JP2019534299A - (s)−n1−(2−アミノエチル)−3−(4−アルコキシフェニル)プロパン−1,2−ジアミン三塩酸塩の製造方法 - Google Patents
(s)−n1−(2−アミノエチル)−3−(4−アルコキシフェニル)プロパン−1,2−ジアミン三塩酸塩の製造方法 Download PDFInfo
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- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 title claims abstract description 10
- GJOSEARIOFWCNW-UHFFFAOYSA-N Cl.Cl.Cl.CC(CN)N Chemical compound Cl.Cl.Cl.CC(CN)N GJOSEARIOFWCNW-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 238000000034 method Methods 0.000 title claims description 29
- 150000001875 compounds Chemical class 0.000 claims description 51
- 239000000203 mixture Substances 0.000 claims description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 125000004069 aziridinyl group Chemical group 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 5
- 238000010168 coupling process Methods 0.000 claims description 5
- 238000005859 coupling reaction Methods 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 150000007517 lewis acids Chemical class 0.000 claims description 3
- 150000002902 organometallic compounds Chemical class 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 claims description 2
- 150000001541 aziridines Chemical class 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 150000002736 metal compounds Chemical class 0.000 claims description 2
- 238000007142 ring opening reaction Methods 0.000 claims description 2
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 12
- 239000000243 solution Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- -1 4-ethoxybenzyl Chemical group 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- SLYTULCOCGSBBJ-UHFFFAOYSA-I disodium;2-[[2-[bis(carboxylatomethyl)amino]-3-(4-ethoxyphenyl)propyl]-[2-[bis(carboxylatomethyl)amino]ethyl]amino]acetate;gadolinium(3+) Chemical compound [Na+].[Na+].[Gd+3].CCOC1=CC=C(CC(CN(CCN(CC([O-])=O)CC([O-])=O)CC([O-])=O)N(CC([O-])=O)CC([O-])=O)C=C1 SLYTULCOCGSBBJ-UHFFFAOYSA-I 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001540 azides Chemical group 0.000 description 3
- 229940075342 gadoxetate disodium Drugs 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- JFEKJQFDERWHQN-SNVBAGLBSA-N (2R)-1-azido-3-(4-ethoxyphenyl)propan-2-ol Chemical compound N(=[N+]=[N-])C[C@@H](CC1=CC=C(C=C1)OCC)O JFEKJQFDERWHQN-SNVBAGLBSA-N 0.000 description 2
- CRCIASUNXSOPCW-SNVBAGLBSA-N (2R)-1-chloro-3-(4-ethoxyphenyl)propan-2-ol Chemical compound ClC[C@@H](CC1=CC=C(C=C1)OCC)O CRCIASUNXSOPCW-SNVBAGLBSA-N 0.000 description 2
- OFBDJBKDYABGSR-JNQXMBDASA-N (2s)-1-n-(2-aminoethyl)-3-(4-ethoxyphenyl)propane-1,2-diamine;trihydrochloride Chemical compound Cl.Cl.Cl.CCOC1=CC=C(C[C@H](N)CNCCN)C=C1 OFBDJBKDYABGSR-JNQXMBDASA-N 0.000 description 2
- WVUYYXUATWMVIT-UHFFFAOYSA-N 1-bromo-4-ethoxybenzene Chemical compound CCOC1=CC=C(Br)C=C1 WVUYYXUATWMVIT-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000004985 diamines Chemical class 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 238000002595 magnetic resonance imaging Methods 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- BRLQWZUYTZBJKN-VKHMYHEASA-N (-)-Epichlorohydrin Chemical compound ClC[C@H]1CO1 BRLQWZUYTZBJKN-VKHMYHEASA-N 0.000 description 1
- QYIXEVDRZCBQCV-LBPRGKRZSA-N (2s)-1-n-(2-aminoethyl)-3-(4-ethoxyphenyl)propane-1,2-diamine Chemical compound CCOC1=CC=C(C[C@H](N)CNCCN)C=C1 QYIXEVDRZCBQCV-LBPRGKRZSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N acetoacetic acid Chemical compound CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000005298 paramagnetic effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/22—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of other functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/20—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C219/22—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
- C07C247/10—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated and containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
(1)一般式(1)の化合物のグリニャールカップリングによって一般式(2)の化合物を製造する段階;(2)アジ化ナトリウムとの反応において、一般式(2)の化合物をアジド置換によって一般式(3)の化合物を製造する段階;(3)トリフェニルホスフィンを用いて一般式(3)の化合物を環化によって保護されたアミノ基を有する一般式(4)のアジリジン誘導体を製造する段階;(4)一般式(4)の化合物を開環することによって一般式(5)の化合物を製造する段階;及び(5)一般式(5)の化合物のアミノ保護基を除去するための反応によって一般式(6)の化合物を製造する段階:
RはC1-6アルキルである。)。
窒素雰囲気で置換した反応器中で、マグネシウム(14.50g、596.84mmol)を600mLのTHFに加え、混合物を撹拌して溶解させた。温度を20℃〜30℃に保ちながら、4−ブロモフェネトール(120.0g、596.84mmol)をゆっくり加えた。滴下終了後、温度を60℃に上げ、混合物を2時間攪拌してから−5℃に冷却し、続いてヨウ化銅(0.76g、2.98mmol)を加えて混合物をさらに30分間攪拌した。その後、(R)−エピクロロヒドリン(49.70g、537.15mmol)をゆっくり加え、混合物を室温で1時間撹拌した。反応終了後、5℃に温度を下げ、塩酸水溶液(3M、600mL)及びイソプロピルエーテル(360mL)を添加して層に分離した。有機層を10%EDTA水溶液(480mL)及び20%塩化ナトリウム水溶液(240mL)で2回洗浄し、硫酸ナトリウムで乾燥し、混合物をろ過した。ろ液を濃縮して表題化合物である(R)−1−クロロ−3−(4−エトキシフェニル)プロパン−2−オール(123.2g、収率100%)を収得した。
実施例1で製造した(R)−1−クロロ−3−(4−エトキシフェニル)プロパン−2−オール(115.33g、537.15mmol)をジメチルホルムアミド580mLに加え、混合物を撹拌して溶解させた。その後、ヨウ化ナトリウム(8.05g、53.72mmol)とアジ化ナトリウム(69.85g、1074.39mmol)とをこれに添加した。反応器内の温度を85℃に上げ、16時間攪拌した。反応終了後、混合物を室温まで冷却し、精製水580mL及びイソプロピルエーテル580mLを添加して層に分離した。その後、前記得られた水層をさらにイソプロピルエーテル(190mL)で2回抽出した。回収した有機層を塩酸水溶液(1M、580mL)、5%炭酸水素ナトリウム水溶液(580mL)、及び10%塩化ナトリウム水溶液(580mL)で洗浄し、硫酸ナトリウムで乾燥し、混合物を濾過した。ろ液を濃縮して表題化合物である(R)−1−アジド−3−(4−エトキシフェニル)プロパン−2−オール(113.5g、収率95.5%)を収得した。
窒素雰囲気に置換した反応器中で、実施例2で製造した(R)−1−アジド−3−(4−エトキシフェニル)プロパン−2−オール(113.0g、510.71mmol)をアセトニトリル(AN、1130mL)に加え、混合物を撹拌し、続いてトリフェニルホスフィン(PPh3、120.56g、459.64mmol)を加えて室温で2時間撹拌し、4時間還流した。反応完了後、混合物を20℃に冷却し、4−ジメチルアミノピリジン(DMAP、0.62g、122.17mmol)及びジ−tert−ブチルジカーボネート((Boc)2O、100.32g、459.64mmol)をゆっくり加え、混合物を30分間撹拌した。前記混合物に過酸化水素(11.60g、102.14mmol)を加えて、さらに30分間撹拌した後、生成物を濃縮し、アセトニトリルを除去した。得られた濃縮物にヘプタン(1130mL)を入れ、20℃〜25℃で30分間攪拌した後、前記生成物をろ過した。ろ液を濃縮して表題化合物である(S)−tert−ブチル2−(4−エトキシベンジル)アジリジン−1−カルボキシレート(113.05g、収率93.9%)を収得した。
実施例3で製造した(S)−tert−ブチル2−(4−エトキシベンジル)アジリジン−1−カルボキシレート(133.05g、479.70mmol)をアセトニトリル(400mL)に加えて、混合物を攪拌して溶解させた後、エチレンジアミン(432.45g、7195.52mmol)を加え、50℃で6時間撹拌した。反応終了後、生成物を濃縮し、内部温度を5℃に下げて、塩酸水溶液(2M、480mL)及び酢酸エチル(266mL)を添加して層に分離した。水層に50%水酸化ナトリウム水溶液(200mL)を加え、混合物を酢酸エチル(530mL)で分離した。有機層を20%塩化ナトリウム(266mL)で洗浄し、硫酸ナトリウムで乾燥して、混合物を濾過した。ろ液を50℃で真空乾燥して表題化合物である(S)−tert−ブチル1−(2−アミノエチルアミノ)−3−(4−エトキシフェニル)プロパン−2−イルカルバメート二塩酸塩(135.5g、収率68.8% )を収得した。
反応器に、メタノール(950mL)及び塩化アセチル(77.75g、990.55mmol)を加え、混合物を撹拌して溶解させた。この溶液に、実施例4で製造した(S)−tert−ブチル1−(2−アミノエチルアミノ)−3−(4−エトキシフェニル)プロパン−2−イルカルバメート二塩酸塩(135.5g、330.18mmol)を加え、混合物を50℃で1時間撹拌した。反応終了後、メチルtert−ブチルエーテル(950mL)を加え、混合物を結晶化して濾過した。 得られた結晶を50℃で真空乾燥して表題化合物である(S)−N1−(2−アミノエチル)−3−(4−エトキシフェニル)プロパン−1,2−ジアミン三塩酸塩 (105.2g、収率99.8%)を収得した。
Claims (21)
- 下記段階を含む(S)-N1−(2-アミノエチル)-3-(4-アルコキシフェニル)プロパン-1,2-ジアミン三塩酸塩の製造方法:
(1)一般式(1)の化合物のグリニャールカップリングによって一般式(2)の化合物を製造する段階;
(2)アジ化ナトリウムとの反応において、一般式(2)の化合物をアジド置換によって一般式(3)の化合物を製造する段階;
(3)トリフェニルホスフィンを用いて一般式(3)の化合物を環化によってアミノ保護基により保護されたアミノ基を有する一般式(4)のアジリジン誘導体を製造する段階;
(4)一般式(4)の化合物を開環することによって一般式(5)の化合物を製造する段階;及び
(5)一般式(5)の化合物のアミノ保護基を除去するための反応によって一般式(6)の化合物を製造する段階:
- 段階(1)が、以下の段階:
(1-1)一般式(1)の化合物と金属または有機金属化合物とを反応させてグリニャール化合物を製造する段階;及び
(1-2)前記グリニャール化合物と一般式(7)の化合物とを反応させる段階:
- 段階(1)が、テトラヒドロフラン(THF)、1,4-ジオキサン、ジエチルエーテル、またはそれらの混合物を溶媒として用いて行われる、請求項1に記載の方法。
- 段階(1-1)が、20℃〜60℃の温度で行われる、請求項2に記載の方法。
- 段階(1-2)が、−20℃〜30℃の温度で行われる、請求項2に記載の方法。
- 段階(1-2)が、ルイス酸をさらに含むことによって行われる、請求項2に記載の方法。
- 段階(2)が、ジメチルホルムアミドを溶媒として用いて行われる、請求項1に記載の方法。
- 段階(2)が、70℃〜100℃の温度で行われる、請求項1に記載の方法。
- 段階(3)が、以下の段階:
(3-1)トリフェニルホスフィンによる環化によって一般式(3-1)のアジリジニル基を形成する段階;及び
(3-2)段階(3-1)により得られるアジリジニル基を含む化合物とジ-tert-ブチルジカーボネートとを反応させることによってアミノ基に保護基を導入する段階:
を含む、請求項1に記載の方法。 - 段階(3-2)が、4-ジメチルアミノピリジン及びヨウ素(I2)から選択される触媒、またはトリエタノールアミド(TEA)、N、N-ジイソプロピルエチルアミン(DIEA)、及びNaHCO3から選択されるアルカリ性物質をさらに含むことによって行われる、請求項9に記載の方法。
- 段階(3)が、アセトニトリル、トルエンまたはそれらの混合物を溶媒として用いて行われる、請求項1に記載の方法。
- 段階(3-1)が、55℃〜70℃の温度で行われる、請求項9に記載の方法。
- 段階(3-2)が、20℃〜30℃の温度で行われる、請求項9に記載の方法。
- 段階(4)が、アセトニトリル、テトラヒドロフラン、トルエンまたはそれらの混合物を溶媒として用いて行われる、請求項1に記載の方法。
- 段階(4)が、45℃〜55℃の温度で行われる、請求項1に記載の方法。
- 段階(5)の反応が、トリフルオロ酢酸、塩酸、メタノール性塩酸、またはそれらの混合物により行われる、請求項1に記載の方法。
- 段階(5)が、メタノール、ジクロロメタン、テトラヒドロフラン、またはそれらの混合物を溶媒として用いて行われる、請求項1に記載の方法。
- 段階(5)の反応が、メタノール溶媒中で塩化アセチルにより行われる、請求項1に記載の方法。
- 段階(5)が、45℃〜55℃の温度で行われる、請求項1に記載の方法。
- 段階(4)及び段階(5)が、製造された化合物を独立して結晶化するためのそれぞれの段階(4-1)または段階(5-1)のいずれか、または両方の段階をさらに含む、請求項1に記載の方法。
- 段階(4-1)が、エタノール、酢酸エチル、またはそれらの混合物を溶媒として用いて行われて、段階(5-1)が、メタノール、アセトン、メチルtert-ブチルエーテル、またはそれらの混合物を溶媒として用いて行われる、請求項20に記載の方法。
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