CN113454066B - 制备6-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)尼克酰胺的工艺 - Google Patents
制备6-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)尼克酰胺的工艺 Download PDFInfo
- Publication number
- CN113454066B CN113454066B CN202080015876.7A CN202080015876A CN113454066B CN 113454066 B CN113454066 B CN 113454066B CN 202080015876 A CN202080015876 A CN 202080015876A CN 113454066 B CN113454066 B CN 113454066B
- Authority
- CN
- China
- Prior art keywords
- inb
- ind
- mixture
- phenoxyphenyl
- ina
- 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.)
- Active
Links
- -1 1-propenoylpiperidin-4-yl Chemical group 0.000 title claims abstract description 20
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims abstract description 6
- 235000005152 nicotinamide Nutrition 0.000 claims abstract description 6
- 239000011570 nicotinamide Substances 0.000 claims abstract description 6
- 229960003966 nicotinamide Drugs 0.000 claims abstract description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 25
- 239000003054 catalyst Substances 0.000 claims description 21
- 229910052763 palladium Inorganic materials 0.000 claims description 21
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 13
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 claims description 12
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 10
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- AJPKQSSFYHPYMH-UHFFFAOYSA-N 2,6-dichloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)N=C1Cl AJPKQSSFYHPYMH-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000011877 solvent mixture Substances 0.000 claims description 4
- 230000009435 amidation Effects 0.000 claims description 3
- 238000007112 amidation reaction Methods 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims 3
- 238000002360 preparation method Methods 0.000 abstract description 9
- 239000012467 final product Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- KRAWVHNDCSMBIP-UHFFFAOYSA-N C(C)(C)(C)OC(=O)N1CC=C(CC1)C1=NC(=C(C=C1)C(N)=O)C1=CC=C(C=C1)OC1=CC=CC=C1 Chemical compound C(C)(C)(C)OC(=O)N1CC=C(CC1)C1=NC(=C(C=C1)C(N)=O)C1=CC=C(C=C1)OC1=CC=CC=C1 KRAWVHNDCSMBIP-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- IXZKHCJOJAZJIV-UHFFFAOYSA-N NC(=O)c1ccc(nc1-c1ccc(Oc2ccccc2)cc1)C1CCNCC1 Chemical compound NC(=O)c1ccc(nc1-c1ccc(Oc2ccccc2)cc1)C1CCNCC1 IXZKHCJOJAZJIV-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 5
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- MUXGLQGODYPTNQ-UHFFFAOYSA-N NC(=O)c1ccc(Cl)nc1-c1ccc(Oc2ccccc2)cc1 Chemical compound NC(=O)c1ccc(Cl)nc1-c1ccc(Oc2ccccc2)cc1 MUXGLQGODYPTNQ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- MAEUHLKTSHMSHY-UHFFFAOYSA-N CC(C)(C)OC(=O)N1CCC(CC1)c1ccc(C(N)=O)c(n1)-c1ccc(Oc2ccccc2)cc1 Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)c1ccc(C(N)=O)c(n1)-c1ccc(Oc2ccccc2)cc1 MAEUHLKTSHMSHY-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- SOKPNCWUQMVNSB-UHFFFAOYSA-N 6-chloro-2-(4-phenoxyphenyl)pyridine-3-carboxylic acid Chemical compound ClC1=NC(=C(C(=O)O)C=C1)C1=CC=C(C=C1)OC1=CC=CC=C1 SOKPNCWUQMVNSB-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 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 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 239000012670 alkaline solution Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000010009 beating Methods 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- JDMFXJULNGEPOI-UHFFFAOYSA-N 2,6-dichloroaniline Chemical compound NC1=C(Cl)C=CC=C1Cl JDMFXJULNGEPOI-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 229940125814 BTK kinase inhibitor Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000005480 nicotinamides Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000002941 palladium compounds Chemical class 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
Abstract
本发明涉及大于1公斤的大量制备6‑(1‑丙烯酰基哌啶‑4‑基)‑2‑(4‑苯氧基苯基)尼克酰胺(化合物I)的工艺。该工艺提供了良好的产率和至少95%纯度的最终产物,并提供可控且安全的反应。
Description
发明领域
本发明涉及制备6-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)尼克酰胺的工艺。
本发明的背景
6-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)尼克酰胺(化合物I)是一种取代的尼克酰胺类Bruton酪氨酸激酶(BTK)抑制剂。化合物I可用于治疗癌症、炎症和自身免疫疾病(WO2015/028662)。WO2015/028662公开了制备约50克化合物I的方法。
现需要有效且可控制纯度的制备化合物I的工艺,特别是超过1公斤的大批量制备。
本发明的详细说明
本发明涉及高纯度和高产率地制备6-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)尼克酰胺(化合物I)的工艺。该工艺适用于大批量生产(超过1公斤、优选超过2公斤、超过4公斤、或超过10公斤)。该工艺提供化合物I的纯度≥90%、或≥95%、或≥98%、或≥99%。
化合物I
在第一个实施方案A中,化合物I由6-氯-2-(4-苯氧基苯基)尼克酰胺(INA)制备,并使用叔丁氧基羰基(t-Boc)作为保护基。该工艺包括以下步骤:
(a)INA、SMC和第一种钯催化剂的混合物在60~140℃下加热,得到INB,
其中PG为叔丁氧基羰基保护基;
(b)INB在H2下由第二种钯催化剂催化氢化,得到1NC;
(c)INC在HCl溶液中去保护,得到固体IND-HCl盐;
(d)IND-HCl盐与丙烯酰氯或3-氯丙酰氯在碱性条件下反应,得到6-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)尼克酰胺。
在步骤(a)中,在低氧含量(<2%)的氮气下的反应器中6-氯-2-(4-苯氧基苯基)尼克酰胺(INA)、4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(SMC)和一个合适的钯催化剂在碱性水/有机溶剂混合溶剂中反应,得到5-氨基甲酰基-6-(4-苯氧基苯基)-3′,6′-二氢-[2,4′-联吡啶]-1′(2′H)-羧酸叔丁酯(INB)粗品。反应温度为60~140℃,优选60~100℃,更优选75~85℃。反应时间通常为1~4小时。Pd负载量(Pd催化剂与反应物INA的摩尔比)为0.5-5%。较高的Pd负载量加速了反应,但也增加了成本和杂质。INB粗品可以不用柱层析而通过重结晶和/或打浆(例如用四氢呋喃和乙酸乙酯)进一步纯化至至少90%纯度。
在本申请中使用的合适的钯催化剂包括有机钯化合物,例如三(二亚苄基丙酮)二钯(0)(Pd2(dba)3)、四(三苯基膦)钯(0)、双(三苯基膦)钯(II)二氯化物(Pd(PPh3)2Cl2)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)(Pd(dppf)Cl2)和无机钯化合物,包括Pd(OAc)2和各种配体,例如Ph3P、Ph2CyP和Cy3P-HBF4。
在步骤(b)中,INB的有机溶液在反应器中氢气下通过合适的钯催化剂催化氢化,得到4-(5-氨基甲酰基-6-(4-苯氧基苯基)吡啶-2-叔丁酯)-哌啶-1-羧酸酯(INC)粗品。反应温度为15~50℃,优选20~45℃。反应时间通常为2~10小时。钯催化剂可以是Pd/C或Pd(OH)2/C,优选Pd(OH)2/C,其更适用于工艺。
在步骤(c)中,将HCl气体或HCl溶液加入到INC的有机溶液中,并在10~40℃下搅拌4~9小时以除去保护基团(t-Boc)并生成2-(4-苯氧基苯基)-6-(哌啶-4-基)尼克酰胺(IND)-HCl盐固体。IND-HCl从反应介质中沉淀出来,并且容易通过过滤或离心收集,适合大批量生产。在一个实施方案中,将HCl气体鼓泡到INC的溶液中。在另一个实施方案中,将HCl的有机溶液(例如,HCl在乙酸乙酯或乙醇中)加入到INC的有机溶液(例如,INC在乙醇或二氯甲烷中)中。或者将INC的有机溶液加入到HCl的有机溶液中。IND-HCl固体在乙酸乙酯中打浆可达到至少90%纯度,优选至少95%。
在步骤(d)中,IND-HCl盐与丙烯酰氯在碱性溶液(pH 8~14,例如碳酸氢盐溶液HCO3 -,碳酸盐溶液CO3 -2,磷酸盐溶液PO4 -3和氢氧化物溶液OH-)中,在低温(0~8℃或2~6℃)下反应以减少杂质生成并获得化合物I。溶液的溶剂可以是有机溶剂(例如THF或二氯甲烷),含水或不含水。反应时间通常为1~5小时或1~3小时。或者,在步骤(d)中,IND-HCl盐先与3-氯丙酰氯在中等碱性强度的溶液(pH 10~12,例如碳酸盐溶液或磷酸盐溶液)中反应生成中间体INE,然后将pH增加至14的强碱性溶液(例如,氢氧化物溶液)以生成化合物I。溶液的溶剂可以是混有水或没混有水的有机溶剂(例如THF或二氯甲烷)。
化合物I可以通过THF/水打浆进一步纯化,以提高纯度至至少90%,优选至少95%。
在第二个实施方案B中,化合物I由6-氯-2-(4-苯氧基苯基)烟酸/酯(INA′)制备,并使用t-Boc作为保护基。该工艺包括以下步骤:
(a)INA′、SMC和第一种钯催化剂的混合物加热至60~140℃,得到INB′,
其中R是H或C1-4烷基,
PG是叔丁氧基羰基保护基;
(b)当R为H,INB′先与草酰氯反应,再与氨水反应而被酰胺化得到INB,或当R为C1-4烷基,INB′与氨水反应而被酰胺化得到INB;
(c)INB在H2下由第二种钯催化剂催化氢化,得到INC;
(d)INC在HCl溶液中去保护,得到固体IND-HCl盐;和
(e)IND-HCl盐与丙烯酰氯或3-氯丙酰氯在碱性条件下反应,得到化合物I。
实施方案B与A类似,不同之处如下。在实施方案B中,原料是INA′(酸或酯),不是INA(酰胺)。步骤(a)的产物是INB′(酸或酯),其在氢化前需要被酰胺化为INB。在步骤(b)中,当R为H,INB′先与草酰氯在有机溶剂(例如THF)中15~50℃下反应2~10小时,得到酰氯中间体,然后再与20~35%(w/w)氨水溶液在15~50℃下反应1~5小时。在步骤(b)中,当R是C1-4烷基,INB′的有机溶液(例如THF)与20~35%(w/w)氨水溶液在15~75℃下反应4~20小时。
在第三个实施方案C中,化合物I由6-氯-2-(4-苯氧基苯基)尼克酰胺(INA)制备,并使用苄基或苄氧羰基作为保护基。该过程包括以下步骤:
(a)INA、SMC′和第一种钯催化剂的混合物在60~140℃下加热,得到INB,
其中PG1是苄基或苄氧羰基保护基;
(b)INB在H2下由第二种钯催化剂催化氢化,得到IND;
(c)IND与丙烯酰氯或3-氯丙酰氯在碱性条件下反应,得到6-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)尼克酰胺。
实施方案C与A类似,不同之处在于实施方案C在步骤(a)中使用不同的保护基团苄基或苄氧羰基作为试剂。这种保护基在氢化过程中不稳定,并在步骤(b)中脱保护生成IND。然后,IND可在碱性条件下与丙烯酰氯或3-氯丙酰氯反应生成化合物I。可选地,在步骤(b)之后,可以将HCl溶液加入到IND中以生成固体IND-HCl盐,然后使其与丙烯酰氯或3-氯丙酰氯反应。
在第四个实施方案D中,化合物I由6-氯-2-(4-苯氧基苯基)烟酸/酯(INA′)制备,并使用苄基或苄氧羰基作为保护基。该过程包括以下步骤:
(a)INA′、SMC′和第一种钯催化剂的混合物在60~140℃加热,得到INB′,
其中R为H或C1-4烷基,
PG1是苄基或苄氧羰基保护基;
(b)当R为H,INB′先与草酰氯反应,再与氨水反应,或当R是C1-4烷基,INB′与氨水反应得到INB;
(c)INB在H2下由第二种钯催化剂催化氢化,得到IND;
(d)IND与丙烯酰氯或3-氯丙酰氯在碱性条件下反应,得到6-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)尼克酰胺。
实施方案D与C类似,不同之处如下。在实施方案D中,原料是INA′(酸或酯),不是INA(酰胺)。步骤(a)的产物是INB′(酸或酯),其在氢化之前需要被酰胺化为INB。在步骤(b)中,当R为H,INB′先与草酰氯在有机溶剂(例如THF)中在15~50℃下反应2~10小时,得到酰氯中间体,然后再与20~35%(w/w)氨水溶液在15~50℃下反应1~5小时。在步骤(b)中,当R是C1-4烷基,INB′的有机溶液(例如THF)与20~35%(w/w)氨水在15~75℃下反应4~20小时。
原料INA可以通过2,6-二氯尼克酰胺(SMA)、SMB和钯催化剂在碱性溶剂或溶剂混合物(例如,碳酸钠或碳酸钾、1,4-二氧六环、二甲基乙酰胺、乙醇/甲醇)中在60~140℃下加热8~12小时来制备,从而得到INA。
原料INA′可以通过2,6-二氯烟酸/酯(SMA′)、SMB和钯催化剂在碱性溶剂或溶剂混合物(例如,碳酸钠或碳酸钾、1,4-二氧六环、二甲基乙酰胺)中在60~140℃下加热8~12小时来制备,从而得到INA′。
在制备INA或INA′的过程中,使用SMB的硼酸酯。SMB比相应的硼酸反应更好,其减少了双偶联副反应并提高了氯的区域选择性。INA粗品可以在四氢呋喃中进一步打浆以提高纯度至至少90%。
2,6-二氯尼克酰胺(SMA)可以从供应商处获得。或者,SMA可以通过2,6-二氯烟酸(SM1)与草酰氯(COCl)2在10~30℃反应4~12小时,其再在有机溶剂中与氨水在10~30℃反应1~3小时来制备。
2,6-二氯烟酸/酯(SMA′)可以从供应商处获得。
本方法提供了化合物I的高产率。从INA或INA′到化合物I的总收率为约55~70%,从SMA或SMA到化合物I的总收率为约30-50%。
以下实施例进一步举例说明了本发明。这些实施例仅用于举例说明本发明,不应被解释为限制。
实施例
实施例1-6总结在方案A中。
实施例1.制备2,6-二氯尼克酰胺(SMA)
在氮气下的反应器中加入2,6-二氯烟酸(SM1,39.8kg,207mol)、DMF1.9kg,26mol)和THF(189.9kg)。将草酰氯(36.0kg,283mol)缓慢加入上述溶液中,同时保持温度在15至25℃之间。加完后,将反应在相同温度下搅拌8小时。保持温度低于50℃,将混合物在减压下浓缩,直到体积减少至2.5~3.5V。然后将混合物冷却至20~30℃,并加入到冷却至0~10℃的THF(106.1kg)和氨水(180.0kg)的搅拌溶液中。加完后,将反应混合物升温至20~30℃并再搅拌1.5小时。然后将混合物在低于50℃的条件下减压浓缩,直到没有馏出物蒸出。将所得浆液冷却至15~25℃,搅拌2~4小时并离心。固体滤饼用水(40.4kg)洗涤并与甲基叔丁基醚(148.5kg)混合。将所得混合物加热至45~55℃并搅拌3~5小时。然后冷却至20~30℃,搅拌1~3小时,离心。固体滤饼用甲基叔丁基醚(6.8kg)洗涤并在35~45℃下减压(低于-0.080MPa)干燥16小时,得到SMA(30.48Kg,产率77%,纯度99.6%)。
实施例2.制备6-氯-2-(4-苯氧基苯基)尼克酰胺(INA)
向SMB(58.7kg,198.2mol)的乙醇(120.0kg)和甲醇(36.3kg)溶液中加入SMA(30.0kg,157mol)和Na2CO3(66.6kg,628mol),所得混合物用N2置换三次。然后加入Pd2(dba)3(三(二亚苄基丙酮)二钯(0),4.32kg,4.7mol),并通入N2鼓泡2~5分钟。将反应混合物加热至75~85℃并搅拌12小时。然后将混合物冷却至15~25℃,搅拌4~6小时并过滤。滤饼在乙醇(30.3kg)中浸泡10~20分钟,过滤。将滤饼溶解在THF(268.4kg)中,加热至45~55℃并搅拌2~4.5小时。将混合物冷却至20~30℃并过滤。收集滤液。滤饼在THF(62.4kg)中浸泡10~20分钟并过滤。收集滤液。滤饼进一步在THF(60.3kg)中浸泡10~20分钟并过滤。收集滤液,与上述两批滤液合并,在50℃以下减压浓缩。向残余物中加入乙醇(60.1kg)并在低于50℃的条件下减压浓缩。向残余物中加入另一批乙醇(60.4kg)并在低于50℃的条件下减压浓缩。残余物中加入乙醇(90.1kg),加热至75~85℃并搅拌1.5~2.5小时。将所得混合物冷却至15~25℃,搅拌4~6小时并离心。固体滤饼用乙醇(30.1kg)洗涤并在35~45℃下减压(低于-0.080MPa)干燥16小时,得到INA(39.23Kg,产率77%,纯度93.1%)。
实施例3.制备5-氨基甲酰基-6-(4-苯氧基苯基)-3′,6′-二氢-[2,4′-联吡啶]-1′(2′H)-羧酸叔丁酯(INB)
在氮气下的反应器中加入INA(31.7kg,90.7mol,93.1%纯度)、4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(30.8kg,99.7mo1)、Na2CO3(25.1kg,237mol)、EtOH(118.7kg)和H2O(148.2kg)。反应器用N2鼓泡直至氧含量低于1.0%。然后加入Pd(PPh3)2Cl2(1.18kg,1.68mol)。将反应混合物加热至75~85℃并搅拌2.5小时。冷却至15~25℃后,将反应混合物搅拌1~3小时并过滤。滤饼依次用乙醇(26.2kg)和H2O(35.8kg)洗涤,溶解在THF(261.7kg)中,在45~55℃下搅拌2~4小时。然后将溶液冷却至20~30℃并过滤。收集滤液。滤饼用THF洗涤两次(分别使用59.3kgTHF和59.7kgTHF)并收集滤液。合并三批滤液,在60℃以下浓缩。向残余物中加入乙酸乙酯(148.1kg),在60℃以下浓缩。然后加入另一批乙酸乙酯(147.5kg)并将混合物60℃以下浓缩。所得残余物加入乙酸乙酯(147.5kg),加热至65~75℃,搅拌2~4小时。然后将混合物冷却至15~25℃,搅拌2~4小时并离心。固体滤饼用乙酸乙酯(59.0kg)洗涤,在35~45℃下减压(-0.08MPa以下)干燥12~16小时,得到INB(30.44kg,产率71%,纯度98.7%)。
实施例4.制备4-(5-氨基甲酰基-6-(4-苯氧基苯基)吡啶-2-基)哌啶-1-羧酸叔丁酯(INC)
在氮气下的反应器中加入Pd(OH)2/C(2.03kg,20%)和THF(32.0kg)并搅拌5~10分钟。然后加入INB(14.85kg,31.5mol)的THF(47kg)溶液。加入更多的THF(32.0kg),保持系统温度在20至25℃之间,将反应混合物用N2置换3次,然后用H2置换3次。将反应混合物加热至35~45℃,在0.10~0.20MPa的H2压力下搅拌4小时。然后将混合物过滤,滤饼用THF洗涤两次(30kg×2)。合并三批滤液,得到INC粗品的溶液(181.5kg)。将两个单独的反应批次(总共使用30.5kg纯的INB)合并,得到INC的THF(365.3kg)溶液,加入活性炭(3.00kg),加热至45~55℃,搅拌1~3小时。然后将混合物冷却至20~30℃,用硅藻土(15.2kg)过滤,用THF洗涤两次(分别使用62.2kg和61.1kgTHF)。合并三批滤液,在低于50℃的条件下减压浓缩。向残余物中加入乙醇(244.0kg)并在低于50℃的条件下减压浓缩。再次加入乙醇(246.1kg),并将所得混合物在低于50℃的条件下减压浓缩。向残余物中加入乙酸乙酯(262.3kg)和乙醇(43.5kg),在20~55℃下搅拌,直至所有固体溶解,得到INC的溶液。
实施例5.制备2-(4-苯氧基苯基)-6-(哌啶-4-基)尼克酰胺(IND)
将上述INC在乙酸乙酯(262.3kg)和乙醇(43.5kg)中的溶液用N2置换3次。然后向溶液中鼓入HCl(气体,11.7kg),反应混合物在10~40℃下搅拌7小时。将混合物冷却至15~25℃,搅拌1~3小时,离心。固体滤饼用乙酸乙酯(60.8kg)洗涤并在30~50℃下减压(低于-70KPa)干燥24小时,得到IND(26.3kg,HCl盐,产率99%,纯度99.4%)。
实施例6.制备6-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)尼克酰胺(INF)
在氮气下的反应器中加入IND(10.0kg,24.4mol)、THF(105.5kg)和H2O(125.4kg),将混合物在15~25℃下搅拌20~40分钟。然后在20~40分钟内加入NaHCO3(10.3kg,123mol)。将反应混合物冷却至-2~6℃,加入丙烯酰氯(3.8kg,42.0mol),搅拌1~3小时。HPLC显示IND未全部消耗,因此再次加入丙烯酰氯并继续搅拌反应混合物直至反应完成(分三批添加0.68kg丙烯酰氯,反应持续16小时)。然后将混合物升温至5~20℃,加入水(98.9kg),搅拌20~40分钟,过滤。滤饼用水(20kg)洗涤,与另一批水(100.8kg)混合,在15~25℃下搅拌1~2小时。将混合物过滤。滤饼依次用水(21.2kg)和乙醇(5.0kg)洗涤。然后将滤饼溶解在二氯甲烷(200.6kg)中,加热至40~45℃,搅拌至溶液变澄清。冷却至15~25℃后,加入HCl溶液(300.7kg,0.18%),搅拌10~20分钟。分液。有机层依次用水洗涤两次(分别使用51.0kg水和50.2kg水)、Na2CO3水溶液(0.42%,调节pH=8~9)和水(50.0kg)洗涤。有机相减压浓缩。向残余物中加入乙醇(100.0kg),在低于45℃的条件下减压浓缩。残余物中再次加入乙醇(80.0kg),在15~25℃下搅拌1~2小时,过滤。滤饼用乙醇洗涤,20~30℃下减压干燥14小时,得到INF(7.47kg,产率72%,纯度99.5%)。
本发明,以及制作和使用它的方式和过程,现在以如此完整、清晰、简洁和准确的术语进行描述,以使得本发明所属领域的任何技术人员能够制作和使用本发明。应当理解,前面描述了本发明的优选实施例,并且可以在不脱离权利要求中阐述的本发明的范围的情况下对其进行修改。为了特别指出并清楚地要求保护被视为发明的主题,以下权利要求对说明书进行了总结。
Claims (5)
1.一种制备6-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)尼克酰胺(化合物I)的方法,包括:
(a)INA,SMC,和第一种含钯催化剂的混合物在60~140℃下加热,得到INB,
其中PG为叔丁氧基羰基保护基;
(b)INB在H2下由第二种含钯催化剂催化氢化,得到包含INC粗品的第一溶液;
(c)加入活性炭纯化1NC粗品,然后将纯化的INC浓缩并溶解于乙酸乙酯和乙醇,得到包含纯化的INC的第二溶液;
(d)向所述第二溶液加入HCl气体以去保护INC并得到固体IND-HCl盐;
(e)加入THF,H2O,和NaHCO3以溶解并中和IND-HCl盐;
(f)IND与丙烯酰氯或3-氯丙酰氯在碱性条件下反应,得到6-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)尼克酰胺
2.一种制备6-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)尼克酰胺(化合物I)的方法,包括:
(a)INA’,SMC,和第一种含钯催化剂的混合物在60~140℃下加热,得到INB’,
其中R是H或C1-4烷基,
PG为叔丁氧基羰基保护基;
(b)当R为H,INB’先与草酰氯反应,再与氨水反应被酰胺化得到INB,或当R为C1-4烷基,INB’与氨水反应而被酰胺化得到INB;
(c)INB在H2下由第二种含钯催化剂催化氢化,得到包含INC粗品的第一溶液;
(d)加入活性炭纯化INC粗品,然后将纯化的INC浓缩并溶解于乙酸乙酯和乙醇,得到包含纯化的INC的第二溶液;
(e)向所述第二溶液加入HCl气体以去保护INC并得到固体IND-HCl盐;
(f)加入THF,H2O,和NaHCO3以溶解并中和IND-HCl盐;
(g)IND与丙烯酰氯或3-氯丙酰氯在碱性条件下反应,得到6-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)尼克酰胺
3.根据权利要求1所述的方法,还包括将2,6-二氯尼克酰胺(SMA),SMB,和含钯催化剂的混合物在碱性溶剂或溶剂混合物中60~140℃下加热8-12小时制备INA的步骤
4.根据权利要求3所述的方法,还包括将2,6-二氯烟酸与草酰氯(COCl)2反应,然后在有机溶剂中与氨水反应得到SMA的步骤。
5.根据权利要求2的方法,还包括将2,6-二氯烟酸/酯(SMA’),SMB,和含钯催化剂的混合物在碱性溶剂或溶剂混合物中60~140℃下加热8-12小时制备INA’的步骤
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201962810305P | 2019-02-25 | 2019-02-25 | |
US62/810,305 | 2019-02-25 | ||
PCT/CN2020/076387 WO2020173407A1 (en) | 2019-02-25 | 2020-02-24 | Process for preparing 6- (1-acryloylpiperidin-4-yl) -2- (4-phenoxyphenyl) nicotinamide |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113454066A CN113454066A (zh) | 2021-09-28 |
CN113454066B true CN113454066B (zh) | 2024-02-09 |
Family
ID=72238782
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202080015876.7A Active CN113454066B (zh) | 2019-02-25 | 2020-02-24 | 制备6-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)尼克酰胺的工艺 |
Country Status (12)
Country | Link |
---|---|
US (1) | US20210380555A1 (zh) |
EP (1) | EP3931182A4 (zh) |
JP (1) | JP7527661B2 (zh) |
KR (1) | KR20210131374A (zh) |
CN (1) | CN113454066B (zh) |
AU (1) | AU2020229919A1 (zh) |
BR (1) | BR112021016787A2 (zh) |
CA (1) | CA3131302A1 (zh) |
MX (1) | MX2021010199A (zh) |
SG (1) | SG11202109213RA (zh) |
TW (1) | TWI830876B (zh) |
WO (1) | WO2020173407A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115894440A (zh) * | 2022-10-27 | 2023-04-04 | 都创(重庆)医药科技有限公司 | 奥布替尼化合物的晶型及其制备方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101460466A (zh) * | 2006-04-11 | 2009-06-17 | 沃泰克斯药物股份有限公司 | 适用作蛋白激酶抑制剂的噻唑类、咪唑类和吡唑类 |
CN104341388A (zh) * | 2013-10-16 | 2015-02-11 | 上海润诺生物科技有限公司 | 芳香族酰胺类衍生物、其制备方法及其在医药上的应用 |
CN107226805A (zh) * | 2016-03-24 | 2017-10-03 | 北京天诚医药科技有限公司 | 芳香族酰胺类衍生物、其制备方法及其在医药上的应用 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BR112015030288B1 (pt) | 2013-06-25 | 2022-10-18 | Ptc Therapeutics, Inc. | Compostos e seu uso no tratamento de atrofia muscular espinhal |
WO2015061247A2 (en) | 2013-10-21 | 2015-04-30 | Merck Patent Gmbh | Heteroaryl compounds as btk inhibitors and uses thereof |
CA3117009A1 (en) * | 2018-11-06 | 2020-05-14 | Beijing Innocare Pharma Tech Co., Ltd. | Amorphous solid dispersion comprising 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide |
-
2020
- 2020-02-24 AU AU2020229919A patent/AU2020229919A1/en active Pending
- 2020-02-24 CA CA3131302A patent/CA3131302A1/en active Pending
- 2020-02-24 MX MX2021010199A patent/MX2021010199A/es unknown
- 2020-02-24 BR BR112021016787A patent/BR112021016787A2/pt unknown
- 2020-02-24 JP JP2021549695A patent/JP7527661B2/ja active Active
- 2020-02-24 SG SG11202109213RA patent/SG11202109213RA/en unknown
- 2020-02-24 WO PCT/CN2020/076387 patent/WO2020173407A1/en unknown
- 2020-02-24 CN CN202080015876.7A patent/CN113454066B/zh active Active
- 2020-02-24 EP EP20762224.2A patent/EP3931182A4/en active Pending
- 2020-02-24 KR KR1020217029894A patent/KR20210131374A/ko active Search and Examination
- 2020-02-25 TW TW109106065A patent/TWI830876B/zh active
-
2021
- 2021-08-20 US US17/407,340 patent/US20210380555A1/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101460466A (zh) * | 2006-04-11 | 2009-06-17 | 沃泰克斯药物股份有限公司 | 适用作蛋白激酶抑制剂的噻唑类、咪唑类和吡唑类 |
WO2015048662A2 (en) * | 2013-09-30 | 2015-04-02 | X-Rx Discovery, Inc. | Substituted nicotinimide inhibitors of btk and their preparation and use in the treatment of cancer, inflammation and autoimmune disease |
CN104341388A (zh) * | 2013-10-16 | 2015-02-11 | 上海润诺生物科技有限公司 | 芳香族酰胺类衍生物、其制备方法及其在医药上的应用 |
CN107226805A (zh) * | 2016-03-24 | 2017-10-03 | 北京天诚医药科技有限公司 | 芳香族酰胺类衍生物、其制备方法及其在医药上的应用 |
Also Published As
Publication number | Publication date |
---|---|
CN113454066A (zh) | 2021-09-28 |
BR112021016787A2 (pt) | 2021-11-16 |
TW202031642A (zh) | 2020-09-01 |
JP7527661B2 (ja) | 2024-08-05 |
JP2022521763A (ja) | 2022-04-12 |
AU2020229919A1 (en) | 2021-10-14 |
CA3131302A1 (en) | 2020-09-03 |
SG11202109213RA (en) | 2021-09-29 |
TWI830876B (zh) | 2024-02-01 |
MX2021010199A (es) | 2021-09-21 |
EP3931182A1 (en) | 2022-01-05 |
US20210380555A1 (en) | 2021-12-09 |
EP3931182A4 (en) | 2023-01-25 |
WO2020173407A1 (en) | 2020-09-03 |
KR20210131374A (ko) | 2021-11-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108129288B (zh) | 一种反式-3-羟基环丁基甲酸的合成方法 | |
EP3988545A1 (en) | Methods for preparing cdk4/6 inhibitor and salt and intermediate thereof | |
TW202319046A (zh) | 用於合成㖠啶衍生物及其中間體之方法 | |
CN107176955A (zh) | 一种巴瑞替尼的制备方法 | |
CN109369545B (zh) | 2-甲基-5-甲酸吡嗪的合成工艺 | |
CN112062767B (zh) | 一种卢美哌隆的制备方法及其中间体 | |
CN113454066B (zh) | 制备6-(1-丙烯酰基哌啶-4-基)-2-(4-苯氧基苯基)尼克酰胺的工艺 | |
CN108640923A (zh) | 一种托法替布关键中间体的制备方法 | |
CN106674084B (zh) | 一种2-异丙基氧基-5-甲基-4-(哌啶-4-基)苯胺二盐酸盐的制备方法 | |
RU2810260C2 (ru) | Способ получения 6-(1-акрилоилпиперидин-4-ил)-2-(4-феноксифенил)никотинамида | |
CN103193763A (zh) | 一种来那度胺的新制备方法 | |
CN105541705A (zh) | 一种马来酸氟吡汀化合物的合成方法 | |
CN115322065A (zh) | 一种采用固载镍与有机碱组合催化工业化生产氘代医药中间体的方法 | |
RU2539298C2 (ru) | Способ получения флупиртина | |
CN114085213A (zh) | 一种arv-471的制备方法 | |
CN110577542A (zh) | 一种西他列汀的制备方法 | |
CN106854200A (zh) | 色瑞替尼及其中间体的制备方法 | |
CN114644636B (zh) | 一种制备托法替尼关键中间体的方法 | |
CN112062754B (zh) | 一种合成Dorzagliatin的中间体的制备方法 | |
CN107235910B (zh) | 一种尼洛胺的合成方法 | |
CN108586331B (zh) | 一种用于合成含氮杂环化合物的中间体及其制备方法 | |
CN117897379A (zh) | 用于合成萘啶衍生物及其中间体的方法 | |
CN116789672A (zh) | 一种氟马西尼的生产工艺 | |
CN117586228A (zh) | 一种三嗪类药物的制备方法 | |
CN117756806A (zh) | 一种托法替布中间体的制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40064146 Country of ref document: HK |
|
GR01 | Patent grant | ||
GR01 | Patent grant |