WO2010035722A1 - Composé peptidique et son procédé de production - Google Patents

Composé peptidique et son procédé de production Download PDF

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WO2010035722A1
WO2010035722A1 PCT/JP2009/066449 JP2009066449W WO2010035722A1 WO 2010035722 A1 WO2010035722 A1 WO 2010035722A1 JP 2009066449 W JP2009066449 W JP 2009066449W WO 2010035722 A1 WO2010035722 A1 WO 2010035722A1
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formula
salt
compound
lower alkyl
optionally substituted
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PCT/JP2009/066449
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English (en)
Japanese (ja)
Inventor
亮毅 織井
理乙 北山
敏夫 山中
真也 奥田
充至 柴▲崎▼
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アステラス製薬株式会社
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Application filed by アステラス製薬株式会社 filed Critical アステラス製薬株式会社
Priority to JP2010530839A priority Critical patent/JP5625910B2/ja
Priority to CA2738280A priority patent/CA2738280A1/fr
Priority to CN2009801381065A priority patent/CN102164947A/zh
Priority to MX2011003259A priority patent/MX2011003259A/es
Publication of WO2010035722A1 publication Critical patent/WO2010035722A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a method for producing a cyclic peptide compound useful as an active ingredient of a pharmaceutical composition, particularly a pharmaceutical composition for treating hepatitis C virus (HCV) known as an inhibitor of hepatitis C virus replicon RNA replication,
  • HCV hepatitis C virus
  • the present invention relates to an intermediate useful for production, and a production method thereof.
  • Patent Document 1 discloses that a compound of formula (A) or a salt thereof can be produced via a compound of formula (I) or a salt thereof using a fermentation product FR901459 substance (Patent Document 2) as a starting material. Yes. Specifically, the following steps ⁇ 1> to ⁇ 6> are performed. ⁇ 1> Production of a compound of formula (I) or a salt thereof by ring-opening the FR901459 substance or a salt thereof after N—O rearrangement. ⁇ 2> Production of a compound of formula (A2-2) or a salt thereof by condensing threonine at the C-terminus of the compound of formula (I) or a salt thereof.
  • a step of producing a compound of the formula (I) or a salt thereof from the FR90159 substance of the formula (A1-1) or a salt thereof Specifically, the compound of formula (A1-2) or a salt thereof obtained by hydrolyzing the ring of the FR901459 substance after the N—O rearrangement reaction under mildly acidic conditions and protecting the amino group was then opened. The compound (I) or a salt thereof is produced.
  • Prot 0 means a protecting group. For other symbols in the formula, see Patent Document 1. ]
  • a step of producing a compound of the formula (A2-2) or a salt thereof from the compound of the formula (I) or a salt thereof A compound of formula (A2-2) or a salt thereof is produced by condensing a compound of formula (A2-1) to a compound of formula (I) or a salt thereof.
  • Prot 0 means a protecting group. For other symbols, see Patent Document 1. ]
  • a step of producing a compound of formula (A3) or a salt thereof from a compound of formula (A2-2) or a salt thereof Edman decomposition is performed on the compound of the formula (A2-2) or a salt thereof three times, that is, by sequentially removing amino acids from the N-terminal of the compound of the formula (A2-2) or a salt thereof, the compound of the formula (A3) The compound or its salt is manufactured.
  • Edman decomposition is performed on the compound of the formula (A2-2) or a salt thereof three times, that is, by sequentially removing amino acids from the N-terminal of the compound of the formula (A2-2) or a salt thereof, the compound of the formula (A3)
  • the compound or its salt is manufactured.
  • a step of producing a compound of formula (A4-4) or a salt thereof from a compound of formula (A3) or a salt thereof A compound of formula (A4-2) or a salt thereof obtained by introducing an amino acid at the N-terminus of the compound of formula (A3) or a salt thereof and deprotecting the compound or a salt thereof was protected. An amino acid is condensed to produce a compound of formula (A4-4) or a salt thereof. [Wherein, Prot 3 and Prot 4 both represent a protecting group. For other symbols, see Patent Document 1. ]
  • the compound of formula (Ab) or a salt thereof is produced by ordinary catalytic reduction. [See Patent Document 1 for symbols in the formula. ]
  • a compound of formula (A) which is directed to an industrial production method and excellent in terms of operability and purity, an intermediate useful for the production, and a production method thereof.
  • the present invention was completed by finding a production method of the compound of the formula (A) from the viewpoint of industrial production, an intermediate useful for the production, and a production method thereof.
  • Edman decomposition may be performed once, and the compound of the formula (A) and an intermediate useful for the production thereof can be provided with high purity without performing purification by column chromatography in the post-treatment associated therewith.
  • this invention relates to the manufacturing method and intermediate body shown below.
  • Formula (II) Wherein two amino acids are eliminated from the compound or a salt thereof in one step, Formula (III) Or a salt thereof.
  • R X represents —H or a protecting group
  • iBu represents isobutyl
  • iPr represents isopropyl
  • Me represents methyl.
  • Formula (I) A compound of formula (II) or a salt thereof is subjected to a deprotection reaction to obtain a compound of formula (II) or a salt thereof, and further a protecting group is added to the compound of formula (III) or a salt thereof obtained by the process according to claim 1.
  • R 3 is cycloalkyl, aryl, an optionally substituted heterocyclic ring, or lower alkyl
  • the lower alkyl is a group consisting of hydroxy, cycloalkyl, lower alkoxy, aryl, alloalkoxy, lower alkoxy-lower alkylene-O—, optionally substituted amino, and —OC (O) NR 6 R 7.
  • R 6 and R 7 are each independently —H or lower alkyl, or R 6 and R 7 together with the nitrogen atom to which R 6 and R 7 are bonded are substituted with lower alkyl.
  • R 4 and R 5 are each independently —H or lower alkyl; ---- represents a single bond or a double bond.
  • R 2 is —H
  • R 3 is cycloalkyl, aryl, an optionally substituted heterocyclic ring, lower alkoxymethyl, alloalkyl, t-butyl, sec-butyl, cycloalkyl, or ethyl.
  • the ethyl represents lower alkyl, hydroxy, lower alkyl-O—, aryl-lower alkylene-O—, lower alkyl-O-lower alkylene-O—, optionally substituted amino, and —OC (O ) Optionally substituted by one suitable substituent selected from the group consisting of NR 6 R 7 , [4]
  • the compound of the formula (VI) obtained by the production method of [2] or a salt thereof is condensed with a threonine protected at the carboxylic acid terminal, and then the amino terminal is deprotected, Formula (VIII) Or a salt thereof.
  • Prot 2 represents a protecting group.
  • the present invention relates to a novel intermediate represented by the following formula.
  • the intermediate obtained by the production method of the present invention is useful from the following points.
  • the compound of formula (VIII) obtained by the above production method [4] or a salt thereof is used for anti-HCV treatment by condensing two amino acids at the N-terminus, deprotecting, and then cyclizing. Since the compound of the formula (A) or a salt thereof reported to be useful as an active ingredient of a pharmaceutical composition can be produced, it is useful as a production intermediate.
  • the compound of the formula (VI) obtained by the above production method [2] or a salt thereof has the formula (VIII) by condensing a protected threonine at the C-terminus and deprotecting the N-terminus.
  • the compound of formula (VIII) or a salt thereof obtained according to the method described in (1) above is useful as an active ingredient of a pharmaceutical composition for anti-HCV treatment. Since it is possible to produce a compound of the formula (A) or a salt thereof that has been reported to be present, it is useful as a production intermediate (3) of the formula (III) obtained by the production method [1] above.
  • the compound or a salt thereof can be produced by protecting the N-terminal after a single Edman decomposition, and the compound of the formula (VI) or a salt thereof can be produced.
  • the method described in (1) and (2) above it is possible to produce a compound of the formula (A) which have been reported to be useful as an active ingredient of a pharmaceutical composition for anti-HCV therapy is useful as a production intermediate.
  • This production method is excellent in operability in that two amino acids can be eliminated in one step.
  • the compound of the formula (III) of the present invention or a salt thereof can be produced by Edman. Since thiohydantoins and the like are not by-produced in the process in which the decomposition reaction can be omitted, the compound of formula (A), an intermediate for its production, Can be obtained. Accordingly, it is possible to scale up on an industrial scale.
  • the “protecting group” is a group that does not prevent the subsequent reaction and does not affect the functional group even during deprotection.
  • protecting groups described in “Green's Protective Groups in Organic Synthesis (4th edition, 2006)” by PG Green Wuts and TW Greene. It can be selected as appropriate according to these reaction conditions.
  • N-terminal and C-terminal are amino acids or carboxy groups at both ends in a linear peptide, the side where the amino group is present is the “N-terminal”, and the side where the carboxy group is present is “ “C-terminal” means.
  • “It may be substituted” means unsubstituted or having 1 to 5 substituents. In addition, when it has a some substituent, those substituents may be the same, or may mutually differ.
  • “Lower” indicates that the number of carbon atoms is 1 to 6 (hereinafter abbreviated as C 1-6 ), preferably 1 to 4 unless otherwise specified.
  • “Lower alkyl” means linear or branched C 1-6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n -Hexyl and the like. Another embodiment is C 1-4 alkyl, and yet another embodiment is methyl, ethyl, or propyl.
  • the “lower alkylene” is linear or branched C 1-6 alkylene such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene and the like. Another embodiment is C 1-4 alkylene.
  • “Lower alkoxy” refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, neopentyloxy, hexyloxy, or isohexyloxy, A branched C 1-6 alkylalkoxy group. Another embodiment is methoxy, ethoxy, or propoxy.
  • Cycloalkyl is a C 3-6 alkyl cyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Aryl includes phenyl, naphthyl, anthryl and the like.
  • “Alloalkyl” is lower alkyl substituted with 1 to 5 aryls such as phenylpropyl, phenethyl, benzyl and the like.
  • “Alloalkoxy” is lower alkoxy substituted with 1 to 5 aryls such as phenylpropoxy, phenethyloxy, benzyloxy and the like.
  • Suitable examples of “optionally substituted amino” are amino optionally substituted by one or two suitable substituents such as lower alkyl, amino protecting groups (eg, benzyloxycarbonyl, Boc, etc.), etc. .
  • Suitable examples of “optionally substituted carbamoyloxy” may be substituted by 1 or 2 appropriate substituents such as lower alkyl, amino protecting group (eg, benzyloxycarbonyl, Boc, etc.), etc. Carbamoyloxy.
  • Heterocycle (1) Pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (example: 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1, 2,3-triazolyl and the like), tetrazolyl (eg 1H-tetrazolyl, 2H-tetrazolyl etc.), 3 to 8 membered (more preferably 5 or 6 membered) unsaturated containing 1 to 4 nitrogen atoms such as azepinyl Monocyclic heterocycle; (2) 3 to 8 members (more preferably 5) containing 1 to 4 nitrogen atoms such as aziridinyl, azetinyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperaziny
  • Suitable examples of the “nitrogen-containing heterocycle” are (1) to (7) of the above-mentioned “heterocycle”.
  • at least one of pyrrolidinyl, piperidyl, morpholinyl, thiazolyl, oxazolyl, etc. A heterocyclic ring containing a nitrogen atom.
  • Suitable examples of “optionally substituted heterocycle” are the above heterocycles optionally substituted with one suitable substituent such as lower alkyl, lower alkoxy, aryl, amino, lower alkoxycarbonyl and the like.
  • Halogen means fluorine, chlorine, bromine and iodine.
  • CPME cyclopentyl methyl ether
  • DIBOC di-tert-butyl dicarbonate
  • DME 1,2-dimethoxyethane
  • DMF N, N-dimethylformamide
  • DMI 1,3-dimethyl-2-imidazolidinone
  • DMSO Dimethyl sulfoxide
  • DIPEA diisopropylethylamine
  • DPPA diphenyl phosphate azide
  • EtOAc ethyl acetate
  • Ex example number
  • HOBt 1-hydroxybenzotriazole
  • IPA isopropyl alcohol
  • KH 2 PO 4 dihydrogen phosphate potassium
  • NMP N-methylpyrrolidone
  • Na 2 CO 3 sodium carbonate
  • Na 2 HPO 4 disodium hydrogen phosphate
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • WSC 1-ethyl-3- (3-d
  • the compound of the present invention may have geometric isomers.
  • the compound of the present invention may be described in only one form of an isomer, but the present invention also includes other isomers, separated isomers, or a mixture thereof. Includes.
  • the compound of the present invention has an asymmetric carbon atom, and there exists an optical isomer based on this.
  • the present invention also includes separated optical isomers of the compounds of the present invention or mixtures thereof.
  • the salt of the compound of the present invention may form an acid addition salt or a salt with a base depending on the kind of the substituent.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid
  • organic acids such as lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid Salts, salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum, salts with organic bases such as methylamine, ethylamine
  • the present invention includes various hydrates and solvates of the compound of the present invention and salts thereof, and polymorphic substances.
  • the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
  • This step is a step of removing two amino acids in one step under heating conditions after deprotecting the N-terminus.
  • R x is a protecting group
  • lower alkyl optionally substituted with phenyl, lower alkyl optionally substituted with aryl, and the like can be mentioned.
  • Other embodiments include lower alkyl, benzyl, tert-butyl.
  • Prot 0 includes carbamate, toluenesulfonyl, nitrobenzenesulfonyl and the like.
  • Another embodiment includes Boc, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl.
  • Deprotection is described, for example, in each of “Green's Protective Groups in Organic Synthesis (4th edition, 2006)” by PG Green Wuts and TW Greene.
  • the deprotection reaction for the protecting group can be referred to, and may be appropriately selected and used according to these reaction conditions.
  • Two amino acids are eliminated by heating the raw material intermediate in a solvent.
  • the reaction temperature is preferably from warming to reflux conditions. Any solvent may be used as long as it does not interfere with the reaction.
  • CPME, dioxane, THF, DMSO, DMF, IPA, tBuOH, NMP, DMI, DME, water or the like is used, and ether or water is preferable.
  • An aqueous system is particularly preferred.
  • the reaction may be a homogeneous system or a two-layer system, but a two-layer system is particularly preferred. It may be advantageous to carry out the reaction in the presence of acids or bases or salts.
  • a buffer solution is added to the reaction solution and the reaction is carried out in a hydrous system.
  • the buffer include a phosphate buffer and a tris buffer, and a phosphate buffer is preferable.
  • the temperature varies depending on the solvent, the temperature is 30 ° C. to the reflux temperature of the solvent, for example, 30 ° C. to 180 ° C. 50 to 120 ° C is preferable, and 60 to 85 ° C is particularly preferable.
  • the product may be obtained as a crystal without adding a seed crystal. However, if a crystal is precipitated by adding a seed crystal, the crystal may be easily precipitated.
  • This step is Edman degradation, which is a step of removing amino acids of the peptide from the N-terminus.
  • the solvent is usually an alcohol such as acetonitrile, acetone, MeOH, EtOH, THF, dioxane, toluene, methylene chloride, chloroform, EtOAc, DMF, and the like, an organic solvent that does not adversely affect the reaction, or a mixed solvent thereof. It is carried out in a normal solvent.
  • the reaction temperature is not limited, and the reaction is usually carried out under cooling to heating. This reaction is described, for example, in M.M. K. Everle et al. Org. Chem. 59, 7249-7258 (1994) or the like, or a method similar thereto.
  • This step is a step of protecting the N-terminus of the chain peptide as an intermediate, condensing the protected threonine to the C-terminus, and then deprotecting the N-terminus.
  • Examples of Prot 2 include lower alkyl which may be substituted with phenyl, lower alkyl which may be substituted with aryl, and the like. Other embodiments include lower alkyl, benzyl, tert-butyl.
  • Examples of Prot 1 include carbamate, toluenesulfonyl, nitrobenzenesulfonyl and the like.
  • Another embodiment includes Boc, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl.
  • Condensation of protected threonine to the C-terminal of the substrate chain peptide can be carried out in the same manner as the so-called amidation reaction.
  • the compound of the formula (VII) or a salt thereof can be obtained by reacting the compound of the formula (VI) or a salt thereof with the protected threonine of the formula (B2).
  • an equivalent amount or an excess amount of the compound of the formula (VI) or a salt thereof and the protected threonine of the formula (B2) is used in an excess amount, and these mixtures are inert to the reaction in the presence of a condensing agent.
  • the mixture is stirred in a solvent under cooling to heating, preferably at ⁇ 20 ° C. to 60 ° C., usually for 0.1 hour to 5 days.
  • the solvent used here are not particularly limited, but are aromatic hydrocarbons such as toluene or xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, diethyl ether, THF, dioxane.
  • Ethers such as dimethoxyethane, DMF, DMSO, EtOAc, MeCN or water, and mixtures thereof.
  • condensing agents include, but are not limited to, WSC, DPPA, and phosphorus oxychloride.
  • an additive eg HOBt
  • Examples of reactive derivatives of carboxylic acids include acid halides obtained by reacting with halogenating agents such as phosphorus oxychloride and thionyl chloride, mixed acid anhydrides obtained by reacting with isobutyl chloroformate, HOBt, etc.
  • Examples include active esters obtained by condensation.
  • the reaction of these reactive derivatives with the protected threonine of the formula (B2) is carried out in a solvent inert to the reaction such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, etc. under cooling to heating. Preferably, it can be carried out at -20 ° C to 60 ° C. [Literature] R. Sandler and W.W. Karo, “Organic Functional Group Preparations”, 2nd edition, Volume 1, Academic Press Inc. 1991, Chemical Society of Japan “Experimental Chemistry Course (5th Edition)", Volume 16 (2005) (Maruzen)
  • the compound of formula (I) or a salt thereof can be produced according to Patent Document 1 using FR901449 as a starting material.
  • the FR901459 substance is a microorganism belonging to the genus Stachybotrys (Tachybotrys chartarum No. 19292), a patent biological deposit center (International Patent Organism Depositary), Tsukuba City East 1-1-5, Ibaraki Pref. It can be obtained from, for example, the method described in Patent Document 2 from a culture solution having a deposit number of FERM BP-3364, which is internationally deposited on April 16, 1991.
  • Example compounds are isolated and purified as free compounds, their salts, hydrates, solvates, or crystalline polymorphic substances.
  • the salt of an Example compound can also be manufactured by attaching
  • Example 1 (Production of a compound in which Prot 0 is Boc in the formula (I)) According to the method described in Patent Document 1, (6S, 12S, 15S, 18S, 21S, 24R, 27S, 30S, 33S, 36S) -6-[(1R) -1-hydroxyethyl] -36-[(1R, 2R, 4E) -1-hydroxy-2-methyl-4-hexen-1-yl] -12,15,18,27,30-pentaisobutyl-33-isopropyl-2,2,8,11,17,21 , 24,26,32,35-decamethyl-4,7,10,13,16,19,22,25,28,31,34-undecaoxo-3-oxa-5,8,11,14,17,20 , 23, 26, 29, 32, 35-Undecaazaheptatritan-37-euic acid was obtained.
  • Example 2 (Production of compound of formula (II)) After dissolving 50.0 g of Example Compound 1 in 500 mL of methylene chloride, the mixture was cooled to 5 ° C., 213.2 g of TFA was added dropwise, and the mixture was stirred for 4 hours. Thereafter, 500 mL of cold city water was added, and the pH was adjusted to 6.5 with a 10 (w / v)% Na 2 CO 3 aqueous solution. After liquid separation, 500 mL of cooled city water was added to the organic layer again, and the pH was adjusted to 6.5 to 7 with a 10 (w / v)% Na 2 CO 3 aqueous solution.
  • Example 3 (Production of compound of formula (III)) About 250 mL of the CPME solution of Example Compound 2, 500 mL of CPME, 500 mL of a phosphate buffer aqueous solution of pH 7.6 (the pH of the Na 2 HPO 4 aqueous solution was adjusted to pH 7.6 with KH 2 PO 4 aqueous solution.
  • the mixture was heated to 80 to 85 ° C., stirred for 5 hours, and then cooled to 25 ° C.
  • the organic layer obtained by liquid separation was washed twice with 500 mL of city water.
  • the organic layer was concentrated to about 105 mL, and then 115 mL of acetonitrile was added dropwise. Thereafter, 75 mg of seed crystals of Example Compound 3 were added at an internal temperature of 22 ° C., and 345 mL of acetonitrile was further added dropwise.
  • the crystallized solution was collected by filtration and dried under reduced pressure to give (2S, 3R, 4R, 6E) -3-hydroxy-4-methyl-2- [methyl (N-methyl-L-leucyl-L-leucyl-N-methyl).
  • Example 3-1 (Method for producing amorphous body) To a CPME solution of Example Compound 2 (equivalent to 40.0 g / 800 mL), pH 7.6 phosphate buffer aqueous solution 400 mL (pH of Na 2 HPO 4 aqueous solution was adjusted to pH 7.6 with KH 2 PO 4 aqueous solution.
  • Example 4 (Production of compound of formula (IV)) After dissolving 10.0 g of Example Compound 3 in 150 mL of EtOAc, pH 7.6 phosphate buffer 50 mL (pH of Na 2 HPO 4 aqueous solution was adjusted to pH 7.6 with KH 2 PO 4 aqueous solution. Na 2 HPO 4 aqueous solution, by dissolving Na 2 HPO 4 ⁇ 12H 2 O 1.04 g prepared in water 87.5 L, KH 2 PO 4 aqueous solution, KH 2 PO 4 0 water 12.5 L. 568 g was dissolved, and 2.54 g of phenyl isothiocyanate was added and stirred for 4 hours. Thereafter, the pH was adjusted to 2.3 with 1M hydrochloric acid.
  • Example 5 (Production of compound of formula (V)) To about 40 mL of the EtOAc solution of Example Compound 4 was further added dropwise into 200 mL of n-heptane. The precipitated powder was collected by filtration, dissolved in 100 mL of acetonitrile, added with 94 mL of 1M hydrochloric acid, and stirred at 20 ° C. for 3 hours and 15 minutes. It was confirmed that Example Compound 5 was obtained. HR-ESIMS Found m / z 937.6712 (M + H) + Calcd for C48H89N8O10, 937.6701
  • Example 6 (Production of a compound in which Prot 1 is Boc in the formula (VI)) To the reaction solution of Example Compound 5, a 10 (w / v)% Na 2 CO 3 aqueous solution was further added to adjust the pH to about 7, and 2.25 g of DIBOC was added, and the mixture was added at 25 ° C. for 3 hours and 20 minutes. After stirring, the pH was adjusted to 2.5 with 1M hydrochloric acid. The organic layer was separated, 100 mL of 20 (w / v)% brine was added, and the mixture was extracted with 100 mL of EtOAc. The organic layer was separated and concentrated to about 40 mL, 150 mL of EtOAc was added again, and the mixture was concentrated to about 40 mL.
  • Example 7 (Production of a compound in which Prot 1 is Boc and Prot 2 is methyl in formula (VII)) 7.5 g of Example Compound 6 was dissolved in 75 mL of methylene chloride, and 1.47 g of L-threonine methyl ester hydrochloride and 1.47 g of HOBt ⁇ monohydrate were added and cooled to 0 to 10 ° C. . Further, 1.12 g of WSC was added and stirred at 5 ° C. for about 20 hours, and then the organic layer was washed with 75 mL of city water. The aqueous layer was re-extracted with 38 mL of methylene chloride, and the organic layers were combined.
  • the organic layer was washed with 68 mL of 0.3M hydrochloric acid, and the aqueous layer was re-extracted again with 38 mL of methylene chloride.
  • the organic layers were combined, then washed sequentially with 5 mL (5 / w)% NaHCO 3 aqueous solution (76 mL) and 20 (w / v)% brine 55 mL, and concentrated to about 30 mL.
  • the concentrated solution was dropped into 300 mL of heptane.
  • the precipitated powder was collected by filtration and dried under reduced pressure, and (N-[(2S, 3R, 4R, 6E) -2- ⁇ [N- (tert-butoxycarbonyl) -L-leucyl-N-methyl-L-leucyl).
  • -L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl] (methyl) amino ⁇ -3-hydroxy-4-methyloct-6-enoyl] -L- Threonine methyl ester was obtained as a white powder, yield: 7.12 g, yield: 85.5%.
  • Example 8 (Production of a compound in which Prot 2 is methyl in formula (VIII)) 20.0 g of Example Compound 7 was dissolved in 120 mL of methylene chloride and cooled to ⁇ 5 ° C. After 98.9 g of TFA was added dropwise and stirred for 2 hours and 40 minutes, the mixture was washed with 200 mL of cooled city water. The organic layer obtained by liquid separation was further washed with 200 mL of cooled city water. 200 mL of cooled city water was added to the organic layer, and the pH was adjusted to 6.5 to 7 using a 10 (w / v)% Na 2 CO 3 aqueous solution.
  • This production method is excellent in operability in that two amino acids can be eliminated in one step.
  • the compound of the formula (III) of the present invention or a salt thereof can be produced by Edman. Since thiohydantoins and the like are not by-produced in the process in which the decomposition reaction can be omitted, the compound of formula (A), an intermediate for its production, Can be obtained. Accordingly, it is possible to scale up on an industrial scale.

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de production efficace qui est conçu pour un procédé de production industrielle et qui a de meilleures caractéristiques en termes de capacité à être mis en œuvre, pureté, etc. Comme conséquence de la mise en œuvre de l'étude d'un procédé de production efficace qui est conçu pour un procédé de production industrielle, et qui a une meilleure capacité à être mis en œuvre, et avec lequel un intermédiaire de pureté élevée peut être obtenu, les inventeurs ont trouvé qu'un procédé avec lequel le nombre d'étapes (d'élimination de l'acide diaminé) peut être réduit, la purification par chromatographie n'est pas nécessaire, et un intermédiaire peut être obtenu avec une pureté élevée. Ils ont également trouvé un procédé de production d'un composé peptidique cyclique connu pour avoir une activité anti-VHC, un intermédiaire peptidique utile pour la production, et un procédé de production de l'intermédiaire, qui sont significatifs pour la présente invention. Dans le procédé, il n'est pas nécessaire de répéter la dégradation d'Edman, il devient possible de fournir une grande quantité de l'intermédiaire peptidique et du composé peptidique cyclique sans effectuer l'étape de chromatographie associée à la réaction.
PCT/JP2009/066449 2008-09-24 2009-09-18 Composé peptidique et son procédé de production WO2010035722A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP2010530839A JP5625910B2 (ja) 2008-09-24 2009-09-18 ペプチド化合物およびその製造方法
CA2738280A CA2738280A1 (fr) 2008-09-24 2009-09-18 Compose peptidique et son procede de production
CN2009801381065A CN102164947A (zh) 2008-09-24 2009-09-18 肽化合物及其制备方法
MX2011003259A MX2011003259A (es) 2008-09-24 2009-09-18 Compuesto de peptido y metodo para producir el mismo.

Applications Claiming Priority (2)

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JP2008-244410 2008-09-24
JP2008244410 2008-09-24

Publications (1)

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WO2010035722A1 true WO2010035722A1 (fr) 2010-04-01

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KR (1) KR20110073473A (fr)
CN (1) CN102164947A (fr)
CA (1) CA2738280A1 (fr)
MX (1) MX2011003259A (fr)
WO (1) WO2010035722A1 (fr)

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US11993629B2 (en) * 2019-02-04 2024-05-28 Nissan Chemical Corporation Method for producing peptide compound

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007049803A1 (fr) * 2005-10-26 2007-05-03 Astellas Pharma Inc. Composes peptidiques cycliques
WO2008139986A1 (fr) * 2007-05-02 2008-11-20 Astellas Pharma Inc., Nouveaux composés peptidiques cycliques

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0320638D0 (en) * 2003-09-03 2003-10-01 Novartis Ag Organic compounds
JP2007015926A (ja) * 2003-10-06 2007-01-25 Fujisawa Pharmaceut Co Ltd Ｃ型肝炎治療剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007049803A1 (fr) * 2005-10-26 2007-05-03 Astellas Pharma Inc. Composes peptidiques cycliques
WO2008139986A1 (fr) * 2007-05-02 2008-11-20 Astellas Pharma Inc., Nouveaux composés peptidiques cycliques

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JP5625910B2 (ja) 2014-11-19
JPWO2010035722A1 (ja) 2012-02-23
KR20110073473A (ko) 2011-06-29
CA2738280A1 (fr) 2010-04-01
CN102164947A (zh) 2011-08-24
MX2011003259A (es) 2011-04-21

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