CN111518016B - 一种csf1r抑制剂中间体及其制备方法 - Google Patents
一种csf1r抑制剂中间体及其制备方法 Download PDFInfo
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 229950004647 emactuzumab Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
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- 230000008595 infiltration Effects 0.000 description 1
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- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- JGWRKYUXBBNENE-UHFFFAOYSA-N pexidartinib Chemical compound C1=NC(C(F)(F)F)=CC=C1CNC(N=C1)=CC=C1CC1=CNC2=NC=C(Cl)C=C12 JGWRKYUXBBNENE-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract
本发明公开了一种具有抗肿瘤活性的CSF1R抑制剂化合物的中间体制备方法，所述化合物具有式I结构，本发明制备所得到的化合物对CSF1R具有高的抑制活性。
Description
本申请是分案申请，其母案的中国申请号是：201980005226.1，国际申请号是PCT/CN2019/088221，申请日是2019年05月24日。
本发明要求中国专利申请CN201810559228.2的优先权，该优先权文件的说明书、说明书附图和权利要求书所记载的内容全文引入本发明的说明书并被作为本发明说明书原始记载的一部分。申请人进一步声明，申请人拥有基于该优先权文件修改本发明的说明书和权利要求书的权利。
技术领域
本发明涉及杂环化合物，具体地涉及一种高活性的CSF1R抑制剂中间体的制备方法。
背景技术
CSF1R(colony stimulating factor 1 receptor)是巨噬细胞分化和募集过程中重要的细胞因子，由肿瘤细胞分泌。研究结果表明CSF1R抑制剂(抗体或小分子)可以降低肿瘤组织TAM(tumor-associated macrophages)浸润，有效抑制肿瘤的进展和转移，是肿瘤免疫治疗中一个新的热点。
由于其在破骨细胞生物学中的作用，CSF1R被认为是骨质疏松症和炎性关节炎的重要治疗靶标。例如，提高的M-CSF信号导致了升高的破骨细胞活性，这导致了伴随关节炎和其它炎性骨质侵蚀的骨丢失(参见Scott等人Rheumatology 2000,39:122-132,Ritchlin等人J.Clin.Invest.2003,111:821-831)。因此，CSF1R的抑制代表了对关节炎和其它炎性骨质侵蚀的具有前景的治疗方案，已知CSF1R抑制剂如Ki-20227和GW2580在关节炎动物模型中的效力数据进一步支持了这一点(参见Conwat等人JPET 2008,326:41-50和Ohno等人Eur.J.Immunol.2008,38:283-291)。导致骨质疏松症的破骨细胞发育的调节异常以及骨质侵蚀和骨生成之间平衡的破坏也可能通过对CSF1R的调节进行治疗。
目前进入临床的CSF1R抗体药物有BMS/FPRX的FPA008，罗氏的emactuzumab，礼来的LY3022855，安进的AMG820等，进入临床的CSF1R小分子药物有BLZ945，Plexxikon的PLX3397，Deciphera的DC-3014等。CSF1R抑制剂与免疫检查点抑制剂的联合用药项目还处于临床早期，国内还没有化合物进入临床申报。对于抑制CSF1R的小分子，特别是可用于治疗CSF1R-介导的疾病的化合物的鉴别存在着持续的需求。
发明内容
本发明提供了一种具有式(I)的化合物的制备方法：
其中，X表示CRaRa’、
NRa、-C(O)-、O、S、S(O)或S(O)2；R1和R2以及与之相连的碳原子共同环合成为饱和或不饱和的3-12元环烷基或杂环烷基，例如所述3-12元环烷基或杂环烷基可以是3、4、5、6、7、8、9、10、11或12元环，所述的杂环烷基中至少含有一个选自O、N和S原子的杂原子，例如1、2、3或4个杂原子，所述环烷基或者杂环烷基可以任意地被0、1、2、3或4个各自独立地选自下述R6的取代基所取代：卤素、羟基、C1-C8烷基、C3-C8环烷基、C3-C8杂环烷基、C2-C8烯基、C2-C8炔基、C1-C8卤代烷基、C1-C8烷氧基、C1-C8卤代烷氧基、C3-C8环烷氧基、C3-C8杂环烷氧基、-S-(C1-C8)烷基、-S-C3-C8环烷基、-S-C3-C8杂环烷基、氰基、硝基、-(C0-C8)烷基-NR9Ra’、-C＝NRa、-O-Cy1、-O-(C0-C8)烷基-Cy1、-(C2-C8)链烯基-Cy1、-(C2-C8)链炔基-Cy1、-C(O)ORa、-C(O)Ra、-O-C(O)Ra、-C(O)-NRaRa’、-NRa-C(O)-Ra、-NRa-C(O)-ORa、-(C1-C8)烷基-NRa-C(O)Ra、-SO2-NRaRa’和-SO2Ra；
R3和R5分别独立地表示氢、卤素、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、C3-C8杂环烷基、卤代C1-C8烷基、羟基、氨基、硝基、氰基、-C(O)ORa、-O-C(O)Ra、-C(O)-NRaRa’、-NRa-C(O)-Ra、-NRa-C(O)-ORa、-(C1-C8)烷基-NRa-C(O)Ra、-SO2-NRaRa’或-SO2Ra；
R4表示Cy2、-NHC(O)Ra、-NHC(O)NRaRa’、-C(O)Ra、-C(O)NRaRa’、-S(O)2Ra、-S(O)2NRaRa’、-NHS(O)2Ra或-NHS(O)2NRaRa’；
其中，Cy1和Cy2分别独立地表示被0、1、2、3或4个取代基独立取代的5-12元环，优选为5-12元芳基或5-12元杂芳基；更优选为5-6元芳基或5-6元杂芳基，其中所述的取代基为卤素、C1-C8烷基、C1-C8烷氧基、C3-C9环烷基、C3-C9杂环烷基、卤代C1-C8烷基、羟基、硝基、氰基、-C(O)ORa、-O-C(O)Ra、-C(O)-NRaRa’、-NRa-C(O)-Ra、-NRa-C(O)-ORa、-(C1-C8)烷基-NRa-C(O)Ra、-SO2-NRaRa’和-SO2Ra；
其中，所述的Ra、Ra’独立地表示氢、C1-C8烷基、C3-C9环烷基、羟基、卤素、氨基、C1-C8卤代烷基、C1-C8烷基氨基、二C1-C8烷基氨基，或者Ra、Ra’以及与之相连的原子环合成为3-9元环烷基或者杂环烷基，优选为氢、C1-C8烷基或C3-C8环烷基；
n为1、2或3，优选为1；m和o分别独立地表示0、1、2或3，
对于上述所定义的烷基、环烷基、杂环烷基、芳基、杂芳基，其可以进一步的被选自下述的取代基所取代：C1-C8烷基、C2-C8烯基、C2-C8炔基、C3-C8环烷基、5-12元芳基、5-12元杂芳基、C1-C8卤代烷基、C1-C8烷氧基、C1-C8烷基硫基、卤素、羟基、氰基、磺酸基和硝基；
在本发明的一个优选实施方案中，R1和R2以及与之相连的碳原子共同形成的环选自如下结构：
其中，Rc选自氢、C1-C6烷基、C3-C8环烷基、-C(O)Ra、-C(O)ORa、-C(O)-NRaRa’、-SO2-NRaRa’和-SO2Ra；*表示R1和R2以及与之相连的碳原子的结合位点，并且上述基团可以任选地被0、1、2、3、4个各自独立地选自下述R6的取代基所取代，其中Ra、Ra’以及R6具有如上述所定义。
在本发明的一个优选实施方案中，X选自CRaRa’、NRa、O和S，优选为O；其中，Ra、Ra’选自氢、C1-C8烷基、C3-C8环烷基、羟基、卤素、C1-C8卤代烷基、C1-C8烷基氨基、二C1-C8烷基氨基，或者Ra、Ra’以及与之相连的原子环合成为3-9元环烷基或者杂环烷基，优选为氢、卤素或C1-C8烷基。
在本发明的一个优选实施方案中，R4优选为Cy2、-NHC(O)Ra、-C(O)NRaRa’或-NHC(O)NRaRa’，其中Cy2、Ra、Ra’如上述所定义。
在本发明的一个优选实施方案中，Cy2选自苯基、吡啶基、吡嗪基、环丙基、环戊基、环己基、呋喃基、噻唑基、哌啶基、哌嗪基、噁唑基、咪唑基或噻吩基；其中Cy2更优选为吡唑基、咪唑基、噁唑基、噻唑基、苯基或吡啶基；并且所述Cy2可以任选地被C1-C8烷基、C1-C8烷氧基、C3-C9环烷基、C3-C9杂环基、C1-C8卤代烷基、卤素、氰基、磺酸基、硝基或羟基所取代。
在本发明的一个优选实施方案中，Ra和Ra’优选为氢、卤素或C1-C8烷基。
本发明的可药用盐可通过常规方法制备，例如通过将本发明的化合物溶解于与水可混溶的有机溶剂(例如丙酮、甲醇、乙醇和乙腈)，向其中添加过量的有机酸或无机酸水溶液，以使得盐从所得混合物中沉淀，从中除去溶剂和剩余的游离酸，然后分离所沉淀的盐。
具体实施方式
术语
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比率、比例、或份数按重量计。
在本发明的优选例中，提供但不局限于以下化合物：
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例当未包括制备途径时，相关中间体是市售的(例如来自Sigma Aldrich,Alfa)。
通用过程
本发明通式I所示化合物可通过如下的方法制得，然而该方法的条件，例如反应物，溶剂，碱，所用化合物的量，反应温度，反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易地进行。
反应式A描述了化合物A4的通用合成方法：
反应式A
其中X、R3、R4、R5、R6、m、o具有如上述所定义；p为1、2或3；q为0、1、2、3或4；
其中步骤I和步骤II中的溶剂选自水、甲醇、乙醇、THF、DMF、DMSO、二氯甲烷、氯仿中的一种或其任意组合。
反应式A1描述了化合物A4的另外一个通用合成方法：
反应式A1
其中X、R3、R4、R5、R6、m、o具有如上述所定义；p为1、2或3；q为0、1、2、3或4；
其中步骤I’和步骤II’中的溶剂选自水、甲醇、乙醇、THF、DMF、DMSO、二氯甲烷、氯仿中的一种或其任意组合；步骤II’中的碱选自NaOH、NaHCO3、KOH、KHCO3、K2CO3、三乙胺中的一种或其任意组合。
反应式B描述了化合物A3的通用合成方法：
反应式B
其中，p为1、2或3；q为0、1、2、3或4；
其中，步骤I”和步骤II”中的溶剂选自水、甲醇、乙醇、THF、DMF、DMSO、二氯甲烷、氯仿中的一种或其任意组合；步骤I”的反应温度为-100℃至室温，优选为-78℃至室温；
步骤II’中的还原反应所使用的还原剂为H2、NaBH4、LiAlH4，其中还原反应使用的催化剂为雷尼镍、氯化亚铁、氯化钴；步骤II’的反应温度为0℃至室温。
反应式B1描述了化合物A3的通用合成方法：
反应式B1
其中，p为1、2或3；q为0、1、2、3或4；
其中，步骤I”’和步骤II”’中的有机溶剂选自甲醇、乙醇、THF、DMF、DMSO、二氯甲烷、氯仿中的一种或其任意组合；
步骤II”’中的相转移催化剂为四丁基氟化铵、四丁基溴化铵、四丁基氯化铵；环状冠醚类：例如：18冠6、15冠5、环糊精；
其中，步骤III”’还原反应使用的催化剂为雷尼镍、氯化亚铁、氯化钴；还原剂为H2、NaBH4、LiAlH4。
LC/MS实验在以下条件下测量：
仪器：Thermo U3000,ALLtech ELSD,MSQ，UV检测器结合ELSD和MSD(流出比为4：1)。柱：Waters X-Bridge C-18,3.5μm，4.6x50mm；柱温：30℃。梯度【时间(min)/溶剂B在A中(％)】：0.00/5.0，0.70/95，1.40/95，1.41/5，1.50/5。(溶剂A＝0.01％三氟乙酸在水中；溶剂B＝0.01％三氟乙酸在乙腈中)。UV检测：214/254/280/300nm；DAD检测：200-400nm；流速：4mL/min；MS：ESI，100-1500m/z制备型HPLC通常使用酸性方法(乙腈和水的梯度，各含有0.1％甲酸)用Thermo U3000 AFC-3000；柱：Globalsil C-18 12nm,250x20mm,10μm,或相当；流速：20mL/min，进行分离。
中间体的合成
化合物INT-1的制备：
在0℃条件下，将碳酸铯(241.0g，0.74mol)和5-溴-2-硝基吡啶(100.0g，0.49mol)依次加入到溶有2-氯-4-羟基吡啶(70.2g，0.54mol)的N,N-二甲基甲酰胺(1.5L)溶液中。反应液在80℃的条件下搅拌24小时。反应液过滤后，滤液减压浓缩除去大部分溶剂，用乙酸乙酯(2L)稀释；有机层依次用水洗(2Lx2)和饱和食盐水洗(1Lx2)后，用无水硫酸镁干燥。滤液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝100：1至1：1)纯化得到黄色油状物INT-1a(43.5g，收率：31.9％)。1H NMR(DMSO-d6,400MHz)δ8.64(s,1H),8.47-8.40(m,2H),8.14–8.02(m,1H),7.39(s,1H),7.25(s,1H)；MS:252.0[M+H]+。
将氯化铵(91.0g，1.7mol)和锌粉(110.5g，1.7mol)依次加入溶有INT-1a(43.5g，0.17mol)的四氢呋喃(500mL)和甲醇(500mL)的混合溶液。反应液在室温条件下搅拌过夜。滤液减压浓缩后得到红棕色固体INT-1b(37.3g，收率：97.5％)。MS:222.0[M+H]+。
在氮气保护下，将化合物INT-1b(37.3g,0.17mol)，化合物INT-1c(42.0g,0.20mol)，碳酸铯(220.0g,0.67mol)和四三苯基磷钯(9.7g，8.4mmol)加入至N’N-二甲基甲酰胺(500mL)和水(200mL)的混合溶液中。反应体系再用氮气反复置换3次后，在90℃的条件下搅拌24小时。反应液过滤后，滤液减压浓缩除去大部分溶剂，用乙酸乙酯(1L)稀释；有机层依次用水洗(1Lx2)和饱和食盐水洗(1Lx2)后，用无水硫酸镁干燥。滤液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝100：1至1：1)纯化得到近白色固体INT-1(23.5g，收率：52.2％)。1H NMR(DMSO-d6,400MHz)δ8.33(d,J＝5.7Hz,1H),8.25(s,1H),7.95(s,1H),7.82(d,J＝2.7Hz,1H),7.30(dd,J＝8.9,2.7Hz,1H),7.16(d,J＝2.4Hz,1H),6.59(dd,J＝5.7,2.4Hz,1H),6.55–6.46(m,1H),6.03(s,2H),3.86(s,3H)。MS:268.0[M+H]+。
化合物INT-2的制备：
在0℃条件下，双(三甲基硅基)氨基钠(2.0M的四氢呋喃溶液，4.68mL)缓慢滴入溶有5-溴-6-甲基-吡啶-2-胺(500mg，2.67mmol)的二氯甲烷(10mL)溶液。反应液在搅拌条件下逐渐升至室温，并在室温条件下搅拌1小时。随后将溶有二碳酸二叔丁酯(700mg，3.21mmol)的四氢呋喃(5mL)溶液缓慢滴入上述反应液中，所得反应液在室温条件下再搅拌1小时。LC/MS显示原料已消耗完全，在反应液中加入水(30mL)和二氯甲烷(20mL)使其分层。有机相用饱和食盐水(30mLx2)洗涤，用无水硫酸钠干燥。滤液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝100：0至5：1)纯化得到白色固体INT-2a(582mg，收率：75.8％)。
在氮气保护下，将化合物INT-2a(582mg，2.03mmol)，化合物INT-2b(148mg，0.20mmol)，联硼酸频哪醇酯(669mg，2.63mmol)和醋酸钾(398mg，4.05mmol)加入至二氧六环(12mL)溶液中。反应体系再用氮气反复置换3次后，在90℃的条件下搅拌16小时。LC/MS显示原料已经消耗完毕；反应液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝100：0至3：1)纯化得到白色固体INT-2c(330mg，收率：41.9％)。1H NMR(DMSO-d6,500MHz)δ9.78(s,1H),7.85(d,J＝8.2Hz,1H),7.60(d,J＝8.2Hz,1H),2.50(s,3H),1.43(s,9H),1.27(s,12H)。
在0℃条件下，双氧水(30％w/w，482mg)加入至溶有化合物INT-2c(330mg，0.85mmol)的四氢呋喃(3mL)溶液中。反应液在搅拌下逐渐升至室温，并在室温条件下搅拌3小时。随后，5％亚硫酸钠溶液(5mL)加入至反应液中淬灭多余的双氧水，并加入乙酸乙酯(30mL)和水(25mL)。有机相用饱和食盐水(30mLx2)洗涤，用无水硫酸钠干燥。滤液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝100：0至3：1)纯化得到白色固体INT-2d(100mg，收率：52.5％)。1H NMR(DMSO-d6,500MHz)δ9.30(s,1H),9.22(s,1H),7.36(d,J＝8.5Hz,1H),7.06(d,J＝8.5Hz,1H),2.21(s,3H),1.43(s,9H)。
将碳酸铯(290mg，0.89mmol)加入至溶有化合物INT-2d(100mg，0.45mmol)和2,4-二氯吡啶(86mg，0.58mmol)的N,N-二甲基甲酰胺(3mL)溶液中，反应液在65℃条件下搅拌小时。LC/MS显示原料已消耗完毕，随后加入乙酸乙酯(20mL)和水(20mL)，所得水相进一步用乙酸乙酯(20mL)萃取。合并有机相用饱和食盐水(40mLx2)洗涤，用无水硫酸钠干燥。滤液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝4：1)纯化得到黄色固体INT-2e(60mg，收率：40％)。
将三氟乙酸(0.5mL)加入溶有化合物INT-2e(60mg，0.18mmol)的二氯甲烷(2mL)溶液中，反应液在室温条件下搅拌3小时。LC/MS显示原料已消耗完毕。反应液减压浓缩后，加入乙酸乙酯(10mL)和饱和碳酸氢钠溶液(10mL)；有机相用饱和食盐水(10mLx2)洗涤，用无水硫酸钠干燥。滤液减压浓缩后得到白色固体INT-2f(35mg，收率：83.1％)。1H NMR(DMSO-d6,500MHz)δ8.24(d,J＝5.8Hz,1H),7.31(d,J＝8.4Hz,1H),6.93(s,1H),6.88(dd,J＝5.8,1.9Hz,1H),6.43(d,J＝8.4Hz,1H),2.06(s,3H)。
从化合物INT-2f开始，参照化合物INT-1的合成，得到白色固体化合物INT-2。1HNMR(DMSO-d6,500MHz)δ8.38(d,J＝6.0Hz,1H),7.87(s,1H),7.25(s,1H),7.21(d,J＝8.7Hz,1H),6.93(d,J＝2.3Hz,1H),6.64-6.57(m,1H),6.47(d,J＝8.7Hz,1H),3.94(s,3H),2.28(s,3H)。MS:282.7[M+H]+。
化合物INT-3的制备：
在-78℃的条件下，将二异丙基氨基锂(2M四氢呋喃溶液，7.8mL)滴加至溶有环己甲酸甲酯(2.0g，14.1mmol)的四氢呋喃(30mL)溶液中。反应液在-78℃的条件下继续搅拌1.5小时，然后将混有溴乙腈(2.0g，16.9mmol)和N’N’-二甲基丙酰基脲(0.90g，7.0mmol)的四氢呋喃(10mL)溶液慢慢滴入。所得反应液缓慢升至室温，并在室温条件下搅拌过夜。TLC确定原料消耗完毕，反应液用盐酸溶液(1M，20mL)小心淬灭，减压条件下浓缩除去大部分四氢呋喃，所得溶液用乙酸乙酯萃取(20mLx3)。合并有机相用饱和食盐水洗涤(50mLx2)，无水硫酸钠干燥。滤液减压浓缩后得到粗品，用用硅胶柱层析(石油醚：乙酸乙酯＝15：1)纯化得到黄色油状物INT-3a(1.10g，收率：43％)。1H NMR(CDCl3，400MHz)δ3.67(s,3H),2.70(s,2H),1.96-1.92(m,2H),1.56-1.50(m,2H),1.47-1.27(m,6H)。
在氮气保护和0℃条件下，硼氢化钠(1.04g，27.6mmol)分批加入到化合物INT-3a(1.0g，5.52mmol)和无水氯化钴(0.36g，2.76mmol)的四氢呋喃(20mL)和水(10mL)的混合溶液中。反应液在室温条件下搅拌过夜；随后在反应液中再次补加无水氯化钴(0.18g，1.38mmol)和硼氢化钠(0.50g，13.8mmol)；所得反应液继续室温搅拌过夜。反应液过滤后，滤液减压浓缩，所得粗品用乙酸乙酯(100mL)溶解，并用饱和食盐水洗涤(100mLx2)，无水硫酸钠干燥。滤液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝3：1)纯化得到白色固体INT-3(230mg，收率：27％)。1H NMR(CDCl3,400MHz)δ5.95(br s,1H),3.30(t,J＝6.8Hz,2H),2.03(t,J＝7.2Hz,2H),1.74-1.62(m,5H),1.46-1.44(m,2H),1.38-1.26(m,3H)。
参照化合物INT-3的制备方法，制备得到了化合物INT-4,INT-5,INT-6,INT-7,INT-8，具体谱图信息如下表：
白色固体；1H NMR(CDCl3,400MHz)δ5.60(brs,1H),3.30(t,J＝6.8Hz,2H),2.00(t,J＝6.8Hz,2H),1.96-1.90(m,2H),1.83-1.76(m,2H),1.67-1.62(m,2H),1.58-1.53(m,2H)
白色固体；1H NMR(CDCl3,400MHz)δ6.21(br s,1H),3.20(t,J＝6.8Hz,2H),2.42-2.31(m,2H),2.17(t,J＝6.8Hz,2H),2.02-1.78(m,4H)
淡黄色固体；1H NMR(CDCl3,400MHz)δ5.65(s,1H),4.00-3.97(m,2H),3.56-3.45(m,2H),3.35(t,J＝6.8Hz,2H),2.12(t,J＝6.8Hz,2H),2.01-1.95(m,2H),1.39-1.35(m,2H).
棕色固体；1H NMR(CDCl3,400MHz)δ5.93(br s,1H),4.06-3.98(m,1H),3.97-3.93(m,1H),3.45-3.39(m,1H),3.29-3.23(m,1H),2.30-2.08(m,4H),1.99-1.89(m,1H),1.88-1.81(m,1H).
白色固体；1H NMR(DMSO-d6,500MHz)δ7.58(br s,1H),3.13(t,J＝6.5Hz,2H),2.20-2.00(m,2H),1.92(t,J＝6.5Hz,2H),1.85-1.75(m,2H),1.70-1.64(m,2H),1.48-1.42(m,2H).
化合物INT-9的制备：
从化合物INT-9a开始，参照化合物INT-3a的合成，得到黄色油状物INT-9b。MS:210.3[M+H]+。
溶有化合物INT-9b(1.60g，7.65mmol)的二乙胺基三氟化硫(3mL)溶液在室温下搅拌过夜。LC/MS显示原料已经消耗完毕后，将冰水(20mL)缓慢滴入反应液中淬灭反应，随后后饱和碳酸氢钠溶液调节pH值至8-9，再用乙酸乙酯(50mLx3)萃取。合并有机相用饱和食盐水洗涤(100mLx2)，无水硫酸钠干燥。滤液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝5：1)纯化得到无色油状物INT-9c(1.00g，收率：57％)。MS:232.3[M+H]+。
从化合物INT-9c开始，参照化合物INT-3的合成，得到淡黄色固体INT-9。1HNMR(CDCl3,400MHz)δ5.64(br s,1H),3.34-3.16(m,2H),2.65-2.55(m,1H),2.50-2.29(m,1H),1.98-1.68(m,5H),1.43-1.33(m,1H)。
参照化合物INT-9的制备方法，制备得到了化合物INT-10,INT-11，具体谱图信息如下表：
化合物INT-12的制备：
对甲基苯磺酰氯(1.11g，5.83mmol)加入到溶有化合物INT-12a(700mg，4.86mmol)，4-二甲基吡啶(59mg，0.49mmol)和三乙胺(1.36mL,9.71mmol)的二氯甲烷溶液(10mL)。所得反应液在室温条件下搅拌过夜后，TLC显示原料已消耗完毕。在反应液中加入二氯甲烷(20mL)和水(40mL)，有机层用饱和食盐水洗涤(40mL x2)，无水硫酸钠干燥。滤液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝100：0到3：1)纯化得到无色油状物INT-12b(1.0g，收率：69％)。1H NMR(500MHz,DMSO-d6)δ7.78(d,J＝8.2Hz,2H),7.49(d,J＝8.2Hz,2H),4.15(s,2H),3.97(q,J＝7.0Hz,2H),2.43(s,3H),1.17(br s,2H),1.07(t,J＝7.0Hz,3H),0.99(br s,2H)；MS:299.4[M+H]+。
四丁基氟化铵(1MinTHF,12.3mL)加入到溶有化合物INT-2b(1.22g,4.1mmol)和三甲基氰硅烷(1.22g,12.3mmol)的四氢呋喃溶液中。反应液在室温条件下搅拌过夜，TLC显示原料已经消耗完毕。在反应液中加入乙酸乙酯(50mL)和水(50mL)，有机层用饱和食盐水洗涤(50mLx2)，无水硫酸钠干燥。滤液减压浓缩后得到粗品，用硅胶柱层析(石油醚：乙酸乙酯＝100：0到3：1)纯化得到淡黄色油状物INT-12c(500mg，收率：79.8％)。1H NMR(500MHz,DMSO-d6)δ4.10(q,J＝7.1Hz,2H),2.79(s,2H),1.19(br s,2H),1.18(t,J＝7.1Hz,3H),1.00(br s,2H)。
雷尼镍(100mg,0.65mmol)加入到溶有化合物INT-12c(100mg,0.65mmol)的氨甲醇溶液(7M,3mL)。反应液在氢气(15psi)条件下室温搅拌48小时。硅藻土过滤除去雷尼镍，滤液减压浓缩后得到粗品，用硅胶柱层析(二氯甲烷：甲醇＝100：0到10：1)纯化得到白色固体INT-12(34mg，收率：46.9％)。1H NMR(500MHz,DMSO-d6)δ7.54(s,1H),3.29(t,J＝7.1Hz,2H),2.08(t,J＝7.1Hz,2H),0.78(br s,2H),0.67(br s,2H)。
实施例1：化合物1的制备
在0℃条件下，将预先溶于四氢呋喃(2mL)的三光气(95mg，0.32mmol)溶液缓慢滴加至化合物INT-1(107mg，0.40mmol)和三乙胺(222μL，1.60mmol)的四氢呋喃(5mL)溶液中。反应液在搅拌条件下逐渐升至室温，并在室温条件下继续搅拌1小时。LC/MS显示原料已消耗完全，反应液减压浓缩后加入水(15mL)与二氯甲烷与甲醇的混合溶液(15mL，v/v＝10/1)。有机相用饱和食盐水(15mLx2)洗涤，无水硫酸钠干燥。滤液减压浓缩后得到化合物1a，该化合物无需分离，直接进入下一步反应。
在0℃条件下，将钠氢(60％w/w在煤油中；80mg，2.0mmol)加入至化合物INT-5(50mg，0.4mmol)的四氢呋喃溶液中。反应液在搅拌条件下逐渐升至室温，并在室温条件下搅拌半小时；随后加入上段描述的预先溶于四氢呋喃(3mL)中的化合物1a；所得反应液继续在室温条件下搅拌1小时。LC/MS显示化合物1a消耗完全，加入水(0.5mL)淬灭多余的钠氢。所得反应液在减压条件下浓缩除去绝大部分溶剂，随后加入二氯甲烷(15mL)和水(15mL)。有机相用饱和食盐水(15mLx2)洗涤，无水硫酸钠干燥。滤液减压浓缩后得到粗品，用制备薄层层析(二氯甲烷：甲醇＝20：1)纯化得到白色固体1。1H NMR(DMSO-d6,500MHz)δ11.09(s,1H),8.37(d,J＝5.0Hz,1H),8.28(s,1H),8.26(s,1H),8.07(d,J＝9.0Hz,1H),7.96(s,1H),7.78-7.72(m,1H),7.23(s,1H),6.70(d,J＝5.0Hz,1H),3.84(s,3H),3.69(t,J＝6.5Hz,2H),2.40-2.25(m,2H),2.18(t,J＝6.5Hz,2H),2.05-1.85(m,4H)。MS:419.5[M+H]+。
参照化合物1的制备方法，制备得到了化合物2,3,4,5,6,7,8,9,10，具体谱图信息如下表：
实施例2：化合物11的制备
从化合物INT-1开始，参照化合物1的合成，得到白色固体11a。1HNMR(DMSO-d6,500MHz)δ11.04(s,1H),8.37(d,J＝5.7Hz,1H),8.27(d,J＝3.0Hz,1H),8.25(s,1H),8.08(d,J＝9.0Hz,1H),7.96(s,1H),7.76(dd,J＝9.0,3.0Hz,1H),7.23(d,J＝3.0Hz,1H),6.69(dd,J＝5.7,3.0Hz,1H),3.84(s,3H),3.79(t,J＝7.1Hz,4H),3.07-2.92(m,2H),2.03(t,J＝7.1Hz,2H),1.65-1.53(m,4H),1.40(s,9H)；MS:548.3[M+H]+。
在溶有化合物11a(350mg,0.64mmol)的二氯甲烷溶液中(6mL)加入盐酸(4Min二氧六环,0.8mL)。反应液在室温条件下搅拌4小时后，LC/MS显示原料已消耗完毕。反应液减压浓缩得到白色固体11。1H NMR(500MHz,DMSO-d6)δ11.05(s,1H),8.78(s,1H),8.56(d,J＝6.0Hz,1H),8.46(s,1H),8.41(s,1H),8.14(d,J＝9.0Hz,1H),7.91(d,J＝9.0Hz,1H),7.75(s,1H),7.21-7.16(m,1H),3.92(s,3H),3.80(t,J＝7.0Hz,2H),3.29-3.24(m,2H),3.04-3.00(m,2H),2.07(t,J＝7.0Hz,2H),1.99-1.95(m,2H),1.83-1.77(m,2H)；MS:448.5[M+H]+。
实施例3：化合物12的制备
在溶有化合物11(120mg,0.25mmol)和乙酸酐(30.4mg，0.30mmol)的二氯甲烷溶液(5mL)中加入三乙胺(50mg，0.50mmol)。反应液在室温条件下搅拌4小时，LC/MS显示原料已经消耗完毕。在反应液中加入二氯甲烷(15mL)和水(20mL)，有机层用饱和食盐水洗涤(20mLx2)，无水硫酸钠干燥。滤液减压浓缩后得到粗品，用制备薄层层析(二氯甲烷：甲醇＝10：1)纯化得到白色固体12(65mg，收率：53％)。1H NMR(500MHz,DMSO-d6)δ11.04(s,1H),8.37(d,J＝6.0Hz,1H),8.27(br s,1H),8.26(s,1H),8.07(d,J＝9.0Hz,1H),7.95(s,1H),7.76(d,J＝9.0Hz,1H),7.23(s,1H),6.69(d,J＝6.0Hz,1H),4.16-4.11(m,1H),3.83(s,3H),3.82–3.71(m,3H),3.24–3.16(m,1H),2.90-2.82(m,1H),2.05(t,J＝7.0Hz,2H),2.00(s,3H),1.72-1.68(m,1H),1.65–1.54(m,3H)；MS:490.4[M+H]+。
实施例4：化合物13的制备
从化合物11和甲磺酸酐开始，参照化合物12的合成，得到白色固体13。1H NMR(500MHz,DMSO-d6)δ11.04(s,1H),8.37(d,J＝5.5Hz,1H),8.27(d,J＝3.0Hz,1H),8.26(s,1H),8.08(d,J＝9.0Hz,1H),7.96(s,1H),7.76(dd,J＝9.0,3.0Hz,1H),7.23(d,J＝2.0Hz,1H),6.69(dd,J＝5.5,2.0Hz,1H),3.84(s,3H),3.80(t,J＝7.1Hz,2H),3.49-3.47(m,2H),2.95-2.91(m,2H),2.89(s,3H),2.02(t,J＝7.1Hz,2H),1.83-1.71(m,4H)；MS:526.3[M+H]+。
实施例5：化合物14的制备
在0℃条件下，将预先溶于四氢呋喃(1mL)的三光气(23.5mg,0.79mmol)缓慢滴入溶有化合物INT-8(20mg,0.15mmol)和三乙胺(21.4mg，0.21mmol)的无水四氢呋喃(2mL)溶液中。反应液在搅拌状态下逐渐升至室温，并在室温条件下搅拌1小时；随后进一步回流2小时。反应液中加入乙酸乙酯(15mL)和水(15mL)，有机层用饱和食盐水洗涤(20mLx2)，无水硫酸钠干燥。滤液减压浓缩后得到粗品化合物14a。
将预先溶于二氯甲烷(1mL)的上述粗品加入溶有化合物INT-2(30mg，0.106mmol)和三乙胺(21.4mg，0.211mmol)的二氯甲烷(3mL)溶液中。反应液在室温条件下搅拌16小时后，LC/MS显示产物为主峰。反应液中加入二氯甲烷(15mL)和水(20mL)，有机层用饱和食盐水洗涤(20mLx2)，无水硫酸钠干燥。滤液减压浓缩后得到粗品，用制备薄层层析(DCM：MeOH＝20：1)纯化得到白色固体14(19mg，收率：36.2％)。1H NMR(500MHz,DMSO-d6)δ10.98(s,1H),8.40(d,J＝6.0Hz,1H),8.31(s,1H),8.01(s,1H),7.93(d,J＝8.8Hz,1H),7.68(d,J＝8.8Hz,1H),7.25(br s,1H),6.68(br s,1H),3.87(s,3H),3.80(t,J＝7.0Hz,2H),2.28(s,3H),2.17-2.07(m,2H),2.05(t,J＝7.0Hz,2H),2.00-1.90(m,2H),1.85-1.75(m,4H)；MS:497.5[M+H]+。
参照化合物14的制备方法，制备得到了化合物15，具体谱图信息如下表：
H NMR(DMSO-d6,500MHz)δ11.04(s,1H),8.37(d,J＝5.5Hz,1H),8.27(s,1H),7.97(s,1H),7.92(d,J＝9.0Hz,1H),7.66(d,J＝9.0Hz,1H),7.18(s,1H),6.64-6.60(m,1H),3.86(s,3H),3.71(t,J＝6.5Hz,2H),2.39-2.32(m,2H),2.28(s,3H),2.18(t,J＝6.5Hz,2H),2.05-1.90(m,4H)；MS:433.5[M+H]+。
以上所述仅是本发明的一些优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为在本发明的保护范围内。
Claims (4)
1.一种具有抗肿瘤活性的CSF1R抑制剂中间体的制备方法，其特征在于包括以下步骤：
其中，p为1或2；q为1或2；
R6表示：Cl、Br或I。
2.如权利要求1所述的方法，其中，步骤I”’和步骤II”’中的有机溶剂选自甲醇、乙醇、THF、DMF、DMSO、二氯甲烷、氯仿中的一种或其任意组合。
3.如权利要求2所述的方法，其中，步骤II”’中的相转移催化剂为四丁基氟化铵、四丁基溴化铵或四丁基氯化铵。
4.如权利要求1所述的方法，其中，步骤III”’还原反应使用的催化剂为雷尼镍、氯化亚铁或氯化钴；还原剂为H2、NaBH4或LiAlH4。
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| EP3744718A4 (en) | 2021-11-17 |
| CN111484442B (zh) | 2021-11-09 |
| WO2019228252A1 (zh) | 2019-12-05 |
| CN111548343A (zh) | 2020-08-18 |
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