CN105461640A - Preparation method of tyrosine kinase inhibitor - Google Patents
Preparation method of tyrosine kinase inhibitor Download PDFInfo
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- CN105461640A CN105461640A CN201510871586.3A CN201510871586A CN105461640A CN 105461640 A CN105461640 A CN 105461640A CN 201510871586 A CN201510871586 A CN 201510871586A CN 105461640 A CN105461640 A CN 105461640A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 title abstract description 7
- 239000005483 tyrosine kinase inhibitor Substances 0.000 title abstract description 7
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- HUFOZJXAKZVRNJ-UHFFFAOYSA-N n-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxyanilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide Chemical compound COC1=CC(N2CCN(CC2)C(C)=O)=CC=C1NC(N=1)=NC=C(C(F)(F)F)C=1NC1=CC=CC(NC(=O)C=C)=C1 HUFOZJXAKZVRNJ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229950009855 rociletinib Drugs 0.000 claims abstract description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-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 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 7
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-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
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- NPSSWQJHYLDCNV-UHFFFAOYSA-N prop-2-enoic acid;hydrochloride Chemical compound Cl.OC(=O)C=C NPSSWQJHYLDCNV-UHFFFAOYSA-N 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000011592 zinc chloride Substances 0.000 claims description 4
- 235000005074 zinc chloride Nutrition 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 229910052742 iron Inorganic materials 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 238000007171 acid catalysis Methods 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 150000003457 sulfones Chemical class 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- 239000012467 final product Substances 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 14
- 239000006227 byproduct Substances 0.000 abstract description 7
- 239000000047 product Substances 0.000 abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000007670 refining Methods 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 3
- TYCYTQLXAIDJNF-UHFFFAOYSA-N 2-chloro-5-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CN=C(Cl)N=C1 TYCYTQLXAIDJNF-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- WBLPIVIXQOFTPQ-UHFFFAOYSA-N oxanamide Chemical compound CCCC1OC1(CC)C(N)=O WBLPIVIXQOFTPQ-UHFFFAOYSA-N 0.000 description 2
- 229950005413 oxanamide Drugs 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PKDPUENCROCRCH-UHFFFAOYSA-N 1-piperazin-1-ylethanone Chemical compound CC(=O)N1CCNCC1 PKDPUENCROCRCH-UHFFFAOYSA-N 0.000 description 1
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical compound ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- 102000003916 Arrestin Human genes 0.000 description 1
- 108090000328 Arrestin Proteins 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- -1 filter Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- RRKWPXMDCPJEHS-UHFFFAOYSA-N n-(3-aminophenyl)prop-2-enamide Chemical compound NC1=CC=CC(NC(=O)C=C)=C1 RRKWPXMDCPJEHS-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 238000011170 pharmaceutical development Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a novel preparation method of a tyrosine kinase inhibitor RociletinibN-[3-[[2-[[4-(4-acetyl-1-piperazinyl)-2-methoxyphenyl]amino]-5-(trifluoromethyl)-4-pyrimidyl]amino]phenyl]-2-acrylamide. A chemical compound (VII)2-[[4-(4--acetyl-1-piperazinyl)-2-methoxyphenyl]amino]-4-chloro-5-(trifluoromethyl)pyrimidine is innovatively used as a key intermediate for synthesis of Rociletinib, the proportion of a target product in a reaction system to isomer byproducts can be higher than 4:1, relatively higher selectivity is realized, and the defects that multiple byproducts are produced and refining and purifying are difficult in an existing synthesis method are overcome. The preparation method is simple to operate, good in reproducibility, economical, environment-friendly and suitable for industrial production, high-purity Rociletinib can be prepared, and the total yield reaches 60%-65%.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of tyrosine kinase inhibitor
-the preparation method that Rociletinib is new.
Background technology
Rociletinib(CO-1686; N-[3-[[2-[[4-(4-ethanoyl-1-piperazinyl)-2-p-methoxy-phenyl] is amino]-5-(trifluoromethyl)-4-pyrimidyl] is amino] phenyl]-2-acrylamide; see compound 1 in reaction formula one) be ClovisOncology company third generation tyrosine kinase inhibitor, to suddenly change the inhibitor of irreversible EGF-R ELISA (EGFR) of nonsmall-cell lung cancer (NSCLC) mainly for producing T790M.Research shows, Rociletinib is a kind of oral efficient tyrosine kinase inhibitor, by producing irreversible covalent bonds thus arrestin kinase activity with the ATP binding pocket place Cys797 of EGFR tyrosine kinase domain.The more important thing is Rociletinib energy Selective depression EGFR activated mutant (as L858R) and acquired resistance sudden change (as T790M), and it is very weak to the effect of Wild type EGFR, therefore, it is possible to effectively reduce or avoid the toxicity that produces because of target Wild type EGFR, be expected to become the two wires medication that the NSCLC patient of EGFR activated mutant is carried in treatment.
This patent documentation CN103269704A of A Wei rummy is built in west, and " Chinese Journal of Pharmaceuticals ", 2014, all report the method preparing Rociletinib and intermediate in 45 (8): 710-713, see reaction formula one.But in the preparation process of this synthetic route compound 2, piperazine two replacement by product is more, and reaction controlling difficulty is large, and yield is low; In addition, in the preparation process of compound 5, in reaction system, the ratio of the target product of pyrimidine 4 nucleophilic substitution and the by product of pyrimidine 2 nucleophilic substitution is almost 1:1, and both solubleness are extremely similar, and purifying difficulty is comparatively large, and yield is lower; Moreover use iron powder reducing nitro in the preparation of compound 6, produce iron mud, environmental pollution is serious.
Reaction formula one
To sum up, with reference to existing patent and document, the maximum difficult point of current Rociletinib synthetic method nearly all concentrates on the intermediate 5 synthesizing above-mentioned route, the chloro-5-trifluoromethyl pyrimidine of N-(3-nitrophenyl)-2--4-amine, the ratio of title intermediate and its by product isomer is almost 1:1, its purifying difficulty is large, yield is low, and effectively solved for a long time, this brings many puzzlements to pharmaceutical developments person, therefore, the synthetic route that urgently exploitation one is new is to solve the problem.
Summary of the invention
For the problems referred to above, the invention provides a kind of simple to operate, favorable reproducibility, economic environmental protection, product purity high prepare tyrosine kinase inhibitor
-the novel method of Rociletinib.
For overcoming the above problems, grope through a large amount of tests, the present invention is achieved through the following technical solutions:
The design of synthetic route of the present invention as shown in the formula:
Reaction formula two
Reaction formula three
In formula, compound (II), compound (III), compound (VI), compound (VIII) and compound (VIII ') are all commercially available, are the reliable raw material of the steady quality be easy to get.The use compound (VII) of the invention, as the key intermediate of synthesis Rociletinib, overcomes the difficult problem not obtaining for a long time effectively solving.Those skilled in the art know, 2, 4 dichloro pyrimidine generation nucleophilic substitution reactions, the active order replaced is 4 and is greater than 2, but the present invention is under the effect of Lewis acid etc., add nucleophilic attack reagent compound (V) own electronic cloud Density Distribution Feature, the target product of pyrimidine 2 nucleophilic substitution in reaction system and compound (VII) can be made to reach more than 4:1 with the isomeric by-products ratio of pyrimidine 4 nucleophilic substitution, it is many that relatively high selectivity avoids existing synthetic method by product well, the drawback of polishing purification difficulty, below announce the detailed preparation method of patent of the present invention.
Compound (IV) can be prepared by existing method: with compound (II) and compound (III) for starting raw material, nucleo philic substitution reaction obtains compound (IV).
Compound (V) can be prepared by palladium carbon catalytic hydrogenation by compound (IV).
It is obtained under Louis acid catalysis that compound (VII) can pass through compound (V) and compound (VI), and conventional Lewis acid is the common Lewis acid reagent such as zinc chloride, aluminum chloride or iron(ic) chloride, preferred zinc chloride; Conventional solvent is inert solvent, if aromatic hydrocarbons (toluene etc.), ethers (ether, tetrahydrofuran (THF) etc.), halo alkanes (methylene dichloride, chloroform etc.), ester class (ethyl acetate etc.), amides are (as N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE etc.), sulfone class (as dimethyl sulfoxide (DMSO) etc.), nitrile (acetonitrile etc.), ketone (as acetone etc.), preferred tetrahydrofuran (THF); The consumption of compound (VI) is generally 1 ~ 1.5 times of compound (V) amount of substance, lewis acidic consumption usually at 2 ~ 5 times of compound (V) amount of substance, preferably 2 ~ 3 times; Temperature of reaction usually at 20 ~ 80 DEG C, preferably 20 ~ 50 DEG C; Reaction times usually at 8 ~ 24h, preferably 16 ~ 24h.
Compound (VII) and (VIII) are obtained by reacting compound (I) i.e. Rociletinib, and reaction is carried out usually in the system of alcohol, and conventional alcohol comprises methyl alcohol, ethanol, Virahol, propyl carbinol etc., particular methanol; 1 ~ 1.5 times of the amount that described compound (VIII) is formula (VII) combinations of materials, the HCl consumption of hydrochloric acid usually at 1 ~ 6 times of compound (VII) amount of substance, preferably 2 ~ 4 times.
Compound (VII) and (VIII ') react to obtain compound (Ⅸ), and reaction is carried out usually in the system of alcohol, and conventional alcohol comprises methyl alcohol, ethanol, Virahol, n-propyl alcohol etc., particular methanol; The consumption of compound (VIII ') usually at 1 ~ 6 times of compound (VII) amount of substance, preferably 1 ~ 1.5 times; Temperature of reaction usually at 20 ~ 80 DEG C, preferably 60 ~ 70 DEG C; Reaction times usually at 8 ~ 24h, preferably 5 ~ 10h.
Compound (Ⅸ) deprotection reaction obtains compound (Ⅹ), and reaction is usually carried out in the system of alcohol or chloroparaffin; Conventional alcohol comprises methyl alcohol, ethanol, Virahol, n-propyl alcohol etc., particular methanol; Conventional chloroparaffin comprises methylene dichloride, chloroform, 1,2-ethylene dichloride etc., preferred methylene dichloride; Conventional acid is hydrochloric acid or trifluoroacetic acid, the effective level of acid usually at 1 ~ 6 times of compound (Ⅸ) amount of substance, preferably 1 ~ 1.5 times; Temperature of reaction usually at 0 ~ 50 DEG C, preferably 20 ~ 30 DEG C; Reaction times usually at 0.5 ~ 10h, preferably 5 ~ 10h.
Compound (Ⅹ) and acrylate chloride are obtained by reacting compound (I) i.e. Rociletinib, and reaction is carried out usually in the system of chloroparaffin, and conventional chloroparaffin comprises methylene dichloride, chloroform, 1,2-ethylene dichloride etc., preferred methylene dichloride; Conventional alkali comprises the mineral alkali such as sodium carbonate, sodium bicarbonate, and the organic bases such as pyridine, triethylamine, diisopropylethylamine, preferred triethylamine, the consumption of alkali usually at 1 ~ 6 times of compound (Ⅹ) amount of substance, preferably 2 ~ 3 times; The consumption of acrylate chloride usually at 1 ~ 6 times of compound (Ⅹ) amount of substance, preferably 1 ~ 1.5 times; Temperature of reaction usually at 20 ~ 50 DEG C, preferably 20 ~ 30 DEG C; Reaction times usually at 4 ~ 24h, preferably 4 ~ 5h.
the present invention has following actively useful effect:
Preparation method of the present invention is simple to operate, favorable reproducibility, economic environmental protection, and can prepare the Rociletinib that purity is high, total recovery reaches 60 ~ 65%, is applicable to suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
the preparation of embodiment 1 compound (IV) 2-methoxyl group-4-(4-ethanoyl-1-piperazinyl) oil of mirbane
Compound (II) 2-methoxyl group-4-fluoronitrobenzene 140g (0.82mol) is added in the 500mL there-necked flask of drying; add 1 again; 4-dioxane 150mL and compound (III) Acetylpiperazine 500g (3.90mol); reflux 2 ~ 3h(100 DEG C); TLC monitors reaction; disappear to raw material; concentration response system after cooling; when removing to the steaming of dioxane major part, add water 250mL, after stir about 0.5h; suction filtration; filter cake water 200mL drip washing obtains yellow solid, and 50 ~ 60 DEG C of dryings obtain product 217.56g, yield 95%.
1HNMR:（d
6-DMSO），δ：2.12(s，3H)；3.61(m，4H)；3.66(m，4H)；3.95(s，3H)；6.59(s，1H)；6.64(d，1H)；7.99(d，1H)。
the preparation of embodiment 2 compound (V) 2-methoxyl group-4-(4-ethanoyl-1-piperazinyl) aniline
Compound (IV) 33g (0.11mol), 10%Pd/C1.5g, anhydrous methanol 150mL is added in the 500mL reaction flask of drying, stir, after nitrogen replacement 3 times, normal pressure passes into hydrogen and stirs, after room temperature reaction 4h, TLC monitoring reaction is complete, system is filtered, concentrates, obtain product 24.68g, yield 90%.
1HNMR:（d
6-DMSO），δ：2.02(s，3H)；2.85～2.94.61(m，4H)；3.52～3.56(m，4H)；3.74(s，3H)；4.28（b，2H）；6.29(d，1H)；6.52～6.54(d，2H)。
the preparation of embodiment 3 compound (VII) 2-[[4-(4-ethanoyl-1-piperazinyl)-2-p-methoxy-phenyl] is amino] the chloro-5-of-4-(trifluoromethyl) pyrimidine
(1) zinc chloride 94.06g (0.69mol), anhydrous tetrahydro furan 350ml is added under nitrogen protection; control temperature is in 15 ~ 20 DEG C; the mixed solution that the chloro-5-trifluoromethyl pyrimidine 49.90g (0.23mol) of slow dropping compound (VI) 2,4-bis-and 150mL tetrahydrofuran (THF) form.Maintain this thermotonus 1h;
(2) by compound
(V)47.8g (0.19mol) be dissolved in 120mL anhydrous tetrahydro furan, be added drop-wise to and above-mentionedly prepare in liquid, stirring reaction 30min, drip 116.37g (1.15mol) triethylamine, add rear room temperature reaction 20 ~ 24h, TLC monitoring reaction complete, with 100mL dichloromethane extraction 3 times.Organic phase is washed, anhydrous sodium sulfate drying, concentrated, with acetonitrile: acetone=3:1 crystallization obtains pink colour to faint yellow solid 84.03g, yield 85%.
1HNMR：（d
6-DMSO），δ：2.05(s，3H)；3.36(m，4H)；3.60(m，4H)；3.76(s，3H)；6.52(s，1H)；6.67(d，1H)；7.22(d，1H)；8.62(m，1H)；9.61(b，1H)。
the preparation of embodiment 4 compound (Ⅹ) N-[3-[2-[[4-(4-ethanoyl-1-piperazinyl)-2-p-methoxy-phenyl] is amino]-5-(trifluoromethyl)-4-pyrimidyl] is amino] aniline
(1) compound (VII) 51.58g (0.12mol) is added in 200mL methyl alcohol with the tertiary fourth oxanamide 31.24g (0.15mol) of compound (VIII ') N-(3-aminophenyl), room temperature adds 1mol/LHCl (250mL), is slowly warmed up to 60 DEG C of reaction 5 ~ 7h.Drop to room temperature, add 200ml water, methylene dichloride 300mL extracts three times, by organic phase washing, saturated salt washing, and dried over sodium sulfate.Removal of solvent under reduced pressure, methylene chloride/methanol recrystallization obtains off-white powder 56g, yield 90%, is compound (Ⅸ);
(2) gained compound (Ⅸ) 50g (0.12mol) is added 150mL methylene dichloride, trifluoroacetic acid 27mL (0.36mol), slowly be heated to 40 ~ 50 DEG C of reactions 8 ~ 10 hours, obtain brown solid, dissociate with aqueous sodium carbonate, dichloromethane extraction, anhydrous sodium sulfate drying, concentrates to obtain white solid 52.3g, yield 87%.
1HNMR：（d
6-DMSO），δ：2.05(s，3H)；3.13(m，4H)；3.39(m，4H)；3.60(s，3H)；4.97(b，2H)；6.37～6.39(m，2H)；6.62～6.64(m，2H)；6.64(b，2H)；6.97(m，1H)；7.56(d，1H)；8.10(s，1H)；8.15(b，1H)；8.24(s，1H)。
the preparation of embodiment 5 compound (Ⅹ) N-[3-[2-[[4-(4-ethanoyl-1-piperazinyl)-2-p-methoxy-phenyl] is amino]-5-(trifluoromethyl)-4-pyrimidyl] is amino] aniline
(1) compound (VII) 51.58g (0.12mol) is added in 200mL methyl alcohol with the tertiary fourth oxanamide 31.24g (0.15mol) of compound (VIII ') N-(3-aminophenyl), room temperature adds 1mol/LHCl (250mL), is slowly warmed up to 60 DEG C of reaction 5 ~ 7h.Drop to room temperature, add 200mL water, extract three times with methylene dichloride 300mL, by organic phase washing, saturated salt washing, dried over sodium sulfate.Removal of solvent under reduced pressure, methylene chloride/methanol recrystallization obtains off-white powder 56g, yield 90%, is compound (Ⅸ)
;
(2) gained compound (Ⅸ) 50g (0.12mol) is added 150mL methyl alcohol, hydrochloric acid 30mL (0.36mol) slowly heat 40 ~ 50 DEG C reaction 8 ~ 10h, 200mL methyl tertiary butyl ether is added after reaction terminates, separate out white solid, filter, filter cake 200mL methyl tertiary butyl ether drip washing.Obtain dark HCl, solid after drying, successively, dichloromethane extraction, anhydrous sodium sulfate drying free with aqueous sodium carbonate, reconcentration obtains white solid 49.95g, yield 83%.
1HNMR：（d
6-DMSO），δ：2.05(s，3H)；3.13(m，4H)；3.39(m，4H)；3.60(s，3H)；4.97(b，2H)；6.37～6.39(m，2H)；6.62～6.64(m，2H)；6.64(b，2H)；6.97(m，1H)；7.56(d，1H)；8.10(s，1H)；8.15(b，1H)；8.24(s，1H)。
the preparation of embodiment 6 compound (I) N-[3-[[2-[[4-(4-ethanoyl-1-piperazinyl)-2-p-methoxy-phenyl] is amino]-5-(trifluoromethyl)-4-pyrimidyl] is amino] phenyl]-2-acrylamide
Compound (VII) 51.58g (0.12mol) and compound (VIII) N-(3-aminophenyl) acrylamide 29.20g (0.18mol) are added in 200mL methyl alcohol, 1mol/LHCl (250mL) is added again under room temperature, slowly be warmed up to 60 DEG C, reaction 5 ~ 7h.Drop to room temperature, add 200mL water, extract 3 times with methylene dichloride 300mL, organic phase washing, saturated sodium-chloride are washed, finally uses dried over sodium sulfate.Removal of solvent under reduced pressure, obtain the white solid of class, methylene chloride/methanol recrystallization obtains off-white powder 60.0g, purity 99.8%, yield 90%.
1HNMR：（d
6-DMSO），δ：2.08(s，3H)；3.10(m，4H)；3.60(m，4H)；3.81(m，4H)；5.81(d，1H)；6.32(d，2H)；6.51(m，1H)；6.64(s，1H)；7.22(b，1H)；7.32(t，1H)；7.52(m，2H)；7.62(b，2H)；8.13(s，1H)；8.32(s，1H)；8.73(b，1H)；10.19(b，1H)。
the preparation of embodiment 7 compound (I) N-[3-[[2-[[4-(4-ethanoyl-1-piperazinyl)-2-p-methoxy-phenyl] is amino]-5-(trifluoromethyl)-4-pyrimidyl] is amino] phenyl]-2-acrylamide
Compound (Ⅹ) 40.12g (0.08mol) is dissolved in 280mL methylene dichloride, then adds 16.2g(0.16mol) triethylamine, drip acrylate chloride 9.05g (0.10mol) under ice bath, then room temperature reaction 4 ~ 5h.Removal of solvent under reduced pressure, residue adds 200mL water, and filter after stirring, obtain off-white color solid, methylene chloride/methanol recrystallization obtains off-white powder 41.0g, purity 99.6%, yield 92%.
1HNMR：（d
6-DMSO），δ：2.08(s，3H)；3.10(m，4H)；3.60(m，4H)；3.81(m，4H)；5.81(d，1H)；6.32(d，2H)；6.51(m，1H)；6.64(s，1H)；7.22(b，1H)；7.32(t，1H)；7.52(m，2H)；7.62(b，2H)；8.13(s，1H)；8.32(s，1H)；8.73(b，1H)；10.19(b，1H)。
The present invention is not limited to above-mentioned embodiment, and those skilled in the art also can make multiple change accordingly, but to be anyly equal to the present invention or similar change all should be encompassed in the scope of the claims in the present invention.
Claims (11)
1. a preparation method of compound (I) Rociletinib, is characterized in that, comprise the following steps:
(1) compound (VII) is prepared;
(2) compound (I) is prepared by compound (VII).
2. preparation method according to claim 1, is characterized in that: described compound (VII) is by compound (V)
with compound (VI)
in inert solvent system, obtain through Louis acid catalysis.
3. preparation method according to claim 2, is characterized in that: the preparation method of described compound (V) comprises the following steps:
1) with compound (II)
with compound (III)
for starting raw material, nucleo philic substitution reaction obtains compound (IV)
;
2) gained compound (IV) obtains compound (V) through palladium carbon catalytic hydrogenation.
4. preparation method according to claim 2, it is characterized in that: described Lewis acid is at least one in zinc chloride, aluminum chloride and iron(ic) chloride, described inert solvent is at least one in aromatic hydrocarbons, ethers, halo alkanes, ester class, amides, sulfone class, nitrile, ketones solvent.
5. preparation method according to claim 4, it is characterized in that: described inert solvent is toluene, ether, tetrahydrofuran (THF), methylene dichloride, chloroform, ethyl acetate, N, at least one in dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile, acetone.
6. preparation method according to claim 2, it is characterized in that: the consumption of described compound (VI) is 1 ~ 1.5 times of compound (V) amount of substance, described lewis acidic consumption is 2 ~ 5 times of compound (V) amount of substance, temperature of reaction is 20 ~ 80 DEG C, and the reaction times is 8 ~ 24h.
7. preparation method according to claim 6, is characterized in that: described lewis acidic consumption is 2 ~ 3 times of compound (V) amount of substance, and temperature of reaction is 20 ~ 50 DEG C, and the reaction times is 16 ~ 24h.
8. preparation method according to claim 1, is characterized in that, prepares compound (I) comprise the following steps described in step (2) by compound (VII):
By compound (VII) and compound (VIII)
add in the system of alcohol, then add hydrochloric acid soln, be slowly warmed up to 55 ~ 65 DEG C, reaction 5 ~ 7h, drop to room temperature, carry out extracting, wash, dry, purifying, to obtain final product.
9. preparation method according to claim 8, it is characterized in that: described alcohol is at least one in methyl alcohol, ethanol, Virahol, propyl carbinol, 1 ~ 1.5 times of the amount that described compound (VIII) is formula (VII) combinations of materials, in described hydrochloric acid, HCl content is 2 ~ 4 times of the amount of formula (VII) combinations of materials.
10. preparation method according to claim 1, is characterized in that, prepares compound (I) comprise the following steps described in step (2) by compound (VII):
1) compound (VII) and compound (VIII ')
react in the system of alcohol, obtain (Ⅸ)
; The consumption of compound (VIII ') is 1 ~ 1.5 times of compound (VII) amount of substance, temperature of reaction 60 ~ 70 DEG C, reaction times 5 ~ 10h;
2) gained compound (Ⅸ) and acid are added in the system of alcohol or chloroparaffin carry out deprotection reaction and obtain compound (Ⅹ)
; The effective level of acid is 1 ~ 1.5 times of compound (Ⅸ) amount of substance, and temperature of reaction is 20 ~ 30 DEG C, and the reaction times is 5 ~ 10h;
3) gained compound (Ⅹ), acrylate chloride and alkali are obtained by reacting compound (I) in the system of chloroparaffin, i.e. Rociletinib; The consumption of acrylate chloride is 1 ~ 1.5 times of compound (Ⅹ) amount of substance, and the consumption of alkali is 2 ~ 3 times of compound (Ⅹ) amount of substance, and temperature of reaction is 20 ~ 30 DEG C, and the reaction times is 4 ~ 5h.
11. preparation methods according to claim 10, is characterized in that, step 1) or 2) described alcohol is at least one in methyl alcohol, ethanol, Virahol and n-propyl alcohol; Step 2) described acid is hydrochloric acid or trifluoroacetic acid; Alkali described in step 3) is at least one in sodium carbonate, sodium bicarbonate, pyridine, triethylamine and diisopropylethylamine; Chloroparaffin described in step 3) is at least one in methylene dichloride, chloroform and 1,2-ethylene dichloride.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105481779A (en) * | 2015-12-24 | 2016-04-13 | 南京华威医药科技开发有限公司 | Anti-cancer drug Rociletinib and preparation of intermediate thereof |
| WO2017049992A1 (en) * | 2015-09-25 | 2017-03-30 | 浙江博生医药有限公司 | Egfr kinase inhibitor and preparation method and use thereof |
| CN114213339A (en) * | 2021-12-20 | 2022-03-22 | 苏州康纯医药科技有限公司 | Preparation method of epidermal cell growth factor receptor mutation inhibitor |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103269704A (en) * | 2010-11-01 | 2013-08-28 | 西建阿维拉米斯研究公司 | Heterocyclic compounds and their uses |
| WO2014182593A1 (en) * | 2013-05-06 | 2014-11-13 | Clovis Oncology, Inc. | Salts of an epidermal growth factor receptor kinase inhibitor |
| CN104284584A (en) * | 2012-03-15 | 2015-01-14 | 西建阿维拉米斯研究公司 | Salts of epidermal growth factor receptor kinase inhibitors |
| WO2015117547A1 (en) * | 2014-02-04 | 2015-08-13 | Jiangsu Medolution Limited | Substituted pyrimidines useful as egfr-t790m kinase inhibitors |
| CN104860890A (en) * | 2015-04-29 | 2015-08-26 | 上海泓博智源医药技术有限公司 | T790M mutant epidermal growth factor receptor (EGFR) inhibitor and application of same in preparation of antitumor drugs |
| WO2015158310A1 (en) * | 2014-04-18 | 2015-10-22 | 山东轩竹医药科技有限公司 | Tyrosine kinase inhibitor and uses thereof |
| CN105198821A (en) * | 2015-10-26 | 2015-12-30 | 苏州明锐医药科技有限公司 | Preparation method of Rociletinib |
-
2015
- 2015-12-02 CN CN201510871586.3A patent/CN105461640B/en not_active Expired - Fee Related
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103269704A (en) * | 2010-11-01 | 2013-08-28 | 西建阿维拉米斯研究公司 | Heterocyclic compounds and their uses |
| CN104284584A (en) * | 2012-03-15 | 2015-01-14 | 西建阿维拉米斯研究公司 | Salts of epidermal growth factor receptor kinase inhibitors |
| WO2014182593A1 (en) * | 2013-05-06 | 2014-11-13 | Clovis Oncology, Inc. | Salts of an epidermal growth factor receptor kinase inhibitor |
| WO2015117547A1 (en) * | 2014-02-04 | 2015-08-13 | Jiangsu Medolution Limited | Substituted pyrimidines useful as egfr-t790m kinase inhibitors |
| WO2015158310A1 (en) * | 2014-04-18 | 2015-10-22 | 山东轩竹医药科技有限公司 | Tyrosine kinase inhibitor and uses thereof |
| CN104860890A (en) * | 2015-04-29 | 2015-08-26 | 上海泓博智源医药技术有限公司 | T790M mutant epidermal growth factor receptor (EGFR) inhibitor and application of same in preparation of antitumor drugs |
| CN105198821A (en) * | 2015-10-26 | 2015-12-30 | 苏州明锐医药科技有限公司 | Preparation method of Rociletinib |
Non-Patent Citations (2)
| Title |
|---|
| 张姗等: "CO-1686的合成", 《中国医药工业杂志》 * |
| 杨爱萍等: "《有机化学》", 31 December 2011, 北京：中国农业出版社 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017049992A1 (en) * | 2015-09-25 | 2017-03-30 | 浙江博生医药有限公司 | Egfr kinase inhibitor and preparation method and use thereof |
| US10710979B2 (en) | 2015-09-25 | 2020-07-14 | Zhejiang Bossan Pharmaceutical Co. Ltd. | EGFR kinase inhibitor and preparation method and use thereof |
| CN105481779A (en) * | 2015-12-24 | 2016-04-13 | 南京华威医药科技开发有限公司 | Anti-cancer drug Rociletinib and preparation of intermediate thereof |
| CN114213339A (en) * | 2021-12-20 | 2022-03-22 | 苏州康纯医药科技有限公司 | Preparation method of epidermal cell growth factor receptor mutation inhibitor |
| CN114213339B (en) * | 2021-12-20 | 2023-10-31 | 苏州康纯医药科技有限公司 | Preparation method of epidermal cell growth factor receptor mutation inhibitor |
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