WO2021166934A1 - Procédé de fabrication de composé pyrrolidine - Google Patents

Procédé de fabrication de composé pyrrolidine 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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English (en)
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

L'invention fournit un procédé de fabrication adapté à une fabrication à échelle industrielle d'un Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３'－difluorobiphényl－３－yl）méthyl］－１－（２－ hydroxy－２－méthylpropanoyl）pyrrolidine－３－yl）éthanesulfonamide, d'un Ｎ－｛（２Ｓ，３Ｓ）－１－（２－hydroxy－２－méthylpropanoyl）－２－［（２，３'，５'－trifluorobiphényl－３－yl）méthyl］pyrrolidine－３－yl｝méthanesulfonamide, et d'un Ｎ－｛（２Ｓ，３Ｓ）－１－（２－hydroxy－２－méthylpropanoyl）－２－［（２，３'，５'－trifluorobiphényl－３－yl）méthyl］pyrrolidine－３－yl｝éthanesulfonamide.　Plus précisément, l'invention concerne un procédé de fabrication de Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３'－difluorobiphényl－３－yl）méthyl］－１－（２－ hydroxy－２－méthylpropanoyl）pyrrolidine－３－yl）éthanesulfonamide, de Ｎ－｛（２Ｓ，３Ｓ）－１－（２－hydroxy－２－méthylpropanoyl）－２－［（２，３'，５'－trifluorobiphényl－３－yl）méthyl］pyrrolidine－３－yl｝méthanesulfonamide, ou de Ｎ－｛（２Ｓ，３Ｓ）－１－（２－hydroxy－２－méthylpropanoyl）－２－［（２，３'，５'－trifluorobiphényl－３－yl）méthyl］pyrrolidine－３－yl｝éthanesulfonamide, lequel procédé inclut une étape au cours de laquelle un hydrochlorure de Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３'－difluorobiphényl－３－yl）méthyl］pyrrolidine－３－yl｝éthanesulfonamide, un hydrochlorure de Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３'，５'－trifluorobiphényl－３－yl）méthyl］pyrrolidine－３－yl｝méthanesulfonamide, ou un hydrochlorure de Ｎ－｛（２Ｓ，３Ｓ）－２－［（２，３'，５'－trifluorobiphényl－３－yl）méthyl］pyrrolidine－３－yl｝éthanesulfonamide, et un acide ２－hydroxy－２－méthylpropanoïque sont soumis à une réaction de condensation.
PCT/JP2021/005848 2020-02-18 2021-02-17 Procédé de fabrication de composé pyrrolidine WO2021166934A1 (fr)

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JP2019527688A (ja) * 2017-08-03 2019-10-03 武田薬品工業株式会社 複素環化合物およびその用途

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019527688A (ja) * 2017-08-03 2019-10-03 武田薬品工業株式会社 複素環化合物およびその用途

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