WO2015029447A1 - Procédé de fabrication de composé carbinol optiquement actif - Google Patents

Procédé de fabrication de composé carbinol optiquement actif Download PDF

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WO2015029447A1
WO2015029447A1 PCT/JP2014/004447 JP2014004447W WO2015029447A1 WO 2015029447 A1 WO2015029447 A1 WO 2015029447A1 JP 2014004447 W JP2014004447 W JP 2014004447W WO 2015029447 A1 WO2015029447 A1 WO 2015029447A1
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稔 小浦
寿史 住田
公幸 渋谷
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興和株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a method for producing an optically active carbinol compound having an LXR ⁇ activation effect and a production intermediate thereof.
  • Liver X receptor is a nuclear receptor in which a part of oxysterols including 22-R-hydroxycholesterol acts as a ligand (Non-Patent Documents 1 to 3).
  • LXR ⁇ is specifically expressed in tissues involved in cholesterol metabolism such as liver, small intestine, adipose tissue, and LXR ⁇ is ubiquitously expressed in almost all tissues examined. It recognizes similar sequences and activates transcription of nearby target genes (Non-Patent Documents 4 and 5).
  • LXR target genes are genes (ApoE, CETP, and LPL) involved in reverse cholesterol transport (RCT) including ABC transporters (ABCA1, ABCG1, ABCG5, ABCG8). is there.
  • RCT reverse cholesterol transport
  • ABCA1, ABCG1, ABCG5, ABCG8 ABC transporters
  • Patent Document 1 The compounds (A) to (J) having the chemical structure represented by are found and a patent application has been filed (Patent Document 1). These compounds are all optically active 2- (4- (2,5-dimethylpiperazin-1-yl) -3-propylphenyl) -1,1,1,3,3,3-hexafluoropropane-2. -Common in that it has an all structure.
  • Patent Document 1 reports a method via production of a piperazine derivative (a13) as shown in the following reaction process diagram. That is, L-alanine methyl ester (a1) is used as a starting material and compound (a3) is obtained in 13 steps in 6 steps, or trans-2,5-dimethylpiperazine (b1) is used as a starting material in 21 steps in 4 steps and compound (a3) is obtained.
  • the compound (a5) is produced by carrying out a coupling reaction with a separately produced benzoic acid ester (a4). After that, 8 steps are taken to carry out side chain construction and protection / deprotection reaction to produce a piperazine derivative (a13) as a common intermediate.
  • the total yield is reduced to 13% at the stage of producing the intermediate (a3) from the starting material (a1) and the reduction reaction of the amide of the diketopiperazine (a2) It has been known that epimerization occurs and has a problem in reproducibility.
  • the production of (a13) from L-alanine methyl ester is as long as 15 steps in total, and since the starting material (a1) has an asymmetric center, asymmetry is controlled in all reaction steps. There was a problem such as being necessary.
  • the preferential crystallization is performed using (L) or (D) -tartaric acid.
  • the total yield is reduced to 21% at the stage of producing the intermediate (a3) by the optical resolution method, the theoretical yield is 50% or less, and trans-2,5-dimethyl Piperazine (b1) is very expensive in terms of market availability, and has problems such as being unsuitable for mass production as a starting material.
  • Non-patent Document 8 a method for producing a homopiperazine derivative
  • the present invention relates to optically active 2- (4- (2,5-dialkylpiperazin-1-yl) -3-alkylphenyl) -1,1,1,3,3,3-hexafluoropropan-2-ol. It is an object of the present invention to provide a method for obtaining an optically active carbinol compound having an LXR ⁇ selective activation action in high yield and high optical purity.
  • the present invention also provides optically active 2- (4- (2,5-dialkylpiperazin-1-yl) -3-alkylphenyl) -1,1,1, which is useful as an intermediate for the production of optically active carbinol compounds.
  • An object is to provide a 3,3,3-hexafluoropropan-2-ol compound.
  • Compound (c15) is obtained by carbinolization reaction using methyltrimethylsilane, and the optically active 2- (4- (2,5-dimethylpiperazin-1-yl) -3 is obtained by deprotecting the piperazine compound.
  • the hydantoin compound (c17) and the compound (c18) are alkylated to give a compound (c19), which is hydrolyzed to give a compound (c20), which is then condensed with the compound (c16).
  • the present inventors have found that the optically active carbinol compound (B) can be obtained in a total of 16 steps with a yield of 17% without impairing the optical purity.
  • the present invention has been completed based on this finding.
  • R 1 may be a C 2-3 alkyl group
  • R 2 and R 3 may be the same or different, each represents a C 1-3 alkyl group
  • * represents an asymmetric carbon atom
  • R 4 represents
  • R 1 may be a C 2-3 alkyl group
  • R 2 and R 3 may be the same or different, each represents a C 1-3 alkyl group
  • * represents an asymmetric carbon atom
  • R 4 represents
  • R 5 represents a C 1-3 alkyl group and X 1 represents a halogen atom
  • R 2 and R 3 may be the same or different and each represents a C 1-3 alkyl group, * represents an asymmetric carbon atom, and P 1 represents an amino-protecting group]
  • the compound is reacted to give the formula (6):
  • R 6 represents a hydrogen atom or a methyl group
  • the wavy line is a single bond
  • the configuration of each double bond is independently an E configuration or a Z configuration, or a mixture thereof
  • R 2 may be the same or different and represents a C 1-3 alkyl group, and * represents an asymmetric carbon atom] :
  • R 3 may be the same or different, each represents a C 1-3 alkyl group, and * has the same definition as above], and a compound represented by formula (16):
  • the method further comprises the step of producing the compound represented by the formula (5) by deprotecting the protecting group P 2 of the compound represented by the formula (18) [2] or [3 ] The manufacturing method of description.
  • R 9 represents a C 1-3 alkyl group and X 2 represents a halogen atom
  • the method further comprises the step of producing a compound represented by the formula (3) by hydrolyzing the compound represented by the formula (21), [1], [3] and [4] The production method according to any one of [4].
  • the compound represented by the formula (1) is 3- (2- ⁇ (2S, 5R) -4- [4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2- Yl) -2-propylphenyl] -2,5-dimethylpiperazin-1-yl ⁇ -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl] -5-methylimidazolidine-2,4- The production method according to any one of [1] to [5], which is dione.
  • R 1 represents a C 2-3 alkyl group
  • R 2 and R 3 represent the same or different C 1-3 alkyl group
  • * represents an asymmetric carbon
  • the method of the present invention can produce the target compound (1) in a higher yield than the conventional method, as shown in the Examples below.
  • the asymmetric carbon of the 2,5-dimethylpiperazine compound (3) introduced as an asymmetric center can be constructed without epimerization by following this method. Further, other than the protecting group of one amino group of the 2,5-dimethylpiperazine compound (3), it can be constructed without using a protecting group. Therefore, by using the method of the present invention, compound (1) useful as an LXR ⁇ selective agonist can be produced with high yield and high optical purity.
  • the C 1-3 alkyl group means a linear or branched alkyl group having 1 to 3 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, and an isopropyl group.
  • the C 1-3 alkyl group for R 1 is preferably a propyl group.
  • the C 1-3 alkyl group for R 2 is preferably a methyl group.
  • the C 1-3 alkyl group for R 3 is preferably a methyl group.
  • the C 1-3 alkyl group for R 5 is preferably a methyl group.
  • R 6 is preferably a methyl group.
  • examples of the acid halide in C (O) R 7 include acid fluorides and acid chlorides.
  • examples of the acid anhydride in C (O) R 7 include aliphatic carboxylic acids such as acetic acid and acid anhydrides with aromatic carboxylic acids such as benzoic acid.
  • examples of the ester in C (O) R 7 include an ester with an aliphatic alcohol such as methanol, an ester with an aromatic alcohol such as pentafluorophenol, and the like.
  • C (O) R 7 is preferably an ester, and more preferably a pentafluorophenoxycarbonyl group.
  • the C 1-3 alkyl group for R 8 is preferably a methyl group.
  • the C 1-3 alkyl group for R 9 is preferably a methyl group.
  • the amino-protecting group includes tert-butoxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz), 9-fluorenylmethyloxycarbonyl group (Fmoc), and 2,2,2-trichloroethoxy.
  • the amino-protecting group P 1 includes a tert-butoxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group (Fmoc), 2, 2,2-trichloroethoxycarbonyl group (Troc), allyloxycarbonyl group (Alloc), trifluoroacetyl group (CF 3 CO-), phthaloyl group (Pht), p-toluenesulfonyl group (Ts), 2-nitrobenzenesulfonyl A group (Ns) and a trityl group (Tr) are preferable, and a tert-butoxycarbonyl group is more preferable.
  • the amino-protecting group P 2 includes a tert-butoxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group (Fmoc), 2, 2,2-trichloroethoxycarbonyl group (Troc), allyloxycarbonyl group (Alloc), trifluoroacetyl group (CF 3 CO-), phthaloyl group (Pht), p-toluenesulfonyl group (Ts), 2-nitrobenzenesulfonyl
  • the group (Ns), 4-nitrobenzenesulfonyl group (Ns) and trityl group (Tr) are preferable, and the 2-nitrobenzenesulfonyl group (Ns) is more preferable.
  • examples of the halogen atom X 1 include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • a fluorine atom and a chlorine atom are preferable, and a fluorine atom is more preferable.
  • the halogen atom X 2 a chlorine atom, a bromine atom, an iodine atom.
  • (12a) and (15b) as raw materials for constructing the three-dimensional structure (2a); (12b) and (15a); (2c) three-dimensional structures as the raw material for constructing the three-dimensional structure (2b) (12b) and (15b) may be used as raw materials for constructing the three-dimensional structure of (12a) and (15a); (2d).
  • (2a) or (2b) is preferable, and (2b) is particularly preferable.
  • (2a) to (2d) can be used as raw materials for constructing the eight steric structures of the general formula (1) of the present invention.
  • As a raw material for constructing the three-dimensional structure of (1g), (2d) may be used as a raw material for constructing the three-dimensional structure of (2c); (1d) and (1h).
  • the steric structure of the general formula (1) of the present invention is preferably (1a), (1b), (1e), or (1f), more preferably (1b) or (1f).
  • a preferred structure of the formula (1) is a compound in which R 1 is propyl, R 2 and R 3 are methyl groups, and R 4 is a 4- (1-methylethoxy) phenyl group.
  • the wavy line is a single bond, and the configuration of the double bond to which the wavy line is bonded is independently an E configuration, a Z configuration, or a mixture thereof. It shows that.
  • the general formula (7) of the present invention is represented by the following (7a) and (7b):
  • reaction process diagrams are shown, and the reaction of each process will be described in detail.
  • Step 1 This step is a step for producing a compound (13) by protecting the amino group of the compound (12).
  • the protecting group represented by P 2 can be protected with reference to, for example, literature (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • compound (13) can be produced by reacting compound (12) with 2-nitrobenzenesulfonyl chloride or the like in the presence or absence of a solvent in the presence of a base.
  • the solvent is not particularly limited, but N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride, and the like can be used. Among these, methylene chloride is preferable. .
  • the base is not particularly limited, and organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, and picoline; inorganic bases such as potassium carbonate and sodium carbonate can be used, and among these, triethylamine is preferable.
  • the reaction conditions are ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C., for 1 minute to 24 hours, preferably 5 minutes to 24 hours.
  • Step 2 This step is a step for producing a compound (14) by carrying out a sulfonylation reaction of the compound (13).
  • Compound (14) is produced by adding compound (13) to a leaving group such as a sulfonyloxy group by adding a sulfonic acid halide reagent or an alkyl or aralkylsulfonic acid anhydride reagent in the presence of a base in a solvent. can do.
  • N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used, among which tetrahydrofuran, dioxane Acetonitrile, benzene, chlorobenzene, toluene, chloroform and methylene chloride are preferred, and methylene chloride is particularly preferred.
  • the base is not particularly limited.
  • alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide
  • Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate
  • metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium
  • lithium Metal amides such as diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide
  • n-butyllithium, sec- Organometallic compounds such as til lithium and tert-butyl lithium; triethylamine, N, N-diisopropylethylamine, N
  • Organic amines such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine, 2-picoline, 3-picoline, 4-picoline, 2,3-lutidine, 2,4- Preferred are lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,5-collidine, 2,4,6-collidine, triethylamine, N-methylmorpholine 2,6-lutidine and 2,4,6-collidine are particularly preferred.
  • the sulfonic acid halide reagent is not particularly limited, and for example, methanesulfonic acid chloride, benzenesulfonic acid chloride, p-toluenesulfonic acid chloride, 2-nitrobenzenesulfonic acid chloride and the like are preferable.
  • the alkyl or aralkyl sulfonic acid anhydride reagent is not particularly limited, but for example, methane sulfonic acid anhydride and trifluoromethane sulfonic acid anhydride are preferable.
  • the reaction conditions are ⁇ 78 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C., for 5 minutes to 48 hours, preferably 30 minutes to 24 hours.
  • Step 3 is a step for producing a compound (16) by reacting the compound (14) with an amino alcohol form (15) in a solvent in the presence or absence of a base.
  • the solvent is not particularly limited.
  • tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, etc. may be used alone or in combination. Of these, tetrahydrofuran and acetonitrile are preferred.
  • Examples of the base include alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; lithium carbonate, sodium carbonate and carbonate Alkali metal carbonates such as potassium and cesium carbonate; metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium and tert-butoxy potassium; lithium diisopropylamide, sodium diisopropylamide Metal amides such as potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; n-butyllithium, sec-butyllithium, t Organometallic compounds such as rt-butyllithium; alkali metal halides such as lithium chloride, lithium bromide, lithium
  • Step 4 This step is a step for producing the compound (17) by protecting the amino group of the compound (16).
  • the protecting group represented by P 1 can be protected with reference to, for example, literature (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • compound (17) can be produced by reacting compound (16) with di-tert-butyl dicarbonate in the presence of a base in a solvent or without a solvent. It can.
  • the solvent is not particularly limited, and N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used, among which acetonitrile, Tetrahydrofuran is preferred.
  • the base is not particularly limited, and organic bases such as triethylamine, diisopropylethylamine, pyridine, lutidine, and picoline; inorganic bases such as potassium carbonate and sodium carbonate can be used. Among them, triethylamine and potassium carbonate are preferable.
  • the reaction conditions are ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C., for 1 minute to 24 hours, preferably 5 minutes to 24 hours.
  • Step 5 is a step for producing a piperazine derivative (18) by carrying out an intramolecular ring closure reaction of the compound (17).
  • Compound (17) is introduced into a leaving group such as a sulfonyloxy group by adding a sulfonic acid halide reagent or an alkyl or aralkylsulfonic acid anhydride reagent in a solvent in the presence of a base to advance the cyclization reaction.
  • a leaving group such as a sulfonyloxy group by adding a sulfonic acid halide reagent or an alkyl or aralkylsulfonic acid anhydride reagent in a solvent in the presence of a base to advance the cyclization reaction.
  • N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used, among which tetrahydrofuran, dioxane, acetonitrile, benzene, Chlorobenzene, toluene, chloroform and methylene chloride are preferred, and toluene and tetrahydrofuran are particularly preferred.
  • the base is not particularly limited.
  • alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide
  • Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate
  • metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium
  • lithium Metal amides such as diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide
  • n-butyllithium, sec- Organometallic compounds such as til lithium and tert-butyl lithium; triethylamine, N, N-diisopropylethylamine, N
  • Organic amines such as triethylamine, N, N-diisopropylethylamine, pyridine, 2-picoline, 3-picoline, 4-picoline, 2,3-lutidine, 2,4-lutidine, 2,5- Preferred are lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,5-collidine, 2,4,6-collidine, pyridine, 2,6-lutidine, 2,4, 6-collidine is particularly preferred.
  • the sulfonic acid halide reagent is not particularly limited, and for example, methanesulfonic acid chloride, benzenesulfonic acid chloride, p-toluenesulfonic acid chloride, 2-nitrobenzenesulfonic acid chloride and the like are preferable.
  • the alkyl or aralkyl sulfonic acid anhydride reagent is not particularly limited, but for example, methane sulfonic acid anhydride and trifluoromethane sulfonic acid anhydride are preferable.
  • the reaction conditions are ⁇ 78 ° C. to 100 ° C., preferably ⁇ 20 ° C. to 0 ° C., for 5 minutes to 24 hours, preferably 30 minutes to 12 hours.
  • the piperazine derivative (18) can also be produced by reacting the compound (17) in a solvent with a phosphine reagent and an azo reagent or ethylenedicarboxylic acid reagent.
  • a solvent N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used alone or in combination.
  • N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile and tetrahydrofuran / toluene are preferred, and N, N-dimethylformamide, tetrahydrofuran and tetrahydrofuran / toluene are particularly preferred.
  • phosphine reagent examples include trialkylphosphine such as trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, triisobutylphosphine, tricyclohexylphosphine, and triarylphosphine, and triarylphosphine such as diphenylphosphinopolystyrene Examples include phosphine, among which trimethylphosphine, tributylphosphine, and triphenylphosphine are preferable.
  • Examples of the azo reagent or ethylenedicarboxylic acid reagent include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1,1′-azobis (N, N-dimethylformamide) (TMAD), 1,1 ′. -(Azodicarbonyl) dipiperidine (ADDP), 1,1'-azobis (N, N-diisopropylformamide) (TIPA), 1,6-dimethyl-1,5,7-hexahydro-1,4,6,7 -Tetrazocine-2,5-dione (DHTD) and the like, with diisopropyl azodicarboxylate being particularly preferred.
  • the reaction conditions are 0 ° C. to 100 ° C., preferably 0 ° C. to room temperature, 30 minutes to 1 day.
  • This process is a process of manufacturing a compound (5) by deprotecting the amino group of a compound (18).
  • the protecting group represented by P 2 can be deprotected with reference to, for example, literature (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).
  • compound (5) can be produced by reacting compound (18) with a thiol compound in the presence of a base in a solvent or without a solvent.
  • the solvent is not particularly limited, and N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used. N-dimethylformamide and acetonitrile are preferred.
  • Inorganic bases such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, can be used, and potassium carbonate is especially preferable.
  • Examples of the thiol compound include benzenethiol and 1-dodecanethiol, and benzenethiol is preferable.
  • the reaction conditions are ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C., for 1 minute to 24 hours, preferably 5 minutes to 24 hours.
  • Step 7 is a step for producing a compound (6) by reacting the compound (4) with a compound (5) in a solvent in the presence or absence of a base.
  • the solvent is not particularly limited, but for example, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, methyl ethyl ketone, water, etc. are used alone or in combination. can do.
  • the base is not particularly limited.
  • alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide
  • Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate
  • metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium
  • lithium Metal amides such as diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide
  • n-butyllithium, sec- Organometallic compounds such as til lithium and tert-butyl lithium
  • lithium fluoride lithium chloride, lithium bromide, lithium iodide, sodium fluor
  • Step 8 This step is a step for producing a compound (7) by reacting the compound (6) with a Wittig reagent or Horner-Wadsworth-Emmons (HWE) reagent in a solvent in the presence or absence of a base. is there.
  • a Wittig reagent or Horner-Wadsworth-Emmons (HWE) reagent in a solvent in the presence or absence of a base. is there.
  • N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used, among which tetrahydrofuran, ethyl acetate, toluene, Chloroform and methylene chloride are preferred.
  • phosphonium salts such as stable ylides and unstable ylides (methyltriphenylphosphonium bromide, ethyltriphenylphosphonium bromide, etc.) can be used.
  • a phosphonic acid ester can be used as the HWE reagent.
  • the base is not particularly limited.
  • alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide
  • Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate
  • metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium
  • lithium Metal amides such as diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide
  • n-butyllithium, sec- Organometallic compounds such as til lithium and tert
  • Step 9 is a step for producing a compound (8) by reacting the compound (7) in a solvent in the presence of metallic carbon under a hydrogen atmosphere.
  • the solvent is not particularly limited, and may be used alone or in combination with toluene, esters such as methyl acetate and ethyl acetate, and alcohols such as methanol, ethanol, 1-propanol and 2-propanol.
  • the metal carbon include palladium carbon, platinum carbon, rhodium carbon, ruthenium carbon and the like.
  • the reaction conditions are ⁇ 80 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.
  • Step 10 is a step for producing a compound (9) by reacting the compound (8) in a solvent in the presence of a base or an acid.
  • the solvent is not particularly limited.
  • the base is not particularly limited.
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide
  • alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate
  • an acid For example, hydrochloric acid, a sulfuric acid, an acetic acid, a tosylic acid etc. can be used.
  • the reaction conditions are ⁇ 80 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.
  • Step 11 is a step of removing the compound (9) in a solvent or in the absence of a solvent, in the presence or absence of a condensing agent, in the presence or absence of a reaction accelerator, in the presence or absence of an acid or a base.
  • compound (10) is produced by the reaction below.
  • the substituent represented by R 7 can be converted into an acid halide, an acid anhydride, or an ester with reference to, for example, literature (Comprehensive Organic Transformations Second Edition, John Wiley & Sons, Inc.).
  • acid halides include acid fluorides and acid chlorides.
  • Examples of the acid anhydride include an acid anhydride with an aliphatic carboxylic acid such as acetic acid, an acid anhydride with an aromatic carboxylic acid such as benzoic acid, and the like.
  • Examples of the ester include an ester with an aliphatic alcohol such as methanol, an ester with an aromatic alcohol such as pentafluorophenol, and the like.
  • R 7 is a pentafluorophenoxy group
  • the solvent is not particularly limited.
  • tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, propionitrile, acetone, Methyl ethyl ketone, ethyl acetate and the like can be used alone or in combination.
  • condensing agent examples include carbodiimide reagents such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), and diisopropylcarbodiimide (DIPCDI).
  • DCC dicyclohexylcarbodiimide
  • EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • DIPCDI diisopropylcarbodiimide
  • dicyclohexylcarbodiimide, Ethyl-3- (3-dimethylaminopropyl) carbodiimide is preferred.
  • the base is not particularly limited, but for example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, triethylamine, Organic amines such as N, N-diisopropylethylamine, N-methylmorpholine, pyridine, 3,4-lutidine, 2,6-lutidine, 2,4,6-collidine and the like can be used.
  • an acid For example, hydrochloric acid, a sulfuric acid, an acetic acid, a tosylic acid etc. can be used.
  • the reaction conditions are ⁇ 80 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.
  • Step 12 is a step for producing the compound (10) into the hexafluorocarbinol compound (11) using a trifluoromethylating reagent in a solvent in the presence of a base.
  • a solvent dimethoxyethane, tetrahydrofuran, toluene, dioxane, ethylene glycol dimethyl ether, N, N-dimethylformamide, N-methylpyrrolidone, tetramethylurea, dimethyl sulfoxide, acetonitrile, propionitrile, etc. should be used alone or in combination.
  • ethylene glycol dimethyl ether is preferable.
  • Trifluoromethylating reagents include (trifluoromethyl) trimethylsilane, triethyl (trifluoromethyl) silane, triisopropyl (trifluoromethyl) silane, methyldiphenyl (trifluoromethyl) silane, dimethyl (diphenyl) trifluoromethylsilane Etc.
  • the reaction conditions are ⁇ 80 ° C. to 150 ° C., preferably ⁇ 30 ° C. to 50 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.
  • Step 13 This step is a step of producing the compound (2) by deprotecting the amino group of the compound (11).
  • the protecting group represented by P 1 can be deprotected with reference to literature (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.), for example.
  • compound (2) can be produced by reacting compound (11) with an acid in a solvent or without a solvent.
  • the solvent is not particularly limited, but N, N-dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride, water, methanol, ethanol, 1-propanol, 2 -Propanol or the like can be used alone or in combination.
  • the acid is not particularly limited, but hydrochloric acid, hydrochloric acid / ethyl acetate solution, hydrochloric acid / dioxane solution, hydrochloric acid / methanol solution, hydrobromic acid, sulfuric acid, nitric acid, etc. can be used. Among them, hydrochloric acid / ethyl acetate solution A hydrochloric acid / methanol solution is preferred.
  • the reaction conditions are ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C., for 1 minute to 24 hours, preferably 5 minutes to 12 hours.
  • Step 14 is a step for producing a compound (21) by reacting the hydantoin derivative (19) and the compound (20) in a solvent in the presence or absence of a base.
  • the solvent is not particularly limited.
  • alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, Alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide; Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate; metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium; lithium Metal amides such as diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; n-butyllithium, sec- Organometallic compounds such as til lithium and tert-butyl lithium; triethylamine, N, N
  • the imidazolidine-2,4-dione derivative (19) used in this step is converted into a diastereomeric salt with a general optically active acid such as tartaric acid, or optically resolved, or optically active column chromatography is used.
  • a general optically active acid such as tartaric acid, or optically resolved, or optically active column chromatography is used.
  • optically pure isomers by general racemic resolution methods such as
  • Step 15 is a step for producing a compound (3) by reacting the compound (21) in a solvent in the presence of a base or an acid.
  • the solvent is not particularly limited.
  • the base is not particularly limited, and examples thereof include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, alkali carbonate metals such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Can be used. Although there is no restriction
  • the reaction conditions are ⁇ 80 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.
  • Step 16 This step comprises reacting compound (2) and compound (3) in a solvent in the presence of a condensing agent, in the presence or absence of a reaction accelerator, in the presence or absence of a base.
  • a condensing agent in the presence or absence of a reaction accelerator, in the presence or absence of a base.
  • This is a process for producing a carbinol derivative (1).
  • the solvent N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used.
  • Dimethyl sulfoxide, acetonitrile and methylene chloride are preferred.
  • the condensing agent include carbodiimide reagents such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), diisopropylcarbodiimide (DIPCDI); (1H-benzotriazol-1-yloxy) Tris (dimethylamino) phosphonium hexafluorophosphate (BOP), (1H-benzotriazol-1-yloxy) tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), 1- [bis (dimethylamino) methylene] -1H- 1,2,3-triazolo (4,5-b) pyridium-3-oxodohexafluorophosphate (HATU), 1- [bis (dimethylamino)
  • reaction accelerator examples include 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (6-Cl-HOBt), 3,4-dihydro-3-hydroxy-4-oxo-1,2 1,3-benzotriazine (HOOBt), 1-hydroxy-7-azabenzotriazole (HOAt) and the like can be used.
  • alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, Alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide; Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate; metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium; lithium Metal amides such as diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; n-butyllithium, sec- Organometallic compounds such as til lithium and tert-butyl lithium; triethylamine, N, N
  • This step can also be carried out by applying a Mitsunobu reaction in which the compound (2) and the compound (3) are reacted with an azo reagent or an ethylenedicarboxylic acid reagent in a solvent in the presence of a phosphine reagent.
  • a Mitsunobu reaction in which the compound (2) and the compound (3) are reacted with an azo reagent or an ethylenedicarboxylic acid reagent in a solvent in the presence of a phosphine reagent.
  • the solvent N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, acetone, ethyl acetate, benzene, chlorobenzene, toluene, chloroform, methylene chloride and the like can be used.
  • phosphine reagent examples include trialkylphosphine such as trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, triisobutylphosphine, tricyclohexylphosphine, and triphenylphosphine, diphenylphosphinopolystyrene, and the like. Can be used.
  • trialkylphosphine such as trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, triisobutylphosphine, tricyclohexylphosphine, and triphenylphosphine, diphenylphosphinopolystyrene, and the like.
  • trialkylphosphine such as trimethylphosphine, trie
  • Examples of the azo reagent or ethylenedicarboxylic acid reagent include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1,1′-azobis (N, N-dimethylformamide) (TMAD), 1,1′- (Azodicarbonyl) dipiperidine (ADDP), 1,1′-azobis (N, N-diisopropylformamide) (TIPA), 1,6-dimethyl-1,5,7-hexahydro-1,4,6,7- Tetrazocine-2,5-dione (DHTD) or the like can be used.
  • the reaction conditions are ⁇ 80 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C., for 1 minute to 5 days, preferably 1 hour to 3 days.
  • compound (3) is reacted with an acid halogenating agent in a solvent to produce an acid halide derivative, and this is then combined with compound (2) in a solvent in the presence or absence of a base.
  • Carbinol derivative (1) can also be produced by reacting.
  • Examples of the acid halogenating agent include N, N-diethylaminosulfur trifluoride (DAST), selenium tetrafluoride or its pyridine adduct, thionyl chloride, oxalyl chloride, pyrocatekylphosphotrichloride, dichlorotriphenylphosphorane, Thionyl bromide, dibromotriphenylphosphorane, 1-dimethyl-1-iodo-2-methylpropene and the like can be used.
  • DAST N-diethylaminosulfur trifluoride
  • selenium tetrafluoride or its pyridine adduct thionyl chloride
  • oxalyl chloride oxalyl chloride
  • pyrocatekylphosphotrichloride dichlorotriphenylphosphorane
  • Thionyl bromide Thionyl bromide
  • dibromotriphenylphosphorane 1-dimethyl-1-i
  • the solvent is not particularly limited, and for example, toluene, N, N-dimethylformamide, N-methylpyrrolidone, acetonitrile, dichloromethane, 1,2-dichloroethane and the like can be used alone or in combination.
  • alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, Alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide; Alkali metal carbonates such as lithium, sodium carbonate, potassium carbonate, cesium carbonate; metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, tert-butoxy sodium, tert-butoxy potassium; lithium Metal amides such as diisopropylamide, sodium diisopropylamide, potassium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; n-butyllithium, sec- Organometallic compounds such as til lithium and tert-butyl lithium; triethylamine, N, N
  • salts allowed in the optically active compound represented by the general formula (2) of the present invention include acid addition salts with inorganic acids and organic acids, or base addition salts with inorganic bases and organic bases. Etc.
  • solvate of the optically active compound represented by the general formula (2) of the present invention and acceptable salts thereof include hydrates and various solvates.
  • Step I Preparation of (R) -N- (1-hydroxypropan-2-yl) -2-nitrobenzenesulfonamide (c2): (R) -2-Aminopropan-1-ol (2.03 g, 29.8 mmol) was dissolved in dichloromethane (27 mL). Triethylamine (3.74 g, 36.9 mmol) and 2-nitrobenzene-1-sulfonyl chloride (6.0 g, 27.1 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 16 hours. After confirming the completion of the reaction, dichloromethane and water were added to the reaction solution at 0 ° C.
  • Step II Preparation of methanesulfonic acid (R) -2- (2-nitrophenylsulfonamido) propyl (c3): (R) -N- (1-hydroxypropan-2-yl) -2-nitrobenzenesulfonamide (8.58 g, 27.1 mmol) was dissolved in dichloromethane (90 mL). Triethylamine (4.10 g, 40.6 mmol) and methanesulfonyl chloride (2.98 g, 29.9 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 18 hours. After confirming the completion of the reaction, water was added to the reaction solution at 0 ° C.
  • Step III Preparation of N-[(R) -1- ⁇ [(S) -1-hydroxypropan-2-yl] amino ⁇ propan-2-yl] -2-nitrobenzenesulfonamide (c5): Methanesulfonic acid (R) -2- (2-nitrophenylsulfonamido) propyl (9.06 g, 27.1 mmol) was dissolved in tetrahydrofuran (135 mL). (S) -2-Aminopropan-1-ol (10.2 g, 135 mmol) was added at room temperature, and the mixture was stirred for 15 hours under reflux. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure. The obtained residue was purified using silica gel column chromatography (chloroform / methanol) to obtain the title compound (5.14 g, yield 60%) as a yellow oily substance.
  • Step IV Preparation of [(S) -1-hydroxypropan-2-yl] [(R) -2- (2-nitrophenylsulfonamido) propyl] carbamate tert-butyl (c6): N-[(R) -1- ⁇ [(S) -1-hydroxypropan-2-yl] amino ⁇ propan-2-yl] -2-nitrobenzenesulfonamide (7.09 g, 22.3 mmol) Dissolved in tetrahydrofuran (110 mL).
  • Step V Preparation of 2,5-dimethyl-4-[(2-nitrophenyl) sulfonyl] piperazine-1-carboxylic acid (2S, 5R) -tert-butyl (c7): [(S) -1-Hydroxypropan-2-yl] [(R) -2- (2-nitrophenylsulfonamido) propyl] carbamate tert-butyl (3.38 g, 8.08 mmol) under vacuum After drying, it was dissolved in tetrahydrofuran (54 mL) under an argon atmosphere.
  • triphenylphosphine (3.18 g, 12.1 mmol) and diisopropyl azodicarboxylate (DIAD) (7.1 mL, 1.7 M toluene solution 12.1 mmol) were added, and 2 at room temperature. Stir for hours. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (chloroform / methanol) to give 3.11 g (yield 96%) of the title compound as an orange oil. Got as.
  • Step VI Preparation of 2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (c8): 2,5-Dimethyl-4-[(2-nitrophenyl) sulfonyl] piperazine-1-carboxylic acid (2S, 5R) -tert-butyl (3.21 g, 8.04 mmol) in acetonitrile (47 mL) Dissolved. At room temperature, potassium carbonate (3.33 g, 24.1 mmol) and benzenethiol (1.33 g, 12.1 mmol) were added, and the mixture was stirred at 50 ° C. for 3 hours.
  • Step VII Preparation of 4- [2-formyl-4- (methoxycarbonyl) phenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (c10): Cesium fluoride (14.0 g, 91.89 mmol) was dried at 120 ° C. under reduced pressure for 2 hours, and N, N-dimethylformamide (52 mL) was added at room temperature under an argon atmosphere.
  • Step VIII 4- [4- (methoxycarbonyl) -2- (prop-1-en-1-yl) phenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl
  • Ethyltriphenylphosphonium bromide 25.8 g, 69.46 mmol
  • potassium methoxide 4.87 g, 69.46 mmol
  • cis-c11 4- ⁇ 4- (methoxycarbonyl) -2-[(Z) -prop-1-en-1-yl] phenyl ⁇ -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl
  • trans-c11 4- ⁇ 4- (methoxycarbonyl) -2-[(E) -prop-1-en-1-yl] phenyl ⁇ -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl
  • Step IX Preparation of 4- [4- (methoxycarbonyl) -2-propylphenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (c12): 4- [4- (Methoxycarbonyl) -2- (prop-1-en-1-yl) phenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (4.76) g, 12.25 mmol) was dissolved in methanol (123 mL), and palladium on carbon was added under an argon atmosphere. Thereafter, the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere.
  • Step X Preparation of 4-[(2R, 5S) -4- (tert-butoxycarbonyl) -2,5-dimethylpiperazin-1-yl] -3-propylbenzoic acid (c13): 4- [4- (methoxycarbonyl) -2-propylphenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S, 5R) -tert-butyl (4.72 g, 12.09 mmol) was added to methanol ( 121N), 4N-aqueous sodium hydroxide solution (18.1 mL, 72.52 mmol) was added at 0 ° C., and the mixture was stirred at 60 ° C. for 2 hours.
  • Step XI Preparation of 2,5-dimethyl-4- ⁇ 4-[(perfluorophenoxy) carbonyl] -2-propylphenyl ⁇ piperazine-1-carboxylic acid (2S, 5R) -tert-butyl (c14): 4-[(2R, 5S) -4- (tert-butoxycarbonyl) -2,5-dimethylpiperazin-1-yl] -3-propylbenzoic acid (1.0 g, 2.656 mmol) was added to ethyl acetate ( 18 mL), and 2,3,4,5,6-pentafluorophenol (513 mg, 2.789 mmol), N, N′-dicyclohexylcarbodiimide (575 mg, 2.789 mol) in this order at room temperature.
  • Step XII 4- [4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl] -2,5-dimethylpiperazine-1-carboxyl
  • 2S, 5R -tert-butyl
  • 2S, 5R 2,5-Dimethyl-4- ⁇ 4-[(perfluorophenoxy) carbonyl] -2-propylphenyl ⁇ piperazine-1-carboxylic acid (2S, 5R) -tert-butyl (5.75 g, 10.6 mmol)
  • 2S, 5R -tert-butyl
  • Step XIII 2- ⁇ 4-[(2R, 5S) -2,5-dimethylpiperazin-1-yl] -3-propylphenyl ⁇ -1,1,1,3,3,3-hexafluoropropane-2 -Manufacture of all (c16): 4- [4- (1,1,1,3,3,3-Hexafluoro-2-hydroxypropan-2-yl) -2-propylphenyl] -2,5-dimethylpiperazine-1-carboxylic acid (2S , 5R) -tert-butyl (4.53 g, 9.08 mmol) dissolved in methanol (14 mL), 2N hydrochloric acid methanol solution (41 mL, 81.7 mmol) was added at 0 ° C., and 35 Stir at 5 ° C.
  • Step XIV 2- ⁇ 4- [4- (1-methylethoxy) phenyl] -4-methyl-2,5-dioxoimidazolidin-1-yl ⁇ acetic acid (S) -methyl ((S) -c19) Manufacturing of: Obtained by optical resolution of 5- [4- (1-methylethoxy) phenyl-4-yl] -5-methylimidazolidine-2,4-dione produced according to WO2009 / 144961 using the optical column described below.
  • Step XV (S) -2- ⁇ 4- [4- (1-methylethoxy) phenyl] -4-methyl-2,5-dioxoimidazolidin-1-yl ⁇ acetic acid ((S) -c20) Manufacturing: 2- ⁇ 4- [4- (1-methylethoxy) phenyl] -4-methyl-2,5-dioxoimidazolidin-1-yl ⁇ acetic acid (S) -methyl (6.05 g, 18.9 mmol) was dissolved in methanol (30 mL), 2M aqueous potassium carbonate solution (18.9 mL, 37.8 mmol) was added at 0 ° C., and the mixture was stirred at 45 ° C.
  • Step XVI-1 (S) -3- (2- ⁇ (2S, 5R) -4- [4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) ) -2-Propylphenyl] -2,5-dimethylpiperazin-1-yl ⁇ -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl] -5-methylimidazolidine-2,4-dione Production of ((S) -B): 2- ⁇ 4-[(2R, 5S) -2,5-dimethylpiperazin-1-yl] -3-propylphenyl ⁇ -1,1,1,3,3,3-hexafluoropropan-2-ol ( 200 mg, 0.502 mmol) was dissolved in dichloromethane (2.0 mL) and (S) -2- ⁇ 4- [4- (1-methylethoxy) phenyl] -4-methyl-2,
  • Step XVI-2 (S) -3- (2- ⁇ (2S, 5R) -4- [4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) ) -2-Propylphenyl] -2,5-dimethylpiperazin-1-yl ⁇ -2-oxoethyl) -5- [4- (1-methylethoxy) phenyl] -5-methylimidazolidine-2,4-dione Production of ((S) -B): (S) -2- ⁇ 4- [4- (1-Methylethoxy) phenyl] -4-methyl-2,5-dioxoimidazolidin-1-yl ⁇ acetic acid (100 mg, 0.326 mmol) was dissolved in toluene.
  • the present invention provides a method for producing a high yield and high optical purity of the optically active carbinol compound (1) represented by the general formula (1).
  • Compound (1) has an LXR ⁇ agonistic action, and atherosclerosis such as atherosclerosis, arteriosclerosis, and diabetes caused by diabetes; dyslipidemia; hypercholesterolemia; lipid-related disease; inflammation Inflammatory diseases caused by sex cytokines; skin diseases such as allergic skin diseases; diabetes; or Alzheimer's disease preventive and / or therapeutic agents, etc. Has the above applicability.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
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Abstract

La présente invention concerne un procédé de fabrication d'un composé carbinol optiquement actif présentant des effets d'activation de LXR β et un intermédiaire de production de celui-ci. Selon la présente invention, un composé carbinol optiquement actif représenté par la formule (1) est fabriqué par réaction d'un composé représenté par la formule (2) avec un composé représenté par la formule (3). Dans les formules (1) à (3), R1 représente un groupe alkyle en C2 à C3, R2 et R3 peuvent être identiques ou différents et représentent des groupes alkyle en C1 à C3, * représente un atome de carbone asymétrique, et R4 représente une structure choisie parmi A à E.
PCT/JP2014/004447 2013-08-30 2014-08-29 Procédé de fabrication de composé carbinol optiquement actif WO2015029447A1 (fr)

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PL120693B1 (en) * 1979-05-21 1982-03-31 Inst Farmakologii Pan Process for preparing novel derivatives of 5,5-diphenyl-3-n-hydantoinacetic acididantoinuksusnojj kisloty
JPH1059947A (ja) * 1996-06-20 1998-03-03 Hoechst Ag キラルで、非ラセミの（４−アリール−２，５−ジオキソイミダゾリジン−１−イル）酢酸の製造方法
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JP2004534826A (ja) * 2001-06-21 2004-11-18 アベンティス・フアーマ・リミテッド アザインドール
WO2005040109A1 (fr) * 2003-10-22 2005-05-06 Neurocrine Biosciences, Inc. Ligands du recepteur de la melanocortine et compositions et methodes associees
JP2009541318A (ja) * 2006-06-22 2009-11-26 メルク エンド カムパニー インコーポレーテッド チロシンキナーゼ阻害剤
WO2010125811A1 (fr) * 2009-04-29 2010-11-04 興和株式会社 Composé carbinol ayant un groupe de liaison hétérocyclique
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PL120693B1 (en) * 1979-05-21 1982-03-31 Inst Farmakologii Pan Process for preparing novel derivatives of 5,5-diphenyl-3-n-hydantoinacetic acididantoinuksusnojj kisloty
JP2000508310A (ja) * 1996-04-05 2000-07-04 ソシエテ・ド・コンセイユ・ド・ルシエルシエ・エ・ダアツプリカーシヨン・シヤンテイフイツク・（エス．セー．エール．アー．エス） α▲下１▼―交感神経受容体拮抗薬
JPH1059947A (ja) * 1996-06-20 1998-03-03 Hoechst Ag キラルで、非ラセミの（４−アリール−２，５−ジオキソイミダゾリジン−１−イル）酢酸の製造方法
JP2004534826A (ja) * 2001-06-21 2004-11-18 アベンティス・フアーマ・リミテッド アザインドール
WO2005040109A1 (fr) * 2003-10-22 2005-05-06 Neurocrine Biosciences, Inc. Ligands du recepteur de la melanocortine et compositions et methodes associees
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WO2012161812A1 (fr) * 2011-02-28 2012-11-29 Abbott Laboratories Inhibiteurs tricycliques de kinases

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