CN104356112A - 一种色瑞替尼的制备方法 - Google Patents
一种色瑞替尼的制备方法 Download PDFInfo
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- VERWOWGGCGHDQE-UHFFFAOYSA-N ceritinib Chemical compound CC=1C=C(NC=2N=C(NC=3C(=CC=CC=3)S(=O)(=O)C(C)C)C(Cl)=CN=2)C(OC(C)C)=CC=1C1CCNCC1 VERWOWGGCGHDQE-UHFFFAOYSA-N 0.000 title abstract description 10
- 229960001602 ceritinib Drugs 0.000 title abstract description 6
- 238000000034 method Methods 0.000 title abstract description 5
- -1 BOC acid anhydride Chemical class 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 238000006722 reduction reaction Methods 0.000 claims abstract description 7
- 230000008878 coupling Effects 0.000 claims abstract description 6
- 238000005859 coupling reaction Methods 0.000 claims abstract description 6
- 238000010168 coupling process Methods 0.000 claims abstract description 5
- 125000006239 protecting group Chemical group 0.000 claims abstract description 5
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 7
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 108010001535 sulfhydryl oxidase Proteins 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 239000004323 potassium nitrate Substances 0.000 claims description 4
- 235000010333 potassium nitrate Nutrition 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- 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 4
- GMZKNRDHSHYMHG-UHFFFAOYSA-N 3-bromo-4-methylphenol Chemical compound CC1=CC=C(O)C=C1Br GMZKNRDHSHYMHG-UHFFFAOYSA-N 0.000 claims description 3
- 230000000802 nitrating effect Effects 0.000 claims description 3
- RSFWNLJMHKGRRM-UHFFFAOYSA-N 1,2,6-trichloro-2h-pyrimidine Chemical class ClC1N=CC=C(Cl)N1Cl RSFWNLJMHKGRRM-UHFFFAOYSA-N 0.000 claims description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 2
- 229940073608 benzyl chloride Drugs 0.000 claims description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000012286 potassium permanganate Substances 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 abstract description 4
- 238000007254 oxidation reaction Methods 0.000 abstract description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000006396 nitration reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 6
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 229940049068 xalkori Drugs 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 3
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 235000014121 butter Nutrition 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 150000003053 piperidines Chemical class 0.000 description 3
- UMLDUMMLRZFROX-UHFFFAOYSA-N pyridin-2-ylboronic acid Chemical compound OB(O)C1=CC=CC=N1 UMLDUMMLRZFROX-UHFFFAOYSA-N 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 230000008707 rearrangement Effects 0.000 description 2
- 229940052129 zykadia Drugs 0.000 description 2
- 101150023956 ALK gene Proteins 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- BQFFVVNEVALGAX-UHFFFAOYSA-N Cc(ccc(N=O)c1)c1Br Chemical compound Cc(ccc(N=O)c1)c1Br BQFFVVNEVALGAX-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 230000009286 beneficial effect 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
- 229910052796 boron Inorganic materials 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000010808 liquid waste Substances 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
-
- 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
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种色瑞替尼的制备方法，属于化学制药领域，以3-溴-4-甲基苯酚为起始原料经过酚羟基异丙基化、硝化、偶联、还原反应得到中间体1，再以邻硝基氟苯为另一起始原料经异巯基化、氧化、还原、嘧啶化得中间体2，1与2偶联反应得BOC酸酐保护的色瑞替尼，最后脱除叔丁氧羰基保护基得到色瑞替尼。本发明是一种操作简单易行，收率比较高，污染小，适合工业化生产的方法。
Description
技术领域
本发明属于化学制药领域，具体涉及一种色瑞替尼的制备方法。
背景技术
肺癌是导致癌症死亡的主要原因之一。非小细胞肺癌（NSCLC）占到了肺癌病例的85%-90%，其中2%-7%病例由ALK基因的重排（rearrangement）所驱动，导致癌细胞的加速生长。尽管ALK+NSCLC群体的临床治疗已取得显著进展，但病情恶化往往是不可避免的，因此需要更多的治疗选择。Xalkori是一种变性淋巴瘤激酶（ALK）抑制剂，于2011年获FDA加速批准，并于2013年获FDA正式批准，用于经FDA批准的一款检测试剂盒证实其肿瘤为间变性淋巴瘤激酶（ALK）阳性的转移性非小细胞肺癌（NSCLC）患者的治疗。
Xalkori是首个对间变性淋巴瘤激酶(ALK)进行靶向治疗的药物。目前，该药已获全球60多个国家批准，包括美国、欧盟、加拿大、中国、韩国、日本、澳大利亚。Xalkori的上市，已极大地改变了晚期ALK+NSCLC患者的临床治疗。
色瑞替尼,英文名：ceritinib,5-Chloro-N2-[2-isopropoxy-5- methyl-4-(4-piperidinyl) phenyl]-N4-[2-(isopropylsulfonyl)phenyl]-2,4-pyrimidinediamine,CAS号： 1032900-25-6,结构式如下：
诺华（Novartis）2014年4月29日宣布，抗癌药Zykadia（ceritinib）获FDA批准，用于经Xalkori（crizotinib）治疗后病情恶化或对Xalkori不耐受的间变性淋巴瘤激酶阳性（ALK+）转移性非小细胞肺癌（NSCLC）患者的治疗。此前，FDA已授予Zykadia突破性疗法认定。
目前市场上合成色瑞替尼中间体2,5-二氯-N-[2-[(1-甲基乙基)磺酰]苯基]-4-氨基嘧啶用双氧水氧化巯基，存在氧化不完全，收率低等缺点，还原硝基用二氧化铂还原虽然收率高，但是成本太高，不适合工业化生产，氨基接嘧啶，用LDA脱氢，存在温度过低，溶剂无水，条件苛刻，另一个中间体N-BOC-4-(4-氨基-5-异丙氧基-2-甲基苯基)哌啶，一般都做成吡啶硼酸与氯苯偶联再还原生成中间体，存在价格昂贵，收率低等缺点，首先吡啶硼酸价格昂贵，再把吡啶硼酸还原成哌啶用到二氧化铂，也难以工业化，硼酸与氯偶联，由于氯的活性比较低，导致原料反应不完全，收率低。
发明内容
本发明的目的是克服现有技术存在的收率低，难以产业化，成本高等缺点，提供一条工艺合理，步骤较少，操作简单，反应收率较高的色瑞替尼的化学合成方法。
本发明采取的技术方案为，一种色瑞替尼的制备方法，其特征在于，包括以下步骤：
1）以3-溴-4-甲基苯酚为起始原料经过酚羟基异丙基化、硝化、偶联、还原反应得到中间体1；
2）再以临硝基氟苯为另一起始原料经异巯基化、巯基氧化、硝基还原、2,3,4-三氯嘧啶取代得中间体2；
3）中间体 1与中间体2偶联反应得BOC酸酐保护的色瑞替尼，最后脱除叔丁氧羰基保护基得到色瑞替尼。
步骤1）中硝化所用的硝化试剂为浓硝酸、发烟硝酸、硝酸钾。优选硝酸钾。
步骤1）中所述的酚羟基异丙基化采用的异丙基化试剂为苄氧羰基氯、叔丁氧羰基氯或氯苄。优选叔丁氧羰基氯。
步骤2）中所述的巯基氧化中所用的氧化剂为双氧水、间氯过氧苯甲酸或高锰酸钾。优选间氯过氧苯甲酸。
步骤2）中所述的硝基还原中所用的还原剂为钯碳、铂碳、锌粉或铁粉。优选钯碳。
步骤3）中所述脱除叔丁氧羰基保护基所用的脱保护剂为：三氟乙酸、盐酸。优选三氟乙酸。
本发明的有益效果：
(1)本发明生产过程中产生废液通入酸碱池进行中和，再流入废水处理池进行废水处理，反应或后处理过程中涉及到的溶剂可通过蒸馏回收再利用，蒸馏完的残留物可通过管道送入焚烧炉焚烧。整个生产过程中的三废处理可基本保持封闭，对环境污染大大减少，而且溶剂的回收利用也可大大降低生产成本；
（2）本发明色瑞替尼的制备方法，所需原料及试剂价廉易得，成本低；
（3）本发明合成路线短，合成方法操作简单，条件温和，我们用间氯过氧苯甲酸代替双氧水，氧化完全，收率能大幅度提高，用溴苯代替氯苯，偶联反应活性提高，收率也提高了，同时避免了用二氧化铂还原吡啶环，降低成本，收率可达32%，纯度99%以上，适合工业化大生产，且产品质量稳定，符合作为原料药的要求。
具体实施方式
实施例1：邻异丙巯基硝基苯的制备
邻氟硝基苯（10g，10mmol），加DMF100ml，加入2-巯基异丙醇（5.4g，70mmol），碳酸钾25g，升温至100度反应16h，冷至室温，加入500ml水，乙酸乙酯（100ml*3）萃取，合并有机层，水洗涤，饱和食盐水洗涤，无水硫酸钠干燥，浓缩得淡黄油状物13.3g，收率大于100%，未纯化。
实施例2：2-(异丙基磺酰基)硝基苯的制备
邻异丙巯基硝基苯（13g，65.97mmol），二氯甲烷120ml，室温下分批加入间氯过氧苯甲酸（25.67g，149.42mmol），室温搅拌16h，过滤，浓缩干，得黄棕色固体12g，收率80%，未纯化。
实施例3：2-(异丙基磺酰基)苯胺的制备
2-(异丙基磺酰基)硝基苯（2g，8.73mmol），加甲醇30ml，10%钯碳0.2g，常压氢化6h，抽滤，浓缩旋去甲醇，得淡黄油状物1.5g，收率88%，未纯化。
实施例4：4-氨基嘧啶, 2,5-二氯-N-[2-[(1-甲基乙基)磺酰]苯基]-;2,5-二氯-N-[2-[(1-甲基乙基)磺酰]苯基]的制备
2-(异丙基磺酰基)苯胺（3g，14mmol），加DMF30ml，冰水浴下分批加入氢化钠（0.73g，30mmol），加毕，室温搅拌30min，加入2,4,5-三氯嘧啶（3.31g，18mmol），室温搅拌16h，冰水淬灭反应，乙酸乙酯萃取（30ml*3），合并有机层，水洗涤，食盐水洗涤，浓缩干得类白色固体1.7g，收率37%，以2-(异丙基磺酰基)苯胺计算。
实施例5：3-溴-4-甲基异丙氧基苯酚的制备
3-溴-4-甲基苯酚（18.7g，100mmol），2-溴丙烷（14.4g，110mmol），碳酸钾（15.1g，110mmol）,DMF100ml,100反应4h，冷至室温，加入水500ml，乙酸乙酯萃取（100ml*3），合并有机层，水洗浓缩干得棕色油状物21g，收率91.&%。未纯化，直接做下一步。
实施例6：1-氯-5-异丙氧基-2-甲基-4-硝基苯的制备
3-溴-4-甲基异丙氧基苯酚(20g,87.33mmol)，加入发烟硝酸100ml，室温搅拌2h，倒入1l碎冰中，析出淡黄色固体，抽滤，烘干得黄色固体19g，收率79.1%，未纯化，直接做下一步。
实施例7：N-BOC-4-(4-硝基-5-异丙氧基-2-甲基苯基)哌啶的合成
氮气保护下，1-氯-5-异丙氧基-2-甲基-4-硝基苯（27.4g，100mmol），4-(4,4,5,5-四甲基-1,3,2-二氧杂环硼戊烷-2-基)-哌啶-1-羧酸叔丁酯（34.4g，110mmol），2:1水/二氧六环 200ml，加入醋酸钯0.3g，回流反应1h，旋去大部分二氧六环，乙酸乙酯（100ml*3）,合并有机层水洗涤，食盐水洗涤，浓缩干得淡黄油状物32g，收率85.5%，未纯化，直接做下一步。
实施例8：N-BOC-4-(4-胺基-5-异丙氧基-2-甲基苯基)哌啶的合成
N-BOC-4-(4-硝基-5-异丙氧基-2-甲基苯基)哌啶（37.8g，100mmol），甲醇200ml，10%钯碳0.3g，常压氢化2h，抽滤浓缩干得淡棕油状物31g，收率80%，HPLC96%。
实施例9：色瑞替尼的合成
1 （1.7g，4.88mmol），2（1.69g，4.88mmol），醋酸钯55mg，碳酸铯4.7g，无水四氢呋喃40ml，回流2h，冷至室温，浓缩至干，加入100ml二氧甲烷，滴加20ml三氟乙酸，室温搅拌1h，20%氢氧化钠调节pH至 中性，加水100ml，搅拌片刻，分出有机层，食盐水洗涤，浓干得粗品色瑞替尼2g，乙腈精制得纯品色瑞替尼1.3g，乙腈重结晶得纯品1.5g。收率39%，以1计算。（MS(ES+) 559(M+1)+。
Claims (10)
1.一种色瑞替尼的制备方法，其特征在于，包括以下步骤：
1）以3-溴-4-甲基苯酚为起始原料经过酚羟基异丙基化、硝化、偶联、还原反应得到中间体1；
2）再以临硝基氟苯为另一起始原料经异巯基化、巯基氧化、硝基还原、2,3,4-三氯嘧啶取代得中间体2；
3）中间体 1与中间体2偶联反应得BOC酸酐保护的色瑞替尼，最后脱除叔丁氧羰基保护基得到色瑞替尼；
。
2.根据权利要求1所述的色瑞替尼的制备方法，其特征在于，步骤1）中硝化所用的硝化试剂为浓硝酸、发烟硝酸或硝酸钾。
3.根据权利要求2所述的色瑞替尼的制备方法，其特征在于，步骤1）中硝化所用的硝化试剂为硝酸钾。
4.根据权利要求1所述的色瑞替尼的制备方法，其特征在于，步骤1）中所述的酚羟基异丙基化采用的异丙基化试剂为苄氧羰基氯、叔丁氧羰基氯或氯苄。
5.根据权利要求4所述的色瑞替尼的制备方法，其特征在于，步骤1）中所述的酚羟基异丙基化采用的异丙基化试剂为叔丁氧羰基氯。
6.根据权利要求1所述的色瑞替尼的制备方法，其特征在于，步骤2）中所述的巯基氧化中所用的氧化剂为双氧水、间氯过氧苯甲酸或高锰酸钾。
7.根据权利要求6所述的色瑞替尼的制备方法，其特征在于，步骤2）中所述的巯基氧化中所用的氧化剂为间氯过氧苯甲酸。
8.根据权利要求1所述的色瑞替尼的制备方法，其特征在于，步骤2）中所述的硝基还原中所用的还原剂为钯碳、铂碳、锌粉或铁粉。
9.根据权利要求8所述的色瑞替尼的制备方法，其特征在于，步骤2）中所述的硝基还原中所用的还原剂为钯碳。
10.根据权利要求1所述的色瑞替尼的制备方法，其特征在于，步骤3）中所述脱除叔丁氧羰基保护基所用的脱保护剂为：三氟乙酸或盐酸。
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