JP2019511512A - ドロキシドパを製造するための改良された方法及びその中間体 - Google Patents
ドロキシドパを製造するための改良された方法及びその中間体 Download PDFInfo
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- JP2019511512A JP2019511512A JP2018551796A JP2018551796A JP2019511512A JP 2019511512 A JP2019511512 A JP 2019511512A JP 2018551796 A JP2018551796 A JP 2018551796A JP 2018551796 A JP2018551796 A JP 2018551796A JP 2019511512 A JP2019511512 A JP 2019511512A
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- JP
- Japan
- Prior art keywords
- compound
- threo
- serine
- dihydroxyphenyl
- following formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 238000000034 method Methods 0.000 title claims abstract description 81
- 229960001104 droxidopa Drugs 0.000 title claims abstract description 48
- 239000000543 intermediate Substances 0.000 title abstract description 9
- QXWYKJLNLSIPIN-SFYZADRCSA-N droxidopa Chemical compound OC(=O)[C@H](N)[C@@H](O)C1=CC=C(O)C(O)=C1 QXWYKJLNLSIPIN-SFYZADRCSA-N 0.000 title 1
- -1 aldehyde compound Chemical class 0.000 claims abstract description 68
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- QXWYKJLNLSIPIN-JGVFFNPUSA-N droxidopa Chemical compound OC(=O)[C@@H](N)[C@H](O)C1=CC=C(O)C(O)=C1 QXWYKJLNLSIPIN-JGVFFNPUSA-N 0.000 claims abstract description 50
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 150000004696 coordination complex Chemical class 0.000 claims abstract description 21
- 239000002253 acid Substances 0.000 claims abstract description 20
- 229910052751 metal Inorganic materials 0.000 claims abstract description 17
- 239000002184 metal Substances 0.000 claims abstract description 17
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 239000002245 particle Substances 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 15
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 14
- 229910052759 nickel Inorganic materials 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 230000003301 hydrolyzing effect Effects 0.000 claims description 8
- 239000012535 impurity Substances 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 150000004703 alkoxides Chemical class 0.000 claims description 7
- 229910052987 metal hydride Inorganic materials 0.000 claims description 7
- 150000004681 metal hydrides Chemical class 0.000 claims description 7
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000012458 free base Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- 239000003849 aromatic solvent Substances 0.000 claims description 3
- 150000004678 hydrides Chemical class 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 claims description 3
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000106 rubidium hydride Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims 2
- 239000011734 sodium Substances 0.000 claims 2
- 229910052708 sodium Inorganic materials 0.000 claims 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- 229910052782 aluminium Inorganic materials 0.000 claims 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims 1
- 229910052744 lithium Inorganic materials 0.000 claims 1
- 235000017550 sodium carbonate Nutrition 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 18
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- 230000007062 hydrolysis Effects 0.000 abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- BXPMJVXEFLMHOY-UHFFFAOYSA-N 2-ethoxy-1,3-benzodioxole-5-carbaldehyde Chemical compound C1=C(C=O)C=C2OC(OCC)OC2=C1 BXPMJVXEFLMHOY-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 150000003840 hydrochlorides Chemical class 0.000 description 7
- 238000003801 milling Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- KWGRBVOPPLSCSI-PSASIEDQSA-N (1s,2r)-2-(methylamino)-1-phenylpropan-1-ol Chemical compound CN[C@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-PSASIEDQSA-N 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 2
- ZBTMRBYMKUEVEU-UHFFFAOYSA-N 1-bromo-4-methylbenzene Chemical compound CC1=CC=C(Br)C=C1 ZBTMRBYMKUEVEU-UHFFFAOYSA-N 0.000 description 2
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 208000001089 Multiple system atrophy Diseases 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 239000005456 alcohol based solvent Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 208000002173 dizziness Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 231100000024 genotoxic Toxicity 0.000 description 2
- 230000001738 genotoxic effect Effects 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- 229940103724 northera Drugs 0.000 description 2
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Classifications
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- C07B53/00—Asymmetric syntheses
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/30—Preparation of optical isomers
- C07C227/32—Preparation of optical isomers by stereospecific synthesis
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
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- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
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Abstract
Description
この薬剤は、1989年に日本で住友大日本製薬ファーマが発売したものであり、パーキンソン病に伴うすくみ足やめまいの経口治療や、シャイ・ドレーガー症候群及び家族性アミロイド性多発神経障害に伴う起立性低血圧、失神、及びめまいの経口治療に使用されている。
を提供する。
(a) 下記式:
で表される金属錯体(IV)を、下記式:
で表されるアルデヒド(III)と、下記式:
を、金属アルコキシドの存在下で反応させることによって調製する工程;及び
(b) 工程(a)から得られた化合物(IV)を、酸の存在下で加水分解する工程
を含む方法に関する。
(i) 下記式:
(ii) 工程(i)で得られた化合物(IVa)を酸の存在下で加水分解して、下記式:
(iii) 工程(ii)で得られた化合物(I)の酸塩を塩基で処理する工程
を含む方法に関する。
(1) 化合物(III)を溶媒に添加する工程、
(2) 工程(1)の反応混合物に、金属アルコキシド及び化合物(II)を添加する工程、
(3) 任意選択で、化合物(IV)を単離する工程、
(4) 撹拌している化合物(IV)を含む溶液に、酸を添加する工程、
(5) 任意選択で、工程(4)の化合物(I)の塩を単離する工程、
(6) 撹拌している、化合物(I)の塩を含有する溶液に、塩基を添加する工程、
(7) 所望の生成物を単離する工程
を含む。
を提供する。
で表される化合物(IV)の酸の存在下での加水分解を含む方法に関する。
(p) ドロキシドパ(I)の塩を溶媒に添加する工程、
(q) 撹拌している工程(p)の溶液に、金属水素化物を添加する工程、
(r) 純粋なドロキシドパ(I)の塩又はその遊離塩基を単離する工程
を含む。
フラスコ内に300mLのメタノールを充填し、続いて約25〜30℃の温度でニッケル錯体(IIa)(100g)を添加した。撹拌しているこの溶液に、25%ナトリウムメトキシド溶液120mL及びアルデヒド化合物(IIIa)(40.9g)を加えた。反応混合物を約1時間撹拌し、酢酸:水混合物(20%酢酸200mL及び脱塩水(DM)1000mL)中で反応を停止させた。反応混合物を濾過し、固体を300mLのDM水で洗浄した。残渣を(600mL)で処理して所望の生成物を得た(HPLC純度:83.4%)。
フラスコ内に300mLのメタノールを充填し、続いて約25〜30℃の温度でニッケル錯体(IVa)(30g)を添加した。撹拌しているこの溶液に、5N HCl(75mL)を加え、反応混合物を40℃に加熱した。2時間後、反応物を25〜30℃に冷却し、真空下で濃縮した。粗ドロキシドパ塩酸塩の残渣を、(HCl塩の重量の)5容量倍(V)のDM水媒体中で約1時間の間、メタノール溶液中の25%トリエチルアミンでそのpHを7.5〜8.5に調整することによって、その遊離塩基に変換した。固体を濾過し、DM水(2×4V)及びメタノール(2×7V)で洗浄して所望の生成物を得た(収率76%、キラル純度99.65%(ee))。
フラスコ内にメタノール420mLを充填した後、ナトリウムメトキシド溶液(55mL)、ニッケル錯体(IIa)(100g)、及びアルデヒド化合物(IIIa)を添加した。反応混合物を約15〜20℃の温度で約1時間撹拌した。反応混合物をさらに約10℃の温度に冷却した。この反応混合物に濃塩酸(100mL)を加え、約40℃に昇温させて3時間撹拌した。反応混合物を濾過し、HCl水溶液で洗浄した。水性濾液を、メチレンジクロライド(350mL)で処理し、酢酸エチル(350mL)で処理した。分離した水層を−5〜5℃の温度に冷却し、約3時間攪拌して、L−スレオ−(2S,3R)−3−(3,4−ジヒドロキシフェニル)セリン(I)HCl塩の固体沈殿物を得た。得られた(I)HCl塩をイソプロピルアルコールから再結晶させた(収率85%、キラル純度99.99%ee)。
ドロキシドパ塩酸塩(100g)を、メタノール(150mL)中のトリエチルアミン(150mL)の溶液を用いてその水溶液のpHを7.5〜8.5に調整することによって、遊離塩基に変換した。固体を濾過し、水(100mL)で洗浄し、続いてメタノール(100mL)で洗浄して、所望の生成物を得た(収量:65g(76.5%)、キラル純度99.99%ee)。
フラスコ内にドロキシドパ塩酸塩(35g)を充填し、続いて脱塩水(10V)及び濃HCl(0.5V)(それぞれHCl塩の重量に対する容量)を加えた。反応混合物を約25〜30℃の温度で撹拌した。この反応物に、(HCl塩の重量に対して)4VのDM水中の0.1重量%水素化ホウ素ナトリウムを添加し、さらに約25〜30℃の温度で約30分間攪拌を続けた。この反応混合物を濾過し、活性炭で処理し、hyfro bedに通した。不純物が0.06%未満のL−スレオ−(2S,3R)−3−(3,4−ジヒドロキシフェニル)セリン(I)塩酸塩の純粋な水溶液を得た。
Claims (24)
- 下記式:
(a) 下記式:
の化合物(III)を、下記式;
の金属錯体(II)と反応させる工程;及び
(b) 工程(a)から得られた下記式:
を含む、方法。 - 下記式:
(i) 下記式:
の化合物(III)を、下記式;
(ii) 工程(i)から得られた下記式:
(iii) 工程(ii)から得られた下記式:
を含む、方法。 - 工程(a)又は工程(i)を、ナトリウムメトキシド、ナトリウムエトキシド、ナトリウムイソプロポキシド、カリウムメトキシド、ナトリウムtert-ブトキシド、カリウムtert-ブトキシド、及び/又はこれらの混合物からなる群から選択される金属アルコキシドの存在下で行う、請求項1または2に記載の方法。
- 工程(b)又は工程(ii)の前記酸が、塩酸、臭化水素酸、フッ化水素酸、硝酸、硫酸、リン酸、又はこれらの混合物からなる群から選択される、請求項1または2に記載の方法。
- 工程(iii)の前記塩基が、トリエチルアミン(TEA)、N,N−ジイソプロピルエチルアミン、トリプロピルアミン、ピリジン、炭酸ナトリウム、重炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、炭酸リチウム、重炭酸ナトリウム、重炭酸カリウム、水素化ナトリウム、又はこれらの混合物からなる群から選択される有機塩基又は無機塩基である、請求項2に記載の方法。
- 生成物であるドロキシドパ(I)が、99%を超える鏡像体過剰率(ee)を有するものとして得られる、請求項1または2に記載の方法。
- 99%を超える鏡像体過剰率(ee)を有する、化合物:L−スレオ−(2S,3R)−3−(3,4−ジヒドロキシフェニル)セリン(I)(ドロキシドパ)。
- 99.5%を超える鏡像体過剰率(ee)を有する、化合物:L−スレオ−(2S,3R)−3−(3,4−ジヒドロキシフェニル)セリン(I)(ドロキシドパ)。
- 化合物:下記式:
の金属錯体(IV)。 - 化合物:下記式:
- 下記式:
の化合物(VI)を酸の存在下で加水分解する工程を含む、方法。 - 下記式:
(i) 下記式:
(ii) 工程(i)から得られた下記式:
(iii) 工程(ii)から得られた下記式:
を含む、方法。 - 30ppmより低いニッケル(Ni)含量を有する、化合物:L−スレオ−(2S,3R)−3−(3,4−ジヒドロキシフェニル)セリン(I)(ドロキシドパ)。
- 20ppmより低いニッケル(Ni)含量を有する、化合物:L−スレオ−(2S,3R)−3−(3,4−ジヒドロキシフェニル)セリン(I)(ドロキシドパ)。
- L−スレオ−(2S,3R)−3−(3,4−ジヒドロキシフェニル)セリン(I)を精製する方法であって、金属水素化物を用いて式(I)の化合物又はその塩を処理する工程を含む、方法。
- L−スレオ−(2S,3R)−3−(3,4−ジヒドロキシフェニル)セリン(I)を精製する方法であって、
(p) ドロキシドパ(I)の塩を溶媒に添加する工程、
(q) 撹拌している工程(p)の溶液に、金属水素化物を添加する工程、
(r) 純粋なドロキシドパ(I)の塩又はその遊離塩基を単離する工程
を含む、方法。 - 生成物であるドロキシドパ(I)が、0.06%未満の総不純物含量を有するものとして得られる、請求項15又は16に記載の方法。
- 前記金属水素化物が、水素化ホウ素、水素化ホウ素リチウム、水素化ホウ素ナトリウム、水素化ホウ素カリウム、シアノ水素化ホウ素ナトリウム、ジアルキルアミノ水素化ホウ素ナトリウム、水素化ジアルキルアルミニウム、水素化アルミニウム、水素化アルミニウムナトリウム、水素化アルミニウムリチウム、水素化ナトリウム、水素化カリウム、水素化ルビジウム、水素化セシウム又はこれらの混合物からなる群から選択される、請求項15又は16に記載の方法。
- 前記溶媒が、水、ハロゲン化溶媒、アルコール系溶媒、エーテル溶媒、ケトン溶媒、芳香族溶媒、非プロトン性溶媒〔例えば、アセトニトリル、N,N−ジメチルホルムアミド(DMF)、N,N−ジメチルアセトアミド、ジメチルスルホキシド(DMSO)、及びN−メチルピロリドン(NMP)等〕、又はこれらの混合物からなる群から選択される、請求項16に記載の方法。
- 約1〜約20μmのd(0.1)を有する粒径範囲を有する、化合物:L−スレオ−(2S,3R)−3−(3,4−ジヒドロキシフェニル)セリン(I)(ドロキシドパ)。
- 約5〜約105μmのd(0.5)を有する粒径範囲を有する、化合物:L−スレオ−(2S,3R)−3−(3,4−ジヒドロキシフェニル)セリン(I)(ドロキシドパ)。
- 約10〜約210μmのd(0.9)を有する粒径範囲を有する、化合物:L−スレオ−(2S,3R)−3−(3,4−ジヒドロキシフェニル)セリン(I)(ドロキシドパ)。
- 約1〜約20μmのd(0.1)、約5〜約105μmのd(0.5)、約10〜約210μmのd(0.9)、又はこれらのいずれかの組合せを有する粒径範囲を有する、L−スレオ−(2S,3R)−3−(3,4−ジヒドロキシフェニル)セリン(I)を治療に有効な量で含む、医薬組成物。
- 0.1〜3m2/gの比表面積値を有する、化合物:L−スレオ−(2S,3R)−3−(3,4−ジヒドロキシフェニル)セリン(I)(ドロキシドパ)。
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- 2017-03-28 EP EP17773401.9A patent/EP3436426A4/en not_active Withdrawn
- 2017-03-28 JP JP2018551796A patent/JP2019511512A/ja active Pending
- 2017-03-28 US US16/088,196 patent/US11447443B2/en active Active
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WO2017168313A1 (en) | 2017-10-05 |
EP3436426A1 (en) | 2019-02-06 |
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