CN117343068A - 一种FGFR2抑制剂Lirafugratinib(RLY-4008)的制备方法 - Google Patents
一种FGFR2抑制剂Lirafugratinib(RLY-4008)的制备方法 Download PDFInfo
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- CN117343068A CN117343068A CN202311277749.6A CN202311277749A CN117343068A CN 117343068 A CN117343068 A CN 117343068A CN 202311277749 A CN202311277749 A CN 202311277749A CN 117343068 A CN117343068 A CN 117343068A
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- 229940125831 FGFR2 inhibitor Drugs 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- XOQVZSSDIQQUGO-UHFFFAOYSA-N CC1=NC(=NC=C1)OC2=C(C=C(C=C2)C3=C(N(C4=NC=NC(=C34)N)C)C5=CC=C(C=C5)NC(=O)C(=C)C)F Chemical compound CC1=NC(=NC=C1)OC2=C(C=C(C=C2)C3=C(N(C4=NC=NC(=C34)N)C)C5=CC=C(C=C5)NC(=O)C(=C)C)F XOQVZSSDIQQUGO-UHFFFAOYSA-N 0.000 title claims description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims abstract description 6
- MBUPVGIGAMCMBT-UHFFFAOYSA-N 2-bromo-1-(4-nitrophenyl)ethanone Chemical compound [O-][N+](=O)C1=CC=C(C(=O)CBr)C=C1 MBUPVGIGAMCMBT-UHFFFAOYSA-N 0.000 claims abstract description 3
- VHRYZQNGTZXDNX-UHFFFAOYSA-N methacryloyl chloride Chemical compound CC(=C)C(Cl)=O VHRYZQNGTZXDNX-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000005915 ammonolysis reaction Methods 0.000 claims abstract 5
- 238000007069 methylation reaction Methods 0.000 claims abstract 5
- 238000005658 halogenation reaction Methods 0.000 claims abstract 4
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract 3
- 230000026030 halogenation Effects 0.000 claims abstract 3
- 230000011987 methylation Effects 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 41
- -1 5- (2-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -7-methyl-6- (4-nitrophenyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine Chemical compound 0.000 claims description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 9
- 239000011734 sodium Substances 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 229910021529 ammonia Inorganic materials 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 5
- AWFOZCHHTUUXAI-UHFFFAOYSA-N 6-(4-nitrophenyl)-1,7-dihydropyrrolo[2,3-d]pyrimidin-4-one Chemical compound C=1C=2C(O)=NC=NC=2NC=1C1=CC=C([N+]([O-])=O)C=C1 AWFOZCHHTUUXAI-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 4
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- HAXXOPWEDLHULE-UHFFFAOYSA-N ethyl 2-amino-5-(4-nitrophenyl)-1h-pyrrole-3-carboxylate Chemical compound N1C(N)=C(C(=O)OCC)C=C1C1=CC=C([N+]([O-])=O)C=C1 HAXXOPWEDLHULE-UHFFFAOYSA-N 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 15
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 9
- 238000000034 method Methods 0.000 claims 8
- 238000000746 purification Methods 0.000 claims 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 6
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 6
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- 238000001953 recrystallisation Methods 0.000 claims 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 5
- 238000010009 beating Methods 0.000 claims 5
- 239000003054 catalyst Substances 0.000 claims 5
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 4
- 239000003153 chemical reaction reagent Substances 0.000 claims 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims 3
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims 3
- 239000007810 chemical reaction solvent Substances 0.000 claims 3
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- 230000035484 reaction time Effects 0.000 claims 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims 2
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- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims 2
- 125000003277 amino group Chemical group 0.000 claims 2
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- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims 2
- 238000004537 pulping Methods 0.000 claims 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 2
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- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims 1
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- C07D487/04—Ortho-condensed systems
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Abstract
本发明属药物化学合成技术领域，具体为一种FGFR2抑制剂Lirafugratinib(RLY‑4008)的制备方法。本发明合成方法反应步骤为：由2‑溴代对硝基苯乙酮与3‑脒基丙酸乙酯盐酸盐反应，再与甲酰胺(甲脒)关环得到关键中间体4‑羟基‑6‑(4‑硝基‑苯基)‑7H‑吡咯并[2,3‑d]嘧啶，经卤代、氨解、甲基化、suzuki偶联反应、还原、最终与甲基丙烯酰氯反应得到Lirafugratinib(RLY‑4008)。
Description
技术领域
本发明属于药物化学合成领域，涉及一种FGFR2抑制剂Lirafugratinib(RLY-4008)的新的制备方法。
背景技术
胆管癌(CCA)作为一种罕见的恶性肿瘤，预后较差。恶性程度和公认的癌王胰腺癌不相上下。这类癌症及时接受手术治疗，3年复发率也达到85％，患者5年生存率仅有约5％；而无法手术切除的患者5年生存率一度低至0。FGFR2是一种受体酪氨酸激酶，FGFR家族的四个成员之一，是一组密切相关的蛋白质，具有高度相似的蛋白质序列和特性，在许多癌症中经常发生突变，包括肝内胆管癌(10％-16％)、子宫内膜癌(7.5％-11％)、胃或胃食管交界处腺癌(3.7％-7.9％)等。FGFR2的致癌激活可以通过基因扩增、激活突变或染色体重排,胆管癌的FGFR2融合/重排发生率为10-15％的。之前的非选择性FGFR抑制剂通过实现20-40％的客观缓解率(ORR)和5-9个月的缓解持续时间(DOR)验证了FGFR作为CCA的治疗靶点。但是泛FGFR抑制剂(Infigratinib，Pemigatinib，Futibatinib)的二线治疗患者常常出现高磷血症和腹泻等不良反应，同时还会发生FGFR2耐药突变，需要多方面调整剂量，难已达到药物最佳剂量，对于FGFR2的选择性抑制有望提供优越的目标覆盖率，从而大幅提高药物疗效。
尽管在基于结构的药物设计方面进行了大量研究，但FGFR2的选择性靶向仍然存在未知的类似于FGFR1、FGFR3和FGFR4的激酶结构域，RLY-4008是第一个高选择性、强效的FGFR2抑制剂，基于独特的构象动力学选择性地针对驱动程序改变和FGFR抗性突变，具有更强的敏感性和体内活性。RLY-4008的I/II期临床试验结果显示治疗胆管癌的有效率达到了88％，且没有显示出高磷血症(FGFR1)和腹泻(FGFR4)的非目标毒性的限制。这些初步数据表明，RLY-4008具有可控的安全性，并能推动多种FGFR2突变和肿瘤类型的肿瘤消退。
发明内容
鉴于上述情况，FGFR2抑制剂Lirafugratinib(RLY-4008)的制备非常重要。本发明人通过实验研究解决了该化合物的技术问题，其反应路线如下：
具体实验方式
下面通过实施例对本发明作进一步描述说明，但并不因此而限制本发明的内容。
实例1:
步骤A
将化合物3-脒基丙酸乙酯盐酸盐(8.3g,50.0mmol)和NaOEt(5.1g,75.0mmol)溶于无水乙醇中，并在氩气条件下搅拌20min,将混合物加热至60℃，并在5分钟内分批加入2-溴代对硝基苯乙酮(6.1g,25.0mmol),反应1.5h后，混合物冷却至20℃，减压蒸发溶剂。残留物用蒸馏水(20mL)稀释，并用乙酸乙酯(3×80mL)萃取。有机层用水(3×20mL)和盐水(3×20mL)洗涤。合并的水溶液再用EtOAc(2×20mL)萃取。有机相MgSO4干燥，减压蒸干。残余物通过硅胶柱层析纯化得到2-氨基-5-(4-硝基苯基)-1H-吡咯-3-羧酸乙酯(4.14g，产率60％)。LC-MS(ESI)：m/z＝275.3[M+H]+.
步骤B
在无水DMF(28mL)溶液中加入甲酸(11.3mL)、2-氨基-5-(4-硝基苯基)-1H-吡咯-3-羧酸乙酯(4.60g，16.57mmol)和过量甲酰胺(75mL)，升温至120℃反应20小时。然后加入2-丙醇(12mL)，混合物冷却至20℃。过滤，用2-丙醇(10mL)和正己烷(2×15mL)洗涤，减压干燥，得到化合物4-羟基-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(2.52g，产率60％)。LC-MS(ESI)：m/z＝256.2[M+H]+
步骤C
将4-羟基-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(1.9g，7.43mmol)和POCl3(13.3mL)混合，在90℃下反应3小时。用冰盐浴冷却,然后加入水(60mL)。用NaOH(8M，80mL)将pH值调至12。过滤，用水和正戊烷洗涤，干燥后得到化合物4-氯-6-(4-硝基苯基)-7h-吡咯并[2,3-d]嘧啶(1.93g，产率92％)。LC-MS(ESI)：m/z＝274.7[M+H]+
步骤D
将4-氯-6-(4-硝基苯基)-7h-吡咯并[2,3-d]嘧啶(179mg，0.653mmol)和碳酸铯(319mg，0.980mmol)溶于无水DMF(2mL)中，在30min内加入碘甲烷(0.65mL，1.31mmol，2M在叔丁基甲基醚中)，溶液在室温下搅拌反应90min。用H2O(50mL)淬灭反应，并用EtOAc(2×30mL)萃取。合并的有机相用饱和NaHCO3(15mL)和饱和NaCl(20mL)洗涤，用无水硫酸钠干燥，过滤并浓缩。残余物通过硅胶柱层析纯化,得到化合物4-氯-7-甲基-6-(4-硝基苯基)-7h-吡咯并[2,3-d]嘧啶(169mg，产率90％)。LC-MS(ESI)：m/z＝288.7[M+H]+步骤E
将化合物4-氯-7-甲基-6-(4-硝基苯基)-7H-吡咯并[2,3-d]嘧啶(531g，1.84mol)悬浮于在氨水(30％H2O中，3.63L)中，在压力容器中搅拌下120℃反应18h，冷却到20℃，过滤，用H2O(1.80L)和甲醇(900mL)洗涤，干燥，得到化合物4-氨基-7-甲基-6-(4-硝基苯基)-7H-吡咯并[2,3-d]嘧啶(371g，产率75％)。LC-MS(ESI)：m/z＝269.3[M+H]+
步骤F
将化合物4-氨基-7-甲基-6-(4-硝基苯基)-7H-吡咯并[2,3-d]嘧啶(18.9g,70mmol)，N-碘代丁二酰亚胺溶于400mLDMF中，在室温黑暗环境中反应过夜，蒸干溶剂。将残留物悬浮于10％Na2SO3热溶液中，过滤，用热水洗涤两次，然后从乙醇中结晶得到化合物4-氨基-5-碘-7-甲基-6-(4-硝基苯基)-7H-吡咯并[2,3-d]嘧啶(27.7g，产率100％)。LC-MS(ESI)：m/z＝395.2[M+H]+
步骤G
在一个可密封的反应瓶中装入4-氨基-5-碘-7-甲基-6-(4-硝基苯基)-7H-吡咯并[2,3-d]嘧啶(122mg，0.31mmol)、2-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧代硼烷-2-基)苯氧基)-5-甲基嘧啶(122mg,0.373mmol)，加入Pd(DtBPF)Cl2(20.1mg，0.031mmol)、CsF(240mg，0.930mmol)、DMF(4mL)、H2O(0.5mL)和搅拌棒，抽换N2三次，混合物在90℃下搅拌反应2h。反应混合物在真空中浓缩。所得粗物质通过TLC纯化，真空浓缩后，得到化合物5-(2-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-6-(4-硝基苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(8.8mg，产率6％)。LC-MS(ESI)：m/z＝471.5[M+H]+
步骤H
在氩气条件下将5-(2-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-6-(4-硝基苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(0.2g，0.45mmol)和三乙基硅烷(0.45mmol)溶于乙醇(5mL)中，加入催化量的氯化钯(II)(10mol％)，将所得的混合物搅拌反应2h,蒸发溶剂，然后加水倾析,水相用二乙醚萃取,有机相经无水硫酸钠干燥，减压蒸干。残余物通过硅胶柱层析纯化得到5-(2-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-6-(4-胺基苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(0.14g，产率70％)。LC-MS(ESI)：m/z＝441.5[M+H]+
步骤I
将5-(2-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-6-(4-胺基苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(4.4g，10mmol)和甲基丙烯酰氯(1.06mL，11mmol)溶于THF(100mL)中在0℃氩气环境下搅拌,并用碳酸钾(1.38g 10mmol)处理。反应混合物搅拌2h，然后加入2M HCl并用乙酸乙酯萃取。水层进一步用乙酸乙酯(2×50mL)萃取，合并的有机相在无水硫酸钠干燥,通过旋转蒸发去除溶剂,粗产物经柱层析纯化得到化合物RLY-4008(4.1g，产率80％)；LC-MS(ESI)：m/z＝509.5[M+H]+.1H NMR(400MHz,DMSO-d6)δ1.95(s,3H),2.42(s,3H),3.59(s,3H),5.54(s,1H),5.80(s,1H),5.99(s,2H),7.09(d,1H),7.18(d,2H),7.26-7.50(m,3H),7.75(d,2H),8.21(s,1H),8.47(d,1H),9.94(s,1H).
实施例2
用与实施例1步骤A、B类似的方法得到化合物4-羟基-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶
步骤C
将化合物4-羟基-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(17.9g,70mmol)，N-碘代丁二酰亚胺溶于400mL DMF中，在室温黑暗环境中反应过夜，蒸干溶剂。将残留物悬浮于10％Na2SO3热溶液中，过滤，用热水洗涤两次，然后从乙醇中结晶得到化合物4-羟基-5-碘-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(28g，产率100％)。LC-MS(ESI)：m/z＝400.6[M+H]+
步骤D
将化合物4-羟基-5-碘-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(0.78g，2.03mmol)和三氯氧磷(10mL)的混合物回流反应3h,浓缩悬浮液，除去氧氯化磷,残留物用乙酸乙酯稀释，有机层用饱和NaHCO3水溶液洗涤无水硫酸钠干燥，减压蒸干,得到化合物4-氯-5-碘-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(0.16g，产率20％)。LC-MS(ESI)：m/z＝400.6[M+H]+
步骤E
将化合物4-氯-5-碘-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(260mg，0.65mmol)和碳酸铯(319mg，0.980mmol)溶于无水DMF(2mL)中，在30min内加入碘甲烷(0.65mL，1.31mmol，2M在叔丁基甲基醚中)，溶液在室温下搅拌反应90min。用H2O(50mL)淬灭反应，并用EtOAc(2×30mL)萃取。合并的有机相用饱和NaHCO3(15mL)和饱和NaCl(20mL)洗涤，用无水Na2SO4干燥，过滤并浓缩。残余物通过硅胶柱层析纯化,得到化合物4-氯-5-碘-7-甲基-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(215mg，产率80％)。LC-MS(ESI)：m/z＝414.6[M+H]+
步骤F
将化合物4-氯-5-碘-7-甲基-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(762g，1.84mol)悬浮于在氨水(30％H20中，3.63L)中，在压力容器中120℃搅拌下反应18h，冷却到20℃，过滤，用H20(1.80L)和甲醇(900mL)洗涤，干燥，得到化合物4-氨基-5-碘-7-甲基-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(545g，产率75％)。LC-MS(ESI)：m/z＝395.2[M+H]+
接下来的三步用与实施例1中同样的方法制备得到目标化合物RLY-4008。
实施例3
用与实施例1步骤A、B类似的方法得到化合物4-氯-6-(4-硝基苯基)-7h-吡咯并[2,3-d]嘧啶
步骤C
将化合物4-羟基-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(0.52g，2.03毫摩尔)和三氯氧磷(10mL)的混合物回流反应3小时,浓缩悬浮液，除去氧氯化磷,残留物用乙酸乙酯稀释，有机层用饱和NaHCO3水溶液洗涤无水硫酸钠干燥，减压蒸干,得到化合物4-氯-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(0.11g，产率20％)。LC-MS(ESI)：m/z＝274.7[M+H]+
步骤D
将化合物4-氯-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(19.2g,70mmol)，N-碘代丁二酰亚胺溶于400mL DMF中，在室温黑暗环境中反应过夜，蒸干溶剂。将残留物悬浮于10％Na2SO3热溶液中，过滤，用热水洗涤两次，然后从乙醇中结晶得到化合物4-氯-5-碘-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(27.5g，产率98％)。LC-MS(ESI)：m/z＝400.6[M+H]+
步骤E
将化合物4-氯-5-碘-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(260mg，0.65mmol)和碳酸铯(319mg，0.980mmol)溶于无水DMF(2mL)中，在30分钟内加入碘甲烷(0.65mL，1.31mmol，2M在叔丁基甲基醚中)，溶液在室温下搅拌反应90分钟。用H2O(50mL)淬灭反应，并用EtOAc(2×30mL)萃取。合并的有机相用饱和NaHCO3(15mL)和饱和NaCl(20mL)洗涤，用无水Na2SO4干燥，过滤并浓缩。残余物通过硅胶柱层析纯化,得到化合物4-氯-5-碘-7-甲基-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(238mg，产率88％)。LC-MS(ESI)：m/z＝414.6[M+H]+
步骤F
将化合物4-氯-5-碘-7-甲基-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(762g，1.84mol)悬浮于在氨水(30％，H2O中，3.63L)中，在压力容器中搅拌下120℃反应18h，冷却到20℃，过滤，用H20(1.80L)和甲醇(900mL)洗涤，干燥，得到化合物4-氨基-5-碘-7-甲基-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(545g，产率75％)。LC-MS(ESI)：m/z＝395.2[M+H]+
接下来的三步用与实施例1中同样的方法制备得到目标化合物RLY-4008。
实施例4
用与实施例1步骤A、B、C、D类似的方法得到化合物4-氯-7-甲基-6-(4-硝基苯基)-7h-吡咯并[2,3-d]嘧啶
步骤E
将化合物4-氯-7-甲基-6-(4-硝基苯基)-7h-吡咯并[2,3-d]嘧啶(20.21g，70mmol)，N-碘代丁二酰亚胺溶于400mLDMF中，在室温黑暗环境中反应过夜，蒸干溶剂。将残留物悬浮于10％Na2SO3热溶液中，过滤，用热水洗涤两次，然后从乙醇中结晶得到化合物4-氯-5-碘-7-甲基-6-(4-硝基苯基)-7h-吡咯并[2,3-d]嘧啶(27.65g，产率75％)。LC-MS(ESI)：m/z＝414.6[M+H]+
步骤F
将化合物4-氯-5-碘-7-甲基-6-(4-硝基苯基)-7h-吡咯并[2,3-d]嘧啶(763g，1.84mol)悬浮于在氨水(30％，H20，3.63L)中，在压力容器中搅拌下120℃反应18h，冷却到20℃，过滤，用H20(1.80L)和甲醇(900mL)洗涤，干燥，得到化合物4-氨基-5-碘-7-甲基-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶(545g，产率75％)。LC-MS(ESI)：m/z＝395.2[M+H]+。
接下来的三步用与实施例1中同样的方法制备得到目标化合物RLY-4008。
上述实例仅用于说明本发明的实施方式，但本发明不仅仅局限于上述实例。在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内，本发明要求保护范围由权利要求书及其等效物界定。
Claims (10)
1.一种FGFR2抑制剂Lirafugratinib(RLY-4008)的制备方法，其特征在于，具体步骤为：
1)由原料2-溴代对硝基苯乙酮与3-脒基丙酸乙酯盐酸盐进行反应得到2-氨基-5-(4-硝基苯基)-1H-吡咯-3-羧酸乙酯
2)经过的与过量甲酰胺反应得到4-羟基-6-(4-硝基-苯基)-7H-吡咯并[2,3-d]嘧啶
3)经卤代、氨解、甲基化制备得到化合物4-氨基-5-卤代-7-甲基-6-(4-硝基苯基)-7H-吡咯并[2,3-d]嘧啶
4)步骤3)中所得到的化合物经过与2-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧代硼烷-2-基)苯氧基)-5-甲基嘧啶的Suzuki偶联反应得到5-(2-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-6-(4-硝基苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺
5)将5-(2-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-6-(4-硝基苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺的硝基还原为胺基得到化合物5-(2-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-6-(4-胺基苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺
6)最后化合物5-(2-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-6-(4-胺基苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺中的胺基与甲基丙烯酰氯反应得到目标化合物RLY-4008。
2.如权利要求1所述的一种FGFR2抑制剂Lirafugratinib(RLY-4008)的制备方法，其特征在于，步骤(1)中，反应时间选自0-36h，温度选自10-120℃，溶剂选自乙醇、乙醚、二甲基亚砜、水、甲醇、二甲基甲酰胺或其他有机溶剂中的一种或者几种，纯化可以选自过柱、打浆或者重结晶。
3.如权利要求1所述的一种FGFR2抑制剂Lirafugratinib(RLY-4008)的制备方法，其特征在于，步骤(2)中,反应溶剂选自乙醚、乙腈、THF、DMF、DME、1,4-二氧六环、H2O、NMP、DMA、DMSO、苯、甲苯、氯苯、二苯甲醚、二甲苯、DCM、1,2-二氯乙烷中的一种或者几种。温度选自10-200℃，时间选自0-24h，酸选自三氟乙酸、乙酸、甲酸等中的一种或几种，纯化可以选过滤时洗涤滤饼、过柱、打浆或者重结晶。
4.如权利要求1所述的一种FGFR2抑制剂Lirafugratinib(RLY-4008)的制备方法，其特征在于，步骤(3)中卤代、氨解、甲基化反应顺序可以发生改变。
5.如权利要求1所述的一种FGFR2抑制剂Lirafugratinib(RLY-4008)的制备方法，其特征在于，步骤(3)甲基化反应中，反应温度选自0-200℃，反应时间为1-20h，溶剂选自乙醚、二甲基亚砜、水、甲醇、二甲基甲酰胺或其他有机溶剂中的一种或者几种，甲基化试剂选自三氟甲磺酸甲酯、三氟甲基磺酸甲酯、二甲基亚砜、甲基三氧化钴、碘甲烷、一卤代甲烷、甲醛与甲酸混合溶液、格氏试剂、甲基锌试剂或甲基酮试剂中的一种或者几种，所用的催化剂可选自氢氧化钾、氢氧化钠、碘化钠、碘化铜、碳酸铯等金属氧化物或其他碱性催化剂中的一种或几种，纯化可以选自过柱、打浆或者重结晶。
6.如权利要求1所述的一种FGFR2抑制剂Lirafugratinib(RLY-4008)的制备方法，其特征在于，步骤(3)中氨解反应中，反应溶剂选自DMF、水、乙醇中的一种或几种，反应温度选自50-120℃，时间选自0-24h，胺化剂可选自各种形式的氨、胺，以及它们碱金属盐、尿素、羟胺等中的一种。使用氨水芳香氯化物氨解时理论氨比约为10-17，纯化可以选自过柱、打浆或者重结晶。
7.如权利要求1所述的一种FGFR2抑制剂Lirafugratinib(RLY-4008)的制备方法，其特征在于，步骤(3)中卤代反应X为Br、I基团。反应中的卤代试剂选自NBS、Br2、PBr3、POBr3、CuBr、TBAB、二溴海因、NIS、I2、ICl中的一种或几种。反应温度为-50-30℃，反应时间为0-5h小时，反应溶剂选自THF、DME、MTBE、乙醚、丁醚等醚类溶剂和正己烷、正庚烷、正戊烷、石油醚、苯、甲苯等烃类溶剂中的一种或几种。
8.如权利要求1所述的一种FGFR2抑制剂Lirafugratinib(RLY-4008)的制备方法，其特征在于，步骤(4)中，suzuki偶联反应的反应温度选自10-200℃，反应时间选自0-72h，溶剂选自乙醚、乙腈、THF、DMF、DME、1,4-二氧六环、H2O、NMP、DMA、DMSO、苯、甲苯中的一种或者几种。反应所用的催化剂可选自为双(三苯基膦)-二氯化钯、二(三苯基膦)二茂铁二氯化钯、二(三苯基膦)二茂铁二氯化钯二氯甲烷复合物、Pd2(dba)3、pd(dppe)Cl2、四三苯基磷钯、二(三苯基膦)二茂铁二氯化镍中的一种或几种，化合物的0.01％-20％(M/M摩尔比)，反应中所用的碱选自三乙胺、乙二胺、二异丙基乙胺、咪唑、哌啶、吡啶、CsCO3、KOAc、NaOAc、K2CO3、Na2CO3、Li2CO3、tBuOK、tBuONa、K3PO4、NaOH、KOH、Ba(OH)2中的一种。用量的1-10倍(M/M摩尔比)。纯化可以选自过柱、打浆或者重结晶。
9.如权利要求1所述的一种FGFR2抑制剂Lirafugratinib(RLY-4008)的制备方法，其特征在于，步骤(5)中，硝基还原为胺基的反应中，反应温度选自50-120℃，溶剂选自水、乙醇、乙醚或其他有机溶剂中的一种或者几种，所用的催化剂可选自Ag、Ti、Zn、Al、Cu、Yb、Si、Na、K、Mg、Pd等贵金属催化剂中的一种，纯化可以选自过柱、打浆或者重结晶。
10.如权利要求1所述的一种FGFR2抑制剂Lirafugratinib(RLY-4008)的制备方法，其特征在于，步骤(6)中，最后一步与甲基丙烯酰氯的反应温度选自-50-100℃，反应时间选自0-24h，溶剂选自DCM、1,2-二氯乙烷，氯苯、乙腈、THF、2-MeTHF、DMF、DME、1,4-二氧六环、H2O、NMP、DMAC、DMSO中的一种或几种,所用的碱选自三乙胺、乙二胺、二异丙基乙胺、咪唑、哌啶、吡啶、DMAP、CsCO3、KOAc、NaOAc、K2CO3、Na2CO3中的一种或几种，产品纯化可以选自过柱子、打浆、Prep-TLC、Prep-HPLC或者重结晶。
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