CN108864050B - Method for synthesizing Arotinib and hydrochloride thereof - Google Patents
Method for synthesizing Arotinib and hydrochloride thereof Download PDFInfo
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- CN108864050B CN108864050B CN201810824114.6A CN201810824114A CN108864050B CN 108864050 B CN108864050 B CN 108864050B CN 201810824114 A CN201810824114 A CN 201810824114A CN 108864050 B CN108864050 B CN 108864050B
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- methyl
- fluoro
- indol
- methoxyquinolin
- yloxy
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- 238000000034 method Methods 0.000 title claims abstract description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 6
- 230000008569 process Effects 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 17
- -1 tert-butyl (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamate Chemical compound 0.000 claims description 15
- MGURPNCXRLKQAR-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinolin-7-ol Chemical compound C1=C2NC(C)=CC2=C(F)C(OC2=C3C=C(C(=CC3=NC=C2)O)OC)=C1 MGURPNCXRLKQAR-UHFFFAOYSA-N 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 14
- UPBWJLRILPHZOI-UHFFFAOYSA-N 4-[4-amino-2-fluoro-3-[(2-methyl-1,3-dioxolan-2-yl)methyl]phenoxy]-6-methoxyquinolin-7-ol Chemical compound NC1=C(C(=C(OC2=CC=NC3=CC(=C(C=C23)OC)O)C=C1)F)CC1(OCCO1)C UPBWJLRILPHZOI-UHFFFAOYSA-N 0.000 claims description 12
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical group [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 12
- KSMZEXLVHXZPEF-UHFFFAOYSA-N 1-[[4-[(4-fluoro-2-methyl-1h-indol-5-yl)oxy]-6-methoxyquinolin-7-yl]oxymethyl]cyclopropan-1-amine Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)C=CN=C2C=C1OCC1(N)CC1 KSMZEXLVHXZPEF-UHFFFAOYSA-N 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 9
- GTAUHBAHFJIAQT-UHFFFAOYSA-N 1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinolin-7-yl]oxymethyl]cyclopropan-1-amine hydrochloride Chemical compound Cl.FC1=C2C=C(NC2=CC=C1OC1=CC=NC2=CC(=C(C=C12)OC)OCC1(CC1)N)C GTAUHBAHFJIAQT-UHFFFAOYSA-N 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 7
- HJZVTFHHHWHSKQ-UHFFFAOYSA-N 4-[2-fluoro-3-[(2-methyl-1,3-dioxolan-2-yl)methyl]-4-nitrophenoxy]-6-methoxy-7-phenylmethoxyquinoline Chemical compound C1=CN=C2C=C(OCC=3C=CC=CC=3)C(OC)=CC2=C1OC(C=1F)=CC=C([N+]([O-])=O)C=1CC1(C)OCCO1 HJZVTFHHHWHSKQ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
- 238000001308 synthesis method Methods 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- DXKHGBZNWWPNBC-UHFFFAOYSA-N [1-[(2-methylpropan-2-yl)oxycarbonylamino]cyclopropyl]methyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1(NC(=O)OC(C)(C)C)CC1 DXKHGBZNWWPNBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 235000009518 sodium iodide Nutrition 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 239000005536 L01XE08 - Nilotinib Substances 0.000 abstract description 5
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 abstract description 5
- 229960001346 nilotinib Drugs 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 3
- 229960001433 erlotinib Drugs 0.000 description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- UUAKQNIPIXQZFN-UHFFFAOYSA-N 1-[[4-[(4-fluoro-2-methyl-1h-indol-5-yl)oxy]-6-methoxyquinolin-7-yl]oxymethyl]cyclopropan-1-amine;dihydrochloride Chemical compound Cl.Cl.COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)C=CN=C2C=C1OCC1(N)CC1 UUAKQNIPIXQZFN-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- 108091008794 FGF receptors Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000003527 anti-angiogenesis Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- SIIJRCRHAIMFNT-UHFFFAOYSA-N cyclopropanamine;hydrochloride Chemical compound Cl.NC1CC1 SIIJRCRHAIMFNT-UHFFFAOYSA-N 0.000 description 1
- 150000001942 cyclopropanes Chemical class 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 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
- C07D401/12—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 chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
The invention relates to a method for synthesizing nilotinib and hydrochloride thereof, and particularly relates to the method comprising steps (1) to (3) and step (4) or (5) as described in the specification. The method greatly simplifies the process flow and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of drug synthesis, and relates to a novel method for synthesizing Arotinib and hydrochloride thereof.
background
the erlotinib is a novel small-molecule multi-target tyrosine kinase inhibitor, can effectively inhibit VEGFR, PDGFR, FGFR, c-Kit and other kinases, and has double effects of resisting tumor angiogenesis and inhibiting tumor growth. The nilotinib is only a single-drug effective oral preparation in the existing anti-angiogenesis targeting drugs for the advanced non-small cell lung cancer, has light adverse reaction and good patient tolerance, and is expected to become a standard drug for three-line treatment of patients with the advanced non-small cell lung cancer. In addition, the nilotinib has a good treatment effect on the non-small cell lung cancer, and also on a plurality of cancer types such as soft tissue sarcoma, ovarian cancer and the like.
The chemical name of the nilotinib is 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine, and the chemical structural formula is as follows:
Currently marketed is the hydrochloride salt of nilotinib,
Patents US2010/0048599 and US2016/030483 of the original research company disclose a synthetic route for the preparation of aritinib hydrochloride and its free base, as follows:
the route is relatively long, the steps are more, and the operation is more complicated. The product of the iron powder reduction step has poor solubility and is difficult to separate from the byproduct iron mud. The cyclopropane segment raw material used in the fifth step has poor stability, which is not beneficial to the quality control and preservation of the raw material. The palladium catalysis step is too close to the API step, which is detrimental to heavy metal residue control in the final product quality. In order to more effectively and simply prepare the erlotinib, a synthetic method of the erlotinib, which is short in process flow, simple to operate and low in cost and is suitable for industrial production, needs to be explored.
Disclosure of Invention
Aiming at the defects and defects in the prior art, the invention aims to provide a synthesis method of 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinoline-7-yloxy) methyl) cyclopropylamine hydrochloride (Arotinib hydrochloride), which has the advantages of reasonable process route, simple operation, easily obtained reagents and high yield, and can meet the requirement of industrial scale-up production.
The invention relates to a method for synthesizing 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinoline-7-yloxy) methyl) cyclopropylamine or hydrochloride thereof, which comprises the following steps:
(1) Preparation of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) phenoxy) -6-methoxyquinolin-7-ol: carrying out reduction reaction on 7- (benzyloxy) -4- (2-fluoro-3- ((2-methyl-1, 3-dioxolane-2-yl) methyl) -4-nitrophenoxy) -6-methoxyquinoline in an organic solvent under the action of a catalyst to obtain 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolane-2-yl) methyl) phenoxy) -6-methoxyquinoline-7-ol;
(2) preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol: deprotecting an organic solvent solution of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) phenoxy) -6-methoxyquinolin-7-ol under the action of an acid and self-cyclizing to obtain 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol in one step;
(3) Preparation of tert-butyl (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamate: condensing 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinoline-7-ol and (1- ((tert-butoxycarbonyl) amino) cyclopropyl) methyl 4-methylbenzenesulfonate in an organic solvent under the action of a catalyst and a base to obtain (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinoline-7-yl) oxy) methyl) cyclopropyl) carbamic acid tert-butyl ester; and
(4) Preparation of 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine hydrochloride: (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamic acid tert-butyl ester in an organic solvent with hydrogen chloride to deprotect and recrystallize to give 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine hydrochloride; or
(5) preparation of 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine: (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamic acid tert-butyl ester after deprotection in an organic solvent under the action of hydrogen chloride and base liberation gave 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine.
in one embodiment of the present invention, the catalyst in step (1) is palladium on carbon; the using amount of the catalyst is 1-10 wt% of 7- (benzyloxy) -4- (2-fluoro-3- ((2-methyl-1, 3-dioxolane-2-yl) methyl) -4-nitrophenoxy) -6-methoxyquinoline; the hydrogen pressure is 0.1MPa to 1 MPa; and/or the reaction temperature is 40-60 ℃.
In another specific embodiment of the invention, the acid in the step (2) is 1-36% aqueous solution of hydrogen chloride; and/or the reaction temperature is 40-60 ℃.
In another embodiment of the present invention, in the steps (1) and (2), the organic solvent is N-methylpyrrolidone, dimethylformamide or dimethylacetamide.
In another specific embodiment of the present invention, the catalyst in step (3) is potassium iodide or sodium iodide; the using amount of the catalyst is 1-10 wt% of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinoline-7-ol; the alkali is potassium carbonate, sodium carbonate or potassium tert-butoxide; and/or the reaction temperature is 70-90 ℃.
in another embodiment of the present invention, the organic solvent in step (3) is dimethylformamide.
In another embodiment of the present invention, the reaction temperature in step (4) is 20 to 50 ℃ (preferably room temperature).
In another embodiment of the present invention, the base in step (5) is selected from the group consisting of: sodium carbonate, sodium hydroxide, or a combination thereof.
in another embodiment of the present invention, the organic solvent in steps (4) and (5) is selected from the group consisting of: ethanol, dioxane, ethyl acetate, or a combination thereof.
In another embodiment of the present invention, in the step (4), the recrystallization includes the steps of: concentrating the reaction solution after the protective group is removed, adding ethanol, heating to reflux, cooling to 0-10 ℃, and precipitating 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinoline-7-yloxy) methyl) cyclopropylamine hydrochloride.
The technical scheme provided by the invention has the following technical effects:
1. The reaction steps are few, the original 6-step reaction operation for preparing the Arotinib hydrochloride is reduced to 4-step reaction operation, and the overall yield of the route is high;
2. The reaction operation in each step is simple, only conventional post-treatment or additional purification operation is needed, and an additional column chromatography separation process is not needed;
3. the separation operation of the insoluble intermediate and the iron mud is avoided;
4. Two groups are reduced simultaneously by metal catalytic reaction, so that the reaction efficiency is improved;
5. The raw material cyclopropane derivative used in the route has a stable structure and is easy to obtain.
Therefore, the technical scheme provided by the invention greatly simplifies the process flow and is suitable for industrial production.
Detailed Description
The principles and features of this invention are described below in conjunction with specific embodiments, which are set forth merely to illustrate the invention and are not intended to limit the scope of the invention.
Example synthesis of- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine hydrochloride:
1. preparation of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) phenoxy) -6-methoxyquinolin-7-ol:
Placing 7- (benzyloxy) -4- (2-fluoro-3- ((2-methyl-1, 3-dioxolane-2-yl) methyl) -4-nitrophenoxy) -6-methoxyquinoline (52g, 0.1mol) in a 500mL three-necked bottle, adding 280mL of N-methylpyrrolidone, adding wet palladium carbon (5g, 10 wt%), and reacting at 50-55 ℃ under the hydrogen pressure of 0.1-0.2 MPa until the reaction is completely detected by HPLC. The catalyst was removed by filtration, and the mother liquor was distilled under reduced pressure to remove the toluene formed, to give a solution of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) phenoxy) -6-methoxyquinolin-7-ol in N-methylpyrrolidone, which was used directly in the next reaction.
1H NMR(DMSO-d6,400MHz):δ＝10.0(br,1H),8.37(d,J＝5.2Hz,1H),7.50(s, 1H),7.26(s,1H),7.01(t,J＝8.8Hz,1H),6.58(d,J＝8.8Hz,1H),6.26(d,J＝5.2Hz, 1H),5.22(s,2H),3.95(s,3H),3.84(m,4H),2.98(s,2H),1.28(s,3H)ppm
2. preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol:
And (3) putting the obtained N-methylpyrrolidone solution of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolane-2-yl) methyl) phenoxy) -6-methoxyquinoline-7-ol into a 500mL three-necked bottle, adding concentrated hydrochloric acid (20g), and reacting at 50-55 ℃ until the reaction is completely detected by HPLC. Water (560mL) was added dropwise at room temperature. Filtering, and washing the filter cake once. Drying gave 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol as a yellowish solid in 23g, purity 98% and overall yield in two steps of 71%.
1H NMR(DMSO-d6,400MHz):δ＝11.42(s,1H),10.11(s,1H),8.35(d,J＝5.2Hz, 1H),7.57(s,1H),7.28(s,1H),7.21(d,J＝8.8Hz,1H),6.98(t,J＝8.0Hz,1H),6.27(s,1H),6.25(d,J＝5.2Hz,1H),3.97(s,3H),2.41(s,3H)ppm
3. Preparation of tert-butyl (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamate:
4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol (50g, 148mmol) and (1- ((tert-butoxycarbonyl) amino) cyclopropyl) methyl 4-methylbenzenesulfonate (75.7g, 222mmol) were placed in a 500mL three-necked flask and 300mL of N, N-dimethylformamide was added. Potassium carbonate (40.9g, 296mmol) and potassium iodide (2.45g, 14.8mmol) were added. And (4) reacting at 75-85 ℃ until the reaction is completely detected by HPLC. The reaction mixture was taken up in dichloromethane and washed with saturated brine 6 times. The organic phase was concentrated and the crude product was crystallized from ethanol to give the title compound as a yellow powder 39g with a yield of 52%.
1H NMR(DMSO-d6,400MHz):δ＝11.42(s,1H),8.41(d,J＝5.2Hz,1H),7.59(s, 1H),7.37(s,1H),7.36(s,1H),7.22(d,J＝8.8Hz,1H),6.99(t,J＝8.0Hz,1H),6.32(d, J＝8.8Hz,1H),6.27(s,1H),4.18(s,2H),3.97(s,3H),2.42(s,3H),1.36(s,9H), 0.95-0.70(m,4H)ppm
4. Preparation of 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine hydrochloride:
tert-butyl (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamate (10g, 19.7mmol) was placed in a 250mL three-necked flask and 50mL of ethanol was added. An ethanol solution of hydrogen chloride (30% wt, 100mL) was added with stirring in an ice water bath. The reaction is completed at room temperature until HPLC detection. And concentrating the reaction solution under reduced pressure to 1-2 volumes, and adding 100mL of ethanol. Heating to reflux temperature, slowly cooling to 0-10 ℃, and filtering to obtain a white solid, namely 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinoline-7-yloxy) methyl) cyclopropylamine dihydrochloride, 7.6g, purity: 99% and yield 80.3%.
1H NMR(DMSO-d6,400MHz):δ＝11.82(s,1H),9.02(s,3H),8.75(d,J＝6.4Hz, 1H),7.84(s,1H),7.83(s,1H),7.30(d,J＝8.4Hz,1H),7.10(t,J＝8.0Hz,1H),6.79(d, J＝6.4Hz,1H),6.31(s,1H),4.44(s,2H),4.08(s,3H),2.43(s,3H),1.3-1.0(m,4H) ppm
example synthesis of- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine:
1. preparation of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) phenoxy) -6-methoxyquinolin-7-ol:
Placing 7- (benzyloxy) -4- (2-fluoro-3- ((2-methyl-1, 3-dioxolane-2-yl) methyl) -4-nitrophenoxy) -6-methoxyquinoline (52g, 0.1mol) in a 500mL three-necked bottle, adding 280mL of N, N-dimethylacetamide, adding wet palladium carbon (5g, 10 wt%), and reacting at 50-55 ℃ under the hydrogen pressure of 0.1-0.2 MPa until the reaction is completely detected by HPLC. The catalyst was removed by filtration, and the mother liquor was distilled under reduced pressure to remove the toluene formed, to give a solution of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) phenoxy) -6-methoxyquinolin-7-ol in N, N-dimethylacetamide which was used directly in the next reaction.
2. Preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol:
Putting the obtained N, N-dimethylacetamide ketone solution of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolane-2-yl) methyl) phenoxy) -6-methoxyquinoline-7-ol into a 500mL three-necked bottle, adding concentrated hydrochloric acid (20g), and reacting at 50-55 ℃ until the reaction is completely detected by HPLC. Water (560mL) was added dropwise at room temperature. Filtering, and washing the filter cake once. Drying gave 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol as a yellowish solid in 23g, purity 98% and overall yield in two steps of 71%.
3. Preparation of tert-butyl (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamate:
4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol (50g, 148mmol) is placed in a 500mL three-necked flask and 300mL of N, N-dimethylformamide is added. Potassium carbonate (40.9g, 296mmol) and potassium iodide (2.22g, 14.8mmol) were added. (1- ((tert-butoxycarbonyl) amino) cyclopropyl) methyl 4-methylbenzenesulfonate (75.7g, 222mmol) was added in portions at 75-85 ℃. Stirring was continued until the reaction was complete as detected by HPLC. The reaction mixture was taken up in dichloromethane and washed with saturated brine 6 times. The organic phase was concentrated and the crude product was crystallized from ethanol to yield the title compound as a yellow powder 42g with a yield of 56%.
4. preparation of 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine:
Tert-butyl (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamate (10g, 19.7mmol) was placed in a 250mL three-necked flask and 50mL of ethanol was added. An ethanol solution of hydrogen chloride (30% wt, 100mL) was added with stirring in an ice water bath. The reaction is completed at room temperature until HPLC detection. Concentrating the reaction solution under reduced pressure to 1-2 volumes, adding the reaction solution into dichloromethane, washing with saturated sodium carbonate, concentrating an organic phase, and pulping the concentrate with n-heptane to obtain 7.2g of a light yellow solid, namely 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine, wherein the purity is as follows: 99% and yield 90%.
1H NMR(DMSO-d6,400MHz):δ＝11.50(s,1H),8.42(d,J＝5.2Hz,1H),7.61(s, 1H),7.38(s,1H),7.22(d,J＝8.8Hz,1H),6.99(t,J＝8.0Hz,1H),6.33(d,J＝5.2Hz, 1H),6.27(s,1H),4.12(s,2H),3.99(s,3H),2.42(s,3H),0.85-0.65(m,4H)ppm
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (15)
1. a method for synthesizing 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine or its hydrochloride salt, comprising the steps of:
(1) Preparation of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) phenoxy) -6-methoxyquinolin-7-ol: carrying out reduction reaction on 7- (benzyloxy) -4- (2-fluoro-3- ((2-methyl-1, 3-dioxolane-2-yl) methyl) -4-nitrophenoxy) -6-methoxyquinoline in an organic solvent under the action of a catalyst to obtain an organic solvent solution of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolane-2-yl) methyl) phenoxy) -6-methoxyquinoline-7-ol; the catalyst is palladium carbon;
(2) Preparing 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol, i.e. an organic solvent solution of 4- (4-amino-2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) phenoxy) -6-methoxyquinolin-7-ol is deprotected under the action of an acid and is subjected to a one-step self-cyclization reaction to obtain 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol, wherein the acid is a 1 3536% aqueous hydrogen chloride solution;
(3) Preparation of tert-butyl (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamate: condensing 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinoline-7-ol and (1- ((tert-butoxycarbonyl) amino) cyclopropyl) methyl 4-methylbenzenesulfonate in an organic solvent under the action of a catalyst and a base to obtain (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinoline-7-yl) oxy) methyl) cyclopropyl) carbamic acid tert-butyl ester; and
(4) Preparation of 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine hydrochloride: (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamic acid tert-butyl ester in an organic solvent with hydrogen chloride to deprotect and recrystallize to give 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine hydrochloride; or
(5) preparation of 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine: (1- (((4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-yl) oxy) methyl) cyclopropyl) carbamic acid tert-butyl ester after deprotection in an organic solvent under the action of hydrogen chloride and base liberation gave 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine.
2. The method of claim 1, wherein in step (1), the catalyst is used in an amount of 1 ~ 10wt% of 7- (benzyloxy) -4- (2-fluoro-3- ((2-methyl-1, 3-dioxolan-2-yl) methyl) -4-nitrophenoxy) -6-methoxyquinoline.
3. The synthesis method according to claim 1, wherein in the step (1), the pressure of hydrogen used in the reduction reaction is 0.1MPa ~ 1 MPa.
4. the synthesis method according to claim 1, wherein in the step (1), the reaction temperature is 40 ~ 60 ℃.
5. the method according to claim 1, wherein in the step (2), the reaction temperature is 40 ~ 60 degrees.
6. the method according to claim 1, wherein in the steps (1) and (2), the organic solvent is N-methylpyrrolidone, dimethylformamide or dimethylacetamide.
7. The synthesis method according to claim 1, wherein in the step (3), the catalyst is potassium iodide or sodium iodide.
8. the process of claim 1, wherein in step (3), the catalyst is used in an amount of 1 ~ 10wt% of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-methoxyquinolin-7-ol.
9. The method according to claim 1, wherein in the step (3), the base is potassium carbonate, sodium carbonate or potassium tert-butoxide.
10. The method of claim 1, wherein in step (3), the reaction temperature is 70 ~ 90 degrees.
11. the method according to claim 1, wherein in the step (3), the organic solvent is dimethylformamide.
12. The method according to claim 1, wherein in the step (4), the reaction temperature is 20 ~ 50 ℃.
13. The method of claim 1, wherein in step (5), the base is selected from the group consisting of: sodium carbonate, sodium hydroxide, or a combination thereof.
14. The method according to claim 1, wherein in the steps (4) and (5), the organic solvent is selected from the group consisting of: ethanol, dioxane, ethyl acetate, or a combination thereof.
15. The synthesis method according to claim 1, wherein in the step (4), the recrystallization comprises the steps of concentrating the reaction solution from which the protective group is removed, adding ethanol, heating to reflux, and cooling to 0 ~ 10oand C, 1- ((4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxyquinolin-7-yloxy) methyl) cyclopropylamine hydrochloride is precipitated.
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