CN113583001A - 依鲁替尼的制备 - Google Patents
依鲁替尼的制备 Download PDFInfo
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- CN113583001A CN113583001A CN202110793515.1A CN202110793515A CN113583001A CN 113583001 A CN113583001 A CN 113583001A CN 202110793515 A CN202110793515 A CN 202110793515A CN 113583001 A CN113583001 A CN 113583001A
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- phenoxyphenyl
- ibrutinib
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- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 title claims abstract description 26
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 title claims abstract description 25
- 229960001507 ibrutinib Drugs 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- HNIMEQCLCNSCGH-UHFFFAOYSA-N 3-amino-5-(4-phenoxyphenyl)-1h-pyrazole-4-carbonitrile Chemical compound NC1=NNC(C=2C=CC(OC=3C=CC=CC=3)=CC=2)=C1C#N HNIMEQCLCNSCGH-UHFFFAOYSA-N 0.000 claims abstract description 7
- ZIYCMWSAXJKKHX-GOSISDBHSA-N 5-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]pyrazole-4-carbonitrile Chemical compound Nc1c(C#N)c(nn1[C@@H]1CCCN(C1)C(=O)C=C)-c1ccc(Oc2ccccc2)cc1 ZIYCMWSAXJKKHX-GOSISDBHSA-N 0.000 claims abstract description 7
- 238000006482 condensation reaction Methods 0.000 claims abstract description 7
- GEXJGXKSILFZQH-ZETCQYMHSA-N 1-[(3S)-3-hydroxypiperidin-1-yl]prop-2-en-1-one Chemical compound O[C@@H]1CN(CCC1)C(C=C)=O GEXJGXKSILFZQH-ZETCQYMHSA-N 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 3
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 claims description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 3
- 238000006751 Mitsunobu reaction Methods 0.000 claims 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 208000016025 Waldenstroem macroglobulinemia Diseases 0.000 description 4
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 4
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 4
- -1 4-phenoxyphenyl Chemical group 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NTSAEGNFPKKRLX-LJQANCHMSA-N tert-butyl (3r)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC[C@H]1N1C2=NC=NC(N)=C2C(C=2C=CC(OC=3C=CC=CC=3)=CC=2)=N1 NTSAEGNFPKKRLX-LJQANCHMSA-N 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- QUKPALAWEPMWOS-UHFFFAOYSA-N 1h-pyrazolo[3,4-d]pyrimidine Chemical group C1=NC=C2C=NNC2=N1 QUKPALAWEPMWOS-UHFFFAOYSA-N 0.000 description 2
- IRVRZQLHMPWLLY-UHFFFAOYSA-N 2-[methoxy-(4-phenoxyphenyl)methylidene]propanedinitrile Chemical compound C1=CC(C(=C(C#N)C#N)OC)=CC=C1OC1=CC=CC=C1 IRVRZQLHMPWLLY-UHFFFAOYSA-N 0.000 description 2
- YYVUOZULIDAKRN-UHFFFAOYSA-N 3-(4-phenoxyphenyl)-2h-pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C=12C(N)=NC=NC2=NNC=1C(C=C1)=CC=C1OC1=CC=CC=C1 YYVUOZULIDAKRN-UHFFFAOYSA-N 0.000 description 2
- HQAIUXZORKJOJY-UHFFFAOYSA-N 3-iodo-2h-pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound NC1=NC=NC2=NNC(I)=C12 HQAIUXZORKJOJY-UHFFFAOYSA-N 0.000 description 2
- RYAQFHLUEMJOMF-UHFFFAOYSA-N 4-phenoxybenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1OC1=CC=CC=C1 RYAQFHLUEMJOMF-UHFFFAOYSA-N 0.000 description 2
- 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 description 2
- 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007859 condensation product Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 201000003444 follicular lymphoma Diseases 0.000 description 2
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 description 2
- 208000021937 marginal zone lymphoma Diseases 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- LHCPRYRLDOSKHK-UHFFFAOYSA-N 7-deaza-8-aza-adenine Chemical compound NC1=NC=NC2=C1C=NN2 LHCPRYRLDOSKHK-UHFFFAOYSA-N 0.000 description 1
- 229940125814 BTK kinase inhibitor Drugs 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000005577 Kumada cross-coupling reaction Methods 0.000 description 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 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
- 102000015098 Tumor Suppressor Protein p53 Human genes 0.000 description 1
- 108010078814 Tumor Suppressor Protein p53 Proteins 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- ANSXAPJVJOKRDJ-UHFFFAOYSA-N furo[3,4-f][2]benzofuran-1,3,5,7-tetrone Chemical compound C1=C2C(=O)OC(=O)C2=CC2=C1C(=O)OC2=O ANSXAPJVJOKRDJ-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011125 single therapy Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
本发明涉及依鲁替尼的制备工艺。具体为化合物式I(5‑氨基‑3‑(4‑苯氧基苯基)‑1H‑吡唑‑4‑甲腈)和化合物式II((S)‑1‑(3‑羟基哌啶‑1‑基)丙‑2‑烯‑1‑酮)发生Mitsunobu缩合反应，得到化合物式III((R)‑1‑(1‑丙烯酰基哌啶‑3‑基)‑5‑氨基‑3‑(4‑苯氧基苯基)‑1H‑吡唑‑4‑甲腈),随后化合物式III和甲酰胺反应，制备得到依鲁替尼。
Description
技术领域
本发明属于医药技术及药物合成领域，更具体的说涉及依鲁替尼的制备方法。
背景技术
Ibrutinib(依鲁替尼)是一种口服的布鲁顿酪氨酸激酶(BTK)抑制药，中文化学名为1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)1H-吡唑并[3，4-d]嘧啶-1-基]-1-哌啶基]-2丙烯-1-酮。依鲁替尼可与BTK活性位点上的半胱氨酸残基(Cys-481)选择性地共价结合，不可逆地抑制BTK的活性，进而抑制BCR信号通路的激活，有效阻止肿瘤从B细胞迁移至适宜肿瘤生长的淋巴组织，减少B细胞恶性增殖并诱导细胞的凋亡，从而发挥治疗CLL和MCL的作用。此外，依鲁替尼单药及组合疗法针对广泛类型的血液***恶性肿瘤展现出了强大的疗效，包括慢性淋巴细胞白血病(CLL)、套细胞淋巴瘤(MCL)、Waldenstrom巨球蛋白血症(WM)、弥漫性大B细胞淋巴癌(CLBCL)、滤泡性淋巴瘤(FL)、多发性骨髓瘤(MM)及边缘区淋巴瘤(MZL)等。美国食品药品管理局(FDA)于2013年11月13日加速审批和批准了依鲁替尼的上市申请，剂型为140mg胶囊，商品名Imbruvica，用于治疗套细胞淋巴瘤。2014年2月12日FDA授予依鲁替尼突破性治疗药物的资格，批准依鲁替尼用于先前接受过至少一种药物治疗的慢性淋巴细胞白血病(chroniclymphocytic leukemia，CLL)患者，这是FDA推出突破性新药新政以来，第2个获准享此待遇的药品。自2014年10月，依鲁替尼先后三次获得欧盟EMA的上市批准，治疗复发性或难治性MCL、同时治疗CLL、携带del17p删除突变或TP53突变的CLL、Waldenstrom巨球蛋白血症(WM)。2015年依鲁替尼获得日本PMDA的批准，治疗复发或难治性的CLL。
依鲁替尼的化学名为1-[(3R)-3-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-D]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮，其分子结构中含有吡唑并[3,4-D]嘧啶基团和哌啶基团，同时含有一个手性中心。依鲁替尼的化学结构式如下：
依鲁替尼原研的合成路线(WO2013003629)以4-苯氧基苯甲酸出发，经多步反应实现依鲁替尼的制备。4-苯氧基苯甲酸先后与氯化亚砜、丙二腈反应得到中间体2-(羟基4-苯氧基苯基)甲烯基丙二腈；2-(羟基4-苯氧基苯基)甲烯基丙二腈在氮气保护下与三甲基硅烷基重氮甲烷反应得到中间体2-(甲氧基(4-苯氧基苯基)甲烯基)丙二腈；2-(甲氧基(4-苯氧基苯基)甲烯基)丙二腈与水合肼进行吡唑环化反应得到中间体5-氨基-3-(4-苯氧基苯基)-1H-吡唑-4-甲腈；5-氨基-3-(4-苯氧基苯基)-1H-吡唑-4-甲腈在氮气保护下与甲酰胺进行嘧啶环化反应得到中间体3-(4-苯氧基苯基)-1H-吡唑并[3，4-d]嘧啶-4-胺；3-(4-苯氧基苯基)-1H-吡唑并[3，4-d]嘧啶-4-胺和Boc保护的3-羟基哌啶发生Mitsunobu偶合反应得到缩合产物(R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯；缩合产物脱去Boc保护基后与丙烯酰氯反应制得依鲁替尼。相关合成路线如下：
专利CN104557945描述了(R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯的另外一条合成路线。该路线以1H-吡唑[3,4-d]嘧啶-4-胺为起始物料，经碘代反应制备得到3-碘-1H-吡唑[3,4-d]嘧啶-4-胺；3-碘-1H-吡唑[3,4-d]嘧啶-4-胺再和Boc保护的3-羟基哌啶发生Mitsunobu缩合反应，制备得到(R)-3-(4-氨基-3-碘-1H-吡唑[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯；(R)-3-(4-氨基-3-碘-1H-吡唑[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯在ZnCl2/Pd2(dba)3作用下和4-PhOPhMgBr发生偶联发应(Kumada偶联反应)，实现(R)-3-(4-氨基-3-(4-苯氧基苯基)-1H-吡唑[3,4-d]嘧啶-1-基)哌啶-1-甲酸叔丁酯的制备。该路线虽然可以规避对水/空气敏感且易***存在安全隐患的三甲基硅烷基重氮甲烷的使用，但是涉及到使用昂贵的贵金属催化剂Pd2(dba)3。相关合成路线如下：
发明内容
本发明的目的在于提供一条制备依鲁替尼的合成方法，旨在规避目前合成依鲁替尼的专利壁垒和缺陷。
本发明的技术路线为，化合物式I(5-氨基-3-(4-苯氧基苯基)-1H-吡唑-4-甲腈)和化合物式II((S)-1-(3-羟基哌啶-1-基)丙-2-烯-1-酮)发生Mitsunobu缩合反应，得到化合物式III((R)-1-(1-丙烯酰基哌啶-3-基)-5-氨基-3-(4-苯氧基苯基)-1H-吡唑-4-甲腈),随后化合物式III和甲酰胺反应，制备得到依鲁替尼。具体反应式如下：
步骤1涉及的Mitsunobu缩合反应条件是在PPh3存在下和在缩合剂包括DEAD、EDCI、HOBT、DIAD存在下，将化合物式I和化合物式III缩合，制备得到化合物式III。
步骤1涉及的Mitsunobu缩合反应的溶剂包括THF,Dioxane,CH3CN,2-Me-THF。
步骤1涉及的构建吡唑并[3,4-D]嘧啶环的反应所使用的溶剂包括DMF,Dioxane,DMSO,CH3CN,甲苯等。
具体实施方式
应该理解，本领域技术人员给予此处公开的内容，可以对本发明进行各种不偏离本发明精神和范围内的各种修改和改进。它们都应当落在本申请的权利要求定义的专利保护范围内。此外，应该理解，此处提供的实施例仅用于说明发明的目的，而不应理解为对本发明的限制。
下面结合具体实施例对本发明进一步详细描述。
实施例1制备(R)-1-(1-丙烯酰基哌啶-3-基)-5-氨基-3-(4-苯氧基苯基)-1H-吡唑-4-甲腈
5L反应瓶，配备磁力搅拌和温度计。氮气保护下，向反应瓶中加入化合物式I(5-氨基-3-(4-苯氧基苯基)-1H-吡唑-4-甲腈)(120g,434.3mmol)和无水Dioxane(1.5L),搅拌使体系呈完全均匀的溶液。然后向体系中加入化合物式II((S)-1-(3-羟基哌啶-1-基)丙-2-烯-1-酮)(80.9g,521.3mmol)和Ph3P(284.8g,1.086mol)。加入完毕后体系降温至<0℃,然后通过滴液漏斗向反应体系中加入DIAD(220g,1.088mmol)。加入完毕后，体系自然升温至室温反应，反应至HPLC跟踪反应至5-氨基-3-(4-苯氧基苯基)-1H-吡唑-4-甲腈基本反应完全。反应完毕后，体系在高真空条件下减压脱除有机溶剂，然后向反应体系中加入H2O(1.0L),随后体系用稀盐酸调节体系pH值至6.0-7.0之间。体系使用二氯甲烷萃取(3×1.5L),合并有机相，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压脱除溶剂，残余物柱层析纯化，得化合物式III((R)-1-(1-丙烯酰基哌啶-3-基)-5-氨基-3-(4-苯氧基苯基)-1H-吡唑-4-甲腈)(152.9g,85.3％)。
实施例2制备依鲁替尼
反应瓶中依次加入化合物式III((R)-1-(1-丙烯酰基哌啶-3-基)-5-氨基-3-(4-苯氧基苯基)-1H-吡唑-4-甲腈)(16.54g,40mmol)、甲酰胺(2.70g,59.95mmol)和DMF(150mL)。加入完毕后，体系升温至110℃回流，通过分水器分出含有DMF的溶剂(50mL)，体系自然降温至0℃，过滤，所得固体使用甲苯重结晶，得依鲁替尼(14.66g,83.2％)。
Claims (3)
1.制备依鲁替尼中间体(R)-1-(1-丙烯酰基哌啶-3-基)-5-氨基-3-(4-苯氧基苯基)-1H-吡唑-4-甲腈的方法，具体为化合物式I(5-氨基-3-(4-苯氧基苯基)-1H-吡唑-4-甲腈)和化合物式II((S)-1-(3-羟基哌啶-1-基)丙-2-烯-1-酮)发生Mitsunobu缩合反应，得到化合物式III((R)-1-(1-丙烯酰基哌啶-3-基)-5-氨基-3-(4-苯氧基苯基)-1H-吡唑-4-甲腈)。反应式如下：
2.如权利要求1所示的方法，反应涉及的Mitsunobu缩合反应条件是在PPh3存在下和在缩合剂包括DEAD、EDCI、HOBT、DIAD存在下，将化合物式I和化合物式III缩合。
3.如权利要求1所示的方法，反应涉及的Mitsunobu反应的溶剂包括THF,Dioxane,CH3CN,2-Me-THF。
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101805341A (zh) * | 2006-09-22 | 2010-08-18 | 药品循环公司 | 布鲁顿酪氨酸激酶的抑制剂 |
| WO2013003629A2 (en) * | 2011-06-28 | 2013-01-03 | Pharmacyclics, Inc. | Methods and compositions for inhibition of bone resorption |
| CN103626774A (zh) * | 2013-11-20 | 2014-03-12 | 苏州明锐医药科技有限公司 | 伊鲁替尼的制备方法 |
| CN104557945A (zh) * | 2015-01-27 | 2015-04-29 | 安润医药科技（苏州）有限公司 | 依鲁替尼合成方法 |
| CN105859728A (zh) * | 2016-05-26 | 2016-08-17 | 江苏中邦制药有限公司 | 一种依鲁替尼的制备方法 |
| CN106008526A (zh) * | 2016-06-17 | 2016-10-12 | 上海北卡医药技术有限公司 | 一种依鲁替尼的制备方法 |
-
2021
- 2021-07-13 CN CN202110793515.1A patent/CN113583001A/zh active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101805341A (zh) * | 2006-09-22 | 2010-08-18 | 药品循环公司 | 布鲁顿酪氨酸激酶的抑制剂 |
| WO2013003629A2 (en) * | 2011-06-28 | 2013-01-03 | Pharmacyclics, Inc. | Methods and compositions for inhibition of bone resorption |
| CN103626774A (zh) * | 2013-11-20 | 2014-03-12 | 苏州明锐医药科技有限公司 | 伊鲁替尼的制备方法 |
| CN104557945A (zh) * | 2015-01-27 | 2015-04-29 | 安润医药科技（苏州）有限公司 | 依鲁替尼合成方法 |
| CN105859728A (zh) * | 2016-05-26 | 2016-08-17 | 江苏中邦制药有限公司 | 一种依鲁替尼的制备方法 |
| CN106008526A (zh) * | 2016-06-17 | 2016-10-12 | 上海北卡医药技术有限公司 | 一种依鲁替尼的制备方法 |
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