WO2023127869A1 - N-アルキルアミノ酸、およびn-アルキルアミノ酸を含むペプチドの製造方法 - Google Patents
N-アルキルアミノ酸、およびn-アルキルアミノ酸を含むペプチドの製造方法 Download PDFInfo
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- WO2023127869A1 WO2023127869A1 PCT/JP2022/048135 JP2022048135W WO2023127869A1 WO 2023127869 A1 WO2023127869 A1 WO 2023127869A1 JP 2022048135 W JP2022048135 W JP 2022048135W WO 2023127869 A1 WO2023127869 A1 WO 2023127869A1
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- ester
- peptide
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- 125000000217 alkyl group Chemical group 0.000 claims abstract description 51
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- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000005226 heteroaryloxycarbonyl group Chemical group 0.000 description 1
- 125000005150 heteroarylsulfinyl group Chemical group 0.000 description 1
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 description 1
- 125000005419 heteroarylsulfonylamino group Chemical group 0.000 description 1
- 125000005368 heteroarylthio group Chemical group 0.000 description 1
- AILKHAQXUAOOFU-UHFFFAOYSA-N hexanenitrile Chemical compound CCCCCC#N AILKHAQXUAOOFU-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical class O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- QHDRKFYEGYYIIK-UHFFFAOYSA-N isovaleronitrile Chemical compound CC(C)CC#N QHDRKFYEGYYIIK-UHFFFAOYSA-N 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- UQPSGBZICXWIAG-UHFFFAOYSA-L nickel(2+);dibromide;trihydrate Chemical compound O.O.O.Br[Ni]Br UQPSGBZICXWIAG-UHFFFAOYSA-L 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000001736 nosyl group Chemical group S(=O)(=O)(C1=CC=C([N+](=O)[O-])C=C1)* 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 1
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N pentanal Chemical compound CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 1
- QZWWLNXCLQIASO-UHFFFAOYSA-N pentanenitrile Chemical compound CCCCC#N.CCCCC#N QZWWLNXCLQIASO-UHFFFAOYSA-N 0.000 description 1
- 108010069653 peptide E (adrenal medulla) Proteins 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- FDMCEXDXULPJPG-MERQFXBCSA-N tert-butyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)[C@@H](N)CC1=CC=CC=C1 FDMCEXDXULPJPG-MERQFXBCSA-N 0.000 description 1
- NPDBDJFLKKQMCM-UHFFFAOYSA-N tert-butylglycine Chemical compound CC(C)(C)C(N)C(O)=O NPDBDJFLKKQMCM-UHFFFAOYSA-N 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
- 125000005304 thiadiazolidinyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- AJZGFFKDLABHDD-UHFFFAOYSA-N thiazinane Chemical compound C1CCSNC1 AJZGFFKDLABHDD-UHFFFAOYSA-N 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B61/00—Other general methods
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- R 1 and R 3 each independently represent a hydrogen atom, a C 1 -C 6 alkyl group, a haloC 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a C 3 -C 6 cyclo alkyl C 1 -C 6 alkyl group, carboxy C 1 -C 6 alkyl group, C 6 -C 10 aryl C 1 -C 6 alkyl group optionally having a substituent on the aryl group, heteroaryl group optionally substituted 5- to 10-membered heteroaryl C 1 -C 6 alkyl group, heterocyclyl group optionally substituted 5- to 10-membered heterocyclyl C 1 -C 6 alkyl group , C 3 -C 6 cycloalkoxy C 1 -C 6 alkyl groups, halo C 1 -C 6 alkoxy C 1 -C 6 alkyl groups, protected amino C 3 -C 6 alkyl groups, protected hydroxy C 1
- Amino acid side chain as used herein means, in the case of ⁇ -amino acids, an atomic group bonded to the carbon ( ⁇ -carbon) where the amino group and the carboxyl group are bonded.
- the methyl group of Ala is the side chain of an amino acid.
- the atom group attached to the ⁇ -carbon and/or the ⁇ -carbon becomes the side chain of the amino acid, and in the case of ⁇ -amino acids, the ⁇ -carbon, ⁇ -carbon and/or ⁇ -carbon are attached.
- the atomic group formed by this can be a side chain of an amino acid.
- solvate refers to a compound formed with a solvent to form a single molecular cluster, and if it is a solvate formed with a solvent that is acceptable for ingestion accompanying administration of a drug, It is not particularly limited. Examples include hydrates, alcoholates (ethanolates, methanolates, 1-propanolates, 2-pronolates, etc.), solvates with a single solvent such as dimethylsulfoxide, as well as , solvates formed with a plurality of solvents for one molecule of the compound, and solvates formed with a plurality of types of solvents for one molecule of the compound.
- the alkylation step according to this embodiment selectively N-monoalkylates an amino acid represented by formula A or an ester thereof (also referred to as starting amino acid A) to obtain an N-mono A method for obtaining an alkylamino acid or an ester thereof, and performing a deprotection reaction and an N-alkylation reaction of an N-protected amino acid represented by formula B or an ester thereof (also referred to as starting amino acid B) in one pot to obtain formula C and a method for obtaining an N-monoalkylamino acid represented by or an ester thereof.
- the outline of the method according to this embodiment is shown below.
- cycloalkylalkyl means a group in which one or more hydrogen atoms of "alkyl” defined above are replaced with “cycloalkyl” defined above.
- Specific examples of C 3 -C 6 cycloalkyl C 1 -C 6 alkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and the like.
- arylalkyl (aralkyl) means a group in which at least one hydrogen atom of "alkyl” defined above is replaced with “aryl” defined above.
- arylalkyl C 6 -C 10 arylC 1 -C 6 alkyl are preferred.
- Specific examples of C 6 -C 10 aryl C 1 -C 6 alkyl include benzyl, phenethyl, 3-phenylpropyl and the like.
- heterocyclylalkyl means a group in which one or more hydrogen atoms of "alkyl” as defined above are replaced with “heterocyclyl” as defined above.
- the heterocyclylalkyl is preferably a 5- to 10-membered heterocyclyl C 1 -C 6 alkyl, more preferably a 4- to 7-membered heterocyclyl C 1 -C 6 alkyl, even more preferably a 4- to 7-membered heterocyclyl C 1 -C 2 alkyl.
- Said C 6 -C 10 aryl C 1 -C 6 alkyl aryl, said 5-10 membered heteroaryl C 1 -C 6 alkyl heteroaryl, and said 5-10 membered heterocyclyl C 1 -C 6 alkyl heterocyclyl are Further, it may be substituted with a substituent.
- Halogen-derived substituents include fluoro (-F), chloro (-Cl), bromo (-Br), iodine (-I), and the like.
- substituted methyl halide means a methyl halide in which one of the hydrogen atoms on the carbon of the methyl halide (halogenated methyl) is replaced with another atom or functional group.
- substituted methyl halides include alkoxymethyl halides, alkoxyalkoxymethyl halides, and trialkylsilylalkoxymethyl halides.
- Preferred examples include substituted methyl chlorides.
- Specific examples of substituted methyl chlorides include MOM-Cl (methoxymethyl chloride), EOM-Cl (ethoxymethyl chloride), MEM-Cl (2-methoxyethoxymethyl chloride), SEM-Cl (2-(trimethylsilyl)ethoxymethyl chloride ).
- starting amino acid A When starting amino acid A is used as a raw material in the alkylation step, it is preferable to add a base to the reaction solution. By adding a base to the reaction solution, the ratio of dialkylated products and by-products can be reduced, and the monoalkylation selectivity can be further improved.
- starting amino acid B When starting amino acid B is used as a raw material, it is preferable to add a base to the reaction solution in the N-alkylation step after the deprotection reaction.
- the reaction temperature can be in the range of -40°C to around the boiling point of the solvent, and can be in the range of -20°C to 50°C or in the range of 0°C to 30°C.
- the reaction time can be in the range of 5 minutes to 72 hours, 10 minutes to 48 hours, or 10 minutes to 24 hours.
- the step of cyclizing the peptide (precursor peptide, i.e., linear peptide) or ester thereof obtained by the above production method with the C-terminal group and the N-terminal group to form a cyclic portion is also included in this embodiment.
- Example 4 Monoethylation reaction of H-Phe-OtBu with acetonitrile 5% palladium on carbon (50% wet, 96 mg, 0.023 mmol, 5 mol% metallic Pd standard) and an ethanol solution of compound 1 (15 mL/g substrate, 1.5 mL, 0.452 mmol) were added to a flask containing a stir bar. rice field. Acetonitrile (236 ⁇ L, 4.52 mmol, 10.0 eq.) was added to the resulting mixture. While stirring, the gas phase in the flask was replaced with nitrogen, replaced with hydrogen again, and stirred at 30°C.
- a 2-methyltetrahydrofuran solution of propylphosphonic anhydride (1.6 M, 132 mL, 211 mmol, 2.2 eq.) was added dropwise from the dropping funnel over 1 hour and 20 minutes.
- the internal temperature during dropping was 15.0 to 17.4°C. Sampling was performed 1 hour after the completion of dropping, and completion of the reaction was confirmed by HPLC analysis.
- a 5% aqueous sodium carbonate solution 180 mL was slowly added from the dropping funnel. The internal temperature during dropping was maintained at 30.3° C. or lower. After completion of dropping, the external temperature was set to 23°C. After stirring for 15 minutes or longer, the mixture was allowed to stand, and the aqueous layer was removed.
- a 2-methyltetrahydrofuran solution of propylphosphonic anhydride (1.6 M, 219 mL, 2.2 eq.) was added dropwise from the dropping funnel over 1 hour and 20 minutes.
- the internal temperature during the dropwise addition was 15.5-18.5°C.
- Sampling was performed 1 hour after the completion of dropping, and completion of the reaction was confirmed by HPLC analysis.
- a 5% aqueous sodium carbonate solution (300 mL) was slowly added from the dropping funnel.
- the internal temperature during dropping was maintained at 22.8° C. or lower.
- the external temperature was set to 23°C. After stirring for 15 minutes or longer, the mixture was allowed to stand, and the aqueous layer was removed.
- H-Phe-OtBu Monomethylation Reaction Comparative Experiment Using Formaldehyde Aqueous Solution as Methylation Reagent H-Phe-OtBu (75 mg, 0.339 mmol) was added to a flask containing a stir bar and tetrahydrofuran (1.5 mL) was added. 5% palladium on carbon (50% wet, 72 mg, 0.017 mmol, 5 mol% on Pd metal basis) and 37% formaldehyde aqueous solution (25.1 ⁇ L, 0.339 mmol, 1.0 eq.) were sequentially added. The mixture was purged with nitrogen and hydrogen while stirring, and the reaction was carried out at 25°C.
- Example 32 One-pot deprotection and monohexylation of Cbz-Val-MeAsp(OtBu) -NMe2
- a flask containing a stirrer was charged with 5% palladium on carbon (50% wet, 62 mg, 0.015 mmol, 5 mol% on Pd metal basis) and Cbz-Val-MeAsp(OtBu) -NMe in tetrahydrofuran (15 mL/g substrate, 2.0 mL, 0.291 mmol) was added.
- a deCbz reaction was carried out by purging with nitrogen and purging with hydrogen while stirring.
- Example 38 Synthesis of H-EtPhe(4-Me)-Sar-OtBu hydrochloride A reaction vessel was charged with 5% palladium on carbon (55.31% wet, 2.60 g, 0.546 mmol, 1 mol% on Pd metal basis), Cbz-Phe(4-Me)-Sar-OtBu obtained in Example 37. solution (38.80 g), 2-methyltetrahydrofuran (179 g), acetonitrile (22.29 g, 543 mmol, 10.0 eq.), TsOH.H 2 O (10.85 g, 57.0 mmol, 1.0 eq.) and water (1.03 g, 56.9 mmol) was added.
- 5% palladium on carbon 55.31% wet, 2.60 g, 0.546 mmol, 1 mol% on Pd metal basis
- Cbz-Phe(4-Me)-Sar-OtBu obtained in Example 37. solution (38.80 g
- Example 39 Synthesis of Cbz-Aze-EtPhe(4-Me)-Sar-OtBu Cbz-Aze-OH (12.94 g, 55.0 mmol), 2-methyltetrahydrofuran (132 g), and H-EtPhe(4-Me)-Sar-OtBu hydrochloride synthesized by the same method as in Example 38 were placed in a reaction vessel. (17.01 g, 45.9 mmol), DIPEA (47.41 g, 367 mmol) were added at room temperature.
- Example 43 Synthesis of Cbz-Ile-MeAla-Aze-EtPhe(4-Me)-Sar-OtBu Toluene (92 g), 5% sodium hydrogensulfate monohydrate aqueous solution (100 g) and Cbz-Ile-OH dicyclohexylamine salt (21.43 g, 47.7 mmol) were added to the reactor at 25° C. with stirring. A 5% sodium hydrogensulfate monohydrate aqueous solution (220 g) was added, and after stirring for 10 minutes, the mixture was allowed to stand, and the aqueous layer was removed.
- the resulting organic layer was washed three times with a 5% aqueous solution of sodium hydrogensulfate monohydrate (320 g) and then twice with an aqueous solution of 5% sodium chloride (220 g).
- the obtained organic layer was concentrated to 26 mL under reduced pressure conditions.
- Example 61 Synthesis of compound 11 Cbz-Hph(3,5- F2-4 - CF3 )-Pro-cLeu-MeGcp-MeAsp(OH) -NMe2 diethylamine salt obtained in Example 60 (92.0 w/w%) was added to the reaction vessel. , 20.78 g, 19.2 mmol), acetonitrile (177 mL), dicyclohexylmethylamine (8.2 mL, 38.6 mmol) and DIPEA (10.1 mL, 58.0 mmol) were added and concentrated under reduced pressure to 42.5 mL. bottom.
- Example 65 Synthesis of hydrate crystals (C type) of compound 4 Acetone solution (33.33 g) containing compound 4 (6.00 g, 4.17 mmol) synthesized by the same method as in Example 64 in a reaction vessel ) and acetone (12.53 g) were added. The temperature was raised to 40° C. and water (19.2 mL) was added over 10 minutes while stirring. Compound 4 hydrate crystals (C type) (18 mg) were added to a glass vial, suspended in a mixed solution of acetone/water (5:4 (v/v), 0.24 mL), and then suspended. was added to the crystallization solution.
- Example 66 Crystallization of H-MeAla-Aze-EtPhe(4-Me)-Sar-OtBu
- Amorphous H-MeAla-Aze-EtPhe(4-Me)-Sar-OtBu (14.82 g) and CPME (21.7 g) were mixed to prepare a CPME solution of H-MeAla-Aze-EtPhe(4-Me)-Sar-OtBu (40.6 w/w% content). The prepared solution was allowed to stand at 5° C. for one day to obtain crystals of H-MeAla-Aze-EtPhe(4-Me)-Sar-OtBu.
- Example 69 Crystallization of Cbz-Pro-cLeu-MeGcp-MeAsp(OtBu) -NMe2 CPME ( 5 .94 mL) was added and the slurry was filtered after stirring at room temperature for 4 hours. The obtained solid was washed twice with CPME (2.38 mL) and then dried under reduced pressure conditions to obtain crystals of Cbz-Pro-cLeu-MeGcp-MeAsp(OtBu)-NMe 2 .
- Example 70 Crystallization of H-Pro-cLeu-MeGcp-MeAsp(OtBu) -NMe2 Amorphous H-Pro-cLeu-MeGcp-MeAsp(OtBu) -NMe2 (10 mg) and tetrahydrofuran (0.02 mL) ) was added to the vial and then shaken at room temperature for 6 days. Heptane (0.04 mL) was added to the obtained solution, and the mixture was shaken at room temperature for 6 days to obtain crystals of H-Pro-cLeu-MeGcp-MeAsp(OtBu)-NMe 2 .
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Abstract
Description
N-モノアルキルアミノ酸もしくはそのエステルまたはN-モノアルキルアミノ酸を含むペプチドもしくはそのエステルの製造方法であって、
水素の存在下、出発アミノ酸もしくはそのエステルまたは出発アミノ酸を含むペプチドもしくはそのエステル、C1-C6一級アルキル化剤もしくは置換メチルハライド、および触媒を溶媒中で混合するアルキル化工程を含み、
アルキル化工程が、1気圧以上の圧力下で行われ、かつ、出発アミノ酸もしくはそのエステルのアミノ基にC1-C6一級アルキル化剤もしくは置換メチルハライドに対応する一級アルキル基が結合したN-モノアルキルアミノ酸もしくはそのエステルまたは前記N-モノアルキルアミノ酸を含むペプチドもしくはそのエステルを生成させる、方法。
(1.1)
N-モノアルキルアミノ酸もしくはそのエステルまたはN-モノアルキルアミノ酸を含むペプチドもしくはそのエステルの製造方法であって、
出発アミノ酸もしくはそのエステルまたは出発アミノ酸を含むペプチドもしくはそのエステル、C1-C6一級アルキル化剤もしくは置換メチルハライド、ヒドリド還元剤および触媒を溶媒中で混合するアルキル化工程を含み、
アルキル化工程が、出発アミノ酸もしくはそのエステルのアミノ基にC1-C6一級アルキル化剤もしくは置換メチルハライドに対応する一級アルキル基が結合したN-モノアルキルアミノ酸もしくはそのエステルまたは前記N-モノアルキルアミノ酸を含むペプチドもしくはそのエステルを生成させる、方法。
(1.2) C1-C6一級アルキル化剤もしくは置換メチルハライドが、C1-C6一級アルキル化剤である、(1)または(1.1)に記載の方法。
(2) C1-C6一級アルキル化剤が、C1-C5アルキルニトリルまたはC1-C5アルキルアルデヒドである、(1)~(1.2)のいずれか一項に記載の方法。
(2.1) 置換メチルハライドが、メトキシメチルクロリド(MOM-Cl)、エトキシメチルクロリド(EOM-Cl)、2-メトキシエトキシメチルクロリド(MEM-Cl)、2-(トリメチルシリル)エトキシメチルクロリド(SEM-Cl)からなる群から選択される1つである、(2)に記載の方法。
(2.2) ヒドリド還元剤が、トリアルキルシランである、(1.1)~(2.1)のいずれか一項に記載の方法。
(2.3) トリアルキルシランが、トリエチルシランである、(2.2)に記載の方法。
(3) 触媒が、遷移金属を含む不均一系水素化触媒である、(1)~(2.2)のいずれか一項に記載の方法。
(4) 不均一系水素化触媒が、Pd、RhおよびPtからなる群から選択される遷移金属を含む触媒である、(3)に記載の方法。
(5) 不均一系水素化触媒が、Pd-C、Pd(OH)2-C、Rh-C、およびアダムス触媒からなる群から選択される触媒である、(3)または(4)に記載の方法。
(6) 溶媒が、エーテル系溶媒、アルコール系溶媒、およびエステル系溶媒からなる群から選択される少なくとも1つの溶媒を含む、(1)~(5)のいずれか一項に記載の方法。
(7) 溶媒が、エーテル系溶媒、アルコール系溶媒、エステル系溶媒およびこれらの組合せからなる群から選択される、(1)~(6)のいずれか一項に記載の方法。
(8) 溶媒が、テトラヒドロフラン、2-メチルテトラヒドロフラン、ジメチルエーテル、メチルt-ブチルエーテル、シクロペンチルメチルエーテル、ジイソプロピルエーテル、4-メチルテトロヒドロピラン、ジオキサンおよびジエチルエーテルからなる群から選択されるエーテル系溶媒である、(1)~(7)のいずれか一項に記載の方法。
(9) 溶媒が、メタノール、エタノール、プロパノール、ブタノールおよびペンタノールからなる群から選択されるアルコール系溶媒である、(1)~(7)のいずれか一項に記載の方法。
(10) 溶媒が、酢酸エチル、酢酸プロピルおよび酢酸ブチルからなる群から選択されるエステル系溶媒である、(1)~(7)のいずれか一項に記載の方法。
(11) アルキル化工程における反応混合物に、追加の水素を接触させる工程をさらに含む、(1)~(10)のいずれか一項に記載の方法。
(12) 出発アミノ酸もしくはそのエステルまたは前記出発アミノ酸を含むペプチドもしくはそのエステルのアミノ基が、加水素分解条件で除去可能な保護基と結合している、(1)~(11)のいずれか一項に記載の方法。
(12.1) 前記保護基を除去する工程(保護基の除去)を含む、(12)に記載の方法。
(13) 保護基が、アリールメチルオキシカルボニル基である、(12)または(12.1)に記載の方法。
(14) 保護基の除去が、p-トルエンスルホン酸、メタンスルホン酸、硫酸水素ナトリウム、トリエチルアミン塩酸塩およびプロピルホスホン酸からなる群から選択される添加剤の存在下で行われる、(12)または(13)に記載の方法。
(14.1) 前記アルキル化工程における反応混合物が、塩基を更に含む、(12)~(13)のいずれか一項に記載の方法。
(14.2) 前記保護基の除去と前記アルキル化工程とが、ワンポットで行われる、(12)~(14.1)のいずれか一項に記載の方法。
(15) 出発アミノ酸もしくはそのエステルのアミノ基が、一級アミノ基であり、
アルキル化工程における反応混合物が、塩基を更に含む、(1)~(11)のいずれか一項に記載の方法。
(16) 塩基が、三級アミンである、(14.1)または(15)に記載の方法。
(17) 三級アミンが、1,8-ジアザビシクロ[5.4.0]ウンデセン-7、1,5-ジアザビシクロ[4.3.0]ノネン-5、N-メチルモルホリン、1,4-ジアザビシクロ[2.2.2]オクタン、トリエチルアミン、N,N-ジイソプロピルエチルアミン、ピリジンおよびコリジンからなる群から選択される、(16)に記載の方法。
(18) 以下の工程を含む、ペプチドもしくはそのエステルの製造方法:
(a)(1)~(17)のいずれか一項に記載の方法に従いN-モノアルキルアミノ酸もしくはそのエステルまたはN-モノアルキルアミノ酸を含むペプチドもしくはそのエステルを得る工程、および
(b)前記N-モノアルキルアミノ酸もしくはそのエステルまたは前記N-モノアルキルアミノ酸を含むペプチドもしくはそのエステルに対し、任意で1つもしくは複数のアミノ酸またはペプチドを結合形成反応によって伸長させて、ペプチドもしくはそのエステルを得る工程。
(18.1) 前記工程(a)および(b)を所望のペプチドを得るまで複数回繰り返す、(18)に記載のペプチドもしくはそのエステルの製造方法。
(18.2) 以下の工程を含む、少なくとも4個のアミノ酸より構成される環状部を有するペプチドもしくはそのエステルの製造方法:
(c)(18)または(18.1)に記載の方法に従いペプチドもしくはそのエステルを得る工程、および
(d)前記ペプチドもしくはそのエステルのC末端側の基とN末端側の基とで環化して前記環状部を形成する工程。
(18.3) 前記工程(d)におけるペプチドもしくはそのエステルが、直鎖状のペプチドもしくはそのエステルである、(18.2)に記載の方法。
(18.4) 前記直鎖状のペプチドもしくはそのエステルが、下記式:
(19) 環状部を形成する工程が、ペプチドもしくはエステルのC末端のカルボキシル基とN末端のアミノ基との結合形成によって行われる、(18.2)または(18.3)に記載の方法。
(20) 環状部が、少なくとも8個のアミノ酸により構成されており、
環状部を有するペプチドもしくはそのエステルが、8~15個のアミノ酸により構成されるペプチドもしくはそのエステルである、(18.2)~(19)のいずれか一項に記載の方法。
(20.1) (18)~(20)のいずれか一項に記載の方法を含む、N-アルキルアミノ酸残基を5個以上、6個以上または7個以上含むペプチドもしくはそのエステルの製造方法。
(20.2) 前記環状部を有するペプチドもしくはそのエステルが、下記式(1):
(20.3) 前記環状部を有するペプチド、もしくはその塩またはそれらの溶媒和物が、式(1)で表される環状部を有するペプチドの溶媒和物である、(20.2)に記載の方法。
(20.4) 前記環状部を有するペプチド、もしくはその塩またはそれらの溶媒和物が、式(1)で表される環状部を有するペプチドの水和物である、(20.2)に記載の方法。
(20.5) 前記環状部を有するペプチド、もしくはその塩またはそれらの溶媒和物が、式(1)で表される環状部を有するペプチドである、(20.2)に記載の方法。
(20.6) 前記環状部を有するペプチド、もしくはその塩またはそれらの溶媒和物の単離および/または精製にカラムクロマトグラフィーを用いない、(18)~(20.5)のいずれか一項に記載の方法。
(20.7) 前記環状部を有するペプチド、もしくはその塩またはそれらの溶媒和物を晶析により単離および/または精製して、前記環状部を有するペプチド、もしくはその塩またはそれらの溶媒和物の結晶を得る工程をさらに含む、(18)~(20.6)のいずれかに一項記載の方法。
(20.8) 前記環状部を有するペプチド、もしくはその塩またはそれらの溶媒和物の結晶が、下記式(1):
(20.9) 前記環状部を有するペプチドの結晶が溶媒和物結晶である、(20.8)に記載の方法。
(20.10) 前記環状部を有するペプチド溶媒和物結晶が、水和物結晶である、(20.9)に記載の方法。
(21) 出発アミノ酸もしくはそのエステルまたは出発アミノ酸を含むペプチドもしくはそのエステルのN-モノアルキル化反応において、出発アミノ酸もしくはそのエステルまたは出発アミノ酸を含むペプチドもしくはそのエステルのアミノ基がジアルキル化された化合物の生成を抑制する方法であって、
水素の存在下、出発アミノ酸もしくはそのエステルまたは出発アミノ酸を含むペプチドもしくはそのエステル、C1-C6一級アルキル化剤もしくは置換メチルハライド、および触媒を溶媒中で混合するアルキル化工程を含み、
アルキル化工程が、1気圧以上の圧力下で行われ、かつ、出発アミノ酸もしくはそのエステルのアミノ基にC1-C6一級アルキル化剤もしくは置換メチルハライドに対応する一級アルキル基が結合したN-モノアルキルアミノ酸もしくはそのエステルまたはN-モノアルキルアミノ酸を含むペプチドもしくはそのエステルを生成させる、方法。
(21.1) 出発アミノ酸もしくはそのエステルまたは出発アミノ酸を含むペプチドもしくはそのエステルのN-モノアルキル化反応において、出発アミノ酸もしくはそのエステルまたは出発アミノ酸を含むペプチドもしくはそのエステルのアミノ基がジアルキル化された化合物の生成を抑制する方法であって、
出発アミノ酸もしくはそのエステルまたは出発アミノ酸を含むペプチドもしくはそのエステル、C1-C6一級アルキル化剤もしくは置換メチルハライド、ヒドリド還元剤および触媒を溶媒中で混合するアルキル化工程を含み、
アルキル化工程が、出発アミノ酸もしくはそのエステルのアミノ基にC1-C6一級アルキル化剤もしくは置換メチルハライドに対応する一級アルキル基が結合したN-モノアルキルアミノ酸もしくはそのエステルまたは前記N-モノアルキルアミノ酸を含むペプチドもしくはそのエステルを生成させる、方法。
(21.2) C1-C6一級アルキル化剤もしくは置換メチルハライドが、C1-C6一級アルキル化剤である、(21)または(21.1)に記載の方法。
(22) N-モノアルキルアミノ酸もしくはそのエステルまたはN-モノアルキルアミノ酸を含むペプチドもしくはそのエステルのペプチド鎖を、結合形成反応によって伸長する工程と、
伸長されたペプチドを酸性水溶液で処理し、ジアルキル化された化合物を除去する工程をさらに含む、(21)~(21.2)のいずれか一項に記載の方法。
(23) N-モノアルキルアミノ酸もしくはそのエステルが、式Cで表される化合物である、(1)~(22)のいずれか一項に記載の方法。
(24) 出発アミノ酸もしくはそのエステルが、式Aで表される化合物である、(1)~(11)および(15)~(23)のいずれかに一項に記載の方法。
(25) 出発アミノ酸もしくはそのエステルが、式Bで表される化合物である、(1)~(14)および(18)~(23)のいずれか一項に記載の方法。
(26) N-モノアルキルアミノ酸を含むペプチドもしくはそのエステルが、式Fで表される化合物である、(1)~(22)のいずれか一項に記載の方法。
(27) 出発アミノ酸を含むペプチド(以下、「出発ペプチド」ともいう。)もしくはそのエステルが、式Dで表される化合物である、(1)~(11)、(15)~(22)および(26)のいずれか一項に記載の方法。
(28) 出発アミノ酸を含むペプチドが、式Eで表される化合物である、(1)~(14)、(18)~(22)、(26)および(27)のいずれか一項に記載の方法。
(29) R2のC1-C6アルキル基が、加水素分解条件で除去されない基である、(21)~(26)のいずれか一項に記載の方法。
(30) R2のC1-C6アルキル基が、t-ブチル基、n-ブチル基、1-メチルプロピル基、2-メチルプロピル基、n-プロピル基、イソプロピルメチル基およびエチル基より選択される、(23)~(25)のいずれか一項に記載の方法。
(31) PG1およびPG2が、加水素分解条件で除去可能な保護基である、(25)および(28)~(30)のいずれか一項に記載の方法。
(32) PG1およびPG2が、ベンジルオキシカルボニル基、ベンジルオキシメチル基、およびベンジル基からなる群から選択される保護基である、(25)および(28)~(31)のいずれか一項に記載の方法。
(33) R1およびR3が、アルキル化工程の条件により意図しない構造変換を受けうる基でない、(23)~(32)のいずれか一項に記載の方法。
(34) R1およびR3が、それぞれ独立して、水素原子、C1-C6アルキル基、ハロC1-C6アルキル基、C3-C6シクロアルキル基、C3-C6シクロアルキルC1-C6アルキル基、カルボキシC1-C6アルキル基、アリール基上に置換基を有していてもよいC6-C10アリールC1-C6アルキル基、ヘテロアリール基上に置換基を有していてもよい5員~10員ヘテロアリールC1-C6アルキル基、ヘテロシクリル基上に置換基を有していてもよい5員~10員ヘテロシクリルC1-C6アルキル基、C3-C6シクロアルコキシC1-C6アルキル基、ハロC1-C6アルコキシC1-C6アルキル基、保護されたアミノC3-C6アルキル基、保護されたヒドロキシC1-C6アルキル基、またはC1-C6アルコキシC1-C6アルキル基から選択される、(21)~(31)のいずれか一項に記載の方法。
(35) R1およびR3が、それぞれ独立して、水素原子、C1-C6アルキル基、またはアリール基上に置換基を有していてもよいC6-C10アリールC1-C6アルキル基から選択される、(23)~(34)のいずれか一項に記載の方法。
Bn:ベンジル
Boc:t-ブトキシカルボニル
Cbz:ベンジルオキシカルボニル
CPME:シクロペンチルメチルエーテル
DABCO:1,4-ジアザビシクロ[2.2.2]オクタン
DBN:1,5-ジアザビシクロ[4.3.0]ノネン-5
DBU:1,8-ジアザビシクロ[5.4.0]ウンデセン-7
DCHA:ジシクロヘキシルアミン
DIPEA:N,N-ジイソプロピルエチルアミン
DKP:ジケトピペラジン
DMA:ジメチルアセトアミド
DMI:1,3-ジメチル-2-イミダゾリジノン
DMSO:ジメチルスルホキシド
EOM-Cl:エトキシメチルクロリド
HATU:O-(7-アザベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウムヘキサフルオロリン酸塩
1H-NMRスペクトル:プロトン核磁気共鳴スペクトル
HPLC:高速液体クロマトグラフィー
i-:イソ
LCMS:液体クロマトグラフィー及び質量スペクトル
MEM-Cl:2-メトキシエトキシメチルクロリド
MOM-Cl:メトキシメチルクロリド
MTBE:メチルtert-ブチルエーテル
n-:ノルマル
NMM:N-メチルモルホリン
PFP:ペンタフルオロフェニル
s-:セカンダリー
SEM-Cl:2-(トリメチルシリル)エトキシメチルクロリド
tBu:ターシャリーブチル
TEA:トリエチルアミン
Teoc:2-(トリメチルシリル)エトキシカルボニル
t-:ターシャリー
THF:テトラヒドロフラン
TMSCl:クロロトリメチルシラン
TsOH・H2O:パラトルエンスルホン酸一水和物
Sar:サルコシン
測定装置:TGA/DSC3+(Mettler Toledo製)
昇温速度:10℃/分
雰囲気:乾燥窒素
HPLC純度:100%
測定方法:HPLC Method A
保持時間:2.72分
1H-NMR(500MHz, DMSO-d6) δ:1.32(9H, s), 1.66(2H, bs),2.79(2H, m), 3.44(1H, t, J=6.9Hz), 7.19-7.21(3H, m), 7.25-7.28(2H, m)
質量分析:m/z 166.17([M-tBu+H]+)
保持時間:2.82分(化合物1)、2.93分(化合物1-A)、3.05分(化合物1-B)
質量分析:m/z 236.31(化合物1-A、[M+H]+)、250.30(化合物1-B、[M+H]+)
保持時間:2.44分(化合物1)、2.54分(化合物1-A)、2.66分(化合物1-B)
質量分析:m/z 236.31(化合物1-A、[M+H]+)、250.32(化合物1-B、[M+H]+)
保持時間:2.43分(化合物1)、2.63分(化合物1-C)、2.85分(化合物1-D)
質量分析:m/z 250.31(化合物1-C、[M+H]+)、278.33(化合物1-D、[M+H]+)
保持時間:2.61分(化合物1)、2.83分(化合物1-C)、3.06分(化合物1-D)
質量分析:m/z 250.09(化合物1-C、[M+H]+)、278.06(化合物1-D、[M+H]+)
保持時間:2.42分(化合物1)、2.82分(化合物1-E)、3.27分(化合物1-F)
質量分析:m/z 264.36(化合物1-E、[M+H]+)、306.38(化合物1-F、[M+H]+)
保持時間:2.69分(化合物1)、3.11分(化合物1-E)、3.58分(化合物1-F)
質量分析:m/z 264.29(化合物1-E、[M+H]+)、306.31(化合物1-F、[M+H]+)
保持時間:2.42分(化合物1)、3.04分(化合物1-G)、3.68分(化合物1-H)
質量分析:m/z 278.35(化合物1-G、[M+H]+)、334.43(化合物1-H、[M+H]+)
保持時間:2.67分(化合物1)、3.32分(化合物1-G)、3.99分(化合物1-H)
質量分析:m/z 278.30(化合物1-G、[M+H]+)、334.39(化合物1-H、[M+H]+)
保持時間:2.06分(化合物2)、2.41分(化合物2-E)、2.77分(化合物2-F)
質量分析:m/z 372.68(化合物2-E、[M+H]+)、414.65(化合物2-F、[M+H]+)
保持時間:2.06分(化合物2)、2.64分(化合物2-G)、3.22分(化合物2-H)
質量分析:m/z 386.71(化合物2-G、[M+H]+)、442.87(化合物-H、[M+H]+)
保持時間:2.61分(化合物1)、2.83分(化合物1-C)、3.06分(化合物1-D)
質量分析:m/z 250.09(化合物1-C、[M+H]+)、278.06(化合物1-D、[M+H]+)
HPLC純度:100%
測定方法:HPLC Method A
保持時間:3.83分
質量分析:m/z 295.21([M-tBu+H]+)
保持時間:3.57分(化合物P5)、1.69分(化合物5)、2.04分(化合物5-E)、2.49分(化合物5-F)
質量分析:m/z 295.23(化合物P5、[M-tBu+H]+)、259.32(化合物5-E、[M+H]+)、301.35(化合物5-F、[M+H]+)
HPLC純度:100%
測定方法:HPLC Method B
保持時間:3.80分
質量分析:m/z 385.34([M-tBu+H]+)
保持時間:1.66分(化合物7-DKP)、2.23分(化合物7)、2.32分(化合物7-C)、2.46分(化合物7-D)
質量分析:m/z 233.26(化合物7-DKP、[M+H]+)、307.26(化合物7、[M+H]+)、335.34(化合物7-C、[M+H]+)、363.38(化合物7-D、[M+H]+)
保持時間:2.23分(化合物7)、2.32分(化合物7-C)、2.46分(化合物7-D)
質量分析:m/z 307.26(化合物7、[M+H]+)、335.34(化合物7-C、[M+H]+)、363.38(化合物7-D、[M+H]+)
保持時間:2.47分(化合物7-C)、2.61分(化合物7-D)、3.84分(化合物9)
質量分析:m/z 407.36(化合物9、[M-Sar+H]+)
HPLC純度:99.37%
測定方法:HPLC Method B
保持時間:3.78分
質量分析:m/z 385.32([M-tBu+H]+)
保持時間:2.23分(化合物7)、2.32分(化合物7-C)、2.46分(化合物7-D)
質量分析:m/z 307.26(化合物7、[M+H]+)、335.34(化合物7-C、[M+H]+)、363.38(化合物7-D、[M+H]+)
保持時間:H-Phe-OtBu:2.75 min, mono-Me: 2.84 min, di-Me: 2.98 min
質量分析:H-Phe-OtBu:m/z 166.47 ([M-tBu+H]+), mono-Me: m/z 236.59 ([M+H]+),di-Me: m/z 250.61 ([M+H]+)
保持時間:H-Phe-OtBu:2.82 min, mono-Me: 2.90 min, di-Me: 3.06 min
質量分析:H-Phe-OtBu:m/z 166.42 ([M-tBu+H]+), mono-Me: m/z 236.53 ([M+H]+),di-Me: m/z 250.55 ([M+H]+)
保持時間:H-Phe-OtBu:2.75 min, mono-Me: 2.85 min, di-Me: 2.98 min
質量分析:H-Phe-OtBu: m/z 166.47 ([M-tBu+H]+), mono-Me: m/z 236.59 ([M+H]+),di-Me: m/z 250.61 ([M+H]+)
保持時間:H-Phe-OtBu:2.80 min, mono-Me: 2.88 min, di-Me: 3.03 min
質量分析:H-Phe-OtBu: m/z 166.36 ([M-tBu+H]+), mono-Me: m/z 236.53 ([M+H]+),di-Me: m/z 250.55 ([M+H]+)
保持時間:NH2:2.34 min, mono-Me: 2.39 min, di-Me: 2.48 min
質量分析:NH2: m/z 330.75 ([M+H]+), mono-Me: m/z 344.94 ([M+H]+), di-Me: m/z 358.80 ([M+H]+)
保持時間:mono-Me:3.33 min, di-Me: 3.40 min
質量分析:mono-Me: m/z 420.93 ([M+H]+), di-Me: m/z 434.89([M+H]+)
保持時間:mono-Me: 3.34 min, di-Me: 3.41 min
質量分析:mono-Me: m/z 420.93 ([M+H]+), di-Me: m/z 434.84([M+H]+)
保持時間:NH2: 4.22 min, mono-Me: 4.28 min, di-Me: 4.40 min
質量分析:NH2: m/z 843.93 ([M+H]+), mono-Me: m/z 858.35 ([M+H]+), di-Me: m/z 872.20 ([M+H]+)
保持時間:Cbz-NHR:6.00 min, NH2: 4.21 min, mono-Me: 4.29 min, di-Me: 4.38 min
質量分析:Cbz-NHR: m/z 1000.23 ([M+Na]+), NH2: m/z 844.16 ([M+H]+),mono-Me: m/z 858.35 ([M+H]+), di-Me: m/z 872.43 ([M+H]+)
保持時間:H-Phe-OtBu: 2.70 min, mono-Pr: 3.12 min, di-Pr: 3.61 min
質量分析:H-Phe-OtBu: m/z 166.47 ([M-tBu+H]+), mono-Pr: m/z 264.74 ([M+H]+),di-Pr: m/z 306.81 ([M+H]+)
保持時間:NH2: 3.30 min, mono-Pr: 3.59 min, di-Pr: 3.95 min
質量分析:NH2: m/z 406.85 ([M+H]+), mono-Pr: m/z 449.03 ([M+H]+), di-Pr: m/z 490.92 ([M+H]+)
保持時間:mono-Pr: 4.47 min, di-Pr: 4.79 min
質量分析:mono-Pr: m/z 886.34 ([M+H]+), di-Pr: m/z 928.41 ([M+H]+)
保持時間:NH2:2.28 min, mono-Bu: 2.86 min, di-Bu: 3.49 min
質量分析:NH2:m/z 330.75 ([M+H]+), mono-Bu: m/z 386.90 ([M+H]+), di-Bu: m/z 442.99 ([M+H]+)
保持時間:NH2:3.30 min, mono-Bu: 3.80 min, di-Bu: 4.35 min
質量分析:NH2: m/z 406.85 ([M+H]+), mono-Bu: m/z 463.11 ([M+H]+), di-Bu: m/z 519.03 ([M+H]+)
保持時間:mono-Bu: 4.56 min
質量分析:mono-Bu: m/z 900.31 ([M+H]+)
保持時間:NH2: 2.32 min, mono-Hex: 3.42 min, di-Hex: 4.47 min
質量分析:NH2: m/z ([M+H]+), mono-Hex: m/z 415.11 ([M+H]+), di-Hex: m/z499.02 ([M+H]+)
保持時間:mono-Hex: 3.44 min, di-Hex: 4.47 min
質量分析:mono-Hex: m/z 415.00 ([M+H]+), di-Hex: m/z 499.02 ([M+H]+)
保持時間:mono-Hex: 4.87 min, di-Hex: 5.54 min
質量分析:mono-Hex: m/z 928.41([M+H]+), di-Hex: m/z 1012.54 ([M+H]+)
保持時間:mono-Et: 2.00 min, di-Et: 2.29 min
質量分析:mono-Et: m/z 208.77 ([M+H]+), di-Et: m/z 236.76([M+H]+)
保持時間:H-Phe(4-Me)-OH: 1.88 min, mono-Pr: 2.23 min, di-Pr: 3.00 min
質量分析:H-Phe(4-Me)-OH: m/z 180.50 ([M+H]+), mono-Pr: m/z 222.68 ([M+H]+), di-Pr: m/z 264.63 ([M+H]+)
収率:82%
HPLC純度:100%
測定方法:HPLC Method A
保持時間:4.45 min
質量分析:m/z 486.76 ([M+Na]+)
収率:40%
HPLC純度:99.5%
測定方法:HPLC Method A
保持時間:5.50 min
質量分析:m/z 562.86 ([M+Na]+)
収率:88%
HPLC純度:100%
測定方法:HPLC Method A
保持時間:6.00 min
質量分析:m/z 1000.23 ([M+Na]+)
HPLC純度:99.87%
測定方法:HPLC Method B
保持時間:4.11 min
質量分析:m/z 441([M+H]+)
H-EtPhe(4-Me)-Sar-OtBu塩酸塩の融点:196℃
収率:82%(Cbz-Phe(4-Me)-Sar-OtBuから2工程での収率)
HPLC純度:100%
測定方法:HPLC Method B
保持時間:2.51 min
質量分析:m/z 335([M+H]+)
HPLC純度:98.22%
測定方法:HPLC Method B
保持時間:4.14 min
質量分析:m/z 552([M+H]+)
HPLC純度:96.53%
測定方法:HPLC Method B
保持時間:2.67 min
質量分析:m/z 418([M+H]+)
HPLC純度:97.28%
測定方法:HPLC Method B
保持時間:4.07 min
質量分析:m/z 637([M+H]+)
H-MeAla-Aze-EtPhe(4-Me)-Sar-OtBuの融点:95℃
収率:79%(H-EtPhe(4-Me)-Sar-OtBuから4工程での収率)
HPLC純度:99.76%
測定方法:HPLC Method B
保持時間:2.62 min
質量分析:m/z 503([M+H]+)
Cbz-Ile-MeAla-Aze-EtPhe(4-Me)-Sar-OtBuの融点:70 ℃
収率:93%
HPLC純度:99.84%
測定方法:HPLC Method B
保持時間:4.21 min
質量分析:m/z 750([M+H]+)
HPLC純度:97.95%
測定方法:HPLC Method B
保持時間:5.58 min
質量分析:m/z 428([M-CH2=CH2+H]+)
HPLC純度:98.61%
測定方法:HPLC Method B
保持時間:5.28 min
質量分析:m/z 888([M+H]+)
HPLC純度:98.17%
測定方法:HPLC Method B
保持時間:3.04 min
質量分析:m/z 743.4([M+H]+)
H-MeLeu-Ile-MeAla-Aze-EtPhe(4-Me)-Sar-OtBuL-酒石酸塩の融点:94℃
収率:88%(H-Ile-MeAla-Aze-EtPhe(4-Me)-Sar-OtBuから3工程での収率)
HPLC純度:99.38%
測定方法:HPLC Method B
保持時間:3.01 min
質量分析:m/z 743.6([M+H]+)
HPLC純度:99.85 %
測定方法:HPLC Method C
保持時間:3.37 min
質量分析:m/z 387([M+Na]+)
HPLC純度:98.64%
測定方法:HPLC Method C
保持時間:1.44 min
質量分析:m/z 231([M+H]+)
HPLC純度:98.59%
測定方法:HPLC Method C
保持時間:4.10 min
質量分析:m/z 526([M+Na]+)
HPLC純度:96.86%
測定方法:HPLC Method D
保持時間:2.96 min
質量分析:m/z 370([M+H]+)
H-MeGcp-MeAsp(OtBu)-NMe2塩酸塩の融点:227℃
収率:80% (Cbz-MeAsp(OtBu)-OHジシクロヘキシルアミン塩から5工程での収率)
HPLC純度:99.62%
測定方法:HPLC Method D
保持時間:2.92 min
質量分析:m/z 370([M+H]+)
Cbz-cLeu-MeGcp-MeAsp(OtBu)-NMe2の融点:202℃
収率:84%
HPLC純度:99.86%
測定方法:HPLC Method D
保持時間:6.70 min
質量分析:m/z 637([M+Na]+)
HPLC純度:99.98%
測定方法:HPLC Method C
保持時間:2.42 min
質量分析:m/z 503([M+Na]+)
Cbz-Pro-cLeu-MeGcp-MeAsp(OtBu)-NMe2の融点:178℃
収率:88%
HPLC純度:100%
測定方法:HPLC Method D
保持時間:6.54 min
質量分析:m/z 734([M+Na]+)
H-Pro-cLeu-MeGcp-MeAsp(OtBu)-NMe2の融点:147℃
収率:95.8%
HPLC純度:100%
測定方法:HPLC Method C
保持時間:2.73 min
質量分析:m/z 578.5([M+H]+)
HPLC純度:78.47%
測定方法:HPLC Method E
保持時間:7.40 min
質量分析:m/z 374([M-Boc+2H]+)
窒素置換した反応容器に、臭化ニッケル(II)3水和物(0.07eq.)を溶媒(4.0 v/w of Boc-Glu(NHPI)-OBn)に懸濁させたスラリーと4,4’-ジ-tert-ブチル-2,2’-ビピリジン(0.07eq.)を加えた。国際公開第2020/189540号に記載の方法で合成したBoc-Glu(NHPI)-OBn(X g(表38参照)、1.0eq.)を攪拌しながら加えた後、溶媒(1.0 v/w of Boc-Glu(NHPI)-OBn)、5-ブロモ-1,3-ジフルオロ-2-(トリフルオロメチル)-ベンゼン(1.2eq.)および実施例57-1においてのみNMM(2.5eq.)を順次加えた。10℃に冷却した後、活性亜鉛(3.0eq.)を加えた。TMSCl(Y eq.(表38参照))を1時間かけて滴下しながら,25℃に昇温した。添加終了後Z時間後にサンプリングし、反応率を確認した。反応率はHPLC分析により算出されたBoc-Glu(NHPI)-OBnの面積値とBoc-Hph(3,5-F2-4-CF3)-OBnの面積値を用いて、以下の計算式により算出した。
反応率(%)=Boc-Hph(3,5-F2-4-CF3)-OBnの面積値/(Boc-Glu(NHPI)-OBnの面積値+Boc-Hph(3,5-F2-4-CF3)-OBnの面積値)×100
Cbz-Hph(3,5-F2-4-CF3)-OHジシクロヘキシルアミン塩の融点:154℃
収率:64%(Boc-Glu(NHPI)-OBnから4工程での収率)
HPLC純度:99.70%
測定方法:HPLC Method F
保持時間:9.73 min
質量分析:m/z 418([M+H]+)
HPLC純度:97.90%
測定方法:HPLC Method C
保持時間:4.63 min
質量分析:m/z 999([M+Na]+)
収率:83% (H-Pro-cLeu-MeGcp-MeAsp(OtBu)-NMe2より2工程)
HPLC純度:99.85%
測定方法:HPLC Method C
保持時間:4.18 min
質量分析:m/z 921([M+H]+)
HPLC純度:96.49%
測定方法:HPLC Method G
保持時間:10.27 min
質量分析:m/z 1668([M+Na]+)
HPLC純度:95.41%
測定方法:HPLC Method G
保持時間:9.22 min
質量分析:m/z 1612([M+Na]+)
収率:91.8%(Cbz-Hph(3,5-F2-4-CF3)-Pro-cLeu-MeGcp-MeAsp(OH)-NMe2ジエチルアミン塩から3工程での収率)
HPLC純度:97.56%
測定方法:HPLC Method G
保持時間:6.57 min
質量分析:m/z 1456([M+H]+)
HPLC純度:90.22%
測定方法:HPLC Method H
保持時間:17.99 min
質量分析:m/z 1439([M+H]+)
反応容器に実施例64と同様の手法により合成した化合物4(6.00g、4.17mmol)を含むアセトン溶液(33.33g)とアセトン(12.53g)を加えた。40℃に昇温し、撹拌しながら水(19.2mL)を10分かけて添加した。化合物4の水和物結晶(C型)(18mg)をガラスバイアルに加え、アセトン/水の混合溶液(5:4(v/v)、0.24mL)で懸濁させたのち、懸濁液を晶析液に加えた。さらにガラスバイアルにアセトン/水の混合溶液(5:4(v/v)、0.24mL)を加え、得られた懸濁液を晶析液に加えた。2時間攪拌した後、水(4.8mL)を10分かけて添加した。さらに3時間攪拌した後に、水(4.8mL)を10分かけて添加した。さらに1時間攪拌した後に、1時間かけて25℃まで冷却した。25℃にて1時間攪拌した後、懸濁液を13時間静置保管した。25℃でさらに2時間攪拌した後、懸濁液を濾過した。得られた湿性末をアセトン(16.8mL)と水(13.2mL)の混合溶液により洗浄した後、メタノール(15mL)と水(15mL)の混合溶液により洗浄した。さらに得られた湿性末をメタノール(15mL)と水(15mL)の混合溶液に懸濁させ、14時間静置保管した後、懸濁液を濾過した。得られた湿性末を水(30mL)により懸濁し、2時間静置保管した後に濾過した。前述した水による懸濁洗浄を再度実施した後、得られた湿性末を減圧条件下にて乾燥し、化合物4の水和物結晶(C型)(4.97g)を得た。
HPLC純度:99.74 %
測定方法:HPLC Method H
保持時間:17.91 min
質量分析:m/z 1439([M+H]+)
アモルファス状態のH-MeAla-Aze-EtPhe(4-Me)-Sar-OtBu(14.82g)とCPME(21.7g)を混合し、H-MeAla-Aze-EtPhe(4-Me)-Sar-OtBuのCPME溶液(含量40.6w/w%)を調製した。調製した溶液を5℃にて1日静置することで、H-MeAla-Aze-EtPhe(4-Me)-Sar-OtBuの結晶を得た。
アモルファス状態のCbz-Ile-MeAla-Aze-EtPhe(4-Me)-Sar-OtBu(10mg)とトルエン/ヘプタンの混合溶媒(1:2(v/v)、0.1mL)をバイアルに加えた後、得られた溶液を室温にて2日間振とうすることで、Cbz-Ile-MeAla-Aze-EtPhe(4-Me)-Sar-OtBuの結晶を得た。
アモルファス状態のH-MeLeu-Ile-MeAla-Aze-EtPhe(4-Me)-Sar-OtBu(600mg、0.808mmol)、L-酒石酸(121mg、0.808mmol)とメタノール(6mL)をガラスバイアルに加え、溶液を調製した。調製した溶液のうち、0.1mLを別のガラスバイアルに加えた後、減圧条件下で濃縮乾固することで溶媒を除去した。酢酸n-ブチル(0.02mL)とガラスビーズをバイアルに加え、25℃で7日間振とうすることで、H-MeLeu-Ile-MeAla-Aze-EtPhe(4-Me)-Sar-OtBu L-酒石酸塩の結晶を得た。
アモルファス状態のCbz-Pro-cLeu-MeGcp-MeAsp(OtBu)-NMe2(1.19g)にCPME(5.94mL)を加え、室温にて4時間攪拌した後、スラリーを濾過した。得られた固体をCPME(2.38mL)により2回洗浄した後、減圧条件下で乾燥し、Cbz-Pro-cLeu-MeGcp-MeAsp(OtBu)-NMe2の結晶を得た。
アモルファス状態のH-Pro-cLeu-MeGcp-MeAsp(OtBu)-NMe2(10mg)とテトラヒドロフラン(0.02mL)をバイアルに加えた後、室温にて6日間振とうした。得られた溶液にヘプタン(0.04mL)を加え、さらに室温にて6日間振とうすることで、H-Pro-cLeu-MeGcp-MeAsp(OtBu)-NMe2の結晶を得た。
Claims (26)
- N-モノアルキルアミノ酸もしくはそのエステルまたは前記N-モノアルキルアミノ酸を含むペプチドもしくはそのエステルの製造方法であって、
水素の存在下、出発アミノ酸もしくはそのエステルまたは前記出発アミノ酸を含むペプチドもしくはそのエステル、C1-C6一級アルキル化剤もしくは置換メチルハライド、および触媒を溶媒中で混合するアルキル化工程を含み、
前記アルキル化工程が、1気圧以上の圧力下で行われ、かつ、前記出発アミノ酸もしくはそのエステルのアミノ基に前記C1-C6一級アルキル化剤もしくは置換メチルハライドに対応する一級アルキル基が結合したN-モノアルキルアミノ酸もしくはそのエステルまたは前記N-モノアルキルアミノ酸を含むペプチドもしくはそのエステルを生成させる、方法。 - N-モノアルキルアミノ酸もしくはそのエステルまたは前記N-モノアルキルアミノ酸を含むペプチドもしくはそのエステルの製造方法であって、
出発アミノ酸もしくはそのエステルまたは前記出発アミノ酸を含むペプチドもしくはそのエステル、C1-C6一級アルキル化剤もしくは置換メチルハライド、ヒドリド還元剤および触媒を溶媒中で混合するアルキル化工程を含み、
前記アルキル化工程が、前記出発アミノ酸もしくはそのエステルのアミノ基に前記C1-C6一級アルキル化剤もしくは置換メチルハライドに対応する一級アルキル基が結合したN-モノアルキルアミノ酸もしくはそのエステルまたは前記N-モノアルキルアミノ酸を含むペプチドもしくはそのエステルを生成させる、方法。 - 前記ヒドリド還元剤が、トリアルキルシランである、請求項2に記載の方法。
- 前記C1-C6一級アルキル化剤が、C1-C5アルキルニトリルまたはC1-C5アルキルアルデヒドである、請求項1~3のいずれか一項に記載の方法。
- 前記置換メチルハライドが、メトキシメチルクロリド(MOM-Cl)、エトキシメチルクロリド(EOM-Cl)、2-メトキシエトキシメチルクロリド(MEM-Cl)、2-(トリメチルシリル)エトキシメチルクロリド(SEM-Cl)からなる群から選択される1つである、請求項1~4のいずれか一項に記載の方法。
- 前記触媒が、遷移金属を含む不均一系水素化触媒である、請求項1~5のいずれか一項に記載の方法。
- 前記不均一系水素化触媒が、Pd、RhおよびPtからなる群から選択される遷移金属を含む触媒である、請求項6に記載の方法。
- 前記溶媒が、エーテル系溶媒、アルコール系溶媒、およびエステル系溶媒からなる群から選択される少なくとも1つの溶媒を含む、請求項1~7のいずれか一項に記載の方法。
- 前記溶媒が、エーテル系溶媒、アルコール系溶媒、エステル系溶媒およびこれらの組合せからなる群から選択される、請求項1~8のいずれか一項に記載の方法。
- 以下の工程を含む、ペプチドもしくはそのエステルの製造方法:
(a)請求項1~9のいずれか一項に記載の方法に従いN-モノアルキルアミノ酸もしくはそのエステルまたはN-モノアルキルアミノ酸を含むペプチドもしくはそのエステルを得る工程、および
(b)前記N-モノアルキルアミノ酸もしくはそのエステルまたは前記N-モノアルキルアミノ酸を含むペプチドもしくはそのエステルに対し、任意で1つもしくは複数のアミノ酸またはペプチドを結合形成反応によって伸長させて、ペプチドもしくはそのエステルを得る工程。 - 前記アルキル化工程における反応混合物に、追加の水素を接触させる工程をさらに含む、請求項1~10のいずれか一項に記載の方法。
- 前記出発アミノ酸もしくはそのエステルまたは前記出発アミノ酸を含むペプチドもしくはそのエステルのアミノ基が、加水素分解条件で除去可能な保護基と結合している、請求項1~11のいずれか一項に記載の方法。
- 前記保護基が、アリールメチルオキシカルボニル基である、請求項12に記載の方法。
- 前記保護基の除去が、p-トルエンスルホン酸、メタンスルホン酸、硫酸水素ナトリウム、トリエチルアミン塩酸塩およびプロピルホスホン酸からなる群から選択される添加剤の存在下で行われる、請求項12または13に記載の方法。
- 前記アルキル化工程における反応混合物が、塩基を更に含む、請求項12~13のいずれか一項に記載の方法。
- 前記保護基の除去と前記アルキル化工程とが、ワンポットで行われる、請求項12~15のいずれか一項に記載の方法。
- 前記出発アミノ酸もしくはそのエステルまたは前記出発アミノ酸を含むペプチドもしくはそのエステルのアミノ基が、一級アミノ基であり、
前記アルキル化工程における反応混合物が、塩基を更に含む、請求項1~11のいずれか一項に記載の方法。 - 前記塩基が、三級アミンである、請求項15または17に記載の方法。
- 以下の工程を含む、少なくとも4個のアミノ酸より構成される環状部を有するペプチドもしくはそのエステルの製造方法。
請求項1~18のいずれか一項に記載の方法に従いN-モノアルキルアミノ酸もしくはそのエステルまたは前記N-モノアルキルアミノ酸を含むペプチドもしくはそのエステルを得る工程、
任意で1つまたは複数のアミノ酸を結合形成反応によって伸長させてペプチド鎖を得る工程、
前記ペプチド鎖のC末端側の基とN末端側の基とで環化して前記環状部を形成する工程。 - 前記環状部が、少なくとも8個のアミノ酸により構成されており、
前記環状部を有するペプチドもしくはそのエステルが、8~15個のアミノ酸により構成されるペプチドもしくはそのエステルである、請求項19に記載の方法。 - 前記環状部を有するペプチド、もしくはその塩またはそれらの溶媒和物が、環状部を有するペプチドの溶媒和物である、請求項21に記載の方法。
- 前記環状部を有するペプチドの溶媒和物が、環状部を有するペプチドの水和物である、請求項22に記載の方法。
- 出発アミノ酸もしくはそのエステルまたは前記出発アミノ酸を含むペプチドもしくはそのエステルのN-モノアルキル化反応において、前記出発アミノ酸もしくはそのエステルまたは前記出発アミノ酸を含むペプチドもしくはそのエステルのアミノ基がジアルキル化された化合物の生成を抑制する方法であって、
水素の存在下、出発アミノ酸もしくはそのエステルまたは前記出発アミノ酸を含むペプチドもしくはそのエステル、C1-C6一級アルキル化剤もしくは置換メチルハライド、および触媒を溶媒中で混合するアルキル化工程を含み、
前記アルキル化工程が、1気圧以上の圧力下で行われ、かつ、前記出発アミノ酸もしくはそのエステルのアミノ基に前記C1-C6一級アルキル化剤もしくは置換メチルハライドに対応する一級アルキル基が結合したN-モノアルキルアミノ酸もしくはそのエステルまたは前記N-モノアルキルアミノ酸を含むペプチドもしくはそのエステルを生成させる、方法。 - 出発アミノ酸もしくはそのエステルまたは出発アミノ酸を含むペプチドもしくはそのエステルのN-モノアルキル化反応において、出発アミノ酸もしくはそのエステルまたは出発アミノ酸を含むペプチドもしくはそのエステルのアミノ基がジアルキル化された化合物の生成を抑制する方法であって、
出発アミノ酸もしくはそのエステルまたは出発アミノ酸を含むペプチドもしくはそのエステル、C1-C6一級アルキル化剤もしくは置換メチルハライド、ヒドリド還元剤および触媒を溶媒中で混合するアルキル化工程を含み、
アルキル化工程が、出発アミノ酸もしくはそのエステルのアミノ基にC1-C6一級アルキル化剤もしくは置換メチルハライドに対応する一級アルキル基が結合したN-モノアルキルアミノ酸もしくはそのエステルまたは前記N-モノアルキルアミノ酸を含むペプチドもしくはそのエステルを生成させる、方法。 - N-モノアルキルアミノ酸もしくはそのエステルまたは前記N-モノアルキルアミノ酸を含むペプチドもしくはそのエステルのペプチド鎖を、結合形成反応によって伸長する工程と、
伸長されたペプチドを酸性水溶液で処理し、前記ジアルキル化された化合物を除去する工程をさらに含む、請求項24または25に記載の方法。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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Non-Patent Citations (4)
Title |
---|
CHEN DIAO, DISOTUAR MARIA M., XIONG XIAOCHUN, WANG YUANXIANG, CHOU DANNY HUNG-CHIEH: "Selective N-terminal functionalization of native peptides and proteins", CHEMICAL SCIENCE, ROYAL SOCIETY OF CHEMISTRY, UNITED KINGDOM, vol. 8, no. 4, 1 January 2017 (2017-01-01), United Kingdom , pages 2717 - 2722, XP055959934, ISSN: 2041-6520, DOI: 10.1039/C6SC04744K * |
HAN YINGLIN, CHOREV MICHAEL: "A Novel, One-Pot Reductive Alkylation of Amines by S -Ethyl Thioesters Mediated by Triethylsilane and Sodium Triacetoxyborohydride in the Presence of Palladium on Carbon", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 64, no. 6, 1 March 1999 (1999-03-01), pages 1972 - 1978, XP093076190, ISSN: 0022-3263, DOI: 10.1021/jo982125g * |
SAJIKI HIRONAO, IKAWA TAKASHI, HIROTA KOSAKU: "Reductive and Catalytic Monoalkylation of Primary Amines Using Nitriles as an Alkylating Reagent", ORGANIC LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 6, no. 26, 1 December 2004 (2004-12-01), US , pages 4977 - 4980, XP093076189, ISSN: 1523-7060, DOI: 10.1021/ol047871o * |
TAKASHI IKAWA, YUKI FUJITA, TOMOTERU MIZUSAKI, SAE BETSUIN, HARUKI TAKAMATSU, TOMOHIRO MAEGAWA, YASUNARI MONGUCHI, HIRONAO SAJIKI: "Selective N-alkylation of amines using nitriles under hydrogenation conditions: facile synthesis of secondary and tertiary amines", ORGANIC & BIOMOLECULAR CHEMISTRY, ROYAL SOCIETY OF CHEMISTRY, vol. 10, no. 2, 1 January 2012 (2012-01-01), pages 293 - 304, XP055300329, ISSN: 1477-0520, DOI: 10.1039/C1OB06303K * |
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