JP2021526513A - ティピファニブの合成 - Google Patents
ティピファニブの合成 Download PDFInfo
- Publication number
- JP2021526513A JP2021526513A JP2020564572A JP2020564572A JP2021526513A JP 2021526513 A JP2021526513 A JP 2021526513A JP 2020564572 A JP2020564572 A JP 2020564572A JP 2020564572 A JP2020564572 A JP 2020564572A JP 2021526513 A JP2021526513 A JP 2021526513A
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- JP
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- Prior art keywords
- tipifanib
- mixture
- steps
- racemic
- water
- 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.)
- Withdrawn
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- 230000015572 biosynthetic process Effects 0.000 title description 16
- 238000003786 synthesis reaction Methods 0.000 title description 12
- 238000000034 method Methods 0.000 claims abstract description 137
- 239000000203 mixture Substances 0.000 claims description 115
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 90
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 88
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 75
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 66
- 150000003839 salts Chemical class 0.000 claims description 53
- 239000002904 solvent Substances 0.000 claims description 53
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 52
- 239000003960 organic solvent Substances 0.000 claims description 42
- 239000012452 mother liquor Substances 0.000 claims description 41
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 40
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 39
- 239000002253 acid Substances 0.000 claims description 34
- 230000008569 process Effects 0.000 claims description 33
- 239000007858 starting material Substances 0.000 claims description 31
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 30
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 24
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 229940011051 isopropyl acetate Drugs 0.000 claims description 20
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical group CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 20
- 239000007810 chemical reaction solvent Substances 0.000 claims description 19
- 150000001412 amines Chemical class 0.000 claims description 18
- 239000000654 additive Substances 0.000 claims description 17
- 238000002425 crystallisation Methods 0.000 claims description 15
- 230000008025 crystallization Effects 0.000 claims description 15
- 235000010288 sodium nitrite Nutrition 0.000 claims description 15
- 238000000605 extraction Methods 0.000 claims description 13
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 12
- 230000000996 additive effect Effects 0.000 claims description 9
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 claims description 8
- 239000013078 crystal Substances 0.000 claims description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 6
- 239000000908 ammonium hydroxide Substances 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims 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 abstract description 10
- AXGPLXKWYRKBHB-UHFFFAOYSA-N 4-(3-chlorophenyl)-1-methylquinolin-2-one Chemical compound C=1C(=O)N(C)C2=CC=CC=C2C=1C1=CC=CC(Cl)=C1 AXGPLXKWYRKBHB-UHFFFAOYSA-N 0.000 abstract 1
- 238000010586 diagram Methods 0.000 abstract 1
- 238000002474 experimental method Methods 0.000 description 91
- 238000006243 chemical reaction Methods 0.000 description 79
- 239000000047 product Substances 0.000 description 50
- 238000003756 stirring Methods 0.000 description 45
- 239000011541 reaction mixture Substances 0.000 description 41
- 239000000243 solution Substances 0.000 description 27
- 239000010410 layer Substances 0.000 description 14
- 238000011084 recovery Methods 0.000 description 14
- PLHJCIYEEKOWNM-UHFFFAOYSA-N 6-[amino-(4-chlorophenyl)-(3-methylimidazol-4-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2-one Chemical compound CN1C=NC=C1C(N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-UHFFFAOYSA-N 0.000 description 13
- 239000012535 impurity Substances 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 11
- 230000006340 racemization Effects 0.000 description 11
- MVODTGURFNTEKX-UHFFFAOYSA-N 2-bromo-n-(2-bromoethyl)-n-(thiophen-2-ylmethyl)ethanamine;hydrobromide Chemical compound Br.BrCCN(CCBr)CC1=CC=CS1 MVODTGURFNTEKX-UHFFFAOYSA-N 0.000 description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
- -1 1-methyl-1H-imidazol-5-yl Chemical group 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 230000010354 integration Effects 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000012369 In process control Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 239000002879 Lewis base Substances 0.000 description 4
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000010965 in-process control Methods 0.000 description 4
- 150000007527 lewis bases Chemical class 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 4
- 102000016914 ras Proteins Human genes 0.000 description 4
- 108010014186 ras Proteins Proteins 0.000 description 4
- 238000012552 review Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- QYEMNJMSULGQRD-UHFFFAOYSA-N 1-methyl-2-quinolone Chemical compound C1=CC=C2C=CC(=O)N(C)C2=C1 QYEMNJMSULGQRD-UHFFFAOYSA-N 0.000 description 3
- 239000007848 Bronsted acid Substances 0.000 description 3
- 239000003341 Bronsted base Substances 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 3
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 2
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 2
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 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 description 2
- NVPJTXMOQCANSN-UHFFFAOYSA-N Benzoylmalic acid Chemical compound OC(=O)CC(C(O)=O)OC(=O)C1=CC=CC=C1 NVPJTXMOQCANSN-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 235000012970 cakes Nutrition 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000003821 enantio-separation Methods 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
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- 150000004682 monohydrates Chemical class 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
- 229930185107 quinolinone Natural products 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000002689 soil Substances 0.000 description 2
- IUVCFHHAEHNCFT-INIZCTEOSA-N 2-[(1s)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one Chemical compound C1=C(F)C(OC(C)C)=CC=C1C(C1=C(N)N=CN=C11)=NN1[C@@H](C)C1=C(C=2C=C(F)C=CC=2)C(=O)C2=CC(F)=CC=C2O1 IUVCFHHAEHNCFT-INIZCTEOSA-N 0.000 description 1
- JVGORXTXJUDILP-UHFFFAOYSA-N 4-(3-chlorophenyl)-6-[(4-chlorophenyl)-hydroxy-(3-methylimidazol-4-yl)methyl]-1-methylquinolin-2-one;hydrochloride Chemical compound Cl.CN1C=NC=C1C(O)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 JVGORXTXJUDILP-UHFFFAOYSA-N 0.000 description 1
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 1
- IDKYCLCDTGIFBA-UHFFFAOYSA-N 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methylquinolin-2-one Chemical compound C=1C(=O)N(C)C2=CC=C(C(=O)C=3C=CC(Cl)=CC=3)C=C2C=1C1=CC=CC(Cl)=C1 IDKYCLCDTGIFBA-UHFFFAOYSA-N 0.000 description 1
- VFROHOLBLGBWQD-UHFFFAOYSA-N CN1C(C(c(cc2)ccc2Cl)(c(cc2)cc(C(c3cccc(Cl)c3)=C3)c2N(C)C3=O)O)=CNC1 Chemical compound CN1C(C(c(cc2)ccc2Cl)(c(cc2)cc(C(c3cccc(Cl)c3)=C3)c2N(C)C3=O)O)=CNC1 VFROHOLBLGBWQD-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 101710091417 DNA-binding protein TubR Proteins 0.000 description 1
- 102000007317 Farnesyltranstransferase Human genes 0.000 description 1
- 108010007508 Farnesyltranstransferase Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000005448 Trichomonas Infections Diseases 0.000 description 1
- 206010044620 Trichomoniasis Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- XXXHSQBVHSJQKS-UHFFFAOYSA-N amino benzoate Chemical compound NOC(=O)C1=CC=CC=C1 XXXHSQBVHSJQKS-UHFFFAOYSA-N 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- SXDQRQUWNQKZBL-UHFFFAOYSA-N butanedioic acid;hydrate Chemical compound O.OC(=O)CCC(O)=O SXDQRQUWNQKZBL-UHFFFAOYSA-N 0.000 description 1
- XSIFPSYPOVKYCO-UHFFFAOYSA-N butyl benzoate Chemical compound CCCCOC(=O)C1=CC=CC=C1 XSIFPSYPOVKYCO-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000021463 dry cake Nutrition 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
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- 108091005640 farnesylated proteins Proteins 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
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- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 description 1
- 238000010952 in-situ formation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000000622 liquid--liquid extraction Methods 0.000 description 1
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- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012663 orally bioavailable inhibitor Substances 0.000 description 1
- 229940044205 orally bioavailable inhibitor Drugs 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000004686 pentahydrates Chemical class 0.000 description 1
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- 230000003389 potentiating effect Effects 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
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- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B55/00—Racemisation; Complete or partial inversion
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- 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
-
- 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
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
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| US201862673693P | 2018-05-18 | 2018-05-18 | |
| US62/673,693 | 2018-05-18 | ||
| PCT/US2019/032765 WO2019222565A1 (en) | 2018-05-18 | 2019-05-17 | Synthesis of tipifarnib |
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| JP2021526513A true JP2021526513A (ja) | 2021-10-07 |
| JP2021526513A5 JP2021526513A5 (https=) | 2022-05-24 |
| JPWO2019222565A5 JPWO2019222565A5 (https=) | 2022-05-24 |
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| JP2020564572A Withdrawn JP2021526513A (ja) | 2018-05-18 | 2019-05-17 | ティピファニブの合成 |
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| EP (1) | EP3793966A1 (https=) |
| JP (1) | JP2021526513A (https=) |
| KR (1) | KR20210039987A (https=) |
| CN (1) | CN112424149B (https=) |
| AU (1) | AU2019270163A1 (https=) |
| BR (1) | BR112020023559A2 (https=) |
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| MX (1) | MX2020012305A (https=) |
| PH (1) | PH12020551956A1 (https=) |
| SG (1) | SG11202011378WA (https=) |
| WO (1) | WO2019222565A1 (https=) |
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| KR102839264B1 (ko) | 2023-03-07 | 2025-07-29 | 단국대학교 천안캠퍼스 산학협력단 | 티피파르닙을 유효성분으로 포함하는 근감소증 예방 또는 치료용 약학 조성물 |
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| ATE214695T1 (de) | 1994-09-23 | 2002-04-15 | Darwin Discovery Ltd | Racemisierungsverfahren bei der herstellung von levobupivacaine und analogen |
| AU702594B2 (en) * | 1995-10-13 | 1999-02-25 | Duphar International Research B.V. | Process for the preparation of enantiomerically pure imidazolyl compounds |
| DE69620445T2 (de) | 1995-12-08 | 2002-12-12 | Janssen Pharmaceutica N.V., Beerse | (imidazol-5-yl)methyl-2-chinolinoderivate als farnesyl protein transferase inhibitoren |
| BRPI0208075B8 (pt) * | 2001-03-12 | 2021-05-25 | Janssen Pharmaceutica Nv | processo para a preparação de compostos de imidazol |
| DE602005007604D1 (de) * | 2004-05-03 | 2008-07-31 | Janssen Pharmaceutica Nv | Diastereoselektive addition von lithiiertem n-methylimidazol an sulfinimine |
| JP5008554B2 (ja) * | 2004-05-03 | 2012-08-22 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | イミダゾール化合物の製造用のジアステレオ選択的合成方法 |
| CN100567291C (zh) * | 2004-05-03 | 2009-12-09 | 詹森药业有限公司 | 用6-溴-4-(3-氯苯基)-2-甲氧基喹啉进行的非对映选择性合成方法 |
| EP3221311B1 (en) * | 2014-11-21 | 2019-10-30 | Merck Patent GmbH | Method for the production of praziquantel |
| CN104876856B (zh) | 2015-05-05 | 2017-11-21 | 河北凯力昂生物科技有限公司 | 一种拆分法制备(r)‑(+)‑3‑氨基哌啶二盐酸盐的方法 |
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- 2019-05-17 EA EA202092787A patent/EA202092787A1/ru unknown
- 2019-05-17 KR KR1020207036324A patent/KR20210039987A/ko not_active Withdrawn
- 2019-05-17 CN CN201980047803.3A patent/CN112424149B/zh active Active
- 2019-05-17 AU AU2019270163A patent/AU2019270163A1/en not_active Abandoned
- 2019-05-17 JP JP2020564572A patent/JP2021526513A/ja not_active Withdrawn
- 2019-05-17 EP EP19728818.6A patent/EP3793966A1/en not_active Withdrawn
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| PH12020551956A1 (en) | 2021-08-16 |
| CA3100706A1 (en) | 2019-11-21 |
| US20210246114A1 (en) | 2021-08-12 |
| EA202092787A1 (ru) | 2021-02-09 |
| MX2020012305A (es) | 2021-03-25 |
| KR20210039987A (ko) | 2021-04-12 |
| AU2019270163A1 (en) | 2020-12-03 |
| CN112424149A (zh) | 2021-02-26 |
| CN112424149B (zh) | 2023-06-23 |
| EP3793966A1 (en) | 2021-03-24 |
| SG11202011378WA (en) | 2020-12-30 |
| US11542244B2 (en) | 2023-01-03 |
| WO2019222565A1 (en) | 2019-11-21 |
| BR112020023559A2 (pt) | 2021-02-09 |
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