CN110627704A - 巴多昔芬的制备方法 - Google Patents
巴多昔芬的制备方法 Download PDFInfo
- Publication number
- CN110627704A CN110627704A CN201910541125.8A CN201910541125A CN110627704A CN 110627704 A CN110627704 A CN 110627704A CN 201910541125 A CN201910541125 A CN 201910541125A CN 110627704 A CN110627704 A CN 110627704A
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- Prior art keywords
- benzyloxy
- benzyloxyphenyl
- bazedoxifene
- compound
- 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.)
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- UCJGJABZCDBEDK-UHFFFAOYSA-N bazedoxifene Chemical compound C=1C=C(OCCN2CCCCCC2)C=CC=1CN1C2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C=C1 UCJGJABZCDBEDK-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229960000817 bazedoxifene Drugs 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 42
- KRIJKJMYOVWRSJ-UHFFFAOYSA-N 3-methyl-5-phenylmethoxy-2-(4-phenylmethoxyphenyl)-1h-indole Chemical compound C1=C2C(C)=C(C=3C=CC(OCC=4C=CC=CC=4)=CC=3)NC2=CC=C1OCC1=CC=CC=C1 KRIJKJMYOVWRSJ-UHFFFAOYSA-N 0.000 claims abstract description 39
- OMZAMQFQZMUNTP-UHFFFAOYSA-N acetic acid;1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methylindol-5-ol Chemical compound CC(O)=O.C=1C=C(OCCN2CCCCCC2)C=CC=1CN1C2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C=C1 OMZAMQFQZMUNTP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229960003713 bazedoxifene acetate Drugs 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 23
- UGZZBGXKDUQXDF-UHFFFAOYSA-N 2-morpholin-4-yl-1-(4-phenylmethoxyphenyl)propan-1-one Chemical compound C(C1=CC=CC=C1)OC1=CC=C(C=C1)C(C(C)N1CCOCC1)=O UGZZBGXKDUQXDF-UHFFFAOYSA-N 0.000 claims description 22
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 17
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- NXAHBBRIVLXMQA-UHFFFAOYSA-N 1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-3-methyl-5-phenylmethoxy-2-(4-phenylmethoxyphenyl)indole Chemical compound C=1C=C(OCCN2CCCCCC2)C=CC=1CN1C2=CC=C(OCC=3C=CC=CC=3)C=C2C(C)=C1C(C=C1)=CC=C1OCC1=CC=CC=C1 NXAHBBRIVLXMQA-UHFFFAOYSA-N 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- FGCIQSBZGOVNLI-UHFFFAOYSA-N 1-[2-[4-(chloromethyl)phenoxy]ethyl]azepane Chemical compound C1=CC(CCl)=CC=C1OCCN1CCCCCC1 FGCIQSBZGOVNLI-UHFFFAOYSA-N 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 238000006674 Bischler reaction Methods 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- 239000000543 intermediate Substances 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 12
- 239000012535 impurity Substances 0.000 description 12
- -1 heterocyclic alkylamines Chemical class 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- LSQLSCUJBXFBRB-UHFFFAOYSA-N 2-bromo-1-(4-phenylmethoxyphenyl)propan-1-one Chemical compound C1=CC(C(=O)C(Br)C)=CC=C1OCC1=CC=CC=C1 LSQLSCUJBXFBRB-UHFFFAOYSA-N 0.000 description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- IKFGSOJYHVTNDV-UHFFFAOYSA-N 1-(4-phenylmethoxyphenyl)propan-1-one Chemical compound C1=CC(C(=O)CC)=CC=C1OCC1=CC=CC=C1 IKFGSOJYHVTNDV-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- FIIDVVUUWRJXLF-UHFFFAOYSA-N 4-phenylmethoxyaniline Chemical compound C1=CC(N)=CC=C1OCC1=CC=CC=C1 FIIDVVUUWRJXLF-UHFFFAOYSA-N 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- RARSHUDCJQSEFJ-UHFFFAOYSA-N p-Hydroxypropiophenone Chemical compound CCC(=O)C1=CC=C(O)C=C1 RARSHUDCJQSEFJ-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical class [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- VKFANSPRVJYBAA-UHFFFAOYSA-N n-phenylmethoxyaniline;hydrochloride Chemical compound Cl.C=1C=CC=CC=1CONC1=CC=CC=C1 VKFANSPRVJYBAA-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- KQBDLOVXZHOAJI-UHFFFAOYSA-N (4-phenylmethoxyphenyl)azanium;chloride Chemical compound Cl.C1=CC(N)=CC=C1OCC1=CC=CC=C1 KQBDLOVXZHOAJI-UHFFFAOYSA-N 0.000 description 3
- XAWIJTNBVSPOPV-UHFFFAOYSA-N 1-(4-phenylmethoxyphenyl)-2-piperidin-1-ylpropan-1-one Chemical compound C(C1=CC=CC=C1)OC1=CC=C(C=C1)C(C(C)N1CCCCC1)=O XAWIJTNBVSPOPV-UHFFFAOYSA-N 0.000 description 3
- WBHWZTRUJMDNPU-UHFFFAOYSA-N 1-(4-phenylmethoxyphenyl)-2-pyrrolidin-1-ylpropan-1-one Chemical compound C(C1=CC=CC=C1)OC1=CC=C(C=C1)C(C(C)N1CCCC1)=O WBHWZTRUJMDNPU-UHFFFAOYSA-N 0.000 description 3
- MDPAFFFAYMYOCG-UHFFFAOYSA-N 2-(diethylamino)-1-(4-phenylmethoxyphenyl)propan-1-one Chemical compound C(C1=CC=CC=C1)OC1=CC=C(C=C1)C(C(C)N(CC)CC)=O MDPAFFFAYMYOCG-UHFFFAOYSA-N 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical compound BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 150000001448 anilines Chemical class 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 2
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- NNFOTEQKNPUXGR-UHFFFAOYSA-N 1-(4-phenylmethoxyphenyl)propan-2-one Chemical compound C1=CC(CC(=O)C)=CC=C1OCC1=CC=CC=C1 NNFOTEQKNPUXGR-UHFFFAOYSA-N 0.000 description 1
- CIRFNKPOUGQGOF-UHFFFAOYSA-N 1-phenyl-2-(4-phenylmethoxyphenyl)propan-1-one Chemical compound C(C1=CC=CC=C1)OC1=CC=C(C=C1)C(C(=O)C1=CC=CC=C1)C CIRFNKPOUGQGOF-UHFFFAOYSA-N 0.000 description 1
- LAOHJLHFQSYRBG-UHFFFAOYSA-N 2-(4-phenylmethoxyanilino)-1-(4-phenylmethoxyphenyl)propan-1-one Chemical compound C=1C=C(OCC=2C=CC=CC=2)C=CC=1C(=O)C(C)NC(C=C1)=CC=C1OCC1=CC=CC=C1 LAOHJLHFQSYRBG-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- 238000008214 LDL Cholesterol Methods 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 230000008416 bone turnover Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000004803 chlorobenzyl group Chemical group 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000003799 water insoluble solvent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
- C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
本发明涉及制备巴多昔芬的方法,特别涉及制备式(5)的3‑甲基‑5‑苄氧基‑2‑(4‑苄氧基苯基)‑1H‑吲哚的方法,该化合物是用于合成巴多昔芬和醋酸巴多昔芬的中间体。
Description
发明领域
本发明涉及制备化合物3-甲基-5-苄氧基-2-(4-苄氧基苯基)-1H-吲哚(5)的方法,该化合物是合成巴多昔芬及其类似物的中间体。
发明背景
式(1)的醋酸巴多昔芬(1-[4-(2-氮杂环庚烷-1-基-乙氧基)苄基]-2-(4-羟基苯基)-3-甲基-5-羟基吲哚醋酸盐)是选择性雌激素受体调节剂(SERM),在欧洲注册用于治疗骨折风险增加的女性绝经后骨质疏松症。
取决于细胞和组织的类型,该化合物充当受体激动剂和/或拮抗剂。它在骨(骨转换和再吸收的生化标志物的减少)和肝脏(LDL胆固醇和脂蛋白的减少)中具有雌激素样作用,在子宫内膜和乳房中具有抗雌激素作用。目前正在研究其在乳腺癌和胰腺癌治疗中的潜在用途。
巴多昔芬及其盐的制备记载于众多专利文献,例如US 5998402、US 6479535、US6005102、EP 0802183 B1、EP 1025077 B、WO 2011022596 A2和WO2008/098527 A1,以及出版物Journal of Medicinal Chemistry,Vol 44,1564-1567,2001中。
所记载的大多数合成的关键中间体是通过方案1中描述的合成方法获得的化合物3-甲基-5-苄氧基-2-(4-苄氧基苯基)-1H-吲哚(5),其中关键步骤是式(4)的1-(4-苄氧基苯基)-2-(4-苄氧基苯基氨基)丙-1-酮与式(2)的4-苄氧基苯胺盐酸盐之间的Bischler-反应。式(4)的化合物又得自苄氧基苯胺盐酸盐(2)和式(3)的4-苄氧基苯基-2-溴丙-1-酮。
WO2008/098527 A1描述了通过将式(3)的溴衍生物与式(2)的苯胺反应制备式(5)化合物的方法,其中分离式(4)的中间体1-(4-苄氧基苯基)-2-(4-苄氧基苯基氨基)丙-1-酮然后与式(2)的化合物进行Bischler-反应。
然后通过方案2中描述的合成方法将中间体(5)转化为醋酸巴多昔芬,其包括用式(6)的1-[2-[4-(氯甲基)苯氧基]乙基]氮杂环庚烷将(5)烷基化,得到中间体(7)。将(7)催化氢化得到巴多昔芬(8),最后将其用醋酸成盐得到(1)。
Bischler-反应是用于从α-溴-烷基-芳基酮如α-溴苯乙酮或α-溴苯丙酮和过量的(每当量溴酮至少2摩尔当量)苯胺制备2-芳基-吲哚的通用方法(Bischler,A.;Brion,H.Ber.Dtsch.Chem.Ges.1892,25,2860-2879;Bischler,A.;Fireman,P.Ber.Dtsch.Chem.Ges.1893,26,1336-1349)。
最初开发的方法需要相当剧烈的反应条件,因此开发了涉及较温和条件的变化形式,例如使用溴化锂作为催化剂或用微波辐射。合成的变化形式也是已知的,其允许通过缩醛环化制备在2和3位未被取代的吲哚(Pchalek,K.等人,Tetrahedron 2005,61,77-82;Sridharan,V.等人,Synlett2006,91-95;Nordlander,J.E.等人,J.Org.Chem.1981,46,778-782;Sundberg,R.J.等人,J.Org.Chem.1984,49,249-254)。
除了α-苯胺酮,例如方案1中描述的未分离的或在WO2008/098527中分离的中间体(4)(它们是利用Bischler-反应合成2-芳基-吲哚的经典中间体)外,迄今为止在文献中描述的这种反应的唯一中间体(无论是否分离)是α-铵酮或α-吡啶酮。迄今已知的用于Bischler-合成的中间体的通式结构如方案3中所示。
利用在α位被伯或仲脂族/脂环族胺取代的芳基-烷基酮中间体(例如α-单烷基氨基或α-双烷基氨基苯乙酮或苯丙酮)或在α位被杂环烷基胺取代的芳基-烷基酮中间体通过Bischler-反应来获得吲哚类化合物、特别是式(5)的化合物,是未知的。
发明概述
现已发现,式(I)的化合物是用于制备化合物3-甲基-5-苄氧基-2-(4-苄氧基苯基)-1H-吲哚(5)的中间体,而该化合物是用于合成巴多昔芬(8)和醋酸巴多昔芬(1)的中间体
其中R1和R2彼此独立地选自氢、C1-C4烷基和C3-C7环烷基,条件是R1和R2不都是氢;或者R1和R2与它们键合的氮原子一起形成选自吡咯烷、哌啶和吗啉的杂环烷基环。
发明详述
本发明涉及合成巴多昔芬(8)或醋酸巴多昔芬(1)的方法,该方法包括如下步骤:
a)使式(I)化合物
其中R1和R2彼此独立地选自氢、C1-C4烷基和C3-C7环烷基,条件
是R1和R2不都是氢;或者R1和R2与它们键合的氮原子一起形成
选自吡咯烷、哌啶和吗啉的杂环烷基环;
与式(II)化合物进行Bischler-反应
其中X-表示有机或无机酸的阴离子;
生成式(5)的化合物3-甲基-5-苄氧基-2-(4-苄氧基苯基)-1H-吲哚
b)通过已知的方法将(5)转化成巴多昔芬(8)或醋酸巴多昔芬(1)。
在本发明的一个实施方案中,R1和R2与它们键合的氮原子一起形成如上所定义的杂环烷基环。
在本发明的一个优选实施方案中,R1和R2与它们键合的氮原子一起形成吗啉环。
式(I)化合物的制备方法总结于下面的方案4中,其中,将4-苄氧基苯基苯丙酮(9)与溴化剂反应,得到式(3)的4-苄氧基苯基-2-溴丙-2-酮。然后将溴代酮(3)与式(IV)的伯胺或仲胺反应,其中R1和R2如式(I)化合物所定义,得到式(I)化合物。化合物(I)可以任选地进行分离,或者可以在Bischler-反应的经典条件下就地与式(II)化合物反应,得到式(5)化合物。
通过用于溴化与羰基相邻的亚甲基的常规方法将4-苄氧基苯丙酮(9)转化为4-苄氧基苯基-2-溴丙-1-酮(3),例如在路易斯酸如三氯化铝的存在下、在选自甲苯、甲醇或其混合物的溶剂中与溴反应。溴代酮(3)与胺(IV)的反应通常以每摩尔当量(3)至少两摩尔当量的(IV)的比例,在不存在溶剂的情况下或在选自甲苯、氯苯、乙酸乙酯、N,N-二甲基甲酰胺和N,N-二甲基乙酰胺的溶剂中进行,优选甲苯。反应优选在不存在溶剂的情况下进行。
式(I)化合物与式(II)化合物之间的Bischler-反应可在通常用于所述反应的溶剂中进行,例如N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、甲苯和氯苯,在所述溶剂的回流温度下操作。本申请的发明人发现,使用氯苯代替通常用于该步骤的溶剂DMF,可以防止形成苯胺(II)的N-甲酰基衍生物,这是由DMF在环化所需的高温下分解所引起的。所述N-甲酰基衍生物代表需要从最终产物中除去的额外杂质,并且最重要的是,其从反应中除去了苯胺(II)。特别优选使用氯苯。
在本发明的方法中,相对于式(I)化合物,通常使用1.1摩尔当量的苯胺衍生物(II)来制备式(5)化合物,而不是以α-溴-烷基-芳基酮为原料的经典方法所需的2.2当量。
此外,用于进行Bischler-环化的式(I)化合物由脂族胺、环脂族胺或杂环烷基胺获得,它们比通常用于制备α-苯胺酮中间体的苯胺衍生物便宜。
如果在进行环化之前分离式(I)的中间体,则式(5)化合物的产率和纯度大于通过经典方法获得的产率和纯度。
如果不分离中间体(I),则式(5)化合物的产率和纯度与经典方法的产率和纯度相当,但无论如何,鉴于上述因素,本发明的方法在经济上是有利的。
1-(4-苄氧基苯基)丙-1-酮(9)可通过将式(10)的1-(4-羟基苯基)丙-1-酮与氯苄反应制备
该反应通常在烷基化苯酚基团的经典条件下,在有机溶剂如甲苯、氯苯或DMF中进行,或在相转移条件下在水和不溶于水的溶剂如甲苯或氯苯的混合物中、在存在或不存在2-甲氧基乙醇的情况下,在四烷基卤化铵的存在下进行。反应在有机或无机碱如碱金属或碱土金属氢氧化物或碳酸盐、醇盐或碱金属氢化物存在下进行。步骤a)优选在四丁基溴化铵存在下,使用氢氧化钠作为碱,在水和甲苯的混合物中进行。
在本发明的一个实施方案中,式(I)化合物选自:
1-(4-苄氧基苯基)-2-(哌啶-1-基)丙-1-酮;
1-(4-苄氧基苯基)-2-(吡咯烷-1-基)丙-1-酮;
1-(4-苄氧基苯基)-2-(吗啉-4-基)丙-1-酮;
1-(4-苄氧基苯基)-2-二乙基氨基丙-1-酮;
1-(4-苄氧基苯基)-2-环己基氨基丙-1-酮。
在本发明的一个实施方案中,式(I)化合物是1-(4-苄氧基苯基)-2-(吗啉-4-基)丙-1-酮。
3-甲基-5-苄氧基-2-(4-苄氧基苯基)-1H-吲哚(5)可以通过制备巴多昔芬(8)或醋酸巴多昔芬(1)所述的任何方法,例如通过上述方案2中描述的方法转化为巴多昔芬(8)或醋酸巴多昔芬(1),包括如下步骤:
-将3-甲基-5-苄氧基-2-(4-苄氧基苯基)-1H-吲哚(5)用1-[2-[4-(氯甲基)苯氧基]乙基]氮杂环庚烷(6)进行N-烷基化,得到化合物1-{4-[2-(氮杂环庚烷-1-基)乙氧基]苄基}-5-(苄氧基)-2-[4-(苄氧基)苯基]-3-甲基-1H-吲哚(7);
-从化合物(7)中除去苄氧基,得到巴多昔芬(8),并任选地将其转化为醋酸盐(1)。
在一个实施方案中,在本发明的制备巴多昔芬或醋酸巴多昔芬的方法中,化合物3-甲基-5-苄氧基-2-(4-苄氧基苯基)-1H-吲哚(5)由选自以下的化合物获得:
1-(4-苄氧基苯基)-2-(哌啶-1-基)丙-1-酮;
1-(4-苄氧基苯基)-2-(吡咯烷-1-基)丙-1-酮;
1-(4-苄氧基苯基)-2-(吗啉-4-基)丙-1-酮;
1-(4-苄氧基苯基)-2-二乙基氨基丙-1-酮;
1-(4-苄氧基苯基)-2-环己基氨基丙-1-酮。
在本发明的制备巴多昔芬或醋酸巴多昔芬的方法中,化合物3-甲基-5-苄氧基-2-(4-苄氧基苯基)-1H-吲哚(5)优选由1-(4-苄氧基苯基)-2-(吗啉-4-基)丙-1-酮获得。
如在本申请的对比例中详细描述的,本发明的制备中间体(5)的方法与WO2008/098527中描述的方法相比具有许多优点,在分离的化合物(5)的纯度方面远远优于后者,并且更易于在工业规模上进行。
具体地讲,按照WO2008/098527中描述的方法获得的中间体(5)的HPLC纯度(总杂质3.35%)比通过本发明的方法获得的中间体(总杂质0.24-0.29%)低得多。应注意,根据WO2008/098527获得的中间体(5)中存在的主要杂质是4-苄氧基苯胺,这是一种潜在的遗传毒性杂质。其含量为1.97%,远高于通过本发明方法获得的中间体(5)中的含量(0.01%)。
此外,WO2008/098527的方法在N-(4-苄氧基苯基)-α-氨基-4-苄氧基苯丙酮(4)的制备步骤中涉及两次过滤,并且随后的Bischler-反应在异丙醇中于110-115℃,或在压力(3-4巴)下进行,而本发明的方法仅涉及一次式(I)化合物的分离,并且Bischler-反应在大气压下进行,因此在更安全的条件下进行。
最后,本发明方法的式(I)中间体用脂族胺、环脂族胺或杂环烷基胺获得,它们均为液体,而WO2008/098527的中间体(4)为固体。在制备本发明的式(I)中间体、特别是其中NR1R2代表吗啉环的中间体(I)(化合物11)的情况下,易于除去过量的胺(吗啉)。相反,用于制备WO2008/098527的中间体(4)的4-苄氧基苯胺是难以除去的固体,即使经过三次分离,其在由WO2008/098527的方法获得的吲哚中的含量仍接近2%,而在通过本发明的方法获得的吲哚(5)中,其含量为0.01%。技术优势显而易见。
本发明的另一主题是式(I)化合物1-(4-苄氧基苯基)-2-(吗啉-4-基)丙-1-酮(11)。
现在通过以下实施例说明本发明。
实施例1:1-(4-苄氧基苯基)-2-(吗啉-4-基)丙-1-酮(11)的制备
步骤I:4-苄氧基苯丙酮的制备
将蒸馏水(15Kg)、氢氧化钠(4.50Kg;0.1125摩尔)、甲苯(57.0Kg)、4-羟基苯丙酮(15.0Kg;0.10摩尔)和四丁基溴化铵(0.75Kg)装入反应器中。将物料回流加热(约90℃),然后加入氯苄(14.25Kg;0.1125摩尔)。将物料保持回流直至完全转化,然后分离并除去水相。将得到的甲苯溶液冷却至15-25℃,不经进一步处理直接送至下一步骤。
步骤II:4-苄氧基-α-溴苯丙酮的制备
将步骤I中由15.0Kg 4-羟基苯丙酮得到的4-苄氧基-苯丙酮的全部甲苯溶液、甲醇(24.0Kg)和催化量的氯化铝加入反应器中。将物料加热至40-45℃,并在保持所述温度的同时,倒入溴(17.25Kg;0.108摩尔)。倾倒后,将物料保持在40-45℃直至完全转化,然后加入蒸馏水。
分离并除去下层水相,得到的甲苯溶液不经进一步处理直接送至下一步骤。
步骤III:1-(4-苄氧基苯基)-2-(吗啉-4-基)丙-1-酮的制备
将步骤II中由15.0Kg(0.10摩尔)4-羟基苯丙酮得到的4-苄氧基-α-溴苯丙酮的全部甲苯溶液和吗啉(18.0Kg;0.2066摩尔)加入到反应器中。将物料回流加热(约110℃)2小时,然后向物料中加入蒸馏水。分离水相并弃去。
真空蒸馏有机相直至得到油状残余物,然后倒入甲醇(90Kg)。将物料在55-65℃搅拌直至完全溶解,将其冷却至10℃。将沉淀的物质离心,用甲醇洗涤并干燥。得到26.0Kg 1-(4-苄氧基苯基)-2-(吗啉-4-基)丙-1-酮。产率:80.0%,基于步骤I中使用的4-羟基苯丙酮的Kg数计算。
HPLC分析显示总杂质含量为0.64%。
实施例2
按照实施例1中描述的方法,用选自哌啶、吡咯烷、二乙胺和环己胺的胺代替步骤III中的吗啉,制得下列产物:
1-(4-苄氧基苯基)-2-(哌啶-1-基)丙-1-酮;
1-(4-苄氧基苯基)-2-(吡咯烷-1-基)丙-1-酮;
1-(4-苄氧基苯基)-2-二乙基氨基丙-1-酮;
1-(4-苄氧基苯基)-2-环己基氨基丙-1-酮。
实施例3:1-(4-苄氧基苯基)-2-(吗啉-4-基)丙-1-酮(11)的制备
重复实施例1中描述的方法,在步骤II中分离4-苄氧基-α-溴苯丙酮(3),然后使其与吗啉反应。
得到1-(4-苄氧基苯基)-2-(吗啉-4-基)丙-1-酮(11),产率为90.2%。
HPLC分析显示总杂质含量为0.12%。
实施例4:3-甲基-5-苄氧基-2-(4-苄氧基苯基)-1H-吲哚(5)的制备
将实施例1中得到的1-(4-苄氧基苯基)-2-(吗啉-4-基)丙-1-酮(26.0Kg;0.08摩尔)、氯苯(104Kg)和4-(苄氧基)苯胺盐酸盐(20.8Kg;0.088摩尔)加入到反应器中。将物料在125-130℃下加热8小时。然后将物料冷却至80-90℃并向其中加入蒸馏水。分离下层有机相,除去上层水相。将有机相蒸馏得到残余物,然后加入甲醇(104Kg)。将物料冷却至20-25℃,然后离心,用甲醇洗涤。干燥后,得到28.0Kg 3-甲基-5-(苄氧基)-2-(4-苄氧基苯基)-1H-吲哚。收率:83.5%。
HPLC分析显示总杂质含量为0.24%。
4-(苄氧基)苯胺含量为0.01%。
实施例5:3-甲基-5-苄氧基-2-(4-苄氧基苯基)-1H-吲哚(5)的制备
重复实施例4中描述的方法,使用实施例3中得到的1-(4-苄氧基苯基)-2-(吗啉-4-基)丙-1-酮(11)作为起始产物。
3-甲基-5-苄氧基-2-(4-苄氧基苯基)-1H-吲哚(5)的产率相对于中间体(11)为83.5%,相对于溴衍生物(3)为75%。
HPLC分析显示总杂质含量为0.29%。
4-(苄氧基)苯胺含量为0.01%。
实施例6
重复实施例4中描述的方法,使4-苄氧基苯胺盐酸盐与实施例2中得到的α-氨基苯丙酮反应,得到化合物3-甲基-5-苄氧基-2-(4-苄氧基苯基)-1H-吲哚(5)。
实施例7:醋酸巴多昔芬的制备
步骤I:1-{4-[2-(氮杂环庚烷-1-基)乙氧基]苄基}-5-(苄氧基)-2-[4-(苄氧基)苯基]-3-甲基-1H-吲哚的制备
将60%氢化钠(6.0Kg;0.15摩尔)和N,N-二甲基乙酰胺(10.0Kg)加入中和的反应器中。将温度调节至0-10℃,然后向其中滴加另外制备的3-甲基-5-(苄氧基)-2-(4-苄氧基苯基)-1H-吲哚(25.0Kg,0.0596摩尔)和N,N-二甲基乙酰胺(37.5Kg)的溶液。然后向其中倒入通过溶解1-{2-[4-(氯甲基)苯氧基]乙基}六氢-1H-氮杂盐酸盐(20.0Kg;0.0657摩尔)和N,N-二甲基乙酰胺另外制备的溶液。倒入后,将物料在0-10℃保持30分钟,然后加入甲苯(50Kg)和水。将物料加热至70℃,然后分离并除去下层水相。加入甲醇(175Kg),将混合物冷却至20-25℃并离心,用甲醇(50Kg)洗涤。干燥后,得到约32.0kg 1-{4-[2-(氮杂环庚烷-1-基)乙氧基]苄基}-5-(苄氧基)-2-[4-(苄氧基)苯基]-3-甲基-1H-吲哚。收率:82.6%。
步骤II:醋酸巴多昔芬的制备
将1-{4-[2-(氮杂环庚烷-1-基)乙氧基]苄基}-5-(苄氧基)-2-[4-(苄氧基)苯基]-3-甲基-1H-吲哚(28.0Kg;0.043摩尔)、四氢呋喃(140Kg)和5%Pd/C(2.80Kg)加入反应器中。将混合物在60℃和4atm的氢气压力下氢化8小时,然后过滤催化剂。将过滤的溶液在真空下蒸馏,并向得到的油状残余物中加入蒸馏水(22.4Kg)、乙酸乙酯(67.2Kg)和80%乙酸(3.64Kg;0.0485摩尔)。将混合物冷却至20-30℃以获得良好的沉淀,然后冷却至0-5℃并离心,用蒸馏水(22.4Kg)和乙酸乙酯(22.4Kg)洗涤。得到约20.6kg醋酸巴多昔芬。产率:90.3%。
对比例1:N-(4-苄氧基苯基)-α-氨基-4-苄氧基苯丙酮(4)的制备
按照WO2008/098527第7页的实施例2、即报告所述产物的最高产率的实施例中所述制备N-(4-苄氧基苯基)-α-氨基-4-苄氧基苯丙酮(4)。
在两次制备(对比例1A和对比例1B)中,在反应5小时并通过两次过滤分离后,得到产物(4),产率分别为89.8%和92%,总杂质含量分别为0.23%和0.26%。
对比例2:3-甲基-5-苄氧基-2-(4-苄氧基苯基)-1H-吲哚(5)的制备
按照WO2008/098527第9页的实施例2、即报告所述产物的最高产率的实施例中所述,将对比例1中获得的产物(4)转化为式(5)的化合物。反应在异丙醇中于110-115℃,在压力(3-4巴)下进行。
在WO2008/098527中关于4(由对比例1A获得)与4-苄氧基苯胺盐酸盐的反应所示的5小时的反应时间后,反应不完全,并且以低产率分离得到产物(5),其相对于(4)的产率为62.4%,相对于溴衍生物(3)的产率为56%,并且HPLC纯度非常低(所有杂质的总和为27.3%)(对比例2A)。
通过增加反应时间直至获得完全转化(远超过15小时),以与本发明方法相当的收率得到化合物(5)(相对于对比例1B中得到的(4)为86.1%,相对于溴衍生物(3)为79.2%),但其HPLC纯度低得多(所有杂质的总和为3.35%,4-苄氧基苯胺含量为1.97%)(对比例2B)。
表1比较了本发明的中间体1-(4-苄氧基苯基)-2-(吗啉-4-基)丙-1-酮(11)(实施例1和3)和WO2008/098527(对比例1)的中间体N-(4-苄氧基苯基)-α-氨基-4-苄氧基苯丙酮(4)的产率和纯度。
表2比较了通过本发明方法(实施例4和5)或通过WO2008/098527(对比例2)所述的方法获得的产物3-甲基-5-苄氧基-2-(4-苄氧基苯基)-1H-吲哚(5)的产率和纯度。
表1
*分离中间体(3)以达到与WO2008/098527相同的条件
Claims (7)
1.合成巴多昔芬或醋酸巴多昔芬的方法,包括如下步骤:
a)使式(I)化合物
其中R1和R2彼此独立地选自氢、C1-C4烷基和C3-C7环烷基,条件是R1和R2不都是氢;或者R1和R2与它们键合的氮原子一起形成选自吡咯烷、哌啶和吗啉的杂环烷基环;
与式(II)化合物进行Bischler-反应
其中X-表示有机或无机酸的阴离子;
生成式(5)的化合物3-甲基-5-苄氧基-2-(4-苄氧基苯基)-1H-吲哚
b)通过已知的方法将(5)转化成巴多昔芬或醋酸巴多昔芬。
2.权利要求1所述的方法,其中R1和R2与它们键合的氮原子一起形成如上所定义的杂环烷基环。
3.权利要求2所述的方法,其中R1和R2与它们键合的氮原子一起形成吗啉环。
4.前述权利要求任意一项所述的方法,其中X-是氯或溴阴离子。
5.前述权利要求任意一项所述的方法,其中X-是氯阴离子。
6.前述权利要求任意一项所述的方法,其中式(I)化合物向巴多昔芬或醋酸巴多昔芬的转化包括如下步骤:
-将3-甲基-5-苄氧基-2-(4-苄氧基苯基)-1H-吲哚(5)用1-[2-[4-(氯甲基)苯氧基]乙基]氮杂环庚烷(6)进行N-烷基化,得到化合物1-{4-[2-(氮杂环庚烷-1-基)乙氧基]苄基}-5-(苄氧基)-2-[4-(苄氧基)苯基]-3-甲基-1H-吲哚(7);
-从化合物(7)中除去苄氧基,得到巴多昔芬(8),并任选地将其转化为醋酸盐(1)。
7.化合物1-(4-苄氧基苯基)-2-(吗啉-4-基)丙-1-酮(11)
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB933507A (en) * | 1960-04-07 | 1963-08-08 | Thomae Gmbh Dr K | ª -pyrrolidino-ketones |
EP0802183A1 (en) * | 1996-04-19 | 1997-10-22 | American Home Products Corporation | Estrogenic agents |
WO1999019293A1 (en) * | 1997-10-15 | 1999-04-22 | American Home Products Corporation | Novel aryloxy-alkyl-dialkylamines |
US5998402A (en) * | 1996-04-19 | 1999-12-07 | American Home Products Corporation | 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents |
US6005102A (en) * | 1997-10-15 | 1999-12-21 | American Home Products Corporation | Aryloxy-alkyl-dialkylamines |
US6380166B1 (en) * | 1999-09-13 | 2002-04-30 | American Home Products Corporation | Glucopyranosides conjugates of 2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2-amin-1-yl-ethoxy)-benzyl]-1H-indol-5-ols |
WO2008098527A1 (en) * | 2007-02-12 | 2008-08-21 | Zentiva A.S. | Method for the preparation of 5-benzyloxy-2-(4-benzyloxphenyl)-3-methyl-1h-indole |
CN104098499A (zh) * | 2013-04-08 | 2014-10-15 | 上海医药工业研究院 | 5-苄氧基-2-(4-苄氧基苯基)-3-甲基-1h-吲哚的制备方法 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PT1076558E (pt) * | 1998-05-15 | 2003-11-28 | Wyeth Corp | 2-fenil-1-¬4-(2-aminoetoxi)-benzil|-indole em combinacao com estrogenios |
-
2018
- 2018-06-21 IT IT102018000006562A patent/IT201800006562A1/it unknown
-
2019
- 2019-06-19 US US16/445,474 patent/US10844047B2/en active Active
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Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB933507A (en) * | 1960-04-07 | 1963-08-08 | Thomae Gmbh Dr K | ª -pyrrolidino-ketones |
EP0802183A1 (en) * | 1996-04-19 | 1997-10-22 | American Home Products Corporation | Estrogenic agents |
US5998402A (en) * | 1996-04-19 | 1999-12-07 | American Home Products Corporation | 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents |
WO1999019293A1 (en) * | 1997-10-15 | 1999-04-22 | American Home Products Corporation | Novel aryloxy-alkyl-dialkylamines |
US6005102A (en) * | 1997-10-15 | 1999-12-21 | American Home Products Corporation | Aryloxy-alkyl-dialkylamines |
US6380166B1 (en) * | 1999-09-13 | 2002-04-30 | American Home Products Corporation | Glucopyranosides conjugates of 2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2-amin-1-yl-ethoxy)-benzyl]-1H-indol-5-ols |
WO2008098527A1 (en) * | 2007-02-12 | 2008-08-21 | Zentiva A.S. | Method for the preparation of 5-benzyloxy-2-(4-benzyloxphenyl)-3-methyl-1h-indole |
CN104098499A (zh) * | 2013-04-08 | 2014-10-15 | 上海医药工业研究院 | 5-苄氧基-2-(4-苄氧基苯基)-3-甲基-1h-吲哚的制备方法 |
Non-Patent Citations (2)
Title |
---|
T. TAKASHI: "Local anesthetic action of the propiophenone derivatives", FOLIA PHARMACOLOGICA JAPONICA NIPPON YAKURIGAKU ZASSHI, vol. 58, no. 1, pages 76 * |
W. CHITI. ET AL.: "Su Alcuni nuovi derivati del p-ossipropiofenone ad attivita´anestetica locale", IL FARMACO EDIZIONE SCIENTIFICA, no. 12, pages 777 * |
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