ４．６ｘ１５０ｍｍ、粒子径３μｍ
カラム温度：３５℃付近の一定温度
移動相：Ａ液）０．１％リン酸水素水溶液：ＭｅＣＮ：ＴＨＦ＝７０：２５：５
グラジエントプログラム Column: CHIRALPAK IE-3 (DAICEL), column size 4.6x150 mm, particle size 3 μm
Column temperature: Constant temperature mobile phase around 35 ° C.: Liquid A) 0.1% aqueous hydrogen phosphate solution: MeCN: THF = 70: 25: 5
Gradient program
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
流量：１．０ｍｌ／ｍｉｎ
保持時間：化合物Ｂセスキ水和物　約１２分、Ｎ－｛（２Ｒ，３Ｒ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミド　セスキ水和物　約１４分 Flow rate: 1.0 ml / min
Retention time: Compound B sesquihydrate about 12 minutes, N-{(2R, 3R) -1- (2-hydroxy-2-methylpropanol) -2-[(2,3', 5'-trifluoro) Biphenyl-3-yl) methyl] pyrrolidine-3-yl} methanesulfonamide sesquihydrate Approximately 14 minutes
実施例２－１
Ｎ－｛（２Ｓ，３Ｓ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミド（化合物Ｂ）セスキ水和物
　窒素雰囲気下で、化合物ｂ１の結晶１５ｇにジメチルアセトアミド９０ｍｌを添加した。２０～３０℃で２－ヒドロキシ－２－メチルプロパン酸４．０８ｇ、１－ヒドロキシベンゾトリアゾール水溶液７．１０ｇ、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩８．８８ｇを添加して、ジメチルアセトアミド７．５ｍｌで洗浄した。混合液を２５℃で３０分以上攪拌して溶解させた。溶解液にトリエチルアミン７．４５ｍｌを滴下したのち、ジメチルアセトアミド７．５ｍｌで洗浄した。この混合物を２５℃で１時間以上攪拌したものに、３０℃以下で精製水３０ｍｌを滴下した。６０℃に加温してから精製水１２７．５ｍｌを滴下した。ここに化合物Ｂセスキ水和物の種結晶７．５ｍｇを添加し、６０℃で１時間以上攪拌した。６０℃で精製水１０５ｍｌを滴下し１時間以上撹拌した。混合液を３０分以上かけて徐々に５０℃まで冷却してから１時間以上攪拌し、その後徐々に２５℃まで冷却してから１時間以上攪拌した。析出した結晶を分離し、エタノール１５ｍｌと精製水４５ｍｌの混合液で２回洗浄した。液切りをしたのち、外温５０℃で減圧乾燥し、化合物Ｂセスキ水和物の粗結晶１６．７１ｇを得た。
　このようにして得られた化合物Ｂセスキ水和物の粗結晶３ｇとエタノール２７ｍｌ、精製水３．０ｍｌを反応器に添加し、４０℃で攪拌し溶解液を得た。５３℃で精製水２４ｍｌを滴下し、化合物Ｂセスキ水和物の種結晶１．５ｍｇを加えた。晶析を確認してからさらに１時間以上攪拌した。４８℃で精製水２７ｍｌをゆっくりと滴下したのち、徐々に２５℃まで冷却し、さらに１時間以上攪拌した。結晶を分離し、エタノール６ｍｌと精製水１８ｍｌの混合液で洗浄した。これを外温５０℃で減圧乾燥し、標題の化合物Ｂセスキ水和物の結晶２．７９ｇ（純度９９．９５％）を得た。
　なお、化合物Ｂセスキ水和物の種結晶としては、本実施例に示した手順に沿って、ただし化合物Ｂセスキ水和物の種結晶を用いずに晶出させた化合物Ｂセスキ水和物の結晶を用いた。
（化合物ＮＭＲデータ）
1H NMR (400 MHz, DMSO-d6) δ 1.04-1.19 (6H, m), 1.90-2.07 (1H, m), 2.11-2.23 (1H, m), 2.59-2.70 (1H, m), 2.85-2.95 (3H, m), 2.95-3.10 (1H, m), 3.69-3.99 (3H, m), 4.50-4.68 (1H, m), 5.00 (1H, s), 7.08-7.18 (1H, m), 7.21-7.51 (6H, m). Example 2-1
N-{(2S, 3S) -1- (2-Hydroxy-2-methylpropanol) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl } Methanesulfonamide (Compound B) Sesquihydrate Under a nitrogen atmosphere, 90 ml of dimethylacetamide was added to 15 g of crystals of compound b1. Add 4.08 g of 2-hydroxy-2-methylpropanoic acid, 7.10 g of 1-hydroxybenzotriazole aqueous solution, and 8.88 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride at 20 to 30 ° C. Then, it was washed with 7.5 ml of dimethylacetamide. The mixture was dissolved by stirring at 25 ° C. for 30 minutes or longer. After 7.45 ml of triethylamine was added dropwise to the solution, the mixture was washed with 7.5 ml of dimethylacetamide. 30 ml of purified water was added dropwise at 30 ° C. or lower to the mixture obtained by stirring the mixture at 25 ° C. for 1 hour or longer. After heating to 60 ° C., 127.5 ml of purified water was added dropwise. 7.5 mg of a seed crystal of compound B sesquihydrate was added thereto, and the mixture was stirred at 60 ° C. for 1 hour or more. 105 ml of purified water was added dropwise at 60 ° C., and the mixture was stirred for 1 hour or longer. The mixture was gradually cooled to 50 ° C. over 30 minutes and then stirred for 1 hour or longer, and then gradually cooled to 25 ° C. and then stirred for 1 hour or longer. The precipitated crystals were separated and washed twice with a mixed solution of 15 ml of ethanol and 45 ml of purified water. After draining the liquid, the mixture was dried under reduced pressure at an outside temperature of 50 ° C. to obtain 16.71 g of crude crystals of compound B sesquihydrate.
3 g of crude crystals of compound B sesquihydrate thus obtained, 27 ml of ethanol, and 3.0 ml of purified water were added to the reactor, and the mixture was stirred at 40 ° C. to obtain a solution. 24 ml of purified water was added dropwise at 53 ° C., and 1.5 mg of seed crystals of compound B sesquihydrate was added. After confirming the crystallization, the mixture was further stirred for 1 hour or more. After slowly dropping 27 ml of purified water at 48 ° C., the mixture was gradually cooled to 25 ° C. and further stirred for 1 hour or more. The crystals were separated and washed with a mixed solution of 6 ml of ethanol and 18 ml of purified water. This was dried under reduced pressure at an outside temperature of 50 ° C. to obtain 2.79 g (purity 99.95%) of the title compound B sesquihydrate crystals.
As the seed crystal of the compound B sesquihydrate, the compound B sesquihydrate crystallized according to the procedure shown in this example, but without using the seed crystal of the compound B sesquihydrate. Crystals were used.
(Compound NMR data)
1 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.04-1.19 (6H, m), 1.90-2.07 (1H, m), 2.11-2.23 (1H, m), 2.59-2.70 (1H, m), 2.85 -2.95 (3H, m), 2.95-3.10 (1H, m), 3.69-3.99 (3H, m), 4.50-4.68 (1H, m), 5.00 (1H, s), 7.08-7.18 (1H, m) , 7.21-7.51 (6H, m).
（ＨＰＬＣ分析条件）
カラム：ＹＭＣ－Ｐａｃｋ　Ｐｒｏ Ｃ１８（株式会社ワイエムシィ）、カラムサイズ４．６ｘ１５０ｍｍ、粒子径５μｍ
カラム温度：２５℃付近の一定温度
移動相：Ａ液）０．０１ｍｏｌ／Ｌリン酸バッファー（ｐＨ３．０）：ＭｅＣＮ＝７：３
　　　　Ｂ液）ＭｅＣＮ：０．０１ｍｏｌ／Ｌリン酸バッファー（ｐＨ３．０）＝４：１グラジエントプログラム (HPLC analysis conditions)
Column: YMC-Pack Pro C18 (YMC Co., Ltd.), column size 4.6x150 mm, particle size 5 μm
Column temperature: Constant temperature around 25 ° C. Mobile phase: Solution A) 0.01 mol / L Phosphate buffer (pH 3.0): MeCN = 7: 3
Liquid B) MeCN: 0.01 mol / L phosphate buffer (pH 3.0) = 4: 1 gradient program
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
流量：１．０ｍｌ／ｍｉｎ
保持時間：化合物Ｂセスキ水和物　約１７分 Flow rate: 1.0 ml / min
Retention time: Compound B sesquihydrate about 17 minutes
カラム：ＣＨＩＲＡＬＰＡＫ　ＩＥ－３（ＤＡＩＣＥＬ）、カラムサイズ４．６ｘ１５０ｍｍ、粒子径３μｍ
カラム温度：２５℃付近の一定温度
移動相：Ａ液）０．１％リン酸水素水溶液：ＭｅＣＮ：ＴＨＦ＝７０：２５：５
グラジエントプログラム Column: CHIRALPAK IE-3 (DAICEL), column size 4.6x150 mm, particle size 3 μm
Column temperature: Constant temperature mobile phase around 25 ° C.: Liquid A) 0.1% aqueous hydrogen phosphate solution: MeCN: THF = 70: 25: 5
Gradient program
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
流量：１．０ｍｌ／ｍｉｎ
保持時間：化合物Ｂセスキ水和物　約１２分、Ｎ－｛（２Ｒ，３Ｒ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミド　セスキ水和物　約１４分 Flow rate: 1.0 ml / min
Retention time: Compound B sesquihydrate about 12 minutes, N-{(2R, 3R) -1- (2-hydroxy-2-methylpropanol) -2-[(2,3', 5'-trifluoro) Biphenyl-3-yl) methyl] pyrrolidine-3-yl} methanesulfonamide sesquihydrate Approximately 14 minutes
実施例３
Ｎ－｛（２Ｓ，３Ｓ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミド（化合物Ｃ）
　窒素雰囲気下３５～４０℃で、ジメチルアセトアミド４ｍｌに２－ヒドロキシ－２－メチルプロパン酸０．１８０ｇを添加した。添加１０分後に撹拌を開始し１０℃以下で、１－ヒドロキシベンゾトリアゾール水和物０．２２９ｇを添加して溶解確認した。混合液を２℃まで冷却した後、１，１－カルボニルジイミダゾール（ＣＤＩ）０．２８０ｇを２回に分けて添加した。混合液を２℃まで冷却した後、トリエチルアミン０．１９８ｍｇを滴下した。混合液を２℃まで冷却した後、化合物ｃ１の結晶０．５００ｇを少しずつ添加した。４時間かけて２０℃まで温度を上げたのち１晩撹拌した。２０～３０℃でエタノール精製水０．５ｍｌと５ｍｌを添加した。３０～４０℃で精製水１０ｍｌを滴下し、化合物Ｃを種結晶として微量２ｍｇ添加して結晶の析出が始まってから、２５℃まで徐々に冷却した。２０～３０℃で精製水１０ｍｌを滴下し、１時間撹拌した。析出した結晶を分離し、エタノールと精製水の容量比１：３混合液１ｍｌで２回洗浄した。液切りをしたのち、外温５０℃で減圧乾燥し、化合物Ｃの結晶０．４３０ｇを得た。
（化合物ＮＭＲデータ）
1H NMR (400MHz, CDCl3) δ 1.24 (3H,t,J=7.3Hz), 1.39 (3H,s), 1.41 (3H,s), 1.83-2.03 (1H,m), 2.23-2.43 (1H,m), 2.83-2.97 (3H,m), 3.12 (1H,dd,J=14.0,7.5Hz), 3.58-3.76 (2H,m), 3.84 (1H,brs), 3.91-4.07 (1H,m), 4.45-4.63 (1H,m), 4.67-4.89 (1H, m), 6.77-6.87 (1H,m), 6.99-7.10 (2H,m), 7.16-7.22 (1H,m), 7.26-7.30 (1H,m), 7.37-7.46 (1H,m). Example 3
N-{(2S, 3S) -1- (2-hydroxy-2-methylpropanol) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl } Ethane sulfonamide (Compound C)
0.180 g of 2-hydroxy-2-methylpropanoic acid was added to 4 ml of dimethylacetamide at 35-40 ° C. under a nitrogen atmosphere. Stirring was started 10 minutes after the addition, and 0.229 g of 1-hydroxybenzotriazole hydrate was added at 10 ° C. or lower to confirm dissolution. After cooling the mixed solution to 2 ° C., 0.280 g of 1,1-carbonyldiimidazole (CDI) was added in two portions. After cooling the mixed solution to 2 ° C., 0.198 mg of triethylamine was added dropwise. After cooling the mixed solution to 2 ° C., 0.500 g of crystals of compound c1 were added little by little. The temperature was raised to 20 ° C. over 4 hours and then stirred overnight. 0.5 ml and 5 ml of purified ethanol water were added at 20-30 ° C. 10 ml of purified water was added dropwise at 30 to 40 ° C., and a small amount of 2 mg of compound C was added as a seed crystal to start precipitation of the crystals, and then the mixture was gradually cooled to 25 ° C. 10 ml of purified water was added dropwise at 20 to 30 ° C., and the mixture was stirred for 1 hour. The precipitated crystals were separated and washed twice with 1 ml of a 1: 3 volume mixture of ethanol and purified water. After draining the liquid, the mixture was dried under reduced pressure at an outside temperature of 50 ° C. to obtain 0.430 g of compound C crystals.
(Compound NMR data)
1 1 H NMR (400MHz, CDCl 3 ) δ 1.24 (3H, t, J = 7.3Hz), 1.39 (3H, s), 1.41 (3H, s), 1.83-2.03 (1H, m), 2.23-2.43 (1H) , m), 2.83-2.97 (3H, m), 3.12 (1H, dd, J = 14.0, 7.5Hz), 3.58-3.76 (2H, m), 3.84 (1H, brs), 3.91-4.07 (1H, m) ), 4.45-4.63 (1H, m), 4.67-4.89 (1H, m), 6.77-6.87 (1H, m), 6.99-7.10 (2H, m), 7.16-7.22 (1H, m), 7.26-7.30 (1H, m), 7.37-7.46 (1H, m).
（ＨＰＬＣ分析条件）
カラム：ＩｎｅｒｔＳｕｓｔａｉｎＳｗｉｆｔ　Ｃ８　ＨＰシリーズ（ジーエルサイエンス株式会社）、カラムサイズ４．６ｘ１５０ｍｍ、粒子径３μｍ
カラム温度：２５℃付近の一定温度
移動相：Ａ液）０．１％リン酸水溶液
　　　　Ｂ液）ＭｅＣＮ
グラジエントプログラム (HPLC analysis conditions)
Column: InertSsteinSwift C8 HP series (GL Sciences Co., Ltd.), column size 4.6x150 mm, particle size 3 μm
Column temperature: Constant temperature around 25 ° C Mobile phase: Liquid A) 0.1% aqueous phosphoric acid solution Liquid B) MeCN
Gradient program
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
流量：１．０ｍｌ／ｍｉｎ
保持時間：化合物Ｃ　約９分 Flow rate: 1.0 ml / min
Retention time: Compound C about 9 minutes
　本発明の製造方法によれば、Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］－１－（２－ヒドロキシ－２－メチルプロパノイル）ピロリジン－３－イル）エタンスルホンアミド（化合物Ａ）、Ｎ－｛（２Ｓ，３Ｓ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミド（化合物Ｂ）、およびＮ－｛（２Ｓ，３Ｓ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミド（化合物Ｃ）を、高純度で取得することができるので、本発明の製造方法は工業的製造に適している。 According to the production method of the present invention, N-{(2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] -1- (2-hydroxy-2-methylpropanol) Pyrrolidine-3-yl) ethanesulfonamide (Compound A), N-{(2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2-[(2,3', 5'-tri" Fluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} methanesulfoneamide (Compound B), and N-{(2S, 3S) -1- (2-hydroxy-2-methylpropanol) -2-[ (2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} ethanesulfoneamide (Compound C) can be obtained with high purity, so that the production method of the present invention can be used. Suitable for industrial manufacturing.
　本出願は、日本で２０２０年２月１８日に出願された特願２０２０－０２５５７４を基礎としており、その内容は本明細書にすべて包含されるものである。 This application is based on Japanese Patent Application No. 2020-025574 filed in Japan on February 18, 2020, the contents of which are incorporated herein by reference.

Claims (3)

  1. 　Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミド　塩酸塩と、２－ヒドロキシ－２－メチルプロパン酸とを縮合反応に付す工程を含む、Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’－ジフルオロビフェニル－３－イル）メチル］－１－（２－ヒドロキシ－２－メチルプロパノイル）ピロリジン－３－イル）エタンスルホンアミドの製造方法。 N-{(2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} ethanesulfone amide hydrochloride and 2-hydroxy-2-methylpropanoic acid N-{(2S, 3S) -2-[(2,3'-difluorobiphenyl-3-yl) methyl] -1- (2-hydroxy-2-methylpropanol) A method for producing pyrrolidine-3-yl) ethanesulfone amide.
  2. 　Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミド　塩酸塩と、２－ヒドロキシ－２－メチルプロパン酸とを縮合反応に付す工程を含む、Ｎ－｛（２Ｓ，３Ｓ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝メタンスルホンアミドの製造方法。 N-{(2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} methanesulfonamide hydrochloride and 2-hydroxy-2- N-{(2S, 3S) -1- (2-hydroxy-2-methylpropanoyl) -2-[(2,3', 5'-trifluoro), including the step of subjecting methylpropanoic acid to a condensation reaction. A method for producing biphenyl-3-yl) methyl] pyrrolidine-3-yl} methanesulfonamide.
  3. 　Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミド　塩酸塩と、２－ヒドロキシ－２－メチルプロパン酸とを縮合反応に付す工程を含む、Ｎ－｛（２Ｓ，３Ｓ）－１－（２－ヒドロキシ－２－メチルプロパノイル）－２－［（２，３’，５’－トリフルオロビフェニル－３－イル）メチル］ピロリジン－３－イル｝エタンスルホンアミドの製造方法。 N-{(2S, 3S) -2-[(2,3', 5'-trifluorobiphenyl-3-yl) methyl] pyrrolidine-3-yl} ethanesulfone amide hydrochloride and 2-hydroxy-2- N-{(2S, 3S) -1- (2-hydroxy-2-methylpropanol) -2-[(2,3', 5'-trifluoro), including the step of subjecting methylpropanoic acid to a condensation reaction. A method for producing biphenyl-3-yl) methyl] pyrrolidine-3-yl} ethanesulfone amide.
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JP2019527688A (en) * 2017-08-03 2019-10-03 武田薬品工業株式会社 Heterocyclic compounds and uses thereof

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JP2019527688A (en) * 2017-08-03 2019-10-03 武田薬品工業株式会社 Heterocyclic compounds and uses thereof

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