Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
  • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/14—Extraction; Separation; Purification
  • C07K1/30—Extraction; Separation; Purification by precipitation
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/14—Extraction; Separation; Purification
  • C07K1/30—Extraction; Separation; Purification by precipitation
  • C07K1/306—Extraction; Separation; Purification by precipitation by crystallization
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
  • C07K1/14—Extraction; Separation; Purification
  • C07K1/34—Extraction; Separation; Purification by filtration, ultrafiltration or reverse osmosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
  • C07K7/52—Cyclic peptides containing at least one abnormal peptide link with only normal peptide links in the ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/64—Cyclic peptides containing only normal peptide links

Definitions

• the present invention relates to a method for producing a cyclic peptide compound, in particular a method for producing a cyclic peptide compound that has selective KRAS inhibitory activity against HRAS and NRAS.
• RAS is a protein belonging to the small GTPase family, and KRAS, NRAS, and HRAS are known.
• the activated or inactivated state of RAS is determined by its binding state with GDP or GTP. It is activated by the exchange reaction of GDP to GTP by GEF (guanine nucleotide exchange factor) and inactivated by the hydrolysis of GTP by GAP (GTPase-activating proteins) (Non-patent Document 1).
• GEF renal nucleotide exchange factor
• GAP GTPase-activating proteins
• Activated RAS induces cell proliferation, survival, and differentiation by activating various downstream signals such as the MAPK pathway, the PI3K/Akt pathway, and the RAL pathway, and the constitutive activation of RAS plays an important role in the development and progression of cancer.
• Non-patent Document 2 It is known that the RAS-RAF-MEK-ERK pathway is activated in cancer due to activation of upstream signals of RAS, constitutive activation of RAS, and/or activating mutations of RAS. These activating mutations of RAS have been observed in many types of cancer. G12, G13, and Q61 are known to be hotspots for RAS mutations, with high frequency mutations observed at G12 in KRAS and at Q61 in NRAS. It is also known that these mutations are associated with patient prognosis (Non-Patent Document 3).
• cyclic peptide compound (1) represented by the following formula (1) (hereinafter also referred to as cyclic peptide compound (1)) has been reported, which has selectivity in RAS, specifically, a selective KRAS inhibitory effect over HRAS and NRAS (Patent Document 1).
• Patent Document 1 describes a method for producing a cyclic peptide compound (1) by a cyclization reaction at cyclization position A.
• a cyclic dimer was confirmed as a by-product in addition to the desired cyclic peptide compound (1), and the ratio of the cyclic peptide compound (1) to the cyclic dimer was 75:25, indicating low selectivity.
• the cyclized precursor peptide compound described in Patent Document 1 is produced by sequentially linking amino acids or some tripeptides by the Fmoc method and synthesizing on a solid phase.
• Solid phase synthesis requires excessive amounts of amino acids and reagents, and large amounts of organic solvents are required for washing in each step, so it has been desirable to avoid solid phase synthesis as much as possible when producing large quantities.
• crystals of cyclic peptide compound (1) there have been no reports of crystals of cyclic peptide compound (1).
• the present invention has been made in light of the above circumstances, and an objective of the present invention is to provide an efficient method for producing a cyclic peptide compound (1) having a double bond bridged between amino acids. Another object of the present invention is to provide crystals of the cyclic peptide compound (1) that are highly stable.
• the present invention provides a cyclization method for producing a cyclic peptide compound (1) having a double bond bridged between amino acids, which is a cyclization method based on the cyclization position, capable of reducing the amount of cyclic dimer produced as a by-product.
• the present invention provides an efficient production method for producing a cyclized precursor peptide compound, in which three fragment peptides are each synthesized and synthesized by liquid phase fragment coupling.
• the present invention provides crystals of the cyclic peptide compound (1) and a method for producing the crystals by crystallization.
• the present invention includes, in one non-limiting specific embodiment, the following.
• a method for producing a cyclic peptide compound represented by formula (1), or a salt thereof, or a solvate thereof comprising a step of cyclizing the compound by reacting an N-terminal amino acid residue with a C-terminal amino acid residue of a peptide compound represented by formula (2) or (3) in a solvent (cyclization step).
• R 1 is C 1 -C 6 alkyl
• P1 is C1 - C6 alkyl
• R2 is C1 - C6 alkyl
• R 3 is hydrogen or R 3 together with P 3 , the carbon atom to which R 3 is attached, and the nitrogen atom to which P 3 is attached form a 4- to 7-membered saturated heterocyclic ring
• P3 is C1 - C6 alkyl, or C3 - C8 cycloalkyl, or P3 together with R3, the carbon atom to which R3 is attached, and the nitrogen atom to which P3 is attached form a 4- to 7-membered saturated heterocycle
• P4 is C1 - C6 alkyl
• R 5 is benzyl optionally substituted with one or more groups selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 3 -C 8 cycloalkyl
• P6 is C1 - C6 alkyl
• a method for producing a cyclic peptide compound represented by formula (1), or a salt thereof, or a solvate thereof comprising the steps of: (a) preparing a peptide compound represented by any one of formulas (4) to (6), or a salt thereof, or a solvate of said peptide compound or salt; (b) a step of reacting and linking the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound represented by formulae (4) to (6) in a solvent (linking step); and (c) the step of cyclizing the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound obtained in the step (b) by reacting them in a solvent (cyclization step).
• R 1 is C 1 -C 6 alkyl
• P1 is C1 - C6 alkyl
• R2 is C1 - C6 alkyl
• R 3 is hydrogen or R 3 together with P 3 , the carbon atom to which R 3 is attached, and the nitrogen atom to which P 3 is attached form a 4- to 7-membered saturated heterocyclic ring
• P3 is C1 - C6 alkyl, or C3 - C8 cycloalkyl, or P3 together with R3, the carbon atom to which R3 is attached, and the nitrogen atom to which P3 is attached form a 4- to 7-membered saturated heterocycle
• P4 is C1 - C6 alkyl
• R 5 is benzyl optionally substituted with one or more groups selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 3 -C 8 cycloalkyl
• P6 is C1 - C6 alkyl
• step (b) (b-1)
• the method according to [A2] comprising a step (linking step) of reacting and linking the N-terminal amino acid residue of a peptide compound represented by formula (5) and the C-terminal amino acid residue of a peptide compound represented by formula (6) in a solvent to convert them into a peptide compound represented by formula (7).
• step (b) further (b-2) a step of reacting and linking the N-terminal amino acid residue of the peptide compound represented by formula (4) and the C-terminal amino acid residue of the peptide compound represented by formula (7) in a solvent to convert them into the peptide compound represented by formula (2) (linking step); and
• step (c) (c-1)
• step (b) further (b-3) a step of reacting and linking the N-terminal amino acid residue of the peptide compound represented by formula (7) and the C-terminal amino acid residue of the peptide compound represented by formula (4) in a solvent to convert them into a compound represented by formula (3) (linking step); and
• step (c) (c-2)
• the method according to [A3] which comprises a step of cyclizing the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound represented by formula (3) in a solvent (cyclization step).
• [A6] The method according to any of [A1] to [A5], wherein the linkage between the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound is a linkage between the amino group of the N-terminal amino acid residue and the carboxyl group of the C-terminal amino acid residue.
• [A7] The method according to any of [A1] to [A6], wherein the link between the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound is an amide bond between the amino group of the N-terminal amino acid residue and the carboxyl group of the C-terminal amino acid residue.
• [A8] The method according to any one of [A1] to [A7], wherein the solvent in the cyclization step comprises one or more selected from the group consisting of nitrile-based solvents, halogen-based solvents, ether-based solvents, amide-based solvents, ester-based solvents, and carbonate-based solvents.
• the nitrile-based solvent is one or more selected from the group consisting of acetonitrile and propionitrile;
• the halogen-based solvent is one or more selected from the group consisting of dichloromethane, chloroform, and 1,2-dichloroethane;
• the ether-based solvent is one or more selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, 4-methyltetrahydropyran, 1,3-dioxolane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, t-butyl methyl ether, diglyme, triglyme, anisole, and tetraglyme;
• the amide solvent is one or more selected from the group consisting of DMF, NMP, DMA, NEP, NBP, and formamide;
• the ester solvent is one or
• [A12] The method according to [A8], wherein the solvent in the cyclization step is acetonitrile, 2-methyltetrahydrofuran, or ethyl acetate.
• [A13] The method according to any one of [A1] to [A12], wherein the cyclization step is carried out in the presence of a condensation reagent.
• the condensation reagent in the cyclization step is one or more selected from the group consisting of HATU, COMU, DMT-MM, PyOxim, PyBOP, HCTU, T3P, EDCI, BEP, and PyClop.
• [A15] The method according to [A13], wherein the condensation reagent in the cyclization step is one selected from the group consisting of HATU, COMU, PyOxim, PyBOP, HCTU, and T3P.
• [A16] The method according to [A13], wherein the condensation reagent in the cyclization step is HATU.
• [A17] The method according to [A13], wherein the condensation reagent in the cyclization step is COMU.
• [A18] The method according to [A13], wherein the condensation reagent in the cyclization step is HATU, and the solvent in the cyclization step is acetonitrile.
• the base in the cyclization step is 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-collidine, 2,6-lutidine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenzo[ij]quinolizine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 7-methyl-1,5
• DBU 1,8-diazabicyclo[5.4.0]-7-undecene
• DBU 1,8-diazabicyclo[5.4.0]-7-undecene
• DBU 1,8-diazabicyclo[5.4.0]-7-undecene
• DBU 1,8-di
• [A30] The method according to [A22], wherein the condensation reagent in the cyclization step is COMU, the solvent in the cyclization step is 2-methyltetrahydrofuran, and the base in the cyclization step is 2,6-lutidine.
• [A31] The method according to any one of [A1] to [A30], wherein the cyclization step is carried out by a liquid phase method.
• [A32] The method according to any of [A1] to [A31], wherein in the cyclization step, the peptide compound and the base are mixed into a mixed solution obtained by mixing a solvent for the cyclization step with the condensation reagent.
• [A33] The method according to any one of [A1] to [A32], characterized in that the content of all by-products produced in the cyclization step is less than 20%, less than 15%, less than 10%, less than 5%, or less than 3%, based on the total amount of the product, as determined by a UVarea value at 220 nm by HPLC analysis.
• [A34] The method according to any one of [A1] to [A33], characterized in that the content of each by-product generated in the cyclization step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or an undetectable amount, based on the total amount of the product, as determined by a UVarea value at 220 nm by HPLC analysis.
• [A35] The method according to any one of [A1] to [A34], characterized in that the content of each by-product produced in the cyclization step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or an undetectable amount, based on the total amount of the product, as determined by a UV area value at 220 nm by HPLC analysis, and the by-products include epimers and/or cyclic dimers.
• the solvent in the linking step comprises one or more selected from the group consisting of nitrile-based solvents, halogen-based solvents, ether-based solvents, amide-based solvents, ester-based solvents, and carbonate-based solvents.
• the nitrile solvent is one or more selected from the group consisting of acetonitrile and propionitrile;
• the halogen-based solvent is one or more selected from the group consisting of dichloromethane, chloroform, and 1,2-dichloroethane;
• the ether-based solvent is one or more selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, 4-methyltetrahydropyran, 1,3-dioxolane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, t-butyl methyl ether, diglyme, triglyme, anisole, and tetraglyme;
• the amide solvent is one or more selected from the group consisting of DMF, NMP, DMA, NEP, NBP, and formamide;
• the ester solvent is one or more selected
• [A40] The method according to [A38], wherein the solvent in the linking step is one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, THF, ethyl acetate, isopropyl acetate, DMF, and anisole.
• the solvent in the linking step is a mixed solvent of one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-methyltetrahydrofuran, 4-methyltetrahydropyran P, THF, ethyl acetate, isopropyl acetate, and anisole, and DMF.
• [A42] The method according to [A38], wherein the solvent in the linking step is a mixed solvent of acetonitrile, 2-methyltetrahydrofuran, and DMF.
• [A43] The method according to [A38], wherein the solvent in the linking step is a mixed solvent of 2-methyltetrahydrofuran and DMF.
• [A44] The method according to any one of [A1] to [A43], wherein the linking step is carried out in the presence of a condensation reagent.
• [A52] The method according to [A44], wherein the condensation reagent in the linking step is COMU, and the solvent in the linking step is acetonitrile or 2-MeTHF.
• [A53] The method according to [A44], wherein the condensation reagent in the linking step is COMU, and the solvent in the linking step is a mixed solvent of acetonitrile, 2-MeTHF, and DMF.
• [A54] The method according to any one of [A1] to [A53], wherein the linking step is carried out in the presence of a base.
• [A55] The method according to [A54], wherein the base in the linking step is an organic base.
• the base in the linking step is 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-collidine, 2,6-lutidine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenzo[ij]quinolizine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 7-methyl-1,5
• DBU 1,8-diazabicyclo[5.4.0]-7-undecene
• DBU 1,8-diazabicyclo[5.4.0]-7-undecene
• [A58] The method according to [A54], wherein the base in the linking step is one or more selected from the group consisting of 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-collidine, 2,6-lutidine, and pyridine.
• the condensation reagent in the linking step is HATU
• the solvent in the linking step is acetonitrile or 2-MeTHF
• the base in the linking step is N,N-diisopropylethylamine (DIPEA).
• [A62-2] The method according to [A54], wherein the condensation reagent in the linking step is HATU, the solvent in the linking step is acetonitrile, and the base in the linking step is N-methylmorpholine.
• [A63] The method according to any one of [A1] to [A62], wherein the linking step is carried out by a liquid phase method.
• [A64] The method according to any one of [A1] to [A63], wherein column chromatography is used for isolating and/or purifying the cyclic peptide compound, or a salt thereof, or a solvate thereof.
• [A65] The method according to any one of [A1] to [A63], wherein column chromatography is not used for isolation and/or purification of the cyclic peptide compound, or a salt thereof, or a solvate thereof.
• [A66] The method according to any one of [A1] to [A65], further comprising a step of isolating and/or purifying the cyclic peptide compound, or a salt thereof, or a solvate thereof by crystallization to obtain the cyclic peptide compound, or a salt thereof, or a crystal thereof.
• [A67] The method according to any one of [A1] to [A66], wherein R 1 is C 3 -C 4 alkyl.
• [A67-1] The method according to any one of [A1] to [A66], wherein R 1 is n-propyl.
• [A67-2] The method according to any one of [A1] to [A66], wherein R 1 is 2-methylpropyl.
• [A68] The method according to any one of [A1] to [A67], wherein P 1 is C 1 -C 4 alkyl.
• [A68-1] The method according to any one of [A1] to [A67], wherein P 1 is methyl.
• [A69] The method according to any one of [A1] to [A68], wherein R 2 is C 3 -C 4 alkyl.
• [A69-1] The method according to any one of [A1] to [A68], wherein R 2 is 1-methylpropyl.
• [A70] The method according to any one of [A1] to [A69], wherein R 3 is hydrogen or R 3 forms a 5-membered saturated heterocycle together with P 3 , the carbon atom to which R 3 is bonded, and the nitrogen atom to which P 3 is bonded.
• [A70-1] The method according to any one of [A1] to [A69], wherein R 3 is hydrogen.
• [A70-2] The method according to any one of [A1] to [A69], wherein R 3 forms a 5-membered saturated heterocycle together with P 3 , the carbon atom to which R 3 is bonded, and the nitrogen atom to which P 3 is bonded.
• [A71] The method according to any one of [A1] to [A70], wherein P3 is C 1 -C 4 alkyl, or P3 forms a 5-membered saturated heterocycle together with R3 , the carbon atom to which R3 is bonded, and the nitrogen atom to which P3 is bonded.
• [A71-1] The method according to any one of [A1] to [A70], wherein P3 is methyl.
• [A71-2] The method according to any one of [A1] to [A70], wherein P3 forms a 5-membered saturated heterocycle together with R3 , the carbon atom to which R3 is bonded, and the nitrogen atom to which P3 is bonded.
• [A72] The method according to any one of [A1] to [A71], wherein P4 is C 1 -C 4 alkyl.
• [A72-1] The method according to any one of [A1] to [A71], wherein P4 is methyl.
• [A73] The method according to any one of [A1] to [A72], wherein R 5 is benzyl optionally substituted by C 1 -C 4 haloalkyl.
• [A73-1] The method according to any one of [A1] to [A72], wherein R 5 is 4-trifluoromethylbenzyl.
• [A74] The method according to any one of [A1] to [A73], wherein P6 is C 1 -C 4 alkyl.
• [A74-1] The method according to any one of [A1] to [A73], wherein P6 is methyl.
• [A75] The method according to any one of [A1] to [A74], wherein R 7 is phenethyl optionally substituted with one or more groups selected from the group consisting of halogen, trifluoromethyl, and methoxy.
• [A75-1] The method according to any one of [A1] to [A74], wherein R 7 is 3-methoxy-4-trifluoromethylphenethyl.
• [A75-2] The method according to any one of [A1] to [A74], wherein R 7 is 3,5-difluoro-4-trifluoromethylphenethyl.
• [A76] The method according to any one of [A1] to [A75], wherein R 8 together with P 8 , the carbon atom to which R 8 is bonded, and the nitrogen atom to which P 8 is bonded forms a 5-membered saturated heterocycle, and the 5-membered saturated heterocycle is substituted with C 1 -C 4 alkyl.
• [A76-1] The method according to any one of [A1] to [ A75 ], wherein R 8 forms a 5-membered saturated heterocycle together with P 8 , the carbon atom to which R 8 is bonded, and the nitrogen atom to which P 8 is bonded, and the 5-membered saturated heterocycle is substituted with ethoxy.
• [A77] The method according to any one of [A1] to [A76], wherein R 9 forms a 4- to 6-membered alicyclic ring together with Q 9 and the carbon atom to which R 9 and Q 9 are bonded.
• [A77-1] The method according to any one of [A1] to [A76], wherein R 9 forms a 4-membered alicyclic ring together with Q 9 and the carbon atom to which R 9 and Q 9 are bonded.
• [A77-2] The method according to any one of [A1] to [A76], wherein R 9 forms a 5-membered alicyclic ring together with Q 9 and the carbon atom to which R 9 and Q 9 are bonded.
• [A78] The method according to any one of [A1] to [A77], wherein P 9 is hydrogen or C 1 -C 4 alkyl.
• [A78-1] The method according to any one of [A1] to [A77], wherein P 9 is hydrogen.
• [A81] The method according to any one of [A1] to [A80], wherein R 11 is diC 1 -C 4 alkylaminocarbonyl, or 5- to 6-membered cyclic aminocarbonyl.
• [A81-1] The method according to any one of [A1] to [A80], wherein R 11 is dimethylaminocarbonyl.
• [A82] The method according to any one of [A1] to [A81], wherein P 11 is C 1 -C 4 alkyl.
• [A82-1] The method according to any one of [A1] to [A81], wherein P 11 is methyl.
• the carbamate protecting group is one selected from the group consisting of an Fmoc group, a Cbz group, a Troc group, an Alloc group, a Teoc group, a TSoc group, a BIBSoc group, an IPCSoc group, a BBSoc group, a CHBSoc group, a CDBSoc group, and a Boc group.
• the acyl-based protecting group is one selected from the group consisting of a trifluoroacetyl group, an acetyl group, and a benzoyl group.
• [A86] The method according to [A83], wherein the sulfonamide protecting group is one selected from the group consisting of a 2-nitrobenzenesulfonyl group, a 4-nitrobenzenesulfonyl group, and a 2,4-dinitrobenzenesulfonyl group.
• the silyl protecting group is one selected from the group consisting of a TMS group, a TBDMS group, a TES group, a TIPS group, and a TBDPS group.
• X 1 is hydrogen or a carbamate protecting group.
• [A88-1] The method according to any one of [A1] to [A87], wherein X 1 is hydrogen.
• [A88-2] The method according to any of [A1] to [A87], wherein X 1 is an Fmoc group.
• [A89] The method according to any one of [A1] to [A88], wherein X3 is hydrogen or a carbamate protecting group.
• [A89-1] The method according to any one of [A1] to [A88], wherein X 3 is hydrogen.
• [A89-2] The method according to any of [A1] to [A88], wherein X 3 is a Cbz group.
• [A90] The method according to any one of [A1] to [A89], wherein X 5 is hydrogen or a carbamate protecting group.
• [A90-1] The method according to any one of [A1] to [A89], wherein X 5 is hydrogen.
• [A90-2] The method according to any of [A1] to [A89], wherein X5 is a Cbz group.
• [A91-1] The method according to any one of [A1] to [A90], wherein the halogen is chlorine or bromine.
• [A91-2] The method according to any one of [A1] to [A90], wherein the optionally substituted alkoxy is t-butoxy, methoxy, ethoxy, or isopropoxy.
• [A91-3] The method according to any one of [A1] to [A90], wherein the optionally substituted aryloxy is pentafluorophenyloxy or nitrophenyloxy.
• [A91-4] The method according to any one of [A1] to [A90], wherein the optionally substituted aralkoxy is optionally substituted benzyloxy.
• [A91-5] The method according to any of [A1] to [A90], wherein the optionally substituted cyclic aminooxy is N-hydroxysuccinic acid iminoxy.
• [ A91-6 ] The method according to any one of [A1] to [A90 ] , wherein the group represented by -OSiRxRyRz is trimethylsilyloxy, triethylsilyloxy, triisopropylsilyloxy, triphenylsilyloxy, tri-t-butylsilyloxy, di-t-butylisobutylsilyloxy, or tris(triethylsilyl)silyloxy.
• [A92] The method according to any one of [A1] to [A91], wherein X 2 is a hydroxyl group, t-butoxy, or benzyloxy.
• [A92-1] The method according to any one of [A1] to [A91], wherein X 2 is a hydroxyl group.
• [A92-2] The method according to any of [A1] to [A91], wherein X 2 is t-butoxy.
• [A93] The method according to any one of [A1] to [A92], wherein X 4 is a hydroxyl group, t-butoxy, or benzyloxy.
• [A93-1] The method according to any one of [A1] to [A92], wherein X 4 is a hydroxyl group.
• [A93-2] The method according to any of [A1] to [A92], wherein X 4 is t-butoxy.
• [A94] The method according to any one of [A1] to [A93], wherein X 6 is a hydroxyl group, t-butoxy, or benzyloxy.
• [A94-1] The method according to any one of [A1] to [A93], wherein X 6 is a hydroxyl group.
• [A94-2] The method according to any one of [A1] to [A93], wherein X 6 is t-butoxy.
• the cyclic peptide compound is represented by formula (1a): The method according to any one of [A1] to [A95], [A97] The cyclic peptide compound is represented by formula (1a): The method according to any one of [A1] to [A95], wherein the crystal is a crystal of a cyclic peptide compound represented by the formula: [A97-1] The method according to [A97], wherein the crystal of the cyclic peptide compound is a non-solvate crystal or a solvate crystal. [A97-2] The method according to [A97], wherein the crystal of the cyclic peptide compound is a solvate crystal.
• [A97-3] The method according to [A97-2], wherein the solvate crystal of the cyclic peptide compound is a hydrate crystal.
• [B1] A method for producing a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof, comprising a step of cyclization (cyclization step) of reacting an N-terminal amino acid residue with a C-terminal amino acid residue of a peptide compound represented by formula (2a) or (3a) in a solvent.
• X1 and X5 each independently represent a hydrogen atom or a protecting group for an amino group
• X2 and X4 each independently represent a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted aryloxy group, an optionally substituted aralkoxy group, an optionally substituted cyclic aminooxy group, or a group represented by -OSiRxRyRz (wherein Rx , Ry , and Rz each independently represent an alkyl group or an aryl group).
• a method for producing a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof comprising the steps of: (a) providing a peptide compound represented by any one of formulas (4a) to (6a), or a salt thereof, or a solvate of said peptide compound or salt; (b) a step of reacting and linking the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound represented by formulae (4a) to (6a) in a solvent (linking step); and (c) the step of cyclizing the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound obtained in the step (b) by reacting them in a solvent (cyclization step).
• X 1 , X 3 and X 5 each independently represent a hydrogen atom or a protecting group for an amino group
• X 2 , X 4 and X 6 each independently represent a hydroxyl group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy, or a group represented by -OSiR x R y R z (wherein R x , R y and R z each independently represent an alkyl or an aryl).
• step (b) (b-1)
• the method according to [B2] which comprises a step (linking step) of reacting and linking the N-terminal amino acid residue of a peptide compound represented by formula (5a) and the C-terminal amino acid residue of a peptide compound represented by formula (6a) in a solvent to convert them into a peptide compound represented by formula (7a).
• step (b) further (b-2) a step of reacting and linking the N-terminal amino acid residue of the peptide compound represented by formula (4a) and the C-terminal amino acid residue of the peptide compound represented by formula (7a) in a solvent to convert them into the peptide compound represented by formula (2a) (linking step); and
• step (c) (c-1)
• the method according to [B3] which comprises a step of cyclizing the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound represented by formula (2a) in a solvent (cyclization step).
• step (b) further (b-3) a step of reacting and linking the N-terminal amino acid residue of the peptide compound represented by formula (7a) and the C-terminal amino acid residue of the peptide compound represented by formula (4a) in a solvent to convert them into the peptide compound represented by formula (3a) (linking step); and
• step (c) (c-2)
• the method according to [B3] which comprises a step of cyclizing the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound represented by formula (3a) by reacting them in a solvent (cyclization step).
• [B6] The method according to any one of [B1] to [B5], wherein the solvent in the cyclization step is a solvent according to any one of [A8] to [A12].
• [B7] The method according to any one of [B1] to [B6], wherein the cyclization step is carried out in the presence of a condensation reagent.
• [B8] The method according to [B7], wherein the condensation reagent in the cyclization step is a condensation reagent according to any one of [A14] to [A17].
• [B9] The method according to [B7], wherein the solvent and condensation reagent in the cyclization step are the solvent and condensation reagent according to any one of [A18] to [A21].
• [B10] The method according to any one of [B1] to [B9], wherein the cyclization step is carried out in the presence of a base.
• the method according to [B10], wherein the base in the cyclization step is a base according to any one of [A24] to [A26].
• [B12] The method according to [B10], wherein the solvent, condensation reagent, and base in the cyclization step are the solvent, condensation reagent, and base according to any one of [A27] to [A30].
• [B13] The method according to any one of [B1] to [B12], wherein the cyclization step is carried out by a liquid phase method.
• [B14] The method according to any one of [B1] to [B13], wherein in the cyclization step, the peptide compound and the base are mixed into a mixed solution obtained by mixing a solvent for the cyclization step with the condensation reagent.
• [B15] The method according to any one of [B1] to [B14], characterized in that the content of all by-products produced in the cyclization step is less than 20%, less than 15%, less than 10%, less than 5%, or less than 3%, based on the total amount of the product, as determined by the UVarea value at 220 nm by HPLC analysis.
• [B16] The method according to any one of [B1] to [B15], characterized in that the content of each by-product generated in the cyclization step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or an undetectable amount, based on the total amount of the product, as determined by the UV area value at 220 nm by HPLC analysis.
• [B17] The method according to any one of [B1] to [B16], characterized in that the content of each by-product produced in the cyclization step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or an undetectable amount based on the total amount of the product, as determined by the UV area value at 220 nm by HPLC analysis, and the by-products include epimers and/or cyclic dimers.
• [B21] The method according to any one of [B1] to [B20], wherein the linking step is carried out in the presence of a condensation reagent.
• the condensation reagent in the linking step is a condensation reagent according to any one of [A45] to [A49].
• the solvent and condensation reagent in the linking step are the solvent and condensation reagent according to any one of [A50] to [A53].
• the ligation step is carried out in the presence of a base.
• [B25] The method according to [B24], wherein the base in the linking step is a base according to any one of [A55] to [A59].
• [B26] The method according to [B24], wherein the solvent, condensation reagent and base in the linking step are the solvent, condensation reagent and base according to any one of [A60] to [A62].
• [B27] The method according to any one of [B1] to [B26], wherein the linking step is carried out by a liquid phase method.
• [B28] The method according to any one of [B1] to [B27], wherein column chromatography is used for isolating and/or purifying the cyclic peptide compound, or a salt thereof, or a solvate thereof.
• [B29] The method according to any one of [B1] to [B27], wherein column chromatography is not used for isolating and/or purifying the cyclic peptide compound, or a salt thereof, or a solvate thereof.
• [B30] The method according to any one of [B1] to [B29], further comprising a step of isolating and/or purifying the cyclic peptide compound, or a salt thereof, or a solvate thereof by crystallization to obtain the cyclic peptide compound, or a salt thereof, or a crystal thereof.
• [C1] A compound represented by formula (4a) or a salt thereof.
• X 1 is hydrogen or a protecting group for an amino group
• X2 is a hydroxyl group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy, or a group represented by -OSiRxRyRz (wherein Rx , Ry , and Rz are each independently an alkyl or an aryl).
• Rx , Ry , and Rz are each independently an alkyl or an aryl.
• [C4] The compound or salt thereof according to any one of [C1] to [C3], wherein X 2 is t-butoxy.
• [C6] A compound represented by formula (5a) or a salt thereof.
• X3 is hydrogen or a protecting group for an amino group
• X4 is a hydroxyl group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy, or a group represented by -OSiRxRyRz (wherein Rx , Ry , and Rz are each independently an alkyl or an aryl).
• Rx , Ry , and Rz are each independently an alkyl or an aryl.
• [C9] The compound or salt thereof according to any one of [C6] to [C8], wherein X 4 is t-butoxy.
• [C11] A compound represented by formula (6a) or a salt thereof.
• X5 is hydrogen or a protecting group for an amino group
• X6 is a hydroxyl group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy, or a group represented by -OSiRxRyRz (wherein Rx , Ry , and Rz are each independently an alkyl or an aryl).
• Rx , Ry , and Rz are each independently an alkyl or an aryl.
• [C14] The compound or a salt thereof according to any one of [C11] to [C13], wherein X 6 is a hydroxyl group or t-butoxy.
• [C16] A compound represented by formula (7a) or a salt thereof.
• X5 is hydrogen or a protecting group for an amino group
• X4 is a hydroxyl group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy, or a group represented by -OSiRxRyRz (wherein Rx , Ry , and Rz are each independently an alkyl or an aryl).
• [C17] The compound or a salt thereof according to [C16], wherein X 5 is hydrogen.
• X 5 is a Cbz group.
• [C21] A compound represented by formula (2a) or a salt thereof.
• X5 is hydrogen or a protecting group for an amino group
• X2 is a hydroxyl group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy, or a group represented by -OSiRxRyRz (wherein Rx , Ry , and Rz are each independently an alkyl or an aryl).
• Rx , Ry , and Rz are each independently an alkyl or an aryl.
• [C24] The compound or a salt thereof according to any one of [C21] to [C23], wherein X 2 is a hydroxyl group or t-butoxy.
• [C25] 2-[[(2S)-2-[(4Z,7S)-7-[[(2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-amino-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino ]-2-Cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butanoyl]-methyl-amino]p
• [C26] A compound represented by the formula (3a) or a salt thereof.
• X 1 is hydrogen or a protecting group for an amino group
• X4 is a hydroxyl group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy, or a group represented by -OSiRxRyRz (wherein Rx , Ry , and Rz are each independently an alkyl or an aryl).
• [C27] The compound or a salt thereof according to [C26], wherein X 1 is hydrogen.
• [C28] The compound or salt thereof according to [C26], wherein X 1 is an Fmoc group.
• [C31] A method for producing the compound according to any one of [C1] to [C30], which does not use solid-phase synthesis.
• [C32] A method for producing a cyclic peptide compound represented by formula (1a), which does not use solid-phase synthesis.
• [D1] A crystal of a cyclic peptide compound represented by formula (1a), a salt thereof, or a solvate thereof.
• [D5-2] The crystal according to [D4], wherein the hydrate crystal is a Form A crystal having peaks at the following diffraction angles (2 ⁇ values) in powder X-ray diffraction: 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° ( ⁇ 0.2°).
• [D5-3] The Form A crystal according to any one of [D5] to [D5-2], wherein the diffraction angle (2 ⁇ value) is a diffraction angle (2 ⁇ value) of a hydrate crystal stored at a relative humidity of 10% or more for 15 minutes or more.
• [D7-2] The crystal according to [D3], wherein the solvate crystal is a Form F crystal comprising peaks at the following diffraction angles (2 ⁇ values) in powder X-ray diffraction: 6.99°, 8.49°, 9.49°, 9.88°, 10.21°, 11.81°, 12.32°, 12.75°, 13.17°, 13.94°, 14.92°, 15.20°, 15.64°, 16.78°, 17.01°, and 17.47° ( ⁇ 0.2°).
• [D7-3] The crystal according to any one of [D7] to [D7-2], wherein the solvate crystal is an acetone/heptane/hydrate.
• [D8-3] The Form J crystal according to any one of [D8] to [D8-2], wherein the diffraction angle (2 ⁇ value) is a diffraction angle (2 ⁇ value) of a hydrate crystal stored at a relative humidity of less than 10% for 15 minutes or more.
• [D9-3] The Form Y crystal according to any one of [D9] to [D9-2], wherein the diffraction angle (2 ⁇ value) is a diffraction angle (2 ⁇ value) of a hydrate crystal stored at a relative humidity of less than 30% for 15 minutes or more.
• [D10-2] The crystal according to [D3], wherein the solvate crystal is a Form K crystal comprising peaks at the following diffraction angles (2 ⁇ values) in powder X-ray diffraction: 7.49°, 7.91°, 8.14°, 9.11°, 9.33°, 11.04°, 11.71°, 12.52°, 13.21°, 13.70°, 14.82°, 15.13°, 15.52°, 15.68°, 17.22°, and 17.51° ( ⁇ 0.2°).
• [D11] The crystal according to [D3], wherein the solvate crystal is a dimethylsulfoxide/heptane/hydrate crystal of Form G having the structure shown in Figure 1 by single crystal X-ray analysis.
• [D11-1] The crystal according to [D3], wherein the solvate crystal is a 2-propanol/heptane/hydrate crystal of Form E having the structure shown in FIG. 3 by single crystal X-ray analysis.
• [D11-2] The crystal according to [D3], wherein the solvate crystal is an ethanol/hydrate crystal of Form H having the structure shown in Figure 8 by single crystal X-ray analysis.
• [D11-3] The crystal according to [D3], wherein the solvate crystal is a 1,4-dioxane/hydrate crystal of Form D having the structure shown in FIG. 26 by single crystal X-ray analysis.
• [D11-7] The crystal according to [D3], wherein the solvate crystal is a propylene glycol/hydrate crystal of Form M, the data of which is shown in FIG. 30(A) by simultaneous thermogravimetry and differential thermal analysis.
• [D11-8] The crystal according to [D3], wherein the solvate crystal is a propylene glycol solvate crystal of Form N having the diffraction angle shown in FIG. 29 by powder X-ray diffraction.
• [D11-9] The crystal according to [D3], wherein the solvate crystal is a propylene glycol solvate crystal of Form N showing the data of simultaneous thermogravimetry and differential thermal analysis shown in FIG. 30 (B).
• [D12] A method for producing a crystal of a cyclic peptide compound according to any one of [D1] to [D10-2], comprising the steps of dissolving the cyclic peptide compound in an amount of a polar organic solvent in which the cyclic peptide compound can be dissolved to obtain a solution, and adding a hydrocarbon solvent or water to the solution to obtain a crystal of the cyclic peptide compound.
• [D12-1] The method according to [D12], wherein the purity of the starting cyclic peptide compound is 85% or more.
• [D13] A method for producing a crystal of a cyclic peptide compound according to any one of [D1] to [D10-2], comprising the step of adding a mixture of a hydrocarbon solvent and a polar organic solvent, or a mixture of water and a polar organic solvent, to the cyclic peptide compound in an amorphous state to obtain a crystal of the cyclic peptide compound.
• [D14] The method according to any one of [D12] to [D13-1], wherein the polar organic solvent is one or more selected from the group consisting of DMSO, acetone, 2-butanone, methanol, ethanol, 1-propanol, 2-propanol, propylene glycol, 1,4-dioxane, and ethyl acetate.
• the polar organic solvent is one or more selected from the group consisting of DMSO, acetone, 2-butanone, methanol, ethanol, 1-propanol, 2-propanol, propylene glycol, 1,4-dioxane, and ethyl acetate.
• the polar organic solvent is acetone.
• [D15-1] The method according to [D14], wherein the polar organic solvent is ethanol.
• [D16] The method according to any one of [D12] to [D13-1], wherein the hydrocarbon solvent is one or more selected from the group consisting of heptane, hexane, pentane, toluene, and xylene.
• the hydrocarbon solvent is heptane.
• [D18] A method for producing a crystal of a cyclic peptide compound according to any one of [D1] to [D10-2], comprising the steps of dissolving the cyclic peptide compound in an amorphous state in DMSO to obtain a solution, freeze-drying the solution to obtain a freeze-dried product of the cyclic peptide compound, and adding a mixture of water and a polar organic solvent to the freeze-dried product to obtain a crystal of the cyclic peptide compound.
• [D19] The method according to [D18], wherein the polar organic solvent is one or more selected from the group consisting of DMSO, acetone, 2-butanone, methanol, ethanol, 1-propanol, 2-propanol, 1,4-dioxane and propylene glycol.
• the polar organic solvent is acetone.
• [D22] The method according to any one of [D12] to [D21], further comprising a step of drying the crystals after the step of obtaining the crystals of the cyclic peptide compound.
• [D23] The method according to any one of [D12] to [D22], wherein the crystal of the cyclic peptide compound is a solvate crystal.
• [D24] The method according to [D23], wherein the solvate crystal of the cyclic peptide compound is a hydrate crystal.
• [D25] The method according to [D21] or [D22], wherein the crystals of the cyclic peptide compound are formed as solvate crystals in a solvent and are obtained as hydrate crystals after a filtering step and/or a drying step.
• [D26] A composition comprising a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof, wherein the compound contains an impurity, the cyclic dimer of formula (1a), at a ratio of 1.5 wt % or less.
• [D27] A composition comprising a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof, wherein the compound contains an impurity, the cyclic dimer of formula (1a), at a ratio of 0.001 w/w% or more.
• [D28] A composition comprising a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof, wherein the compound contains acetone in an amount of 2.0 w/w% or less.
• [D29] A composition comprising a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof, wherein the compound contains acetone in a proportion of 0.001 w/w% or more.
• the numbers referred to in the dependent claims include their subnumbers unless otherwise specified.
• [A67] referred to in the dependent claims includes [A67] as well as its subnumber [A67-1]. The same applies to other numbering schemes.
• the present invention it is possible to efficiently produce a cyclic peptide compound, or a salt or solvate thereof, while suppressing the production of the by-product cyclic dimer.
• the production method of the present invention is particularly useful for the synthesis of peptides on a large scale, since it can reduce the production costs of peptide compounds and reduce the environmental burden.
• Example 3-1 The crystal structure of the crystal (Form G) obtained in Example 3-1 is shown.
• Compound 1 is drawn using the Capped Stick model, and the others are drawn using the Ball and Stick model.
• the results of powder X-ray diffraction measurement of the crystal (Form A) obtained in Example 3-2 are shown.
• the vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2 ⁇ (°).
• the crystal structures of the crystals obtained in Example 3-3 are shown.
• Compound 1 is depicted using the Capped Stick model, and the others are depicted using the Ball and Stick model.
• the results of powder X-ray diffraction measurement of the crystal (Form E) obtained in Example 3-3 are shown.
• the vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2 ⁇ (°).
• the results of powder X-ray diffraction measurement of the crystal (Form B) obtained in Example 3-4 are shown.
• the vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2 ⁇ (°).
• the results of powder X-ray diffraction measurement of the crystal (Form B) obtained in Example 3-5 are shown.
• the vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2 ⁇ (°).
• the crystal structure of the crystal (Form H) obtained in Example 3-6 is shown.
• Compound 1 is drawn using the Capped Stick model, and the others are drawn using the Ball and Stick model.
• the results of powder X-ray diffraction measurement of the crystal (Form B) obtained in Example 3-6 are shown.
• the vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2 ⁇ (°).
• the crystal structure of the crystal (Form C) obtained in Example 3-7 is shown.
• Compound 1 is drawn using the Capped Stick model, and the others are drawn using the Ball and Stick model.
• the results of powder X-ray diffraction measurement of the crystal (Form B) obtained in Example 3-7 are shown.
• the vertical axis is the diffraction intensity
• the horizontal axis is the diffraction angle 2 ⁇ (°).
• the results of powder X-ray diffraction measurement of the crystal (Form A) obtained in Example 3-8 are shown.
• the vertical axis is the diffraction intensity
• the horizontal axis is the diffraction angle 2 ⁇ (°).
• the results of simultaneous thermogravimetry and differential thermal analysis of the crystal (Form A) obtained in Example 3-8 are shown.
• the horizontal axis is temperature (°C)
• the right vertical axis is the weight change (%) of the sample in the thermogravimetric analysis.
• the left vertical axis represents the heat flow observed in the differential thermal analysis.
• the results of 1 H-NMR measurement of the crystal (Form A) obtained in Example 3-8 are shown below.
• the vertical axis represents signal intensity
• the horizontal axis represents chemical shift ⁇ (ppm).
• the results of powder X-ray diffraction measurement of the crystal (Form A) obtained in Example 3-9 are shown.
• the vertical axis is the diffraction intensity
• the horizontal axis is the diffraction angle 2 ⁇ (°).
• the results of simultaneous thermogravimetry and differential thermal analysis of the crystal (Form A) obtained in Example 3-9 are shown.
• the horizontal axis is temperature (°C)
• the right vertical axis is the weight change (%) of the sample in the thermogravimetric analysis.
• the left vertical axis represents the heat flow observed in the differential thermal analysis.
• the results of 1 H-NMR measurement of the crystal (Form A) obtained in Example 3-9 are shown below.
• the vertical axis represents signal intensity
• the horizontal axis represents chemical shift ⁇ (ppm).
• the results of powder X-ray diffraction measurement of the crystal (Form F) obtained in Example 3-10 are shown.
• the vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2 ⁇ (°).
• the crystal structure of the crystal (Form F) obtained in Example 3-11 is shown.
• Compound 1 is drawn using the Capped Stick model, and the others are drawn using the Ball and Stick model.
• the results of powder X-ray diffraction measurement of the crystal (Form A) obtained in Example 3-12 are shown.
• the vertical axis is the diffraction intensity
• the horizontal axis is the diffraction angle 2 ⁇ (°).
• the results of simultaneous thermogravimetry and differential thermal analysis of the crystal (Form A) obtained in Example 3-12 are shown.
• the horizontal axis is temperature (°C), and the right vertical axis is the weight change (%) of the sample in the thermogravimetric analysis.
• the left vertical axis represents the heat flow observed in the differential thermal analysis.
• the results of powder X-ray diffraction measurements of the crystals obtained in Example 3-12 at relative humidities of (A) 0% (Form J), (B) 10% (Form A), (C) 20% (Form A), (D) 50% (Form A), and (E) 90% (Form A) are shown.
• the vertical axis represents the diffraction intensity
• the horizontal axis represents the diffraction angle 2 ⁇ (°). The peaks near 4.89° and 6.65° in the figure are peaks derived from the measuring equipment.
• the results of powder X-ray diffraction measurement of the crystal (Form B) obtained in Example 3-13 are shown.
• the vertical axis is the diffraction intensity
• the horizontal axis is the diffraction angle 2 ⁇ (°).
• the results of simultaneous thermogravimetry and differential thermal analysis of the crystal (Form B) obtained in Example 3-13 are shown.
• the horizontal axis is temperature (°C)
• the right vertical axis is the weight change (%) of the sample in the thermogravimetric analysis.
• the left vertical axis represents the heat flow observed in the differential thermal analysis.
• Compound 1 is drawn using the Capped Stick model, and the others are drawn using the Ball and Stick model.
• the crystal structure of the crystal (Form L) obtained in Example 3-16 is shown.
• Compound 1 is drawn using the Capped Stick model, and the others are drawn using the Ball and Stick model.
• the results of powder X-ray diffraction measurement of the crystal (Form L) obtained in Example 3-16 (A: wet powder, B: dry powder) are shown.
• the vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2 ⁇ (°).
• the results of powder X-ray diffraction measurement of the crystals obtained in Example 3-17 are shown (A: Form M, B: Form N).
• the vertical axis is the diffraction intensity
• the horizontal axis is the diffraction angle 2 ⁇ (°).
• the results of simultaneous thermogravimetric and differential thermal analysis of the crystal (Form N) obtained in Example 3-17 are shown.
• the horizontal axis is temperature (°C)
• the right vertical axis is the weight change (%) of the sample in the thermogravimetric analysis.
• the left vertical axis represents the heat flow observed in the differential thermal analysis.
• the crystal structure of the crystal (Form M) obtained in Example 3-18 is shown.
• Compound 1 is drawn using the Capped Stick model, and the others are drawn using the Ball and Stick model.
• the results of powder X-ray diffraction measurement of the crystal (Form K) obtained in Example 3-19 are shown.
• the vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2 ⁇ (°).
• the results of simultaneous thermogravimetry and differential thermal analysis of the crystal (Form K) obtained in Example 3-19 are shown.
• the horizontal axis is temperature (°C), and the right vertical axis is the weight change (%) of the sample in the thermogravimetric analysis.
• the left vertical axis represents the heat flow observed in the differential thermal analysis.
• the results of 1 H-NMR measurement of the crystal (Form K) obtained in Example 3-19 are shown below.
• the vertical axis represents signal intensity, and the horizontal axis represents chemical shift ⁇ (ppm).
• Example 5-9 The results of powder X-ray diffraction measurements of the crystals obtained in (A) Example 5-1, (B) Example 5-2, (C) Example 5-3, (D) Example 5-4, (E) Example 5-5, (F) Example 5-6, (G) Example 5-7, (H) Example 5-8, and (I) Example 5-9 are shown.
• the vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2 ⁇ (°).
• the results of powder X-ray diffraction measurement of the crystal (Form B) obtained in Example 3-22 are shown.
• the vertical axis is the diffraction intensity, and the horizontal axis is the diffraction angle 2 ⁇ (°).
• halogen examples include F, Cl, Br, and I.
• alkyl refers to a monovalent group derived by removing any one hydrogen atom from an aliphatic hydrocarbon, which does not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in the skeleton, and has a subset of hydrocarbyl or hydrocarbon group structures containing hydrogen and carbon atoms. Alkyl includes not only linear but also branched chain alkyls.
• alkyl examples include alkyls having 1 to 20 carbon atoms (C 1 -C 20 , hereinafter "C p -C q " means that the number of carbon atoms is p to q), preferably C 1 -C 10 alkyl, and more preferably C 1 -C 6 alkyl.
• alkyl examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, isobutyl (2-methylpropyl), n-pentyl, s-pentyl (1-methylbutyl), t-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylmethylprop
• alkenyl refers to a monovalent group having at least one double bond (two adjacent sp2 carbon atoms). Depending on the arrangement of the double bond and the substituents (if present), the geometry of the double bond can be in an
• E E
• Z cis or trans configuration.
• Alkenyl includes not only linear but also branched chains. Preferred examples of alkenyl include C 2 -C 10 alkenyl, more preferably C 2 -C 6 alkenyl.
• alkenyl examples include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, hexenyl, and the like.
• alkynyl refers to a monovalent group having at least one triple bond (two adjacent sp carbon atoms). Alkynyl includes not only straight chain but also branched chain. Preferred alkynyl groups include C 2 -C 10 alkynyl groups, more preferably C 2 -C 6 alkynyl groups. Specific examples of alkynyl groups include ethynyl, 1-propynyl, propargyl, 3-butynyl, pentynyl, hexynyl, and the like.
• cycloalkyl refers to a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, including a monocyclic ring, a bicyclo ring, and a spiro ring.
• Preferred examples of cycloalkyl include C 3 -C 8 cycloalkyl, more preferably C 3 -C 7 cycloalkyl, and even more preferably C 3 -C 6 cycloalkyl.
• cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, and spiro[3.3]heptyl.
• aryl refers to a monovalent aromatic hydrocarbon ring, i.e., an aromatic hydrocarbon ring group.
• Preferred examples of aryl include C 6 -C 10 aryl.
• Specific examples of aryl include phenyl, naphthyl (e.g., 1-naphthyl, 2-naphthyl), and the like.
• heteroaryl refers to an aromatic monovalent cyclic group containing 1 to 5 heteroatoms in addition to carbon atoms, i.e., an aromatic heterocyclic group.
• the ring may be a single ring or a condensed ring with other rings, and may be partially saturated.
• the number of atoms constituting the heteroaryl ring is preferably 5 to 10 (5- to 10-membered heteroaryl), and more preferably 5 to 7 (5- to 7-membered heteroaryl).
• heteroaryl examples include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl,
• heteroarylalkyl refers to a group in which one or more hydrogen atoms of an "alkyl” as defined herein are substituted with a “heteroaryl” as defined herein.
• a 5- to 10-membered heteroaryl C 1 -C 6 alkyl is preferred, and a 5- to 10-membered heteroaryl C 1 -C 2 alkyl is more preferred.
• heteroarylalkyl examples include 3-thienylmethyl, 4-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 2-(6-quinolyl)ethyl, 2-(7-quinolyl)ethyl, 2-(6-indolyl)ethyl, 2-(5-indolyl)ethyl, 2-(5-benzofuranyl)ethyl, and the like.
• alkoxy refers to an oxy group bonded to an "alkyl” as defined herein.
• alkoxy C 1 -C 6 alkoxy is preferred, and C 1 -C 4 alkoxy is more preferred.
• Specific examples of the alkoxy include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy, 3-methylbutoxy, and the like.
• alkoxyalkyl refers to a group in which one or more hydrogen atoms of an "alkyl” as defined herein are substituted with an “alkoxy” as defined herein.
• alkoxyalkyl C 1 -C 6 alkoxy C 1 -C 6 alkyl is preferred, and C 1 -C 6 alkoxy C 1 -C 2 alkyl is more preferred.
• alkoxyalkyl examples include methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, i-butoxymethyl, s-butoxymethyl, t-butoxymethyl, pentyloxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, and the like.
• aryloxy refers to an oxy group bonded to an "aryl” as defined herein.
• Preferred examples of aryloxy include C 6 -C 10 aryloxy.
• Specific examples of aryloxy include phenoxy, 1-naphthyloxy, and 2-naphthyloxy.
• aralkoxy refers to an oxy group bonded to an "aralkyl” as defined herein.
• aralkoxy C 7 -C 14 aralkoxy is preferred, and C 7 -C 10 aralkoxy is more preferred.
• Specific examples of the aralkoxy include benzyloxy, phenethyloxy, and 3-phenylpropoxy.
• amino means -NH2 in a narrow sense, and -NRR' in a broad sense, where R and R' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R and R' mean a group forming a ring together with the nitrogen atom to which they are attached.
• Preferred examples of amino include -NH2 , mono- C1 - C6 alkylamino, di- C1 - C6 alkylamino, and 4- to 8-membered cyclic amino.
• monoalkylamino refers to a group in which R is hydrogen and R' is an "alkyl” as defined herein, among “amino” as defined herein.
• Preferred examples of monoalkylamino include mono-C 1 -C 6 alkylamino.
• Specific examples of monoalkylamino include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, s-butylamino, and t-butylamino.
• dialkylamino refers to an "amino" as defined herein, in which R and R' are independently “alkyl” as defined herein.
• Preferred examples of dialkylamino include diC 1 -C 6 alkylamino.
• Specific examples of dialkylamino include dimethylamino and diethylamino.
• cyclic amino refers to a group in which R and R' form a ring together with the nitrogen atom to which they are attached, as defined in this specification.
• Preferred examples of cyclic amino include 4- to 8-membered cyclic amino.
• Specific examples of cyclic amino include 1-azetidyl, 1-pyrrolidyl, 1-piperidyl, 1-piperazyl, 4-morpholinyl, 3-oxazolidyl, 1,1-dioxidethiomorpholinyl-4-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, and the like.
• cyclic aminooxy refers to an oxy group to which "cyclic amino” as defined in this specification is bonded.
• cyclic aminooxy preferably, 4- to 8-membered cyclic aminooxy is mentioned.
• Specific examples of the cyclic amino include 1-azetidyloxy, 1-pyrrolidyloxy, 1-piperidyloxy, 1-piperazyloxy, 4-morpholinyloxy, 3-oxazolidyloxy, 1,1-dioxidethiomorpholinyl-4-yloxy, 3-oxa-8-azabicyclo[3.2.1]octan-8-yloxy, etc.
• aminocarbonyl refers to a carbonyl group bonded to "amino" as defined herein.
• Preferred examples of aminocarbonyl include -CONH 2 , mono C 1 -C 6 alkylaminocarbonyl, mono C 3 -C 6 cycloalkylaminocarbonyl, di C 1 -C 6 alkylaminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl.
• aminocarbonyl examples include -CONH 2 , dimethylaminocarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolidinylcarbonyl, 1,1-dioxidethiomorpholinyl-4-ylcarbonyl, and 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl.
• haloalkyl refers to a group in which one or more hydrogen atoms of an "alkyl” as defined herein are substituted with halogen.
• haloalkyl haloC 1 -C 6 alkyl is preferred, and fluoroC 1 -C 6 alkyl is more preferred.
• Specific examples of haloalkyl include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, 5,5-difluoropentyl, and the like.
• alicyclic ring means a non-aromatic hydrocarbon ring.
• the alicyclic ring may have an unsaturated bond in the ring.
• the carbon atoms constituting the ring may be oxidized to form a carbonyl.
• the alicyclic ring may be a monocyclic ring (referred to as a monocyclic alicyclic ring in this specification) or may form a condensed ring with a saturated alicyclic ring such as a cyclopentane ring or a cyclohexane ring, or an aromatic hydrocarbon ring such as a benzene ring or a naphthalene ring.
• Preferred examples of the alicyclic ring include 3- to 10-membered alicyclic rings, and more preferably 3- to 8-membered alicyclic rings.
• Specific examples of the alicyclic ring include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, and a bicyclo[2.2.1]heptane ring.
• saturated heterocycle refers to a non-aromatic heterocycle that contains preferably 1 to 5, more preferably 1 to 3, heteroatoms in the atoms that constitute the ring and has no unsaturated bonds in the ring.
• a saturated heterocycle does not have double and/or triple bonds in the ring.
• a saturated heterocycle may be a monocycle, or may form a condensed ring or a spiro ring with another ring, for example, a saturated alicyclic ring such as a cyclopentane ring or a cyclohexane ring, or a saturated heterocycle such as a tetrahydropyran ring, a dioxane ring, or a pyrrolidine ring.
• saturated heterocycles include 4- to 10-membered saturated heterocycles, more preferably 4- to 7-membered saturated heterocycles, and even more preferably 5-membered saturated heterocycles.
• Specific examples of saturated heterocyclic rings include an azetidine ring, an oxoazetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, a 2-oxopyrrolidine ring, a 4-oxopyrrolidine ring, a piperidine ring, a 4-oxopiperidine ring, a piperazine ring, a pyrazolidine ring, an imidazolidine ring, an oxazolidine ring, an isoxazolidine ring, a thiazolidine ring, an isothiazolidine ring,
• amino group protecting group includes carbamate protecting groups, acyl protecting groups, sulfonamide protecting groups, and silyl protecting groups.
• carbamate protecting groups include 9-fluorenylmethyloxycarbonyl group (Fmoc group), benzyloxycarbonyl group (Cbz group), 2,2,2-trichloroethoxycarbonyl group (Troc group), allyloxycarbonyl group (Alloc group), 2-(trimethylsilyl)ethoxycarbonyl group (Teoc group), triisopropylsilyloxycarbonyl group (TSoc group), di-t-butylisobutyl
• the protecting group include a silyloxycarbonyl group (BIBSoC group), a di-i-propyl-t-butylsilyloxycarbonyl group (IPCSoc group), a benzyl-di-t-butylsilyloxycarbonyl group (BBSoC group
• acyl protecting group examples include a trifluoroacetyl group, an acetyl group, a benzoyl group, etc.
• sulfonamide protecting group examples include a 2-nitrobenzenesulfonyl group, a 4-nitrobenzenesulfonyl group, a 2,4-dinitrobenzenesulfonyl group, etc.
• silyl-based protecting groups include trimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS), triethylsilyl (TES), triisopropylsilyl (TIPS), and t-butyldiphenylsilyl (TBDPS).
• one or more means one or more than one.
• the term means a number from one to the maximum number of substituents permitted by that group. Specific examples of "one or more” include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and/or more.
• peptide compound as used herein means two or more amino acid residues linked together by amide bonds. Peptides having an ester bond in part of the main chain, such as depsipeptides, are also included in the term “peptide compound” as used herein.
• the number of amino acid residues contained in a peptide in this disclosure is not particularly limited, but may be preferably 5 to 30 residues, more preferably 8 to 15 residues, and even more preferably 9 to 13 residues.
• the peptide compound in this disclosure preferably contains at least three N-substituted amino acids, more preferably contains at least five, and even more preferably contains at least six. These N-substituted amino acids may be present consecutively or discontinuously in the peptide compound.
• the peptide compound in this disclosure may be linear or cyclic, with cyclic peptide compounds being preferred.
• cyclic peptide compound refers to a peptide compound having a cyclic structure composed of four or more amino acid residues.
• the cyclic peptide compound may have amino acids not included in the cyclic structure or a chain peptide structure. It may also have a
• Cyclization of a peptide compound means forming a cyclic structure of a cyclic portion containing four or more amino acid residues.
• the number of amino acids contained in the cyclic portion of the cyclic peptide compound in this specification is not particularly limited, but examples include 4 to 20 residues, 5 to 15 residues, and 6 to 13 residues.
• a method for converting a linear peptide compound to a cyclic peptide compound can be carried out by performing a bond formation reaction within the molecule using a method described in Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 3rd Edition (by R. C. Larock) or March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (by M. B. Smith and J.
• Examples of C-C bond formation reactions using transition metals as catalysts include Suzuki reaction, Heck reaction, and Sonogashira reaction.
• Examples of functional group conversion reactions that are performed after bond-forming reactions include oxidation reactions and reduction reactions. Specifically, examples include reactions in which sulfur atoms are oxidized to convert to sulfoxide groups or sulfone groups.
• Another example is a reduction reaction in which a triple bond or a double bond among carbon-carbon bonds is reduced to a double bond or a single bond.
• amino acid includes natural amino acids and non-natural amino acids.
• amino acid may refer to an amino acid residue.
• natural amino acid refers to Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, and Pro.
• Non-natural amino acids are not particularly limited, but examples thereof include ⁇ -amino acids, D-amino acids, N-substituted amino acids, ⁇ , ⁇ -disubstituted amino acids, amino acids whose side chains are different from those of natural amino acids, and hydroxycarboxylic acids. As used herein, amino acids are allowed to have any configuration.
• the side chain of the amino acid can be freely selected from, in addition to a hydrogen atom, for example, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a heteroarylalkyl group, a cycloalkyl group, and a spiro-linked cycloalkyl group.
• a hydrogen atom for example, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a heteroarylalkyl group, a cycloalkyl group, and a spiro-linked cycloalkyl group.
• substituents are not limited, and may be independently selected from any substituents including, for example, a halogen atom, an oxygen atom, a nitrogen atom, a sulfur atom, a boron atom, a silicon atom, or a phosphorus atom. That is, examples include an optionally substituted alkyl group, an alkoxy group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a cycloalkyl group, or an oxo, an aminocarbonyl, a halogen atom, and the like.
• the amino acid in this specification may be a compound having a carboxyl group and an amino group in the same molecule (even in this case, proline, hydroxyproline, azetidine-2-carboxylic acid, etc., in which the nitrogen atom of the amino group and any atom of the side chain form a ring together, are also included in the amino acid).
• amino acid residues that make up a peptide compound may be simply referred to as "amino acids.”
• N-terminal amino acid residue refers to the amino acid residue located at the N-terminus of a peptide.
• C-terminal amino acid residue refers to the amino acid residue located at the C-terminus of a peptide.
• the "number of amino acids” and “number of amino acid residues” refer to the number of amino acid residues (amino acid units) that make up a peptide compound, and refer to the number of amino acid units that are generated when the amide bonds, ester bonds, and cyclized bonds that link the amino acids are cleaved.
• amino acids constituting the peptide compounds in this specification include all corresponding isotopes.
• An isotope of an "amino acid” is one in which at least one atom is replaced with an atom having the same atomic number (proton number) but a different mass number (sum of the number of protons and neutrons) in a ratio different from that in nature.
• substituents containing a halogen atom include alkyl groups, cycloalkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, and aralkyl groups each having a halogen as a substituent, and more specifically, examples include fluoroalkyl, difluoroalkyl, and trifluoroalkyl.
• Examples of oxy (-OR) include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, aralkyloxy, etc.
• alkoxy C 1 -C 4 alkoxy and C 1 -C 2 alkoxy are preferred, and among these, methoxy and ethoxy are preferred.
• Examples of oxycarbonyl include alkyloxycarbonyl, cycloalkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, and aralkyloxycarbonyl.
• Examples of carbonyloxy include alkylcarbonyloxy, cycloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, and aralkylcarbonyloxy.
• thiocarbonyl examples include alkylthiocarbonyl, cycloalkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, and aralkylthiocarbonyl.
• Examples of carbonylthio include alkylcarbonylthio, cycloalkylcarbonylthio, alkenylcarbonylthio, alkynylcarbonylthio, arylcarbonylthio, heteroarylcarbonylthio, and aralkylcarbonylthio.
• aminocarbonyl examples include alkylaminocarbonyl (e.g., C1 - C6 or C1 - C4 alkylaminocarbonyl, particularly ethylaminocarbonyl, methylaminocarbonyl, etc.), cycloalkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, etc.
• alkylaminocarbonyl e.g., C1 - C6 or C1 - C4 alkylaminocarbonyl, particularly ethylaminocarbonyl, methylaminocarbonyl, etc.
• cycloalkylaminocarbonyl alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl,
• Examples of carbonylamino include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, and aralkylcarbonylamino.
• Examples of oxycarbonylamino include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, and aralkyloxycarbonylamino.
• sulfonylamino examples include alkylsulfonylamino, cycloalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, etc.
• H atom bonded to the N atom in -NH-SO 2 -R is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.
• aminosulfonyl examples include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, etc.
• examples include groups in which the H atom bonded to the N atom in -SO 2 -NHR is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.
• sulfamoylamino examples include alkylsulfamoylamino, cycloalkylsulfamoylamino, alkenylsulfamoylamino, alkynylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino, aralkylsulfamoylamino, etc.
• the two H atoms bonded to the N atom in -NH-SO 2 -NHR may be substituted with substituents independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and these two substituents may form a ring.
• thio examples are selected from alkylthio, cycloalkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, aralkylthio, etc.
• sulfonyl examples include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, and the like.
• secondary amino examples include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, and aralkylamino.
• tertiary amino examples include, for example, alkyl(aralkyl)amino and other amino groups having any two substituents independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, and the like, and these any two substituents may form a ring.
• Specific examples include dialkylamino, particularly C 1 -C 6 dialkylamino, C 1 -C 4 dialkylamino, dimethylamino, diethylamino, and the like.
• C p -C q dialkylamino group refers to a group in which an amino group is substituted with two C p -C q alkyl groups, and both C p -C q alkyl groups may be the same or different.
• substituted amidino examples include those in which the three substituents R, R', and R" on the N atom are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, such as alkyl(aralkyl)(aryl)amidino.
• substituted guanidino examples include groups in which R, R', R", and R''' are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, or groups in which these groups form a ring.
• aminocarbonylamino examples include groups in which R, R', and R" are each independently selected from a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, or groups in which these form a ring.
• the compound of the present invention may be a salt thereof, preferably a chemically acceptable salt thereof.
• the compound of the present invention or a salt thereof may be a solvate thereof, preferably a chemically acceptable solvate thereof.
• the salt of the compound of the present invention may be, for example, hydrochloride; hydrobromide; hydroiodide; phosphate; phosphonate; sulfate; sulfonate such as methanesulfonate and p-toluenesulfonate; carboxylate such as acetate, citrate, malate, tartrate, succinate, salicylate; or alkali metal salt such as sodium salt and potassium salt; alkaline earth metal salt such as magnesium salt and calcium salt; ammonium salt such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, tetraalkylammonium salt, etc.
• a solvate of a compound refers to a compound that forms a molecular group together with a solvent, and is not particularly limited as long as it is a solvate formed by a solvent. If the solvent is water, it is called a hydrate.
• the solvates of the compounds of the present invention are preferably hydrates, and specific examples of such hydrates include monohydrates to decahydrates, preferably monohydrates to pentahydrates, and more preferably monohydrates to trihydrates.
• solvates of the compounds of the present invention include solvates with a single solvent such as water, alcohol (e.g., methanol, ethanol, 1-propanol, 2-propanol, etc.), and dimethylformamide, as well as solvates with multiple solvents.
• a single solvent such as water, alcohol (e.g., methanol, ethanol, 1-propanol, 2-propanol, etc.), and dimethylformamide, as well as solvates with multiple solvents.
• the compound according to the present invention When the compound according to the present invention is obtained as a free form, the compound can be converted into its hydrate or solvate according to a conventional method.
• the compound according to the present invention when the compound according to the present invention is obtained as a free form, the compound can be converted into the salt that the compound may form, or into its hydrate or solvate according to a conventional method.
• the hydrate, ethanol solvate, etc. of the cyclic peptide compound represented by formula (1a) or its salt can be included.
• the cyclic peptide compound represented by formula (1a) may be hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nodahydrate, decahydrate, or monoethanolate, or the sodium salt of the cyclic peptide compound represented by formula (1a) may be hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nodahydrate, decahydrate, or monoethanolate, or the hydrochloride salt of the cyclic peptide compound represented by formula (1a) may be hydrated or ethanolate, but is not limited thereto.
• the hydrate or solvate may be produced in a crystalline or non-crystalline form, and in the case of a crystalline form, it may be a crystalline polymorph.
• a solvent such as ethanol and/or water can be added to the cyclic peptide compound represented by formula (1a) or a peptide compound described in the present specification, and the hydrate or solvate can be obtained by a conventional method, such as stirring, cooling, concentrating, and/or drying.
• the compound according to the present invention when obtained as a salt, hydrate, or solvate of the compound, the compound can be converted to its free form by a conventional method.
• solvent A/hydrate crystal means a crystal in which solvent A molecules and water molecules are contained in the crystal lattice of a compound.
• solvent A/solvent B/hydrate crystal means a crystal in which solvent A molecules, solvent B molecules, and water molecules are contained in the crystal lattice of a compound.
• acetone/heptane/hydrate crystal means a crystal in which acetone, heptane, and water are contained in the crystal lattice of a compound.
• A, B, and/or C includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, (vii) A, B, and C.
• epimer refers to a compound (epimer) in which the configuration of the side chain bonded to the ⁇ -carbon of an amino acid residue constituting a cyclic peptide compound is inverted.
• “Epimer” includes cyclic peptide compounds in which the ⁇ -carbon of the C-terminal amino acid residue of a linear peptide compound is inverted when the linear peptide compound is cyclized to produce the cyclic peptide compound.
• the epimer in the total product containing the cyclic peptide compound produced by the method of the present invention can be determined, for example, by the UVarea value at 210 nm or 220 nm by HPLC analysis.
• cyclic dimer refers to a compound in which peptide compounds, the raw materials of a cyclic peptide compound, are bonded together in a linear chain and then cyclized.
• the amount of cyclic dimers in the total product containing the cyclic peptide compound produced by the method of the present invention can be determined, for example, by the UVarea value at 210 nm or 220 nm by HPLC analysis.
• the present invention relates to a method for producing a cyclic peptide compound represented by formula (1), or a salt or solvate thereof, which comprises a step of cyclizing a peptide compound represented by formula (2) or (3) by reacting the N-terminal amino acid residue with the C-terminal amino acid residue in a solvent (cyclization step) (hereinafter, also referred to as "embodiment 1").
• the present invention relates to a method for producing a cyclic peptide compound represented by formula (1), or a salt thereof, or a solvate thereof, the method comprising: (a) preparing a peptide compound represented by any one of formulas (4) to (6), or a salt thereof, or a solvate of said peptide compound or salt; (b) a step of reacting and linking the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound represented by formulae (4) to (6) in a solvent (linking step); and (c) A step of cyclizing the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound obtained in step (b) by reacting them in a solvent (cyclization step) (hereinafter, also referred to as "Mode 2").
• the step (b) may include (b-1) a step of reacting and linking the N-terminal amino acid residue of the peptide compound represented by formula (5) and the C-terminal amino acid residue of the peptide compound represented by formula (6) in a solvent to convert them into the peptide compound represented by formula (7) (linking step).
• the step (b) includes, in addition to the step (b-1), (b-2) a step (linking step) of reacting and linking the N-terminal amino acid residue of the peptide compound represented by formula (4) and the C-terminal amino acid residue of the peptide compound represented by formula (7) in a solvent to convert them into the peptide compound represented by formula (2), and the step (c) may include (c-1)
• the method may include a step of cyclizing the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound represented by formula (2) by reaction in a solvent (cyclization step).
• the step (b) includes, in addition to the step (b-1), (b-3) a step (linking step) of reacting and linking the N-terminal amino acid residue of the peptide compound represented by formula (7) and the C-terminal amino acid residue of the peptide compound represented by formula (4) in a solvent to convert them into the compound represented by formula (3)
• the step (c) may include (c-2)
• the method may include a step of cyclizing the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound represented by formula (3) by reaction in a solvent (cyclization step).
• the link between the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound is preferably a link between the amino group of the N-terminal amino acid residue and the carboxyl group of the C-terminal amino acid residue, and more preferably a link between the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound is a link between the amino group of the N-terminal amino acid residue and the carboxyl group of the C-terminal amino acid residue via an amide bond.
• the solvent for the cyclization step preferably includes one or more selected from the group consisting of nitrile solvents, halogen solvents, ether solvents, amide solvents, ester solvents, and carbonate solvents.
• nitrile solvents include acetonitrile and propionitrile.
• halogen solvents include dichloromethane, chloroform, and 1,2-dichloroethane.
• ether solvents include diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, 4-methyltetrahydropyran, 1,3-dioxolane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, t-butyl methyl ether, diglyme, triglyme, anisole, and tetraglyme.
• amide solvents include DMF, NMP, DMA, NEP, NBP, and formamide.
• ester solvents include methyl acetate, ethyl acetate, methyl propionate, butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, pentyl acetate, and ⁇ -valerolactone.
• carbonate ester solvents include dimethyl carbonate, diethyl carbonate, and dibutyl carbonate.
• the solvent for the cyclization step is preferably one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, tetrahydrofuran, ethyl acetate, isopropyl acetate, dichloromethane, DMF, and anisole, more preferably one or more selected from the group consisting of acetonitrile, 2-methyltetrahydrofuran, ethyl acetate, and dichloromethane, and even more preferably acetonitrile, 2-methyltetrahydrofuran, or ethyl acetate.
• the cyclization step can be carried out in a solvent, in the presence or absence of a condensation reagent, in the presence or absence of a base, at a temperature between -20°C and the boiling point of the solvent, preferably between -20°C and 100°C, and preferably between -5°C and 60°C, by stirring the reaction mixture for 10 minutes to 48 hours.
• the condensation reagent, base, and amounts thereof used in the cyclization step are not particularly limited, and condensation reagents, bases, and amounts thereof generally used in peptide synthesis are preferred (e.g., Peptide Coupling Reagents, More than a Letter Soup (Chem. Rev. 2011, 111, 6557-6602.)).
• condensation reagents, bases, and amounts thereof generally used in peptide synthesis are preferred (e.g., Peptide Coupling Reagents, More than a Letter Soup (Chem. Rev. 2011, 111, 6557-6602.)).
• a carboxyl group that has been converted into an active ester in advance may be used.
• Condensation reagents for the cyclization step include, for example, N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), HCl), 1-hydroxy-1H-benzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), ethyl 2-cyano-2-(hydroxyimino)acetate (oxyma), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBt or HODhbt), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 2,3,4,5,6-pentafluorophenol (HOPfp), N-hydroxysuccinimide (HOSu), 6-chloro-1-hydroxy-1H-benzo
• the condensation reagent for the cyclization step is preferably one or more selected from the group consisting of HATU, COMU, DMT-MM, PyOxim, PyBOP, HCTU, T3P, EDCI, BEP, and PyClop, more preferably one selected from the group consisting of HATU, COMU, PyOxim, PyBOP, HCTU, and T3P, and even more preferably HATU and COMU.
• HATU and acetonitrile or 2-methyltetrahydrofuran are preferred, since by-products can be further suppressed.
• an organic base is preferably used, and among them, an organic base containing a tertiary amine is preferable.
• Specific examples of such bases include 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-collidine, 2,6-lutidine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenzo[ij]quinolizine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]-5-nonane (NDABCO), and 1,5-diazabicyclo[4.3.0]-5-nonane (NDABCO).
• DMAP dimethylaminopyridine
• the base for the cyclization step is preferably one or more selected from the group consisting of 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-collidine, 2,6-lutidine, and pyridine, and N,N-diisopropylethylamine (DIPEA) and 2,6-lutidine are preferred.
• DIPEA N,N-diisopropylethylamine
• DIPEA N,N-diisopropylethylamine
• the combinations of solvent, condensation reagent, and base are more effective in suppressing by-products, and therefore are preferably HATU, acetonitrile, and N,N-diisopropylethylamine (DIPEA); HATU, 2-methyltetrahydrofuran, and N,N-diisopropylethylamine (DIPEA); COMU, acetonitrile, and 2,6-lutidine; and COMU, 2-methyltetrahydrofuran, and 2,6-lutidine.
• DIPEA N,N-diisopropylethylamine
• DIPEA 2-methyltetrahydrofuran
• DIPEA N,N-diisopropylethylamine
• COMU acetonitrile, and 2,6-lutidine
• COMU 2-methyltetrahydrofuran, and 2,6-lutidine.
• the cyclization step is carried out in a liquid phase process.
• the cyclization step is carried out by mixing the peptide compound and, optionally, a base into a mixture obtained by mixing a solvent and a condensation reagent.
• this operation is sometimes referred to as "reverse dripping.”
• reverse dripping By reverse dripping the peptide compound and base over a long period of time, for example, several hours to several days, preferably 1 to 24 hours, and more preferably 1 to 10 hours, it is possible to suppress the production of by-products without using a large amount of solvent for dilution.
• the cyclic peptide compounds produced by the method of the present invention have a low content of by-products (e.g., epimers, cyclic dimers, etc.) and are highly pure, as described below.
• by-products e.g., epimers, cyclic dimers, etc.
• the content of total by-products produced in the cyclization step is less than 20%, less than 15%, less than 10%, less than 5%, or less than 3% based on the total amount of product, as determined by the UVarea value at 220 nm by HPLC analysis.
• the content of each by-product produced in the cyclization step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or an undetectable amount based on the total amount of product, as determined by the UVarea value at 220 nm by HPLC analysis.
• the content of each by-product produced in the cyclization step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or an undetectable amount based on the total amount of product, as determined by the UVarea value at 220 nm by HPLC analysis, and the by-products include epimers and/or cyclic dimers.
• the by-product produced in the cyclization step includes an epimer, and the epimer content is less than 10%, less than 7.5%, less than 5%, less than 2.5%, or less than 1% based on the total amount of product, as determined by the UVarea value at 220 nm by HPLC analysis.
• the by-products produced in the cyclization step include cyclic dimers, and the content of the cyclic dimers is less than 15%, less than 10%, less than 5%, less than 2.5%, or less than 1% based on the total amount of product, as determined by the UVarea value at 220 nm by HPLC analysis.
• the solvent in the linking step preferably includes one or more selected from the group consisting of nitrile-based solvents, halogen-based solvents, ether-based solvents, amide-based solvents, ester-based solvents, and carbonate-based solvents.
• nitrile-based solvents, halogen-based solvents, ether-based solvents, amide-based solvents, ester-based solvents, and carbonate-based solvents include those exemplified as the solvent in the cyclization step.
• the solvent in the linking step is preferably one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, tetrahydrofuran, ethyl acetate, isopropyl acetate, DMF, and anisole, more preferably a mixed solvent of one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, tetrahydrofuran, ethyl acetate, isopropyl acetate, and anisole and DMF, even more preferably a mixed solvent of acetonitrile, 2-methyltetrahydrofuran, and DMF, and particularly preferably a mixed solvent of 2-methyltetrahydrofuran and DMF.
• the linking step can be carried out in a solvent, in the presence or absence of a condensation reagent, in the presence or absence of a base, at a temperature between -20°C and the boiling point of the solvent, preferably between -20°C and 100°C, and preferably between -5°C and 60°C, by stirring the reaction composition for 10 minutes to 48 hours.
• condensation reagent, base, and amounts thereof used in the coupling step are not particularly limited, and condensation reagents, bases, and amounts thereof generally used in peptide synthesis are preferred (e.g., Peptide Coupling Reagents, More than a Letter Soup (Chem. Rev. 2011, 111, 6557-6602.)).
• condensation reagents, bases, and amounts thereof generally used in peptide synthesis are preferred (e.g., Peptide Coupling Reagents, More than a Letter Soup (Chem. Rev. 2011, 111, 6557-6602.)).
• a reagent in which the carboxyl group has been converted into an active ester in advance may be used.
• Condensation reagents for the linking step include those exemplified as condensation reagents for the cyclization step.
• the condensation reagent for the linking step is preferably one or more selected from the group consisting of HATU, COMU, DMT-MM, PyOxim, PyBOP, HCTU, T3P, EDCI, BEP, and PyClop, more preferably one selected from the group consisting of HATU, COMU, PyOxim, PyBOP, HCTU, and T3P, and even more preferably HATU and COMU.
• solvents and condensation reagents are preferred, since they can further suppress by-products: HATU and acetonitrile or 2-methyltetrahydrofuran; a mixed solvent of HATU and acetonitrile, 2-methyltetrahydrofuran, and DMF; COMU and acetonitrile or 2-methyltetrahydrofuran; and a mixed solvent of COMU and acetonitrile, 2-methyltetrahydrofuran, and DMF.
• the bases in the linking step include those exemplified as the bases in the cyclization step above.
• the bases in the linking step include 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-collidine, 2,6-lutidine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenzo[ij]quinolizine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,1,3,3-tetramethyl
• TMG guanidine
• the combinations of solvent, condensation reagent, and base can further suppress by-products, so the following are preferred: HATU and acetonitrile or 2-methyltetrahydrofuran and N,N-diisopropylethylamine (DIPEA); HATU and a mixed solvent of acetonitrile, 2-methyltetrahydrofuran, and DMF and N,N-diisopropylethylamine (DIPEA); COMU and acetonitrile or 2-methyltetrahydrofuran and N-methylmorpholine or 2,6-lutidine; and COMU and a mixed solvent of acetonitrile, 2-methyltetrahydrofuran, and DMF and N-methylmorpholine or 2,6-lutidine.
• DIPEA HATU and acetonitrile or 2-methyltetrahydrofuran and N,N-diisopropylethylamine
• DIPEA HATU and a mixed solvent of ace
• the linking step is carried out using a liquid phase method.
• the method of the present invention further comprises the step of preparing a peptide compound represented by formulas (4) to (6), or a salt thereof, or a solvate thereof.
• the peptide compound represented by formulas (4) to (6) can be produced, for example, by the following general method.
• Pg4 and Pg5 represent protecting groups for the amino group
• Xg6 represents an oxygen atom and a protecting group bonded thereto
• R5 represents the side chain of the amino acid
• P4 and P6 represent substituents for the nitrogen atom.
• Peptide compound (4) can be prepared using the following method.
• an aldehyde with the protected amino acid according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81)
• an oxazolidinone body with a cyclic protecting group can be obtained.
• an alkyl group having an olefin on the nitrogen atom can be introduced.
• an amino acid with a protected C-terminus can be condensed to extend the amino acid to the C-terminus.
• the condensation reaction can be performed using the condensation reagent and base used in the above-mentioned linking step, and various methods are possible, such as a combination of DIC and Oxyma, a combination of DIC and HOAt, a combination of HATU and DIPEA, or a combination of mixed acid anhydrides or acid halides as a carboxyl group activator.
• a combination of DIC and Oxyma a combination of DIC and HOAt
• a combination of HATU and DIPEA a combination of mixed acid anhydrides or acid halides as a carboxyl group activator.
• the protecting group of the amino group is deprotected, and then the protected amino acid having an olefin on the side chain can be extended.
• the olefins in the molecule can then be cyclized by a metathesis reaction.
• catalysts such as dichloro(2-isopropoxybenzylidene)(tricyclohexylphosphine)ruthenium(II): CAS number 203714-71-0, dichloro(3-phenyl-1H-inden-1-ylidene)bis(tricyclohexylphosphine)ruthenium(II): CAS number 250220-36-1, dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II): CAS number 172222-30-9, [1,3-bis(2,4,6-trimethylphenyl)-2-imido]-2,3-dichloro(2,4,6-trimethylphenyl) ...
• the protecting group at the C-terminus is deprotected to produce peptide compound (4) having an unprotected C-terminus, or the protecting group at the N-terminus is deprotected to produce peptide compound (4) having an unprotected N-terminus.
• Peptide compound (4) can also be prepared using the following method.
• An alkyl group having an olefin can be introduced to the nitrogen atom of an amino acid by reacting an alkylating agent having an olefin in the presence of a base. Then, an amino acid with a protected C-terminus can be condensed to extend the amino acid to the C-terminus.
• the condensation reaction can be carried out using the condensation reagent and base used in the above-mentioned linking step, and various methods are possible, such as a combination of DIC and Oxyma, a combination of DIC and HOAt, a combination of HATU and DIPEA, or a mixed acid anhydride or acid halide as an activator of the carboxyl group.
• the protected amino acid having an olefin in the side chain can be extended.
• the olefin in the molecule can be cyclized by a metathesis reaction.
• the catalyst used in the metathesis reaction is the same as that described above.
• the protecting group of the C-terminus can be deprotected to produce a peptide compound (4) with an unprotected C-terminus, or the protecting group of the N-terminus can be deprotected to produce a peptide compound (4) with an unprotected N-terminus.
• Peptide compound (5) can be prepared using the following method.
• the amino acid can be extended to the N-terminus by condensing a protected amino acid to an amino acid with a protected C-terminus.
• the condensation reaction can be carried out using the condensation reagent and base used in the linking step described above.
• various methods are possible, such as a combination of DIC and Oxyma, a combination of DIC and HOAt, a combination of HATU and DIPEA, or a mixed acid anhydride or acid halide, as an activator of the carboxyl group.
• a fragment consisting of three amino acids can be synthesized by condensing the protected amino acid.
• the protecting group of the C-terminus can be deprotected to produce a peptide compound (5) with an unprotected C-terminus, or the protecting group of the N-terminus can be deprotected to produce a peptide compound (5) with an unprotected N-terminus.
• Peptide compound (5) can also be synthesized by solid-phase synthesis.
• Xg 3 in the above formula is an amino acid bound to a solid-phase support via an oxygen atom and a linker bound thereto, and an amino acid can be extended to the N-terminus by condensing a protected amino acid with this.
• the condensation reaction can be performed using the condensation reagent and base used in the above-mentioned linking step, and various methods are possible, such as a combination of DIC and Oxyma, a combination of DIC and HOAt, a combination of HATU and DIPEA, or a combination via a mixed acid anhydride or acid halide as an activator of the carboxyl group.
• a fragment consisting of three amino acids can be synthesized by sequentially deprotecting the protecting group of the amino group and condensing the protected amino acid. Then, the peptide compound (5) with an unprotected C-terminus can be produced by cutting out from the solid phase.
• Peptide compound (6) can be prepared using the following method.
• the amino acid can be extended to the N-terminus by condensing a protected amino acid to an amino acid having a ⁇ -amino acid skeleton with a protected carboxyl group.
• the condensation reaction can be carried out using the condensation reagent and base used in the above-mentioned linking step.
• various methods are possible, such as a combination of DIC and Oxyma, a combination of DIC and HOAt, a combination of HATU and DIPEA, or a mixed acid anhydride or acid halide, as an activator of the carboxyl group.
• a fragment consisting of five amino acids can be synthesized by sequentially deprotecting the protecting group of the amino group and condensing the protected amino acid. Next, the C-terminal protecting group can be deprotected to produce a peptide compound (6) with an unprotected C-terminus, or the N-terminal protecting group can be deprotected to produce a peptide compound (6) with an unprotected N-terminus.
• Peptide compound (6) can also be synthesized by solid-phase synthesis.
• Xg 11 in the above formula is an amino acid having a ⁇ -amino acid skeleton bound to a solid-phase support via an oxygen atom and a linker bound thereto, and an amino acid can be extended to the N-terminus by condensing a protected amino acid with this.
• the condensation reaction can be performed using the condensation reagent and base used in the above-mentioned linking step, and various methods are possible, such as a combination of DIC and Oxyma, a combination of DIC and HOAt, a combination of HATU and DIPEA, or a combination via a mixed acid anhydride or acid halide as an activator of the carboxyl group.
• a fragment consisting of five amino acids can be synthesized by sequentially deprotecting the protecting group of the amino group and condensing the protected amino acid.
• the peptide compound (6) with an unprotected C-terminus can be produced by cutting out from the solid phase.
• the cyclic peptide compound, or a salt thereof, or a solvate thereof produced by the method of the present invention may or may not be isolated and/or purified using column chromatography.
• the cyclic peptide compound, or its salt, or its solvate produced by the method of the present invention can be isolated and/or purified by crystallization by crystallization. Specifically, for example, the reaction solution after the condensation reaction is subjected to a liquid separation operation, and the organic layer is concentrated and/or filtered as necessary, and then a solvent suitable for crystallization is added to the obtained residue, and seed crystals are optionally added and stirred as necessary to obtain crystals of the cyclic peptide compound, or its salt, or its solvate.
• the solvent added during crystallization is not particularly limited as long as it is a solvent in which the cyclic peptide compound can form crystals, but a solvent in which the solubility of the cyclic peptide compound can be reduced in the solution in which the cyclic peptide compound is dissolved is preferable.
• a solvent in which the solubility of the cyclic peptide compound can be reduced by adding a poor solvent or cooling the solution examples of solvents that allow such operations are exemplified.
• a solvent that allows such operations can be used for crystallization.
• Specific examples of solvents that can be added during crystallization include acetone, water, DMSO, acetonitrile, ethanol, and mixtures of these solvents.
• R 1 is C 1 -C 6 alkyl.
• R 1 is preferably C 3 -C 4 alkyl, more preferably n-propyl, 2-methylpropyl.
• P1 is C1 - C6 alkyl.
• P1 is preferably C1 - C4 alkyl, more preferably methyl.
• R2 is C1 - C6 alkyl.
• R2 is preferably C3 - C4 alkyl, more preferably 1-methylpropyl.
• R 3 is hydrogen or R 3 together with P 3 , the carbon atom to which R 3 is attached, and the nitrogen atom to which P 3 is attached forms a 4- to 7-membered saturated heterocyclic ring.
• R 3 is hydrogen or R 3 together with P 3 , the carbon atom to which R 3 is attached, and the nitrogen atom to which P 3 is attached forms a 5-membered saturated heterocyclic ring.
• R 3 is preferably hydrogen.
• R 3 is preferably together with P 3 , the carbon atom to which R 3 is attached, and the nitrogen atom to which P 3 is attached forms a 5- membered saturated heterocyclic ring.
• P3 is C1 - C6 alkyl, or C3 - C8 cycloalkyl, or P3 together with R3 , the carbon atom to which R3 is attached, and the nitrogen atom to which P3 is attached forms a 4-7 membered saturated heterocyclic ring.
• P3 is C1 - C4 alkyl, or P3 together with R3 , the carbon atom to which R3 is attached, and the nitrogen atom to which P3 is attached forms a 5 membered saturated heterocyclic ring.
• P3 is preferably methyl.
• P3 is preferably together with R3 , the carbon atom to which R3 is attached, and the nitrogen atom to which P3 is attached forms a 5 membered saturated heterocyclic ring.
• P4 is C 1 -C 6 alkyl.
• P4 is preferably C 1 -C 4 alkyl, more preferably methyl.
• R 5 is benzyl optionally substituted by one or more groups selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 3 -C 8 cycloalkyl.
• R 5 is preferably benzyl optionally substituted by C 1 -C 4 haloalkyl, more preferably 4-trifluoromethylbenzyl.
• P6 is C 1 -C 6 alkyl.
• P6 is preferably C 1 -C 4 alkyl, more preferably methyl.
• R 7 is phenethyl optionally substituted with one or more groups selected from the group consisting of halogen, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy.
• R 7 is preferably phenethyl optionally substituted with one or more groups selected from the group consisting of halogen, trifluoromethyl, and methoxy, and is more preferably 3-methoxy-4-trifluoromethylphenethyl or 3,5-difluoro-4-trifluoromethylphenethyl.
• R 8 together with P 8 , the carbon atom to which R 8 is attached, and the nitrogen atom to which P 8 is attached form a 4- to 7-membered saturated heterocyclic ring, which may be substituted by C 1 -C 6 alkoxy.
• R 8 preferably together with P 8 , the carbon atom to which R 8 is attached, and the nitrogen atom to which P 8 is attached form a 5-membered saturated heterocyclic ring, which is substituted by C 1 -C 4 alkyl, and more preferably together with P 8 , the carbon atom to which R 8 is attached, and the nitrogen atom to which P 8 is attached form a 5-membered saturated heterocyclic ring, which is substituted by ethoxy.
• R 9 together with Q 9 and the carbon atom to which R 9 and Q 9 are attached forms a 3-8 membered alicyclic ring, which may be substituted by one or more C 1 -C 6 alkyls.
• R 9 preferably together with Q 9 and the carbon atom to which R 9 and Q 9 are attached forms a 4-6 membered alicyclic ring.
• R 9 preferably together with Q 9 and the carbon atom to which R 9 and Q 9 are attached forms a 4 membered alicyclic ring.
• R 9 preferably together with Q 9 and the carbon atom to which R 9 and Q 9 are attached forms a 5 membered alicyclic ring.
• P 9 is hydrogen or C 1 -C 6 alkyl.
• P 9 is preferably hydrogen or C 1 -C 4 alkyl. In some embodiments, P 9 is preferably hydrogen. In some embodiments, P 9 is preferably methyl.
• R 10 is C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl.
• R 10 is preferably C 4 -C 6 cycloalkyl, more preferably cyclopentyl.
• P 10 is C 1 -C 6 alkyl.
• P 10 is preferably C 1 -C 4 alkyl, more preferably methyl.
• R 11 is diC 1 -C 6 alkylaminocarbonyl, or 4- to 8-membered cyclic aminocarbonyl.
• R 11 is preferably diC 1 -C 4 alkylaminocarbonyl, or 5- to 6-membered cyclic aminocarbonyl, more preferably dimethylaminocarbonyl.
• P 11 is C 1 -C 6 alkyl.
• P 11 is preferably C 1 -C 4 alkyl, more preferably methyl.
• X1 , X3 , and X5 are each independently hydrogen or a protecting group of an amino group.
• X1 , X3 , and X5 are preferably each independently one selected from the group consisting of hydrogen, a carbamate-based protecting group, an acyl-based protecting group, a sulfonamide-based protecting group, and a silyl-based protecting group.
• the carbamate-based protecting group is one selected from the group consisting of an Fmoc group, a Cbz group, a Troc group, an Alloc group, a Teoc group, a TSoc group, a BIBSoc group, an IPCSoc group, a BBSoc group, a CHBSoc group, a CDBSoc group, and a Boc group.
• the acyl-based protecting group is one selected from the group consisting of a trifluoroacetyl group, an acetyl group, and a benzoyl group.
• the sulfonamide protecting group is one selected from the group consisting of 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, and 2,4-dinitrobenzenesulfonyl groups.
• the silyl protecting group is one selected from the group consisting of TMS, TBDMS, TES, TIPS, and TBDPS groups.
• X 1 is hydrogen or a carbamate-based protecting group. In some embodiments, X 1 is preferably hydrogen. In some embodiments, X 1 is preferably an Fmoc group.
• X3 is hydrogen or a carbamate-based protecting group. In some embodiments, X3 is preferably hydrogen. In some embodiments, X3 is preferably a Cbz group.
• X5 is hydrogen or a carbamate protecting group. In some embodiments, X5 is preferably hydrogen. In some embodiments, X5 is preferably a Cbz group.
• X 2 , X 4 , and X 6 are each independently a halogen, a hydroxyl group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy, or a group represented by -OSiR x R y R z (wherein R x , R y , and R z are each independently an alkyl or an aryl).
• X 2 , X 4 , and X 6 are preferably each independently a halogen, a hydroxyl group, an optionally substituted C 1 -C 6 alkoxy, an optionally substituted C 6 -C 10 aryloxy, an optionally substituted C 7 -C 14 aralkoxy, an optionally substituted 4- to 8-membered cyclic aminooxy, or a group represented by -OSiR x R y R z (wherein R x , R y , and R z are each independently a C 1 -C 6 alkyl, or a C 6 -C 10 aryl).
• the halogen is chlorine or bromine.
• the optionally substituted alkoxy is t-butoxy, methoxy, ethoxy, or isopropoxy.
• the optionally substituted aryloxy is pentafluorophenyloxy, or nitrophenyloxy.
• the optionally substituted aralkoxy is an optionally substituted benzyloxy.
• the optionally substituted cyclic aminooxy is N- hydroxysuccinimoxy .
• the group represented by -OSiRxRyRz is trimethylsilyloxy, triethylsilyloxy, triisopropylsilyloxy, triphenylsilyloxy, tri -t-butylsilyloxy, di-t-butylisobutylsilyloxy, or tris(triethylsilyl)silyloxy.
• X2 is hydroxyl, t-butoxy, or benzyloxy. In some embodiments, X2 is preferably hydroxyl. In some embodiments, X2 is preferably t-butoxy.
• X 4 is hydroxyl, t-butoxy, or benzyloxy. In some embodiments, X 4 is preferably hydroxyl. In some embodiments, X 4 is preferably t-butoxy.
• X 6 is hydroxyl, t-butoxy, or benzyloxy. In some embodiments, X 6 is preferably hydroxyl. In some embodiments, X 6 is preferably t-butoxy.
• R 1 is C 1 -C 6 alkyl
• P1 is C1 - C6 alkyl
• R2 is C1 - C6 alkyl
• R 3 is hydrogen or R 3 together with P 3 , the carbon atom to which R 3 is attached, and the nitrogen atom to which P 3 is attached form a 4- to 7-membered saturated heterocyclic ring
• P3 is C1 - C6 alkyl, or C3 - C8 cycloalkyl, or P3 together with R3, the carbon atom to which R3 is attached, and the nitrogen atom to which P3 is attached form a 4- to 7-membered saturated heterocycle
• P4 is C1 - C6 alkyl
• R 5 is benzyl optionally substituted with one or more groups selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 halo
• R 1 is C 3 -C 4 alkyl
• P1 is C1 - C4 alkyl
• R2 is C3 - C4 alkyl
• R3 is hydrogen or R3 together with P3, the carbon atom to which R3 is attached, and the nitrogen atom to which P3 is attached form a 5-membered saturated heterocyclic ring
• P3 is C 1 -C 4 alkyl or P3 together with R3, the carbon atom to which R3 is attached, and the nitrogen atom to which P3 is attached form a 5-membered saturated heterocycle
• P4 is C1 - C4 alkyl
• R 5 is benzyl optionally substituted by C 1 -C 4 haloalkyl
• P6 is C1 - C4 alkyl
• R7 is phenethyl optionally substituted with one or more groups selected from the group consisting of
• R 1 is n-propyl, 2-methylpropyl; P1 is methyl; R2 is 1-methylpropyl; R3 is hydrogen or R3 together with P3, the carbon atom to which R3 is attached, and the nitrogen atom to which P3 is attached form a 5-membered saturated heterocyclic ring; P3 is methyl or forms together with P3 , R3 , the carbon atom to which R3 is attached, and the nitrogen atom to which P3 is attached a 5-membered saturated heterocycle; P4 is methyl; R5 is 4-trifluoromethylbenzyl; P6 is methyl; R 7 is 3-methoxy-4-trifluoromethylphenethyl, or 3,5-difluoro-4-trifluoromethylphenethyl; R 8 together with P 8 , the carbon atom to which R 8 is attached, and
• R 1 is C 1 -C 6 alkyl
• P1 is C1 - C6 alkyl
• R2 is C1 - C6 alkyl
• R 3 is hydrogen or R 3 together with P 3 , the carbon atom to which R 3 is attached, and the nitrogen atom to which P 3 is attached form a 4- to 7-membered saturated heterocyclic ring
• P3 is C1 - C6 alkyl, or C3 - C8 cycloalkyl, or P3 together with R3, the carbon atom to which R3 is attached, and the nitrogen atom to which P3 is attached form a 4- to 7-membered saturated heterocycle
• P4 is C1 - C6 alkyl
• R 5 is benzyl optionally substituted with one or more groups selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 3 -C 8 cycloal
• R 1 is C 3 -C 4 alkyl
• P1 is C1 - C4 alkyl
• R2 is C3 - C4 alkyl
• R3 is hydrogen or R3 together with P3, the carbon atom to which R3 is attached, and the nitrogen atom to which P3 is attached form a 5-membered saturated heterocyclic ring
• P3 is C 1 -C 4 alkyl or P3 together with R3, the carbon atom to which R3 is attached, and the nitrogen atom to which P3 is attached form a 5-membered saturated heterocycle
• P4 is C1 - C4 alkyl
• R 5 is benzyl optionally substituted by C 1 -C 4 haloalkyl
• P6 is C1 - C4 alkyl
• R7 is phenethyl optionally substituted with one or more groups selected from the group consisting of halogen, trifluoromethyl, and methoxy;
• the cyclic peptide compound produced by the method of the present invention has the following formula (1a): or a salt or solvate thereof.
• the present invention relates to a method for producing a cyclic peptide compound represented by formula (1a), or a salt or solvate thereof, the method comprising: (a) providing a peptide compound represented by any one of formulas (4a) to (6a), or a salt thereof, or a solvate of said peptide compound or salt; (b) a step of reacting and linking the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound represented by formulae (4a) to (6a) (linking step); and (c) A step of cyclizing the peptide compound obtained in step (b) by reacting the N-terminal amino acid residue with the C-terminal amino acid residue (cyclization step) (hereinafter, also referred to as "Mode 2'").
• the step (b) may include a step (b-1) of converting the N-terminal amino acid residue of the peptide compound represented by formula (5a) and the C-terminal amino acid residue of the peptide compound represented by formula (6a) into the peptide compound represented by formula (7a).
• the step (b) includes, in addition to the step (b-1), (b-2) a step (linking step) of converting a peptide compound represented by formula (4a) to a peptide compound represented by formula (7a) by linking the N-terminal amino acid residue with the C-terminal amino acid residue of the peptide compound represented by formula (7a) to obtain a peptide compound represented by formula (2a), and the step (c) may include (c-1)
• the method may include a step of cyclizing the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound represented by formula (2a) by reaction in a solvent (cyclization step).
• the step (b) includes, in addition to the step (b-1), (b-3) a step (linking step) of converting a peptide compound represented by formula (7a) to a peptide compound represented by formula (4a) by linking the N-terminal amino acid residue with the C-terminal amino acid residue of the peptide compound represented by formula (4a) to obtain a peptide compound represented by formula (3a), and the step (c) may include (c-2)
• the method may include a step of cyclizing the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound represented by formula (3a) by reaction in a solvent (cyclization step).
• the link between the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound is preferably a link between the amino group of the N-terminal amino acid residue and the carboxyl group of the C-terminal amino acid residue, and more preferably a link between the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound is a link between the amino group of the N-terminal amino acid residue and the carboxyl group of the C-terminal amino acid residue via an amide bond.
• the solvent in the cyclization step, the condensation reagent in the cyclization step, the base in the cyclization step, the by-products generated in the cyclization step, the solvent in the linking step, the condensation reagent in the linking step, the base in the linking step, etc. are the same as those described in embodiments 1 and 2 above.
• the present invention relates to a compound represented by formula (4a):
• X 1 is hydrogen or a protecting group of an amino group.
• the protecting group in X 1 is the same as that described in the above embodiments 1 and 2.
• X 1 is preferably hydrogen.
• X 1 is preferably an Fmoc group.
• X 2 is a hydroxyl group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy, or a group represented by -OSiR x R y R z (wherein R x , R y , and R z are each independently alkyl or aryl).
• R x , R y , and R z are each independently alkyl or aryl.
• the optionally substituted alkoxy, the optionally substituted aryloxy, the optionally substituted aralkoxy, the optionally substituted cyclic aminooxy, and -OSiR x R y R z in X 2 are the same as those explained in the above embodiments 1 and 2.
• X 2 is preferably t-butoxy.
• the compound represented by formula (4a) is preferably tert-butyl 2-[methyl-[(2S)-2-[(4Z,7S)-7-(methylamino)-8-oxo-2,3,6,7-tetrahydroazocin-1-yl]-3-[4-(trifluoromethyl)phenyl]propanoyl]amino]acetic acid (compound 9).
• the compound represented by formula (4a) (peptide compound (4a)) can be prepared using the following method.
• the protected amino acid (4a-1) can be reacted with an aldehyde according to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81) to obtain an oxazolidinone (4a-2) having a cyclic protecting group.
• a ring-opening reaction can be performed using a silicon compound having an olefin according to the method of Nguyen et al. (Synthesis, 2009, 12, 1991) to obtain a compound (4a-3) having an alkyl group having an olefin on the nitrogen atom.
• the amino acid (4a-4) having a protected C-terminus can be condensed to extend the amino acid to the C-terminus.
• the condensation reaction can be performed using the condensation reagent and base used in the above-mentioned linking step, and various methods are possible, such as a combination of DIC and Oxyma, a combination of DIC and HOAt, a combination of HATU and DIPEA, or a combination of mixed acid anhydrides or acid halides as a carboxyl group activator.
• the protected amino acid (4a-6) having an olefin in the side chain can be elongated.
• the olefin in the molecule can then be cyclized by a metathesis reaction.
• catalysts such as dichloro(2-isopropoxybenzylidene)(tricyclohexylphosphine)ruthenium(II): CAS No. 203714-71-0, dichloro(3-phenyl-1H-inden-1-ylidene)bis(tricyclohexylphosphine)ruthenium(II): CAS No. 250220-36-1, dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II): CAS No.
• Peptide compound (4a) can also be prepared using the following method. By reacting an alkylating agent having an olefin in the presence of a base with the amino acid (4a-9), an amino acid (4a-10) having an olefin-containing alkyl group introduced at the N atom can be obtained. Next, the amino acid (4a-4) with a protected C-terminus can be condensed to extend the amino acid to the C-terminus.
• the condensation reaction can be carried out using the condensation reagent and base used in the above-mentioned linking step, and various methods are possible, such as a combination of DIC and Oxyma, a combination of DIC and HOAt, a combination of HATU and DIPEA, or a mixed acid anhydride or acid halide as an activator of the carboxyl group.
• the protecting group of the amino group is deprotected, and then the protected amino acid having an olefin in the side chain can be extended.
• the olefin in the molecule can be cyclized by a metathesis reaction.
• the catalyst used in the metathesis reaction is the same as that described above.
• the protecting group at the C-terminus can be deprotected to produce a peptide compound (4a) with an unprotected C-terminus, or the protecting group at the N-terminus can be deprotected to produce a peptide compound (4a) with an unprotected N-terminus.
• the present invention relates to a compound represented by formula (5a):
• X3 is water or an amino-protecting group.
• the amino-protecting group in X3 is the same as that described in the above embodiments 1 and 2.
• X3 is preferably hydrogen.
• X3 is preferably an Fmoc group or a Cbz group.
• X 4 is a hydroxyl group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy, or a group represented by -OSiR x R y R z (wherein R x , R y , and R z are each independently alkyl or aryl).
• R x , R y , and R z are each independently alkyl or aryl.
• the optionally substituted alkoxy, the optionally substituted aryloxy, the optionally substituted aralkoxy, the optionally substituted cyclic aminooxy, and -OSiR x R y R z in X 2 are the same as those explained in the above embodiments 1 and 2.
• X 4 is preferably t-butoxy.
• the compound represented by formula (5a) is preferably tert-butyl(2S)-1-[(2S,3S)-3-methyl-2-[[(2S)-2-(methylamino)pentanoyl]amino]pentanoyl]pyrrolidine-2-acetic acid (compound 13).
• the compound represented by formula (5a) (peptide compound (5a)) can be prepared using the following method.
• Compound (5a-3) is obtained by condensing protected amino acid (5a-2) to proline (5a-1) whose C-terminus is protected.
• the condensation reaction can be carried out using the condensation reagent and base used in the above-mentioned linking step.
• various methods are possible, such as a combination of DIC and Oxyma, a combination of DIC and HOAt, a combination of HATU and DIPEA, or a mixed acid anhydride or acid halide, as an activator of the carboxyl group.
• a fragment (5a-5) consisting of three amino acids can be synthesized by condensing protected amino acid (5a-4).
• the protecting group of the C-terminus can be deprotected to produce peptide compound (5a) with an unprotected C-terminus, or the protecting group of the N-terminus can be deprotected to produce peptide compound (5a) with an unprotected N-terminus.
• the present invention relates to a compound represented by formula (6a):
• X 6 is a hydroxyl group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy, or a group represented by -OSiR x R y R z (wherein R x , R y , and R z are each independently alkyl or aryl).
• R x , R y , and R z are each independently alkyl or aryl.
• the optionally substituted alkoxy, the optionally substituted aryloxy, the optionally substituted aralkoxy, the optionally substituted cyclic aminooxy, and -OSiR x R y R z in X 6 are the same as those explained in the above embodiments 1 and 2.
• X 6 is preferably t-butoxy.
• the compound represented by formula (6a) is preferably (3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-(benzyloxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyric acid (compound 20).
• the compound represented by formula (6a) (peptide compound (6a)) can be prepared using the following method.
• Compound (6a-3) is obtained by condensing protected amino acid (6a-2) with amino acid (6a-1) having a ⁇ -amino acid skeleton with a protected carboxyl group.
• the condensation reaction can be performed using the condensation reagent and base used in the above-mentioned linking step.
• various methods are possible, such as a combination of DIC and Oxyma, a combination of DIC and HOAt, a combination of HATU and DIPEA, or a mixed acid anhydride or acid halide as an activator of the carboxyl group.
• the present invention relates to a compound represented by formula (7a):
• X5 is hydrogen or a protecting group for an amino group.
• the protecting group for an amino group in X5 is the same as that described in the above embodiments 1 and 2.
• X5 is preferably hydrogen.
• X5 is preferably a Cbz group.
• X 4 is a hydroxyl group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy, or a group represented by -OSiR x R y R z (wherein R x , R y , and R z are each independently alkyl or aryl).
• R x , R y , and R z are each independently alkyl or aryl.
• the optionally substituted alkoxy, the optionally substituted aryloxy, the optionally substituted aralkoxy, the optionally substituted cyclic aminooxy, and -OSiR x R y R z in X 4 are the same as those explained in the above embodiments 1 and 2.
• X 4 is preferably a hydroxyl group or t-butoxy.
• the compound represented by formula (7a) is preferably (2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-(benzyloxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentylacetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butanoyl]-methyl-amino]pentanoyl]amino]-3-methyl-pentanoyl]pyrrolidine-2-carboxylic acid (compound 22).
• the compound represented by formula (7a) is preferably tert-butyl (2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-amino-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butanoyl]-methyl-amino]pentanoyl]amino]-3-methyl-pentanoyl]pyrrolidine-2-carboxylate (compound 37).
• the compound represented by formula (7a) can be produced by reacting and linking the N-terminal amino acid residue of the peptide compound represented by formula (5a) and the C-terminal amino acid residue of the peptide compound represented by formula (6a) in a solvent (linking step).
• the solvent in the linking step, the condensation reagent in the linking step, the base in the linking step, etc. are the same as those described in the above embodiments 1 and 2.
• the present invention relates to a compound represented by formula (2a):
• X5 is hydrogen or a protecting group for an amino group.
• the protecting group for an amino group in X5 is the same as that described in the above embodiments 1 and 2.
• X5 is preferably hydrogen.
• X5 is preferably a Cbz group.
• X 2 is a hydroxyl group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy, or a group represented by -OSiR x R y R z (wherein R x , R y , and R z are each independently alkyl or aryl).
• R x , R y , and R z are each independently alkyl or aryl.
• the optionally substituted alkoxy, the optionally substituted aryloxy, the optionally substituted aralkoxy, the optionally substituted cyclic aminooxy, and -OSiR x R y R z in X 2 are the same as those explained in the above embodiments 1 and 2.
• X 2 is preferably a hydroxyl group or t-butoxy.
• the compound represented by formula (2a) is preferably 2-[[(2S)-2-[(4Z,7S)-7-[[(2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-amino-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbo Nyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butanoyl]-methyl-amino]pentanoyl]amino]-3-methyl-pentanoyl]pyrrolidine-2-carbonyl]-methyl-amino]
• the compound represented by formula (2a) can be produced by reacting and linking the N-terminal amino acid residue of the peptide compound represented by formula (4a) and the C-terminal amino acid residue of the peptide compound represented by formula (7a) in a solvent (linking step).
• the solvent for the linking step, the condensation reagent for the linking step, the base for the linking step, etc. are the same as those described in the above embodiments 1 and 2.
• the present invention relates to a compound represented by formula (3a):
• X1 is hydrogen or an amino-protecting group.
• the amino-protecting group in X1 is the same as that described in the above embodiments 1 and 2.
• X1 is preferably hydrogen.
• X1 is preferably an Fmoc group.
• X 4 is a hydroxyl group, an optionally substituted alkoxy, an optionally substituted aryloxy, an optionally substituted aralkoxy, an optionally substituted cyclic aminooxy, or a group represented by -OSiR x R y R z (wherein R x , R y , and R z are each independently alkyl or aryl).
• R x , R y , and R z are each independently alkyl or aryl.
• the optionally substituted alkoxy, the optionally substituted aryloxy, the optionally substituted aralkoxy, the optionally substituted cyclic aminooxy, and -OSiR x R y R z in X 4 are the same as those explained in the above embodiments 1 and 2.
• X 4 is preferably a hydroxyl group or t-butoxy.
• the compound represented by formula (3a) is preferably (S)-2-[(S)-3-[(S)-2-cyclopentyl-2-[1-[(2S,4R)-4-ethoxy-1-[(S)-4-[3-methoxy-4-(trifluoromethyl)phenyl]-2-[(2-[(S)-N-methyl-2-[(R,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazocin-1(2H)-yl]-3-[4-(trifluoromethyl)phenyl]propanamido]acetamido)butanoyl]-N-methylpyrrolidine-2-carboxamido]-N-methylcyclobutane-1-carboxamido]-N-methylacetamido]-4-(dimethylamino)-N-methyl-4-oxobutanamido]pentanoyl]-L-isoleuc
• the compound represented by formula (3a) can be produced by reacting and linking the N-terminal amino acid residue of the peptide compound represented by formula (7a) and the C-terminal amino acid residue of the peptide compound represented by formula (4a) in a solvent (linking step).
• the solvent in the linking step, the condensation reagent in the linking step, the base in the linking step, etc. are the same as those described in the above embodiments 1 and 2.
• the present invention relates to a crystal of a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof.
• the crystal of this compound include a nonsolvate crystal or a solvate crystal of this compound, or a nonsolvate crystal or a solvate crystal of a salt of this compound.
• a solvate crystal of the cyclic peptide compound represented by formula (1a) is preferred.
• a preferred example of the solvate crystal is a hydrate crystal.
• the diffraction angle 2 ⁇ in powder X-ray diffraction is the diffraction peak measured using CuK ⁇ or CuK ⁇ 1 radiation.
• These solvate crystals further specified by the diffraction angle 2 ⁇ in powder X-ray diffraction are sometimes called "Form A crystals" of the hydrate shown below, for example, but are sometimes simply called "Form A”.
• the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal
• the crystal is a Form A crystal having a powder X-ray diffraction pattern including at least seven of the following peaks as diffraction angles 2 ⁇ in powder X-ray diffraction:
• the following diffraction angles (2 ⁇ values) are preferably those of a hydrate crystal stored at a relative humidity of 10% or more for 15 minutes or more, more preferably those of a hydrate crystal stored at a relative humidity of 10% for 15 minutes.
• the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal
• the crystal is a Form A crystal having a powder X-ray diffraction pattern including at least 8 of the following peaks as diffraction angles 2 ⁇ in powder X-ray diffraction:
• the following diffraction angles (2 ⁇ values) are preferably the diffraction angles (2 ⁇ values) of the hydrate crystal stored at a relative humidity of 10% or more for 15 minutes or more, more preferably the diffraction angles (2 ⁇ values) of the hydrate crystal stored at a relative humidity of 10% for 15 minutes.
• the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal
• the crystal is a Form A crystal having a powder X-ray diffraction pattern including the following peaks as diffraction angles 2 ⁇ in powder X-ray diffraction:
• the following diffraction angles (2 ⁇ values) are preferably the diffraction angles (2 ⁇ values) of the hydrate crystal stored at a relative humidity of 30% or more for 15 minutes or more, more preferably the diffraction angles (2 ⁇ values) of the hydrate crystal stored at a relative humidity of 30% for 15 minutes.
• the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal
• the crystal is a Form B crystal having a powder X-ray diffraction pattern including at least seven of the following peaks as diffraction angles 2 ⁇ in powder X-ray diffraction:
• the following diffraction angles (2 ⁇ values) are preferably those of a hydrate crystal stored at a relative humidity of 30% or more for 15 minutes or more, more preferably those of a hydrate crystal stored at a relative humidity of 30% for 15 minutes.
• the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal
• the crystal is a Form B crystal having a powder X-ray diffraction pattern including at least 8 of the following peaks as diffraction angles 2 ⁇ in powder X-ray diffraction:
• the following diffraction angles (2 ⁇ values) are preferably those of a hydrate crystal stored at a relative humidity of 30% or more for 15 minutes or more, more preferably those of a hydrate crystal stored at a relative humidity of 30% for 15 minutes.
• the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal
• the crystal is a Form B crystal having a powder X-ray diffraction pattern including the following peaks as diffraction angles 2 ⁇ in powder X-ray diffraction:
• the following diffraction angles (2 ⁇ values) are preferably the diffraction angles (2 ⁇ values) of the hydrate crystal stored at a relative humidity of 30% or more for 15 minutes or more, more preferably the diffraction angles (2 ⁇ values) of the hydrate crystal stored at a relative humidity of 30% for 15 minutes.
• the crystal of the cyclic peptide compound of formula (1a) when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a Form F crystal having a powder X-ray diffraction pattern including at least seven of the following peaks as a diffraction angle 2 ⁇ in powder X-ray diffraction. 6.99°, 8.49°, 9.49°, 9.88°, 10.21°, 11.81°, 12.32°, 12.75°, 13.17°, 13.94°, 14.92°, 15.20°, 15.64°, 16.78°, 17.01°, and 17.47° ( ⁇ 0.2°)
• the crystal of the cyclic peptide compound of formula (1a) when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a Form F crystal having a powder X-ray diffraction pattern including at least 8 of the following peaks as a diffraction angle 2 ⁇ in powder X-ray diffraction. 6.99°, 8.49°, 9.49°, 9.88°, 10.21°, 11.81°, 12.32°, 12.75°, 13.17°, 13.94°, 14.92°, 15.20°, 15.64°, 16.78°, 17.01°, and 17.47° ( ⁇ 0.2°)
• the crystal of the cyclic peptide compound of formula (1a) when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a Form F crystal having a powder X-ray diffraction pattern including the following peaks as a diffraction angle 2 ⁇ in powder X-ray diffraction. 6.99°, 8.49°, 9.49°, 9.88°, 10.21°, 11.81°, 12.32°, 12.75°, 13.17°, 13.94°, 14.92°, 15.20°, 15.64°, 16.78°, 17.01°, and 17.47° ( ⁇ 0.2°)
• the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal
• the crystal is a Form J crystal having a powder X-ray diffraction pattern including at least seven of the following peaks as diffraction angles 2 ⁇ in powder X-ray diffraction:
• the following diffraction angles (2 ⁇ values) are preferably the diffraction angles (2 ⁇ values) of the solvate crystal stored at a relative humidity of less than 10% for 15 minutes or more, and more preferably the diffraction angles (2 ⁇ values) of the solvate crystal stored at a relative humidity of less than 10% for 15 minutes.
• the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal
• the crystal is a Form J crystal having a powder X-ray diffraction pattern including at least 8 of the following peaks as diffraction angles 2 ⁇ in powder X-ray diffraction:
• the following diffraction angles (2 ⁇ values) are preferably the diffraction angles (2 ⁇ values) of the solvate crystal stored at a relative humidity of less than 10% for 15 minutes or more, and more preferably the diffraction angles (2 ⁇ values) of the solvate crystal stored at a relative humidity of less than 10% for 15 minutes.
• the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal
• the crystal is a Form J crystal having a powder X-ray diffraction pattern including the following peaks as diffraction angles 2 ⁇ in powder X-ray diffraction:
• the following diffraction angles (2 ⁇ values) are preferably the diffraction angles (2 ⁇ values) of the solvate crystal stored at a relative humidity of less than 10% for 15 minutes or more, and more preferably the diffraction angles (2 ⁇ values) of the solvate crystal stored at a relative humidity of less than 10% for 15 minutes.
• the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal
• the crystal is a Form J crystal having a powder X-ray diffraction pattern including at least seven of the following peaks as diffraction angles 2 ⁇ in powder X-ray diffraction:
• the following diffraction angles (2 ⁇ values) are preferably the diffraction angles (2 ⁇ values) of a hydrate crystal stored at a relative humidity of less than 10% for 15 minutes or more, more preferably the diffraction angles (2 ⁇ values) of a hydrate crystal stored at a relative humidity of less than 10% for 15 minutes.
• the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal
• the crystal is a Form J crystal having a powder X-ray diffraction pattern including at least 8 of the following peaks as diffraction angles 2 ⁇ in powder X-ray diffraction:
• the following diffraction angles (2 ⁇ values) are preferably the diffraction angles (2 ⁇ values) of a hydrate crystal stored at a relative humidity of less than 10% for 15 minutes or more, and more preferably the diffraction angles (2 ⁇ values) of a hydrate crystal stored at a relative humidity of less than 10% for 15 minutes.
• the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal
• the crystal is a Form J crystal having a powder X-ray diffraction pattern including the following peaks as diffraction angles 2 ⁇ in powder X-ray diffraction:
• the following diffraction angles (2 ⁇ values) are preferably the diffraction angles (2 ⁇ values) of a hydrate crystal stored at a relative humidity of less than 10% for 15 minutes or more, and more preferably the diffraction angles (2 ⁇ values) of a hydrate crystal stored at a relative humidity of less than 10% for 15 minutes.
• the crystal of the cyclic peptide compound of formula (1a) when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal has a diffraction angle 2 ⁇ of 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° ( ⁇ 0.2°) in powder X-ray diffraction at a relative humidity of less than 10%.
• Form J crystals having a powder X-ray diffraction pattern containing at least seven peaks, and at a relative humidity of 10% or greater it includes Form A crystals having a powder X-ray diffraction pattern containing at least seven peaks at the following positions: 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° ( ⁇ 0.2°).
• the crystal of the cyclic peptide compound of formula (1a) when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal has a diffraction angle 2 ⁇ of 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° ( ⁇ 0.2°) in powder X-ray diffraction at a relative humidity of less than 10%.
• Form J crystals having a powder X-ray diffraction pattern containing at least eight peaks, and at a relative humidity of 10% or greater it includes Form A crystals having a powder X-ray diffraction pattern containing at least eight peaks at the following positions: 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° ( ⁇ 0.2°).
• the crystal of the cyclic peptide compound of formula (1a) when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal has the following diffraction angles 2 ⁇ in powder X-ray diffraction at a relative humidity of less than 10%: 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97°.
• Form A crystals having a powder X-ray diffraction pattern including peaks at 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° ( ⁇ 0.2°) at a relative humidity of 10% or greater.
• the crystal of the cyclic peptide compound of formula (1a) when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a Form Y crystal having a powder X-ray diffraction pattern including at least seven of the following peaks as diffraction angles 2 ⁇ in powder X-ray diffraction.
• the following diffraction angles (2 ⁇ values) are preferably diffraction angles (2 ⁇ values) of a solvate crystal stored at a relative humidity of less than 30% for 15 minutes or more, more preferably diffraction angles (2 ⁇ values) of a solvate crystal stored at a relative humidity of less than 30% for 15 minutes.
• the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal
• the crystal is a Form Y crystal having a powder X-ray diffraction pattern including at least 8 of the following peaks as diffraction angles 2 ⁇ in powder X-ray diffraction:
• the following diffraction angles (2 ⁇ values) are preferably the diffraction angles (2 ⁇ values) of the solvate crystal stored at a relative humidity of less than 30% for 15 minutes or more, more preferably the diffraction angles (2 ⁇ values) of the solvate crystal stored at a relative humidity of less than 30% for 15 minutes.
• the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal
• the crystal is a Form Y crystal having a powder X-ray diffraction pattern including the following peaks as diffraction angles 2 ⁇ in powder X-ray diffraction:
• the following diffraction angles (2 ⁇ values) are preferably the diffraction angles (2 ⁇ values) of the solvate crystal stored at a relative humidity of less than 30% for 15 minutes or more, and more preferably the diffraction angles (2 ⁇ values) of the solvate crystal stored at a relative humidity of less than 30% for 15 minutes.
• the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal
• the crystal is a Form Y crystal having a powder X-ray diffraction pattern including at least seven of the following peaks as diffraction angles 2 ⁇ in powder X-ray diffraction:
• the following diffraction angles (2 ⁇ values) are preferably the diffraction angles (2 ⁇ values) of a solvate crystal stored at a relative humidity of less than 30% for 15 minutes or more, and more preferably the diffraction angles (2 ⁇ values) of a hydrate crystal stored at a relative humidity of less than 30% for 15 minutes.
• the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal
• the crystal is a Form Y crystal having a powder X-ray diffraction pattern including at least 8 of the following peaks as diffraction angles 2 ⁇ in powder X-ray diffraction:
• the following diffraction angles (2 ⁇ values) are preferably the diffraction angles (2 ⁇ values) of a solvate crystal stored at a relative humidity of less than 30% for 15 minutes or more, and more preferably the diffraction angles (2 ⁇ values) of a hydrate crystal stored at a relative humidity of less than 30% for 15 minutes.
• the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal
• the crystal is a Form Y crystal having a powder X-ray diffraction pattern including the following peaks as diffraction angles 2 ⁇ in powder X-ray diffraction:
• the following diffraction angles (2 ⁇ values) are preferably the diffraction angles (2 ⁇ values) of a hydrate crystal stored at a relative humidity of less than 30% for 15 minutes or more, and more preferably the diffraction angles (2 ⁇ values) of a hydrate crystal stored at a relative humidity of less than 30% for 15 minutes.
• the crystal of the cyclic peptide compound of formula (1a) when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal exhibits, in powder X-ray diffraction, a diffraction angle 2 ⁇ of at least one of 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° ( ⁇ 0.2°) at a relative humidity of less than 30%.
• Form Y crystals having a powder X-ray diffraction pattern containing at least seven peaks at 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° ( ⁇ 0.2°).
• the crystal of the cyclic peptide compound of formula (1a) when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal exhibits, in powder X-ray diffraction, a diffraction angle 2 ⁇ of at least one of 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° ( ⁇ 0.2°) at a relative humidity of less than 30%.
• Form Y crystals having a powder X-ray diffraction pattern containing at least eight peaks at 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° ( ⁇ 0.2°).
• the crystal of the cyclic peptide compound of formula (1a) when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal has diffraction angles 2 ⁇ of 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° ( ⁇ 0.05°) in powder X-ray diffraction at a relative humidity of less than 30%.
• Form Y crystals having a powder X-ray diffraction pattern including peaks at 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° ( ⁇ 0.2°).
• the crystal of the cyclic peptide compound of formula (1a) when the crystal of the cyclic peptide compound of formula (1a) is a water solvate crystal, the crystal is a Form K crystal having a powder X-ray diffraction pattern including at least seven of the following peaks as a diffraction angle 2 ⁇ in powder X-ray diffraction. 7.49°, 7.91°, 8.14°, 9.11°, 9.33°, 11.04°, 11.71°, 12.52°, 13.21°, 13.70°, 14.82°, 15.13°, 15.52°, 15.68°, 17.22°, and 17.51° ( ⁇ 0.2°)
• the crystal of the cyclic peptide compound of formula (1a) when the crystal of the cyclic peptide compound of formula (1a) is a water solvate crystal, the crystal is a Form K crystal having a powder X-ray diffraction pattern including at least eight of the following peaks at a diffraction angle 2 ⁇ in powder X-ray diffraction: 7.49°, 7.91°, 8.14°, 9.11°, 9.33°, 11.04°, 11.71°, 12.52°, 13.21°, 13.70°, 14.82°, 15.13°, 15.52°, 15.68°, 17.22°, and 17.51° ( ⁇ 0.2°)
• the crystal of the cyclic peptide compound of formula (1a) when the crystal of the cyclic peptide compound of formula (1a) is a water solvate crystal, the crystal is a Form K crystal having a powder X-ray diffraction pattern including the following peaks at a diffraction angle 2 ⁇ in powder X-ray diffraction. 7.49°, 7.91°, 8.14°, 9.11°, 9.33°, 11.04°, 11.71°, 12.52°, 13.21°, 13.70°, 14.82°, 15.13°, 15.52°, 15.68°, 17.22°, and 17.51° ( ⁇ 0.2°)
• the present invention relates to a method for producing a crystal of a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof.
• the method includes the steps of dissolving the cyclic peptide compound in an amount of a polar organic solvent in which the cyclic peptide compound can be dissolved to obtain a solution, and adding a hydrocarbon solvent or water to the solution to obtain a crystal of the cyclic peptide compound (hereinafter, also referred to as "embodiment 3").
• the nature of the cyclic peptide compound to be dissolved is not particularly limited, and for example, a cyclic peptide compound in a solid state, an amorphous state, or a crystalline state can be used.
• the present invention relates to a method for producing a crystal of a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof.
• the method includes the step of adding a mixture of a hydrocarbon solvent and a polar organic solvent, or a mixture of water and a polar organic solvent, to the cyclic peptide compound in an amorphous or crystalline state to obtain a crystal of the cyclic peptide compound (hereinafter, also referred to as "embodiment 4").
• the polar organic solvent used in embodiments 3 and 4 include DMSO, acetone, 2-butanone, methanol, ethanol, 1-propanol, 2-propanol, ethyl acetate, propylene glycol, and mixtures thereof, with acetone being a more preferred example.
• the "amount capable of dissolving the cyclic peptide compound” can be in the range of 3 to 10 v/w, preferably 3 to 7 v/w, relative to the cyclic peptide compound of formula (1a).
• hydrocarbon solvent used in embodiments 3 and 4 include heptane, hexane, pentane, toluene, xylene, and mixed solvents thereof, with heptane being a more preferred example.
• the mixture ratio of the hydrocarbon solvent and the polar organic solvent in the mixture of the hydrocarbon solvent and the polar organic solvent can be 0.5 to 10 parts by weight of the hydrocarbon solvent per 1 part by weight of the polar organic solvent, preferably 1 to 7 parts by weight of the hydrocarbon solvent, and more preferably 1 to 5 parts by weight of the hydrocarbon solvent.
• the mixture ratio of the water and the polar organic solvent in the mixture of the water and the polar organic solvent can be 0.5 to 10 parts by weight of water per 1 part by weight of the polar organic solvent, preferably 1 to 7 parts by weight of water, and more preferably 1 to 5 parts by weight of water.
• glass beads e.g., 1 to 5 beads
• the present invention relates to a method for producing a crystal of a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof.
• the method includes the steps of dissolving the cyclic peptide compound in an amorphous state in DMSO to obtain a solution, freeze-drying the solution to obtain a freeze-dried product of the cyclic peptide compound, and adding a mixture of water and a polar organic solvent to the freeze-dried product to obtain a crystal of the cyclic peptide compound (hereinafter, also referred to as "embodiment 5").
• polar organic solvent used in embodiment 5 include DMSO, acetone, 2-butanone, methanol, ethanol, 1-propanol, 2-propanol, propylene glycol, and mixed solvents thereof, with acetone being a more preferred example.
• the mixing ratio of water to polar organic solvent in the mixture of water and polar organic solvent can be 0.5 to 10 parts by weight of water per 1 part by weight of polar organic solvent, preferably 1 to 7 parts by weight of water, and more preferably 1 to 5 parts by weight of water.
• the present invention relates to a method for producing a crystal of a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof.
• the method includes a step of heating the crystal of the cyclic peptide compound to obtain another crystalline polymorph of the cyclic peptide compound (hereinafter, also referred to as "embodiment 6").
• the heating temperature is, for example, 30 to 350°C, and preferably 30 to 120°C.
• a step of filtering the crystals may be further included.
• a step of drying the crystals may be further included.
• the crystals of the cyclic peptide compound produced by the method of the present invention are formed as solvate crystals in a solvent, and are obtained as hydrate crystals after the filtering and/or drying steps. In another embodiment, the crystals of the cyclic peptide compound produced by the method of the present invention are obtained as hydrate crystals by absorbing moisture from the atmosphere after the filtering and/or drying steps.
• compositions containing cyclic peptide compounds in one embodiment, the present invention relates to compositions containing a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof, which contains 1.5 w/w% or less of the cyclic dimer of formula (1a) as an impurity.
• the present invention relates to a composition
• a composition comprising a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof.
• the compound contains the cyclic dimer of formula (1a) as an impurity at a ratio of 0.001 w/w% or more.
• the present invention relates to a composition
• a composition comprising a cyclic peptide compound represented by formula (1a), or a salt thereof, or a solvate thereof.
• the compound contains acetone in an amount of 0.001 w/w% or more.
• Measuring device Bruker Avance III 400 Internal standard substance: 3,5-bis(trifluoromethyl)benzoic acid Measurement conditions ( 19 F-NMR): CDCl 3 or DMSO-d 6 , 24.8° C., pulse angle 90°, digital resolution 0.24 Hz, relaxation Time: 15 seconds, no spin, 64 times
• Sample preparation method 1 A mixture containing the target compound was diluted with acetonitrile.
• Sample preparation method 2 The mixture containing the target compound was diluted with a mixture of acetonitrile and water in a ratio of 9:1.
• Sample preparation method K A mixture containing the target compound was diluted with a mixture of acetonitrile and n-propylamine in a ratio of 100:1.
• the reaction conversion rate was calculated by one of the following formulas using the area values of the raw materials and the target product, or the area values of the raw materials, the area values of the raw materials and the target product, or the area values of the raw materials before the reaction and the area values of the raw materials after the reaction, all calculated by HPLC analysis.
• Reaction conversion rate (%) 100 - (area value of raw material after reaction / area value of raw material before reaction x 100)
• N-methyl-2-pyrrolidone (17.0 L) and compound 3 (2.44 kg) were added to a nitrogen-purged reaction vessel at room temperature and stirred.
• Sarcosine tert-butyl ester hydrochloride (0.87 kg) and HATU (2.18 kg) were then added at 20°C and stirred for 30 minutes.
• DIPEA (1.85 kg) was added dropwise over 60 minutes at an internal temperature of 15-20°C.
• the reaction mixture was stirred at 20-25°C for 3 hours and then diluted with methyl tert-butyl ether (48.8 L).
• the organic layer was washed with water (48.8 L x 2) and 5% saline (24.4 L), and then concentrated under reduced pressure to obtain a concentrated, dry product containing compound 4.
• the combined organic layer was washed with 5% saline (14.9 L x 2), and the organic layer was concentrated under reduced pressure at 30 ⁇ 5°C.
• 2-Chlorotrityl chloride resin (1.12 mmol/g, 70 g, 78.4 mmol) and DCM (560 mL) were placed in a filter-equipped reaction vessel (1 L) and left to stand at room temperature for 30 minutes. After the DCM was filtered under reduced pressure, (3S)-4-(dimethylamino)-3-[9H-fluoren-9-ylmethoxycarbonyl (methyl)amino]-4-oxy-butanoic acid (23.4 g, 56.0 mmol) dissolved in DCM (140 mL) was added and washed with DCM (140 mL).
• DIPEA (27.4 mL) was added to the reaction vessel, and after stirring for 45 minutes, DCM (140 mL) was added and stirred at room temperature for 105 minutes. The reaction solution was filtered under reduced pressure and washed with DCM (280 mL x 2). A solution of methanol (28.0 mL) and DIPEA (14.0 mL) in DMF (238 mL) was added to a reaction vessel and stirred at room temperature for 120 minutes. The reaction solution was filtered under reduced pressure, and then IPA (280 mL) was added and stirred. After 15 minutes, the reaction solution was filtered under reduced pressure, and DMF (280 mL) was added and stirred for 15 minutes.
• Example 1-14 After the reaction solution was filtered under reduced pressure, the entire amount of Compound 14-resin, excluding the amount used for measuring the loading amount, was used to proceed to Example 1-14.
• the amount of amino acid supported on the resin was calculated as follows. The obtained compound 14-resin (4.76 mg) was placed in a reaction vessel, and 20% Pip/DMF solution (50 mL) was added and shaken at room temperature for 1 hour. The absorbance (301 nm) of the solution was measured (Shimadzu, UV-1600PC (cell length 1.0 cm)), and the amount of compound 14-resin supported was calculated to be 0.632 mmol/g.
• the extension reaction was carried out by adding Fmoc-MeGly(cPent)-OH (Cas number 187475-29-2, 42.5 g), oxyma (7.96 g) and DIC (34.9 mL) in a DMF solution (280 mL) to the resin, stirring for 5 minutes, and leaving it at room temperature for 16 hours.
• the solution of the extension reaction was filtered under reduced pressure, and IPA (280 mL) was added and stirred. After 10 minutes, the reaction solution was filtered under reduced pressure, and DMF (280 mL) was added and stirred for 10 minutes. After the reaction solution was filtered under reduced pressure, the entire amount of compound 15-resin except for the amount loaded for measurement was used to proceed to Example 1-15.
• the amount of amino acid supported on the resin was calculated as follows.
• the obtained compound 15-resin (4.91 mg) was placed in a reaction vessel, and 20% Pip/DMF solution (50 mL) was added and shaken at room temperature for 1 hour.
• the absorbance (301 nm) of the solution was measured (Shimadzu, UV-1600PC (cell length 1.0 cm)), and the amount of compound 15-resin supported was calculated to be 0.635 mmol/g.
• a small amount of compound 15 supported on the resin was used to cleave the compound from the resin with TFE/DCM (1/1), and the structure was confirmed by LC/MS.
• LCMS (ESI) of compound 15: Retention time: 2.53 minutes, m/z 536 [M+H] + (LCMS analysis conditions method 2)
• the extension reaction was carried out by adding Fmoc-MecVal-OH (Cas No. 1700368-07-5, 39.4 g) and oxyma (7.96 g) in DMF solution (280 mL), adding DIC (34.9 mL), stirring for 5 minutes, and then leaving it to stand for 94 hours.
• the solution of the extension reaction was filtered under reduced pressure, and the resin was washed with DMF (280 mL), IPA (280 mL), and DMF (280 mL).
• the washing solution was filtered under reduced pressure, and the obtained compound 16-resin was used in its entirety except for the amount measured for the loading amount, and then proceeded to Example 1-17.
• the amount of amino acid supported on the resin was calculated as follows.
• reaction conversion rate calculation formula 1 The external temperature of the reaction vessel was set to 40°C, and the mixture was concentrated under reduced pressure. After concentration under reduced pressure, DCM (214 mL) was added and the operation of concentrating under reduced pressure was repeated twice. The resulting concentrate was dried under reduced pressure overnight to obtain a concentrated, dried product containing compound 17 (45.5 g, 95% yield).
• the obtained resin was subjected to an elongation reaction of compound 17.
• the elongation reaction was performed by sequentially adding a DCM solution (280 mL) of compound 17 (46.0 g) obtained in Example 1-16 and Collidine (74.0 mL) and stirring for 5 minutes, and leaving it at room temperature for 4 hours. After the extension reaction solution was filtered under reduced pressure, the resin was washed with DCM (280 mL), and the entire amount of the obtained Compound 19-resin, excluding the amount used for measuring the loading amount, was used in Example 1-18.
• the amount of amino acid supported on the resin was calculated as follows.
• the obtained resin was subjected to the extension reaction of Cbz-Hph(4-CF3-3-OMe)-OH.
• the extension reaction was carried out by adding a DMF solution (280 mL) of Cbz-Hph(4-CF3-3-OMe)-OH (46.1 g) and oxyma (7.96 g) and DIC (34.9 mL) to the resin, stirring for 5 minutes, and then leaving it to stand for 3.5 hours. After the extension reaction solution was filtered under reduced pressure, the resin was washed twice with DMF (280 mL). IPA (280 mL) was added and stirred for 15 minutes. After draining the solution, DCM (280 mL) was added and stirred for 15 minutes.
• the concentrated dry matter containing compound 20 (80.7 g) and compound 13 (45.8 g) were added to the reaction vessel. After replacing with nitrogen, 2-MeTHF (484 mL), DIPEA (64.5 mL) and DMF (121 mL) were added at room temperature and stirred. After confirming complete dissolution, HATU (48.0 g) was added at room temperature. After 1 hour, the reaction mixture was sampled and sample preparation (sample preparation method 2) was performed, and it was confirmed that the reaction conversion rate was 98% or more by HPLC analysis (calculation formula 1 for reaction conversion rate). The external temperature of the reaction vessel was set to 5°C, and 2.5% aqueous ammonia solution (484 mL) was added to the reaction vessel.
• the concentrated dry product including the concentrated dry product of compound 19 obtained in Example 1-20 (111 g) and 2-MeTHF (666 mL) were added in sequence and stirred at room temperature. After confirming dissolution, the mixture was cooled to an external temperature of 5°C, hexamethyldisilazane (69.5 mL) was added, and trimethylsilyl trifluoromethanesulfonate (44.9 mL) was added so that the internal temperature did not exceed 15°C. After the addition was completed, the external temperature was raised to 10°C and stirred for 1 hour and 20 minutes.
• reaction conversion rate to compound 22 was 99% (calculation formula 1 for reaction conversion rate).
• sample preparation method 2 a mixed solution of 5% aqueous sodium carbonate solution (555 mL) and 5% saline (333 mL) was added so that the internal temperature did not exceed 25°C.
• aqueous layer was discharged by liquid separation.
• the obtained organic layer was washed with a 10% aqueous sodium hydrogen sulfate solution (555 mL), a 5% aqueous sodium carbonate solution (555 mL), and a 5% saline solution (555 mL).
• Example 1-22 Compound 23: tert-butyl 2-[[(2S)-2-[(4Z,7S)-7-[[(2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-(benzyloxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanoyl 2-(4-(trifluoromethyl)phenyl)propanoyl)-methyl-amino]-2-cyclopentyl-acetyl-methyl-amino]-4-(dimethylamino)-4-oxo-butanoyl-methyl-amino]pentanoyl-amino]-3-methyl-
• reaction conversion rate was confirmed to be 98% or more by HPLC analysis (calculation formula 1 for reaction conversion rate).
• a 2.8% aqueous ammonia solution (564 mL) was added to the reaction vessel at room temperature. After the aqueous layer was discharged by liquid separation, a 10% aqueous sodium hydrogen sulfate solution (564 mL) was added to the organic layer and stirred. After liquid separation, the liquid was separated and the aqueous layer was discharged. The obtained organic layer was washed successively with a 5% aqueous sodium carbonate solution (564 mL) and a 5% saline solution (564 mL).
• the concentrated dry solid containing compound 23 (90.8 g), L-cysteine (6.3 g), and 2-MeTHF (363 mL) were added in sequence to the reaction vessel. After replacing the reaction vessel with nitrogen, the external temperature was set to 20 ° C. Hexamethyldisilazane (119 mL) was added while stirring. Then, trimethylsilyl trifluoromethanesulfonate (93.5 mL) was added over 20 minutes. After stirring for 25 minutes, the temperature was raised to 50 ° C. After stirring for 8 hours at an internal temperature of 50 ° C, the reaction vessel was cooled to room temperature.
• the deprotection reaction of the Cbz group is generally carried out under catalytic hydrogen reduction conditions in the presence of a metal catalyst such as palladium/carbon.
• a metal catalyst such as palladium/carbon.
• the present inventors have discovered a method that makes it possible to deprotect the Cbz group without reducing the olefin in the molecule by using the conditions described in Example 1-23, i.e., the TMSOTf/HMDS conditions.
• Example 1-24-1 Compound 1: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 Synthesis of ]pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide (cyclization position B)
• the external temperature of the reaction vessel was set to 40°C, and the mixture was concentrated and dried while stirring.
• the external temperature of the reaction vessel was cooled to 25°C, and isopropyl acetate (627 mL) and 2.5% aqueous ammonia solution (627 mL) were added to the obtained concentrate and stirred.
• Example 1-25 After discharging the aqueous layer by liquid-liquid separation, 10% aqueous sodium hydrogen sulfate solution (627 mL) was added to the obtained organic layer and stirred. After discharging the aqueous layer by liquid-liquid separation, the obtained organic layer was washed successively with 5% aqueous disodium hydrogen phosphate solution (627 mL x 2) and 5% aqueous sodium chloride solution (627 mL). The obtained organic layer was washed with 0.5% aqueous sodium chloride solution (627 mL x 2). The external temperature was set to 40°C, and the obtained organic layer was concentrated under reduced pressure to obtain 92.23 g of a concentrated and dried product containing compound 1. The obtained concentrated and dried product containing compound 1 was used in Example 1-25.
• Example 1-24-2 Compound 1: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 Synthesis of ]pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide (cyclization position B)
• HATU (72.6 mg) and acetonitrile (1.80 mL) were added to the reaction vessel.
• a solution of the concentrated dry product containing compound 24 (100 mg) obtained in Example 1-23 and acetonitrile (5.5 mL) containing DIPEA (40 ⁇ L) was added dropwise over 5 hours and 42 minutes.
• the reaction mixture was sampled and prepared as a sample (sample preparation method 2).
• HPLC of compound 1 retention time: 3.99 minutes (HPLC analysis condition method 1) Cyclic dimer HPLC: Retention time: 4.80 minutes (HPLC analysis condition method 1)
• acetone/heptane/hydrate crystals (Form F) (about 1.00 mg) of compound 1 obtained by the same operation as in Example 3-8 were added to the reaction vessel and stirred at 35 ° C. for 23 hours. The mixture was cooled to 25°C and stirred for another 6 hours. Heptane (4.90mL) was added over 1 hour and stirred at 25°C for 14 hours. Heptane (4.90mL) was further added over 1 hour and stirred for 3 hours. Finally, heptane (4.90mL) was added over 2 hours and stirred for 3 hours.
• the reaction mixture was filtered under reduced pressure, and the obtained crystals were washed with a mixture of acetone (7.76mL) and heptane (11.6mL).
• the obtained crystals were dried for 16 hours with the external temperature set to 40°C.
• the dried powder was collected, and a white powder (6.8g, Form A) was obtained.
• Example 1-26 Compound 1: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0 4,8 .0 26,30 Synthesis of ]pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide (cyclization position A)
• Example 2-2 Compound 27: tert-Butyl (S)-N-(2-(but-3-en-1-ylamino)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycinate hydrochloride
• toluene (751 mL) and 1N NaOH aqueous solution (536 mL) were added to the reaction mixture, and the mixture was stirred for 30 minutes, after which the aqueous layer was discharged by liquid-liquid separation.
• the organic layer was stored overnight at room temperature. After storage, 5% aqueous sodium carbonate solution (536 mL) was added to the organic layer, stirred for 10 minutes, and the aqueous layer was discharged by liquid-liquid separation. Next, 5% aqueous sodium dihydrogen phosphate solution (751 mL) was added to the organic layer, stirred for 10 minutes, and the aqueous layer was discharged by liquid-liquid separation.
• 5% aqueous sodium dihydrogen phosphate solution (751 mL) was added to the organic layer once more, stirred for 10 minutes, and the aqueous layer was discharged by liquid-liquid separation.
• 5% saline solution (751 mL) was added to the organic layer, stirred for 10 minutes, and the aqueous layer was discharged by liquid-liquid separation.
• the organic layer was stored overnight at an external temperature of 5° C. After storage, the organic layer was concentrated under reduced pressure at 40° C. until it became about 215 mL. Toluene (215 mL) was added to the concentrated liquid, and concentrated under reduced pressure at 40° C. until it became about 215 mL, and this operation was repeated twice.
• the precipitated inorganic salt was filtered, the target substance and toluene in the obtained filtrate were quantified, and toluene was added so that the amount was 296 mL.
• pyridine hydrochloride 43.28 g
• acetonitrile 148 mL
• Crystal precipitation was confirmed during the dropwise addition.
• toluene (1.7 L) was added, and after stirring for 1 hour, the external temperature was lowered to 0 ° C. and stirred for another 2 hours.
• Example 2-3 Compound 28: 2-[[(2S)-2-[(4Z,7S)-7-[9H-Fluoren-9-ylmethoxycarbonyl (methyl)amino]-8-oxo-2,3,6,7-tetrahydroazocin-1-yl]-3-[4-(trifluoromethyl)phenyl]propanyl]-methyl-amino]acetic acid
• Toluene (583 g) and 5% aqueous sodium hydrogen sulfate (2066 g) were added to N-cyclohexylcyclohexanaminium (2S,3S)-2- ⁇ [(benzyloxy)carbonyl]amino ⁇ -3-methylpentanoate (135 g), and the mixture was stirred at room temperature for 10 minutes, and the organic layer was separated. The resulting organic layer was washed with 5% aqueous sodium hydrogen sulfate (2066 g) and 5% saline (1397 g) in that order, and the solvent was distilled off under reduced pressure.
• Example 2-7-1 The solvent was distilled off from 9.5346 g of this solution under reduced pressure, and heptane (100 mL) was added to the resulting residue.
• the mixture was dissolved at an external temperature of 50° C., and the seed crystals (11.0 mg) obtained in Example 2-7-1 were added at an internal temperature of 40° C.
• the mixture was stirred at an external temperature of 42° C. for 15 minutes, at an external temperature of 43° C. for 13 minutes, and at an external temperature of 44° C. for 17 minutes, then the external temperature was cooled to 0° C. at a rate of 12° C. per hour, and further stirred for 1.5 hours at an external temperature of 0° C.
• Example 2-7-1 Compound 13: Synthesis of seed crystals of tert-butyl N-methyl-L-norvalyl-L-isoleucyl-L-prolinate A part of the solution containing the title compound obtained in the reaction of Example 2-7 was concentrated under reduced pressure, and heptane (7622 ⁇ L) was added to the resulting residue (0.3811 g). The resulting solid was dissolved at an external temperature of 50° C., cooled to room temperature with stirring, and heptane (3811 ⁇ L) was added to the resulting slurry and stirring was continued.
• 2-Methyltetrahydrofuran (95 g) was added to the obtained residue, and the operation of concentrating under reduced pressure was repeated twice.
• 2-Methyltetrahydrofuran (95 g), acetonitrile (75 g), DIPEA (35.46 g, 274 mmol), and dimethylamine hydrochloride (7.88 g, 96.6 mmol) were added to the obtained residue (47.91 g) at 25° C.
• a solution of propylphosphonic anhydride in 2-methyltetrahydrofuran (50.4 wt %, 61.33 g, 97.1 mmol) was added dropwise over 1 hour and 30 minutes.
• a reaction vessel was charged with 10% palladium carbon (54.33% wet, 3.39 g, 1.45 mmol, 3 mol% on Pd metal basis) and 2-methyltetrahydrofuran (75 g). The atmosphere was replaced with nitrogen and hydrogen at 25°C, and the mixture was stirred under a hydrogen atmosphere (0.40 MPaG) for 2 hours. A solution of compound A11 (42.39 g) obtained in Example 2-8-1 and 2-methyltetrahydrofuran (22 g) were added. After stirring for 1 hour and 30 minutes under a hydrogen atmosphere (0.20 MPaG), a sample was taken, and the completion of the reaction was confirmed by HPLC analysis.
• reaction conversion rate calculation formula 1 The reaction mixture was sampled and sample preparation (sample preparation method K) was performed, and it was confirmed by HPLC analysis that the reaction conversion rate was 99% or more (reaction conversion rate calculation formula 1).
• 5% potassium carbonate aqueous solution (447 mL) and N,N-dimethyl-4-aminopyridine (90 g) were added, and the mixture was further stirred for 1 hour and 30 minutes.
• the internal temperature was cooled to 25°C, toluene (373mL) was added, and the aqueous layer was discharged by liquid separation.
• the organic layer was washed with 4% aqueous sulfuric acid solution (447mL x 2) and 5% aqueous sodium carbonate solution (447mL x 2).
• a THF solution (163.97 g) of compound 26 obtained in Example 2-8, THF (665 mL), and 4.57 wt. % Pd/C (14.71 g) were placed in a pressure-resistant reaction vessel (5 L), and the external temperature was set to 25 ° C. and stirred. The atmosphere was replaced with 0.20 MPa nitrogen three times, and further replaced with 0.20 MPa hydrogen three times, and stirred for 1 hour under a 0.20 MPa hydrogen atmosphere.
• the reaction mixture was sampled and prepared as a sample (sample preparation method 1), and the reaction conversion rate was confirmed to be 99% or more by HPLC analysis (calculation formula 1 for reaction conversion rate).
• the inside of the reaction vessel was replaced with 0.20 MPa nitrogen three times, and Pd/C was removed by filtration.
• reaction mixture was sampled and prepared as a sample (sample preparation method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 99% or more (calculation formula 1 for reaction conversion rate).
• the inside of the reaction vessel was replaced with nitrogen at 0.20 MPa three times, and Pd/C was removed by filtration. The removed Pd/C was washed three times with 2-methyltetrahydrofuran (232 mL). The filtrate and the washings were mixed and concentrated under reduced pressure to 182 mL at an external temperature of 50° C. 2-Methyltetrahydrofuran (774 mL) was added, and the mixture was concentrated under reduced pressure to 182 mL.
• a part of the obtained concentrated liquid (5.5 g) was placed in a reaction vessel (50 mL), and 2-methyltetrahydrofuran (1.34 mL) was added.
• the obtained solution was heated to an internal temperature of 67.5°C and stirred.
• Heptane (35.6 mL) was added, and the crystals of compound 33 (322 mg) obtained by the same operation as in Example 2-11 were suspended in heptane (0.40 mL) and added to the reaction vessel.
• the mixture was stirred at an internal temperature of 67.5°C for 1 hour or more, cooled to 57.5°C over 2 hours or more, and further stirred for 1 hour or more.
• the internal temperature was further cooled to 47.5°C over 1 hour or more, and further stirred for 1 hour or more.
• the internal temperature was further cooled to below 10°C over 2 hours or more, and further stirred for 1 hour or more.
• the reaction mixture was filtered through a Kiriyama funnel, and the obtained crystals were washed twice with heptane (10.0 mL) and with a heptane/2-methyltetrahydrofuran (6/1) solution (10.0 mL) cooled to 10°C.
• the obtained crystals were dried for 2 hours under reduced pressure with an external temperature set to 40°C. The dried powder was collected, and a white powder (1.39 g) was obtained.
• compound 34 (206.8 g) was obtained from 4-bromo-2-methoxy-1-(trifluoromethyl)benzene (190 g).
• Nickel bromide trihydrate (1.23 kg) and 1,3-dimethyl-2-imidazolidinone (98.8 kg) were mixed as a slurry and charged into a reaction vessel (1000 L), followed by charging 4,4'-di-tert-butyl-2,2-dipyridyl (1.21 kg) and stirring at 20.8-22.7°C for 28 minutes.
• reaction conversion rate was confirmed to be 99% or more by HPLC analysis (calculation formula 1 for reaction conversion rate).
• sample preparation method 1 15% aqueous ammonium chloride solution (332 kg) was added dropwise.
• Toluene (135 kg) was added to the resulting mixture, which was stirred for 30 minutes or more, and then filtered using Celite. After washing the Celite with toluene (135 kg), the aqueous layer was discarded.
• reaction conversion rate calculation formula 1 The reaction mixture was sampled and sample preparation (sample preparation method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 99% or more (reaction conversion rate calculation formula 1).
• the mixture was filtered, and the Pd/C residue was washed with toluene (26.7 kg). The filtrate was obtained again by the same operation, then combined, and concentrated to 155 L at an external temperature setting of 40 ° C., to obtain 155 kg of a solution containing the title compound.
• LCMS (ESI) of compound 34- ⁇ 2: Retention time: 5.72 minutes, m/z 278.37 [M-Boc+H] + (LCMS analysis conditions method H)
• Nickel bromide trihydrate (0.198 g) and 1,3-dimethyl-2-imidazolidinone (15 mL) were mixed and charged as a slurry in a reaction vessel (100 mL), then 4,4'-di-tert-butyl-2,2-dipyridyl (0.195 g) was charged and stirred at 25°C for 30 minutes or more.
• reaction conversion rate was confirmed to be 99% or more by HPLC analysis (calculation formula 1 for reaction conversion rate).
• 10% potassium hydroxide aqueous solution 35 mL was added dropwise at an internal temperature of 0 to 25°C.
• the reaction mixture was sampled and sample preparation (sample preparation method H) was performed, and the reaction conversion rate was confirmed to be 99% or more by HPLC analysis (calculation formula H for reaction conversion rate).
• the reaction mixture was cooled, and water (186 kg) was added dropwise over 80 minutes at an internal temperature of 25.9°C to 32.0°C. After removing the organic layer, the mixture was washed three times with toluene (124 kg), and the pH was adjusted to 6.52 with 40% aqueous potassium phosphate tripotassium solution (95.7 kg). Acetonitrile (61.2 kg) was then added, and the pH was adjusted to 7.83 again using 40% tripotassium phosphate aqueous solution (25.4 kg). N-(benzyloxycarbonyloxy)succinimide (16.0 kg) was added to the reaction mixture after pH adjustment to start the reaction.
• reaction mixture was sampled and sample preparation (sample preparation method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 99% or more (calculation formula H for reaction conversion rate).
• the pH of the obtained reaction mixture was adjusted to 7.73 again using 40% tripotassium phosphate aqueous solution (44.7 kg), and then methyl-tert-butyl ether (46.3 kg) and heptane (42.4 kg) were added, and it was confirmed that the mixture was separated into three layers.
• the obtained organic layer was washed four times with a mixed solution of 24% sodium hydroxide aqueous solution (2.1 kg)-sodium chloride (12.4 kg)-water (110.0 kg), and the organic layer was sampled and sampled (sample preparation method 1), and it was confirmed by NMR analysis that the amount of residual acetonitrile was 0.44 v/w or less (calculation formula H for residual acetonitrile).
• the obtained organic layer was washed with a 0.2 M sodium hydroxide aqueous solution (62.1 kg), and then washed with a mixed solution of 24% sodium hydroxide aqueous solution (2.1 kg)-sodium chloride (3.1 kg)-water (72.3 kg).
• sample preparation method 1 The organic layer after washing was sampled and subjected to sample preparation (sample preparation method 1), and it was confirmed by HPLC analysis that the residual impurities were 0.10% or less.
• the obtained organic layer was washed with 1M hydrochloric acid (310 kg), and then the organic layer after washing was sampled and subjected to sample preparation (sample preparation method H), and it was confirmed by HPLC analysis that the residual impurities were 0.10% or less.
• the obtained organic layer was washed with 10% saline (166 kg), concentrated to 62 L, and then toluene (80.9 kg) was added and concentrated again to 62 L to carry out solvent replacement with toluene.
• ((S)-2-(((benzyloxy)carbonyl)amino)-4-(3-methoxy-4-(trifluoromethyl)phenyl)butanoic acid dicyclohexylamine salt) 91.0 g was suspended in a toluene (2.51 kg)-heptane (511 g) mixed solution and charged. After cooling the internal temperature from 67.0 ° C. to 52.1 ° C. over 1 hour 38 minutes, stirring was continued for more than 1 hour, and then the internal temperature was cooled from 50.1 ° C. to 23.0 ° C. over 1 hour 55 minutes.
• sample preparation method H sample preparation method H
• the supernatant concentration was confirmed to be 2 mg / mL or less by HPLC analysis.
• the obtained slurry was filtered and washed with a toluene (47.4 kg) - heptane (37.2 kg) mixed solution to obtain wet powder.
• the obtained wet powder was dried at an external temperature of 38 ° C. for 50 hours to obtain ((S)-2-(((benzyloxy)carbonyl)amino)-4-(3-methoxy-4-(trifluoromethyl)phenyl)butanoic acid dicyclohexylamine salt) (25.6 kg).
• LCMS (ESI) of compound 34: Retention time: 5.89 minutes, m/z 368.41 [M-CO2-DCHA+H] + (LCMS analysis conditions method H)
• HMDS HMDS (19.0 g) was added, the external temperature of the reaction vessel was set to 0 ° C, and the mixture was stirred for 15 minutes.
• TMSOTf (15.4 g) was slowly added dropwise so that the internal temperature did not exceed 20 ° C.
• the external temperature of the reaction vessel was set to 20°C, and the reaction mixture was stirred for 1 hour, then diluted with 2-methyltetrahydrofuran (244mL), and the external temperature of the reaction vessel was set to 10°C.
• 5% aqueous solution of dipotassium hydrogen phosphate (478mL) was slowly added dropwise, and stirring was stopped and the aqueous layer was discharged.
• Example 2-16 Compound 21: Synthesis of tert-butyl (2S)-1-[(2s,3s)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-(benzyloxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butanoyl]-methyl-amino]pentanoyl]amino]-3-methyl-pentanoyl]pyrrolidine-2-carboxylate
• the obtained organic layer was washed in the order of 10% aqueous ammonia (280 mL), 4% dilute sulfuric acid (280 mL), 4% dilute sulfuric acid (280 mL), and 5% aqueous sodium carbonate (280 mL).
• the obtained organic layer was concentrated under reduced pressure to obtain a 2-methyltetrahydrofuran solution of compound 21 (132.34 g).
• Example 2-18 Compound 38: Synthesis of tert-butyl [(S)-2-[(S)-3-[(S)-2-(1-[(2S,4R)-1-[(S)-2-amino-[3-methoxy-4-(trifluoromethyl)phenyl]butanoyl]-4-ethoxy-N-methylpyrrolidine-2-carboxamido]-N-methylcyclobutane-1-carboxamido)-2-cyclopentyl-N-methylacetamido]-4-[dimethylamino]-N-methyl-4-oxobutanamido]pentanoyl]-L-isoleucyl-L-proline tert-butyl
• a 2-MeTHF solution (17.6 kg) of compound 37 (3.41 kg) was added to the reaction vessel at room temperature, followed by the addition of 2-MeTHF (12.3 kg), compound 28 monotoluene solvate (2.38 kg), and acetonitrile (6.20 kg) in that order.
• the external temperature was set to 5°C, and NMM (1.26 kg) and HATU (1.65 kg) were added at an internal temperature of 30°C or less, followed by stirring for 1 hour at an internal temperature of 25°C.
• a 5% aqueous potassium carbonate solution (23.9 kg) and 1-methylimidazole (234 g) were added and stirred at room temperature for 30 minutes, and the aqueous layer was discharged by liquid-liquid separation.
• the resulting organic layer was washed with 10% aqueous ammonia (23.0 kg), 5% aqueous sodium hydrogen sulfate (23.9 kg), and 5% aqueous sodium carbonate (23.9 kg), and then concentrated at an external temperature of 40°C until the volume reached 10 L.
• Acetonitrile (16.2 kg) was added to the concentrated solution, and the concentration was repeated twice until the volume reached 10 L, yielding a solution of Compound 38 in acetonitrile (19.4 kg).
• HATU (949 g) and acetonitrile (25.6 kg) were added to the reaction vessel and dissolved to prepare an acetonitrile solution of HATU.
• Compound 40 (1.31 kg) in acetonitrile (5.52 kg), acetonitrile (19.1 kg), and N-methylmorpholine (504 g) were added to another vessel to prepare an acetonitrile solution of compound 40.
• the acetonitrile solution of compound 40 prepared in the acetonitrile solution of HATU at an external temperature of 25° C. was dropped over 4 hours and 22 minutes, and acetonitrile (1.04 kg) was used to wash it in. After dropping, the mixture was stirred for another hour.
• the reaction conversion rate was confirmed to be 99% or more by HPLC analysis (LC analysis condition method cyc) (calculation formula 1 for reaction conversion rate).
• the external temperature was set to 40°C, and the reaction mixture was concentrated to approximately 12.5 L.
• MTBE (14.5 kg) and 2.5% aqueous ammonia (13.3 kg) were added to the resulting concentrate at room temperature and stirred for 34 minutes.
• cyclization positions B and C in the present invention have a smaller amount of cyclic dimer impurities than the existing cyclization position A, and are therefore efficient cyclization positions for the production of compound 1.
• Example 3 Crystallization Example 3-1 Amorphous compound 1 (77.4 mg) was dissolved in dimethyl sulfoxide (0.387 mL), and the resulting solution (0.015 mL) was freeze-dried at -20°C for 3 days. A 2-butanone-heptane mixture (1:4 (v/v), 0.015 mL) was added to the resulting freeze-dried product, and the mixture was shaken and stirred at room temperature for 7 days to obtain crystals of compound 1. The resulting crystals were confirmed to be dimethyl sulfoxide/heptane/hydrate crystals (Form G) by single crystal X-ray structural analysis (Examples 4-7). The structure is shown in Figure 1.
• Example 3-2 Amorphous Compound 1 (11.4 mg) was dissolved in acetone (34.2 ⁇ L), and about 0.1 mg of the crystals of Example 3-1 was added. Heptane (22.8 ⁇ L) was then added, and the mixture was shaken and stirred at room temperature for 3 hours. Heptane (22.8 ⁇ L) was further added, and the mixture was shaken and stirred at room temperature for 2 hours. Heptane (22.8 ⁇ L) was further added, and the mixture was shaken and stirred at room temperature for 18 hours, after which it was filtered and dried under reduced pressure. The obtained crystals were hydrate crystals of Compound 1 (Form A). Powder X-ray diffraction measurement of the obtained crystals (Example 4-3) is shown in FIG. 2.
• Example 3-3 Amorphous compound 1 (10.7 mg) was dissolved in 2-propanol (32.1 ⁇ L), and about 0.1 mg of the crystals obtained in Example 3-1 was added. Heptane (21.4 ⁇ L) was then added, and the mixture was shaken and stirred at room temperature for 3 hours. Heptane (21.4 ⁇ L) was further added, and the mixture was shaken at room temperature for 2 hours, after which heptane (21.4 ⁇ L) was added, and the mixture was shaken and stirred at room temperature for 3 hours. Heptane (21.4 ⁇ L) was further added, and the mixture was shaken and stirred at room temperature for 15 hours to obtain a crystal of compound 1 (Form E).
• the obtained crystal was subjected to single crystal X-ray structural analysis (Example 4-8), and it was confirmed that the crystal was 2-propanol/heptane/hydrate.
• the crystal structure is shown in FIG. 3.
• the obtained Form E was dried under reduced pressure, and powder X-ray diffraction measurement (Example 4-3) was performed.
• the results are shown in FIG. 4.
• the diffraction pattern showed Form A, and it was confirmed that 2-propanol/heptane/hydrate (Form E) was transformed into a hydrate crystal (Form A) by drying under reduced pressure.
• Examples 3-4 To the Form A crystals of Compound 1 (5.9 mg), an ethanol-heptane mixture (1:1 (v/v), 0.017 mL) and one glass bead were added. The mixture was stirred at 37° C. and 2000 rpm for 7 days using a shaker (TAITEC BioShaker M.BR-022UP), filtered, and dried under reduced pressure to obtain crystals of Compound 1 (Form B). The powder X-ray diffraction measurement of the obtained crystals (Example 4-3) is shown in FIG. 5.
• Examples 3-5 To the Form A crystals of Compound 1 (5.8 mg), an ethyl acetate-heptane mixture (1:1 (v/v), 0.017 mL) and one glass bead were added. The mixture was stirred at 37° C. and 2000 rpm for 7 days using a shaker (TAITEC BioShaker M.BR-022UP), filtered, and dried under reduced pressure to obtain crystals of Compound 1 (Form B). The powder X-ray diffraction measurement of the obtained crystals (Example 4-3) is shown in FIG. 6.
• Example 3-6 Amorphous compound 1 (9.0 mg) was dissolved in ethanol (27.0 ⁇ L), heptane (27.0 ⁇ L) was added, and the mixture was shaken and stirred at room temperature for 4 minutes. When about 0.1 mg of the crystals obtained in Example 3-4 was added and the mixture was shaken and stirred at room temperature for 1 minute, a crystal of compound 1 was obtained. Single crystal X-ray structure analysis (Example 4-9) was performed, and it was confirmed that the crystal was an ethanol/hydrate (Form H). The crystal structure is shown in FIG. 7. The obtained Form H was dried under reduced pressure, and powder X-ray diffraction measurement (Example 4-3) was performed. The results are shown in FIG. 8. The diffraction pattern shows Form B, and it was confirmed that the ethanol/hydrate (Form H) was transformed into a hydrate crystal (Form B) by drying under reduced pressure.
• Examples 3-7 Amorphous compound 1 (10.9 mg) was dissolved in ethyl acetate (32.7 ⁇ L), heptane (32.7 ⁇ L) was added, and the mixture was shaken and stirred at room temperature for 4 minutes. About 0.1 mg of the crystals of Example 3-5 was added, and the mixture was shaken and stirred at room temperature for 1 minute to obtain crystals of compound 1.
• Single crystal X-ray structure analysis (Example 4-9) was performed, and it was confirmed that the crystals were ethyl acetate/hydrate (Form C). The crystal structure is shown in FIG. 9.
• the obtained Form C was dried under reduced pressure, and powder X-ray diffraction measurement (Example 4-3) was performed. The results are shown in FIG. 10.
• the diffraction pattern shows Form B, and it was confirmed that the ethyl acetate/hydrate (Form C) was transformed into a hydrate crystal (Form B) by drying under reduced pressure.
• Examples 3-8 Amorphous compound 1 (112.3 mg) was dissolved in acetone (337 ⁇ L), and about 0.1 mg of Form A crystals was added as seed crystals. Heptane (112 ⁇ L) was added and stirred at room temperature for 2 minutes using a stirrer. Heptane (112 ⁇ L) was added again and stirred at room temperature for 10 minutes. After confirming the dissolution of the seed crystals, about 0.1 mg of Form A crystals was added again and stirred at room temperature for 1 hour. Heptane (225 ⁇ L) was then added and stirred at room temperature for 20 minutes. About 0.1 mg of Form A crystals were further added and stirred at room temperature for 40 minutes.
• Examples 3-9 Amorphous Compound 1 (61.7 mg) was dissolved in 2-propanol (185 ⁇ L), heptane (123 ⁇ L) was added, and the mixture was stirred at room temperature for 3 minutes using a stirrer. After adding about 0.1 mg of Form A crystals as seed crystals, the mixture was stirred at room temperature for 30 minutes. Thereafter, heptane (123 ⁇ L) was added, and the mixture was stirred at room temperature for 2 hours. Furthermore, heptane (185 ⁇ L) was added, and the mixture was shaken and stirred at room temperature for 18 hours. The reaction product was filtered under reduced pressure and dried in vacuum for 1 day to obtain 23.3 mg of Form A crystals.
• Powder X-ray diffraction measurement (Example 4-3) was performed on Form A. The measurement results are shown in FIG. 14. The results of simultaneous thermogravimetry and differential thermal analysis of Form A are shown in FIG. 15, and the results of 1 H-NMR measurement are shown in FIG. 16. Since the powder X-ray diffraction pattern in FIG. 14 coincided with the pattern of Example 3-8, a weight loss of 2 wt % was observed in FIG. 15, and only 1 wt % of 2-propanol was observed in FIG. 16, it was determined that Form A was a hydrate and that 2-propanol was present as a residual solvent.
• Example 3-10 Amorphous compound 1 (60.1 mg) was dissolved in acetone (180 ⁇ L) and stirred using a stirrer. Heptane (120 ⁇ L) was added and stirred at room temperature for 1 minute. About 0.1 mg of Form A crystals was added and stirred for 30 minutes. Heptane (120 ⁇ L) was added again and stirred at room temperature for 1 minute. About 0.1 mg of Form A crystals was added again and stirred at room temperature for 2.5 hours. Heptane (180 ⁇ L) was further added and stirred at room temperature for 18 hours.
• Form F acetone/heptane/hydrate crystals of compound 1 (Form F) were obtained as wet powder.
• the obtained Form F was enclosed in a glass capillary, and powder X-ray diffraction measurement (Example 4-2) was performed, confirming the following main peaks: 6.99°, 8.49°, 9.49°, 9.88°, 10.21°, 11.81°, 12.32°, 12.75°, 13.17°, 13.94°, 14.92°, 15.20°, 15.64°, 16.78°, 17.01°, and 17.47°.
• the measurement results are shown in FIG.
• Example 3-11 Amorphous Compound 1 (10.0 mg) was dissolved in acetone (30 ⁇ L) and stirred using a stirrer. Heptane (20 ⁇ L) was added and stirred at room temperature for 1 minute using a stirrer. Approximately 0.1 mg of Form A crystal was added and stirred for 5 minutes. Heptane (20 ⁇ L) was added again and stirred at room temperature for 2 hours, resulting in a high-quality single crystal. The obtained crystal was confirmed to be acetone/heptane/hydrate (Form F) by single crystal structure analysis (Example 4-8). The crystal structure is shown in FIG. 18.
• Example 3-12 When the powder X-ray diffraction measurement (Example 4-1) of the crystal (Form A) obtained in Example 1-25 was carried out, the main peaks were confirmed as 6.93 °, 7.56 °, 8.26 °, 9.00 °, 9.58 °, 10.35 °, 11.35 °, 12.26 °, 12.85 °, 13.51 °, 14.12 °, 14.69 °, 15.46 °, 15.92 °, 17.43 °, and 17.73 °. The measurement results are shown in FIG. 19. The results of simultaneous thermogravimetry and differential thermal analysis are shown in FIG. 20.
• Form B was maintained at a relative humidity of 30% to 90%, but was transformed to Form Y at a relative humidity of 0%.
• Form Y has major peaks at 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24°.
• Example 3-14 The crystal obtained in Example 3-13 was confirmed to be a hydrate crystal (Form B) by single crystal X-ray structure analysis (Example 4-9). The crystal structure is shown in FIG.
• Example 3-15 Amorphous compound 1 (77.4 mg) was dissolved in dimethyl sulfoxide (0.387 mL), and the solution (0.015 mL) was freeze-dried at -20°C for 3 days. A 1,4-dioxane-heptane mixture (1:4 (v/v), 0.015 mL) was added to the freeze-dried product and stirred with shaking at room temperature for 7 days to obtain crystals of compound 1. The obtained crystals were confirmed to be 1,4-dioxane/hydrate crystals (Form D) by single crystal X-ray structural analysis (Example 4-8). The crystal structure is shown in Figure 26.
• Example 3-16 The crystals of Compound 1 obtained in Example 3-8 (Form A, 6.8 mg) were dissolved in dimethyl sulfoxide (0.12 mL) and stirred at room temperature for 13 days by shaking. Water (1 ⁇ L) was then added and stirred at room temperature for 34 days to obtain crystals of Compound 1. The obtained crystals were confirmed to be dimethyl sulfoxide/hydrate crystals (Form L) by single crystal X-ray structure analysis (Example 4-8). The crystal structure is shown in FIG. 27. Powder X-ray diffraction measurement of the crystals obtained by the same procedure (Example 4-3) confirmed that Form L was a solvate crystal that became amorphous by drying under reduced pressure. The powder X-ray diffraction pattern is shown in FIG. 28.
• Example 3-17 Propylene glycol (0.12 mL) was added to the crystals of Compound 1 (Form B, 45.8 mg) and stirred at room temperature for 5 minutes. Propylene glycol (0.020 mL) was further added and stirred at 40° C. for 5 minutes, then propylene glycol (0.070 mL) was added and stirred at 40° C. for 5 minutes, and the mixture was allowed to stand for another 5 hours. Propylene glycol (0.070 mL) was further added and stirred at 35° C. overnight, then propylene glycol (0.070 mL) was added and stirred for about 1 minute to obtain wet powder of Compound 1.
• the obtained wet powder was confirmed to be Form M crystals by powder X-ray diffraction measurement (Example 4-3). It was confirmed by powder X-ray diffraction measurement that Form M crystals were transformed to Form N crystals when dried under reduced pressure at room temperature overnight.
• the powder X-ray diffraction patterns of Form M and Form N are shown in FIG. 29.
• the results of simultaneous thermogravimetry and differential thermal analysis are shown in FIG. 30. A weight loss of about 11% was observed at 157° C., which corresponds to 2.5 molecules of propylene glycol per compound 1. From the above, it was confirmed that Form M and Form N were propylene glycol solvates.
• Example 3-18 The crystals of Compound 1 (Form B, 12.66 mg) were dissolved in propylene glycol (0.10 mL) and stirred at room temperature for 20 days. Furthermore, about 0.1 mg of the wet powder obtained in Example 3-17 was added and stirred at room temperature for 2.5 hours. Propylene glycol (0.10 mL) was added, and the mixture was heated and stirred at 60° C. for 30 minutes on a hot plate, and then shaken and stirred at room temperature for 4.5 hours to obtain crystals of Compound 1. The obtained crystals were confirmed to be propylene glycol/hydrate crystals (Form M) by single crystal X-ray structure analysis (Example 4-8). The crystal structure is shown in FIG. 31.
• Example 3-19 The crystals (Form A) obtained in Example 1-25 were weighed in amounts of 7.773 mg, 7.258 mg, 8.665 mg, and 13.047 mg (total 36.7 mg) in open aluminum pans, and heated using a simultaneous thermogravimetric and differential thermal analyzer (Example 4-11). The obtained crystals were subjected to powder X-ray diffraction measurement (Example 4-2), and the main peaks were confirmed to be 7.49°, 7.91°, 8.14°, 9.11°, 9.33°, 11.04°, 11.71°, 12.52°, 13.21°, 13.70°, 14.82°, 15.13°, 15.52°, 15.68°, 17.22°, and 17.51°.
• the powder X-ray diffraction pattern of Form K is shown in FIG. 32.
• the results of simultaneous thermogravimetry and differential thermal analysis of the obtained Form K crystals are shown in Figure 33, and the results of 1 H-NMR measurement are shown in Figure 34.
• a weight loss of about 1.8 wt % was observed in Figure 33, while the 1 H-NMR measurement showed no peaks other than those corresponding to the measurement solvent DMSO (containing tetramethylsilane), Compound 1, and water. From these results, it was determined that Form K was a hydrate.
• Example 3-20 The crude solution with low purity was concentrated to dryness and dried under reduced pressure at 40°C to prepare a crude amorphous solid.
• the crude amorphous solid (20 mg) was dissolved in 2-propanol (60 ⁇ L) and stirred using a stirrer. Heptane (60 ⁇ L) was added. Approximately 0.1 mg of Form A seed crystals were added and stirred at room temperature for 1 hour. As no crystal precipitation was observed, further 2-propanol (20 ⁇ L) was added, which resulted in oiling out and no crystals being obtained.
• Example 3-21 The crude solution was concentrated to dryness and dried under reduced pressure at 40°C to prepare a crude amorphous solid.
• the crude amorphous solid (20 mg) was dissolved in ethanol (60 ⁇ L) and stirred using a stirrer. Heptane (60 ⁇ L) was added.
• Two identical solutions were prepared, one of which was added with about 0.1 mg of Form A seed crystals, and the other was added with about 0.1 mg of Form B seed crystals, and the mixture was stirred at room temperature for 1 hour. In both cases, crystals precipitated, and the mixture was filtered to obtain a wet powder.
• Form B was obtained despite the conditions in which Form A seed crystals were added.
• Form B was obtained under the conditions in which Form B seed crystals were added.
• Example 3-22 The crude solution (17.7 kg) was concentrated to 7 L at an external temperature of 50° C. A part of the concentrated solution (4.31 kg) was charged into a reactor, and ethanol (1.16 kg) was added. The external temperature was then set to 42° C. and the mixture was stirred. Purified water (1.01 kg) and seed crystals (Form B, 5.17 g) were added and stirred for 1 hour. Purified water (2.08 kg) was then added dropwise over 80 minutes. Purified water (1.04 kg) was further added dropwise over 40 minutes. The internal temperature was lowered to 25° C. or less over 48 minutes. The mixture was stirred overnight, filtered, and the crystals were washed twice with ethanol/purified water (2.50 L/1.66 L mixture).
• Example 4 Evaluation of crystals
• Example 4-1 Powder X-ray measurements of Examples 3-8, 3-12, 3-13, and 3-19 were carried out under the following conditions.
• Measurement device SmartLab System, D/Tex Ultra detector (manufactured by Rigaku Corporation) Radiation source: CuK ⁇ 1 Tube voltage: 45 kV Tube current: 200mA Scanning range: 4 to 50 degrees Sampling width: 0.005°
• Example 4-2 Powder X-ray measurements of Examples 3 to 10 were carried out under the following conditions to evaluate the crystal forms in the suspensions.
• Measurement device SmartLab System, D/Tex Ultra detector (manufactured by Rigaku Corporation) Radiation source: CuK ⁇ 1 Tube voltage: 45 kV Tube current: 200mA Scanning range: 4 to 50 degrees Sampling width: 0.005° Measurement: The sampled suspension was packed into a capillary for X-ray crystallography and measured.
• Measuring device D8 Discover, 2D VANTEC-500 solid state detector (manufactured by Bruker) Radiation source: CuK ⁇ Tube voltage, tube current: 50 kV, 1000 ⁇ A Measurement range: 5 to 31 degrees Exposure time: 40 seconds
• Example 4-4 Powder X-ray diffraction measurements of Example 3-12 were carried out under the following conditions, and the crystal form at each relative humidity was evaluated. Measurements were taken at 0% (FIG. 21(A)), 10% (FIG. 21(B)), 20% (FIG. 21(C)), 50% (FIG. 21(D)), and 90% (FIG. 21(E)) at points between when the relative humidity was lowered to 0% and when it was raised to 90%.
• Measurement equipment SmartLab System, D/Tex Ultra detector, water vapor generator HUM-SL (manufactured by Rigaku Corporation)
• Anticathode Cu Tube voltage: 45 kV Tube current: 200mA Scanning range: 4 to 35° Scanning speed: 5°/min Sampling width: 0.02° Humidity change conditions:
• Example 3-13 Powder X-ray diffraction measurements of Example 3-13 were carried out under the following conditions, and the crystal form at each relative humidity was evaluated. Measurements were taken at 0% (FIG. 24(A)), 30% (FIG. 24(B)), 50% (FIG. 24(C)), and 90% (FIG. 24(D)) at points between when the relative humidity was lowered to 0% and when it was raised to 90%.
• Measurement equipment SmartLab System, D/Tex Ultra detector, water vapor generator HUM-SL (manufactured by Rigaku Corporation)
• Anticathode Cu Tube voltage: 45 kV Tube current: 200mA Scanning range: 4 to 35° Scanning speed: 5°/min Sampling width: 0.02° Humidity change conditions:
• Examples 4-6 Thermogravimetry and differential thermal analysis (TG-DTA) of Examples 3-8, 3-9, 3-12, 3-13, 3-17, and 3-19 were carried out under the following conditions.
• Measurement device STA7200RV+AS-3T (Hitachi High-Tech Science) Measurement range: 30 to 350°C Heating rate: 10° C./min.
• Atmosphere nitrogen Measurement: A sample was weighed in an open aluminum pan, covered with a mesh and then the measurement was performed.
• Example 4-7 The single crystal X-ray structure analysis of Example 3-1 was carried out under the following conditions. Measurement device: Rigaku XtaLAB Synergy Custom with a VariMax Cu Diffractometer (manufactured by Rigaku Corporation) Anticathode: Cu Tube voltage: 40 kV Tube current: 30mA Temperature: -180°C Measurement: Measurement was performed using a strategy and exposure time that was believed to provide sufficient diffraction spots for structural analysis. Structural analysis: The Olex2 program was used, the initial structure was determined using SIR2008, and the structure was refined using the Full-matrix least-squares method (SHELXL-2018/3).
• Examples 4-8 The single crystal X-ray structure analyses of Examples 3-3, 3-11, 3-15, 3-16, and 3-18 were carried out under the following conditions.
• Measurement device Rigaku XtaLAB Synergy Custom with a VariMax Cu Diffractometer (manufactured by Rigaku Corporation)
• Anticathode Cu Tube voltage: 40 kV Tube current: 30mA
• Temperature: -180°C Measurement Measurement was performed using a strategy and exposure time that was believed to provide sufficient diffraction spots for structural analysis.
• Structural analysis Using the Olex2 program, initial structure determination was performed using the Dual Space method (SHELXD-2008), and structure refinement was performed using the Full-matrix least-squares method (SHELXL-2018/3).
• Examples 4-9 The single crystal X-ray structure analyses of Examples 3-6, 3-7, and 3-14 were carried out under the following conditions.
• Structural analysis Using the Olex2 program, initial structure determination was performed using the Dual Space method (SHELXD-2008), and structure refinement was performed using the Full-matrix least-squares method (SHELXL-2018/3).
• Examples 4-10 The 1 H-NMR measurements of Examples 3-8, 3-9, and 3-19 were carried out under the following conditions.
• Measuring device JNM-ECX500II (manufactured by JEOL)
• Measurement solvent DMSO-d6, contains 0.03% (v/v)
• TMS Measurement temperature: 295K
• Sample preparation A commercially available deuterated solvent was mixed with the compound to be measured to prepare a sample.
• Accumulation number and relaxation waiting time Measurement was performed the number of times (8, 16 or 512) that was considered to provide a sufficient s/n ratio, and for a time (60 seconds) sufficiently longer than the relaxation time.
• the residual solvent ratio (wt %) was calculated based on the integral value: signal area intensity ratio of each signal.
• Example 4-11 The sample preparation for Example 3-19 was carried out under the following conditions. Equipment used: STA7200RV+AS-3T (Hitachi High-Tech Science) Temperature range: 30 to 120°C Heating rate: 20° C./min (30-120° C.), maintained at 120° C. for 60 minutes. Atmosphere: nitrogen. Preparation: A sample was weighed in an open aluminum pan and heated.
• Example 5 Slurry conversion experiment
• Example 5-1 Form A crystals (3.0 mg), Form B crystals (3.0 mg), and Form K crystals (3.0 mg) of Compound 1 were mixed, and an acetone-heptane mixture (1:1 (v/v), 0.030 mL) and one glass bead were added.
• the mixture was stirred at 25°C and 2000 rpm for 9 days using a shaker (TAITEC BioShaker M.BR-022UP), filtered, and dried under reduced pressure to obtain crystals of Compound 1 (Form B).
• Powder X-ray diffraction measurement of the obtained crystals (Example 4-3) is shown in Figure 35 (A). It was confirmed that Form B crystals were the stable form in the acetone-heptane mixture (1:1 (v/v)).
• Example 5-2 Form A crystals (3.1 mg), Form B crystals (3.1 mg), and Form K crystals (3.1 mg) of Compound 1 were mixed, and a 2-propanol-heptane mixture (1:1 (v/v), 0.030 mL) and one glass bead were added. The mixture was stirred at 25°C and 2000 rpm for 9 days using a shaker (TAITEC BioShaker M BR-022UP), filtered, and dried under reduced pressure to obtain crystals of Compound 1 (Form B). Powder X-ray diffraction measurement of the obtained crystals (Example 4-3) is shown in Figure 35 (B). It was confirmed that Form B crystals were the stable form in the 2-propanol-heptane mixture (1:1 (v/v)).
• Example 5-3 Form A crystals (3.0 mg), Form B crystals (3.0 mg), and Form K crystals (3.1 mg) of Compound 1 were mixed, and an ethanol-heptane mixture (1:1 (v/v), 0.030 mL) and one glass bead were added. The mixture was stirred and shaken at 25°C and 2000 rpm for 9 days using a shaker (TAITEC BioShaker M.BR-022UP), filtered, and dried under reduced pressure to obtain crystals of Compound 1 (Form B). Powder X-ray diffraction measurement of the obtained crystals (Example 4-3) is shown in Figure 35 (C). It was confirmed that Form B crystals were the stable form in the ethanol-heptane mixture (1:1 (v/v)).
• Example 5-4 Form A crystals (3.0 mg), Form B crystals (3.0 mg), and Form K crystals (3.0 mg) of Compound 1 were mixed, and an acetone-water mixture (1:1 (v/v), 0.030 mL) and one glass bead were added. The mixture was stirred at 25°C and 2000 rpm for 9 days using a shaker (TAITEC BioShaker M.BR-022UP), filtered, and dried under reduced pressure to obtain crystals of Compound 1 (Form B). Powder X-ray diffraction measurement of the obtained crystals (Example 4-3) is shown in Figure 35 (D). It was confirmed that Form B crystals were the stable form in the acetone-water mixture (1:1 (v/v)).
• Example 5-5 Form A crystals (3.0 mg), Form B crystals (3.1 mg), and Form K crystals (3.1 mg) of Compound 1 were mixed, and a 2-propanol-water mixture (1:1 (v/v), 0.030 mL) and one glass bead were added. The mixture was stirred at 25°C and 2000 rpm for 9 days using a shaker (TAITEC BioShaker M.BR-022UP), filtered, and dried under reduced pressure to obtain crystals of Compound 1 (Form B). Powder X-ray diffraction measurement of the obtained crystals (Example 4-3) is shown in Figure 35 (E). It was confirmed that Form B crystals were the stable form in the 2-propanol-water mixture (1:1 (v/v)).
• Examples 5-6 Form A crystals (3.1 mg), Form B crystals (3.0 mg), and Form K crystals (3.1 mg) of Compound 1 were mixed, and an ethanol-water mixture (1:1 (v/v), 0.030 mL) and one glass bead were added. The mixture was stirred at 25°C and 2000 rpm for 9 days using a shaker (TAITEC BioShaker M.BR-022UP), filtered, and dried under reduced pressure to obtain crystals of Compound 1 (Form B). Powder X-ray diffraction measurement of the obtained crystals (Example 4-3) is shown in Figure 35 (F). It was confirmed that Form B crystals were the stable form in the ethanol-water mixture (1:1 (v/v)).
• Examples 5-7 Form A crystals (3.0 mg), Form B crystals (3.0 mg), and Form K crystals (3.1 mg) of Compound 1 were mixed, and an acetone-water mixture (1:4 (v/v), 0.030 mL) and one glass bead were added. The mixture was stirred at 25°C and 2000 rpm for 9 days using a shaker (TAITEC BioShaker M.BR-022UP), filtered, and dried under reduced pressure to obtain crystals of Compound 1 (Form B). Powder X-ray diffraction measurement of the obtained crystals (Example 4-3) is shown in Figure 35 (G). It was confirmed that Form B crystals were the stable form in the acetone-water mixture (1:4 (v/v)).
• Examples 5-8 Form A crystals (3.0 mg), Form B crystals (3.0 mg), and Form K crystals (3.1 mg) of Compound 1 were mixed, and a 2-propanol-water mixture (1:4 (v/v), 0.030 mL) and one glass bead were added. The mixture was stirred at 25°C and 2000 rpm for 9 days using a shaker (TAITEC BioShaker M.BR-022UP), filtered, and dried under reduced pressure to obtain crystals of Compound 1 (Form B). Powder X-ray diffraction measurement of the obtained crystals (Example 4-3) is shown in Figure 35 (H). It was confirmed that Form B crystals were the stable form in the 2-propanol-water mixture (1:4 (v/v)).
• Examples 5-9 Form A crystals (3.0 mg), Form B crystals (3.1 mg), and Form K crystals (3.0 mg) of Compound 1 were mixed, and an ethanol-water mixture (1:4 (v/v), 0.030 mL) and one glass bead were added. The mixture was stirred at 25°C and 2000 rpm for 7 days using a shaker (TAITEC BioShaker M.BR-022UP), filtered, and dried under reduced pressure to obtain crystals of Compound 1 (Form B). Powder X-ray diffraction measurement of the obtained crystals (Example 4-3) is shown in Figure 35 (I). It was confirmed that Form B crystals were the stable form in the ethanol-water mixture (1:4 (v/v)).
• the present invention provides a method for producing a cyclic peptide compound, or a salt thereof, or a solvate thereof that is useful as a pharmaceutical, and a method for producing a peptide compound used in the production of the cyclic peptide compound, or a salt thereof, or a solvate thereof.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Molecular Biology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Biophysics (AREA)
• General Health & Medical Sciences (AREA)
• Genetics & Genomics (AREA)
• Medicinal Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Biochemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Analytical Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Water Supply & Treatment (AREA)
• Crystallography & Structural Chemistry (AREA)
• Peptides Or Proteins (AREA)

Priority Applications (7)

Applications Claiming Priority (2)

Publications (1)

Family

ID=93152939

Family Applications (1)

Country Status (9)

Cited By (11)

Citations (6)

• 2024
  • 2024-04-19 JP JP2025515295A patent/JPWO2024219480A1/ja active Pending
  • 2024-04-19 AU AU2024257451A patent/AU2024257451A1/en active Pending
  • 2024-04-19 CN CN202480025074.2A patent/CN120936619A/zh active Pending
  • 2024-04-19 TW TW113114671A patent/TW202506706A/zh unknown
  • 2024-04-19 KR KR1020257037736A patent/KR20250174064A/ko active Pending
  • 2024-04-19 EP EP24792752.8A patent/EP4678652A1/en active Pending
  • 2024-04-19 WO PCT/JP2024/015529 patent/WO2024219480A1/ja not_active Ceased
• 2025
  • 2025-09-21 IL IL323506A patent/IL323506A/en unknown
  • 2025-10-14 MX MX2025012255A patent/MX2025012255A/es unknown

Patent Citations (6)

Non-Patent Citations (9)

Also Published As

Similar Documents

Legal Events