CN108659031A - 一种用于制备艾日布林的中间体及其制备方法 - Google Patents
一种用于制备艾日布林的中间体及其制备方法 Download PDFInfo
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- CN108659031A CN108659031A CN201710205342.0A CN201710205342A CN108659031A CN 108659031 A CN108659031 A CN 108659031A CN 201710205342 A CN201710205342 A CN 201710205342A CN 108659031 A CN108659031 A CN 108659031A
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- 150000001875 compounds Chemical class 0.000 claims abstract description 109
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 125000003118 aryl group Chemical group 0.000 claims abstract description 10
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 5
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- OUUQCZGPVNCOIJ-UHFFFAOYSA-N hydroperoxyl Chemical compound O[O] OUUQCZGPVNCOIJ-UHFFFAOYSA-N 0.000 claims description 2
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 3
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- 125000001072 heteroaryl group Chemical group 0.000 description 3
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
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- 125000001424 substituent group Chemical group 0.000 description 3
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Abstract
本发明涉及一种艾日布林中间体及其制备方法。具体而言,本发明涉及一种如式II所示的化合物,其中,Ar为C1‑10烷基取代或烷基氧基取代的芳基;优选为对位被C1‑10烷基取代的苯基,更优选为对位被乙基取代的苯基。本发明还特别涉及一种如式II所示的化合物的制备方法,该方法具有反应条件温和,操作和纯化简便,合成成本低廉等优点,适于大规模生产。
Description
技术领域
本发明涉及一种用于制备艾日布林的中间体及其制备方法。
背景技术
艾日布林(如式I所示)是对海洋天然产物Halichondria okadai中提取的大环内酯类化合物halichondrin B进行结构优化的衍生物,是一种软海绵素类微管动力学抑制剂。自从2010年11月15日FDA首次批准甲磺酸艾日布林(Halaven)注射液用于治疗至少接受过两种化疗方案的转移性乳腺癌患者以来,卫材公司积极拓展艾日布林的新适应症。2016年1月28日FDA批准其用于二线治疗不能手术切除或转移性脂肪肉瘤,成为全球首个可显著延长晚期软组织肉瘤患者生存的新型抗癌药。目前该药已获批用于全球60多个国家的转移性乳腺癌的治疗,以及美国、日本和欧盟批准用于不可切除性或转移性软组织肉瘤。此外,卫材于也在2016年8月向中国食品和药品监督管理总局提交了Halaven治疗局部晚期或转移性乳腺癌的新药申请。近期的非临床研究和转化研究表明,除了具有抗有丝***效果外,Halaven在晚期乳腺癌肿瘤组织中还能够诱导肿瘤血管重塑、提高肿瘤核心区域的血管灌注和渗透性、降低肿瘤微环境缺氧程度。此外,Halaven还能改善上皮细胞状态,降低乳腺癌细胞的迁移能力。
艾日布林分子结构复杂,含有40个碳原子,其中19个碳原子具有手性中心,目前的市场药物供应只能通过全合成的途径来实现,路线非常复杂,因此对合成路线设计和合成工艺开发存在非常大的挑战,尤其需要对各个手性中心进行精确地高选择性控制。
目前对艾日布林的合成主要是通过对复杂程度相当的三个中间体进行汇聚式合成来实现的,如式II所示的手性化合物是其中的一个关键中间体。但是文献和专利中对化合物II的合成报道非常有限。
卫材公司在专利WO2005118565A1中提出从葡醛内酯出发,经过20步合成了化合物II。在将芳基砜基基团引入母环结构的过程中,使用了苯基砜基膦酸酯,但是其所对应的原料苯甲砜成本较高。正大天晴公司在CN104860978A中也披露了类似的中间体及其制备方法。
发明内容
针对现有如式II所示的艾日布林关键中间体的合成方法非常有限,本发明提供了一种新的艾日布林中间体(如式II和IIa所示)及其合成方法,该路线反应条件温和,操作简便,合成成本低廉,适于大规模生产用于合成如式II所示的艾日布林中间体。
其中,Ar为C1-10烷基取代或烷基氧基取代的芳基;优选为对位被C1-10烷基取代的苯基,更优选为对位被乙基取代的苯基。
本发明提供了一条合成式(IIa)所示的艾日布林中间体的制备方法,
具体来说,该合成方法包括以下步骤:
1)如式XI所示的酮化合物与如式XII所示的化合物在丁基锂的作用下发生缩合反应得到如式X所示的化合物;
2)式X化合物在三甲基碘硅烷的作用下去羟基保护得到如式IX所示的化合物;
3)式IX化合物在醋酸硼氢化钠的作用下发生双键还原反应得到如式VIII所示的化合物;
4)式VIII化合物在碳酸钾的作用下去苯甲酸酯保护得到如式VII所示的化合物;
5)式VII化合物的两个羟基选择性进行丙酮叉保护得到如式VI所示的化合物;
6)式VI化合物的裸露羟基在碱性条件下与碘甲烷发生甲基化反应得到如式V所示的化合物。
7)式V化合物的丙酮叉保护基在盐酸作用下发生水解得到如式IV所示的化合物。
8)式IV化合物的两个裸露羟基在碱性条件下与叔丁基二甲基氯硅烷进行羟基硅保护反应得到如式III所示的化合物。
9)式III化合物在臭氧化的作用下发生双键断裂得到如式IIa所示的化合物。
其中,化合物XI可根据文献(Synlett 2013,24,327)制备得到。
如果可以购得,也可使用上述反应步骤中的部分产物依更短路线制得式IIa所示化合物;例如可通过购买前述式VIII、式V所示的中间体,而后依照上述方法中提供的步骤制得式IIa所示的化合物。
本发明还提供一种如式III所示的化合物,
本发明进一步提供一种如式III所示的化合物的制备方法,化合物III通过如式IV所示的化合物进行羟基硅保护反应后制得;所述反应优选在碱(例如,咪唑)的作用下发生。
本发明还提供一种如式IV所示的化合物,
本发明进一步提供一种如式IV所示的化合物的制备方法,化合物IV通过如式V所示的化合物脱除丙酮叉保护基后制得,所述反应优选在酸(例如,盐酸)的作用下发生;
本发明还提供一种如式V所示的化合物,
本发明进一步提供一种如式V所示的化合物的制备方法,化合物V通过如式VI所示的化合物经过羟基甲基化制得,所述分子内环化优选在碱(例如,叔丁醇钾)的作用下发生;
本发明还提供一种如式VI所示的化合物,
本发明进一步提供一种如式VI所示的化合物的制备方法,化合物VI通过如式VII所示的化合物经过羟基的丙酮叉保护反应后制得,所述反应优选在酸(例如,浓硫酸)的作用下发生;
本发明还提供一种如式VII所示的化合物,
本发明进一步提供一种如式VII所示的化合物的制备方法,化合物VII通过如式VIII所示的化合物经过脱除羟基的苯甲酸酯保护基后制得,所述反应优选在碱(例如,碳酸钾)的作用下发生;
本发明还提供一种如式VIII所示的化合物,
本发明进一步提供一种如式VIII所示的化合物的制备方法,化合物VIII通过如式IX所示的化合物经过双键还原后制得,所述还原剂优选为醋酸硼氢化钠;
本发明还提供一种如式IX所示的化合物,
本发明进一步提供一种如式IX所示的化合物的制备方法,化合物IX通过如式X所示的化合物经过脱除羟基的苄基保护基制得,所述反应优选在酸(例如,三甲基碘化硅)的作用下发生;
本发明还提供一种如式X所示的化合物,
本发明进一步提供一种如式X所示的化合物的制备方法,化合物X通过如式XI所示的化合物与如式XII所示化合物经过脱缩合制得,所述反应优选在碱(例如,丁基锂)的作用下发生;
另一方面,本发明还提供了一种制备艾日布林的方法,该方法先依照本发明前述提供的方法制得式IIa所示的化合物,而后依照已知的方法经式IIa所示的化合物制得艾日布林,所述方法可参照文献:Org.Lett.2002,4,4435;Org.Lett.2009,11,4520;J.Am.Chem.Soc.2009,131,15636;Angew.Chem.Intl.Ed.2009,48,2346;Synlett.2013,24,323;Synlett.2013,24,327;Synlett.2013,24,333。
本发明所使用的术语,除有相反的表述外,具有如下的含义:
“烷基”指饱和的脂族烃基团,包括1至10个碳原子的直链和支链基团,优选包括1至6个碳原子。非限制性实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,优选为一个或多个以下基团,独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代。
“烷基氧基”指“RO-”,其中R为饱和的脂族烃基团,包括1至10个碳原子的直链和支链基团,优选包括1至6个碳原子。非限制性实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,优选为一个或多个以下基团,独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代。
本发明的羟基保护基是本领域已知的适当的用于羟基保护的基团,参见文献(“Protective Groups in Organic Synthesis”,5ThEd.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。作为示例,优选地,所述的羟基保护基可以是(C1-10烷基或芳基)3硅烷基,例如:三乙基硅基,三异丙基硅基,叔丁基二甲基硅基,叔丁基二苯基硅基等;可以是C1-10烷基或取代烷基,例如:甲基,叔丁基,烯丙基,苄基,甲氧基甲基,乙氧基乙基,2-四氢吡喃基(THP)等;可以是(C1-10烷基或芳香基)酰基,例如:甲酰基,乙酰基,苯甲酰基等;可以是(C1-6烷基或C6-10芳基)磺酰基;也可以是(C1-6烷氧基或C6-10芳基氧基)羰基。
“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至10元,更优选苯基和萘基,最优选苯基。芳基可以是取代的或未取代的,当被取代时,取代基优选为一个或多个以下基团,独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、硫醇、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
缩写表:
缩写 | 全称 |
Bn | 苄基 |
Bz | 苯甲酸酯基 |
TBS | 叔丁基二甲基硅基 |
Me | 甲基 |
TMSI | 三甲基碘化硅 |
下表为实施例中所涉及的化合物的结构式
具体实施方式
以下将结合具体实例详细地解释本发明,使得本专业技术人员更全面地理解本发明,具体实例仅用于说明本发明的技术方案,并不以任何方式限定本发明。
实施例1:制备化合物XII
向烧瓶中加入化合物XIII(9.3g),用四氢呋喃(50mL)溶解,室温下逐滴加入2.5M丁基锂(28mL),搅拌30min后,加入氯膦酸乙酯(9.36mL),1h后用饱和氯化铵猝灭反应,200mL乙酸乙酯萃取,无水硫酸钠干燥,浓缩后柱层析得到14.35g化合物XII。
1H NMR(400MHz,Chloroform-d)δ7.90(d,J=8.1Hz,2H),7.40(d,J=8.1Hz,2H),4.45-3.94(m,4H),3.76(d,J=16.8Hz,2H),2.75(q,J=7.6Hz,2H),1.51-1.11(m,9H).
实施例2:制备化合物X
在烧瓶中加入化合物XII(27.25g)和四氢呋喃(80mL),冰水浴下,滴加2.5M丁基锂(70mL),继续搅拌20min。向其中加入化合物XI(32g),滴加完后,继续反应45分钟,用200mL1M的盐酸水溶液淬灭反应,分离有机相,使用饱和碳酸氢钠洗剂,浓缩后柱层析得到32.45g化合物X。
MS(ESI)m/z:703(M+Na+)
1H NMR(400MHz,Chloroform-d)δ8.14-8.05(m,2H),8.04-7.96(m,2H),7.83-7.74(m,2H),7.63-7.53(m,2H),7.51-7.30(m,11H),6.37-6.23(m,1H),5.80-5.53(m,2H),5.47(dd,J=2.9,1.0Hz,1H),5.07-4.94(m,2H),4.88-4.74(m,2H),4.60-4.48(m,2H),4.33(ddt,J=7.4,5.7,2.6Hz,1H),3.97(td,J=6.6,2.7Hz,1H),2.73(q,J=7.7Hz,2H),2.52(dt,J=14.0,6.8Hz,1H),2.46-2.30(m,3H),1.40-1.18(m,6H).
实施例3:制备化合物IX
在装有化合物X(27g)的烧瓶中加入甲苯(67mL)溶解,向其中加入TMSI(10g),室温下搅拌2h,饱和碳酸氢钠猝灭反应,分液后无水硫酸钠干燥,浓缩后柱层析得到20.511g化合物IX
MS(ESI)m/z:613(M+Na+)
1H NMR(400MHz,Chloroform-d)δ8.06(ddt,J=11.7,7.0,1.4Hz,4H),7.90-7.80(m,2H),7.63-7.53(m,2H),7.51-7.33(m,6H),6.26(dd,J=2.2,1.3Hz,1H),5.84-5.67(m,2H),5.33-5.22(m,1H),5.14-4.98(m,2H),4.63(d,J=5.0Hz,2H),4.31(td,J=5.8,2.2Hz,1H),3.91(td,J=6.8,4.1Hz,1H),3.45(s,1H),2.76(q,J=7.6Hz,2H),2.52-2.31(m,4H),1.28(t,J=7.4Hz,3H).
实施例4:制备化合物VIII
在烧瓶中加入醋酸硼氢化钠(3g)和化合物IX(5g)用甲苯(40mL)悬浮,反应在室温下搅拌1h,用16mL水进行淬灭反应,分离有机相,并用碳酸氢钠和水洗涤,浓缩后柱层析得到4.083g化合物VIII。
MS(ESI)m/z:615(M+Na+)
1H NMR(400MHz,Chloroform-d)δ8.05(ddt,J=13.8,7.0,1.4Hz,4H),7.84(d,J=8.3Hz,2H),7.63-7.52(m,2H),7.51-7.37(m,6H),5.79-5.55(m,2H),4.96-4.76(m,2H),4.61(dd,J=4.8,2.3Hz,2H),4.41(dt,J=5.6,3.9Hz,1H),4.00(q,J=6.5Hz,1H),3.41(dt,J=8.6,5.7Hz,1H),3.15(dd,J=8.1,4.4Hz,3H),2.78(q,J=7.6Hz,2H),2.36-2.13(m,5H),1.29(td,J=7.4,5.6Hz,3H).
实施例5制备化合物VII
将化合物VIII(3.8g)溶解在15mL的甲醇中,加入碳酸钾固体(0.89g),室温下搅拌1小时,反应粗品直接浓缩除去大部分甲醇,浓缩后柱层析得到2.481g化合物VII。
MS(ESI)m/z:385(M+H+)
1H NMR(400MHz,Chloroform-d)δ7.85(d,J=8.4Hz,2H),7.44(d,J=8.3Hz,2H),5.68(ddt,J=17.2,10.2,7.1Hz,1H),5.07-4.84(m,2H),4.38(dt,J=5.7,4.1Hz,1H),4.09(dt,J=7.6,5.5Hz,1H),4.03-3.91(m,1H),3.67(ddd,J=10.8,6.8,3.7Hz,1H),3.61-3.43(m,3H),3.38(d,J=4.0Hz,1H),3.30-3.07(m,2H),2.79(q,J=7.6Hz,2H),2.43-2.13(m,4H),1.98-1.80(m,2H),1.30(t,J=7.6Hz,3H).
实施例6制备化合物VI
将化合物VII(2.3g)溶于12mL的丙酮,然后滴入浓硫酸(50mg),将反应物在室温度下搅拌反应30分钟,饱和碳酸氢钠猝灭反应,100mL乙酸乙酯萃取,无水硫酸钠干燥,浓缩后柱层析得到2.624g化合物VI。
MS(ESI)m/z:425(M+H+)
1H NMR(400MHz,Chloroform-d)δ7.86(d,J=8.4Hz,2H),7.43(d,J=8.2Hz,2H),5.71(ddt,J=17.3,10.2,7.1Hz,1H),5.05-4.82(m,2H),4.42-4.25(m,2H),4.09(dd,J=8.0,6.1Hz,1H),3.92(dt,J=7.7,5.4Hz,1H),3.65(t,J=7.7Hz,1H),3.48(dt,J=8.2,5.8Hz,1H),3.26-3.16(m,2H),3.07(d,J=4.8Hz,1H),2.78(q,J=7.6Hz,2H),2.41-2.30(m,3H),2.25-2.20(m,1H),2.13-2.05(m,1H),1.96(ddd,J=14.1,7.0,5.5Hz,1H),1.44(s,3H),1.38(s,3H),1.34-1.25(m,3H).
实施例7制备化合物V
将固体叔丁醇钾(0.78g)溶解在THF(7mL)DMF中,加入化合物VI(2.45g,5.8mmol)的THF(7mL)溶液,将碘甲烷(0.54mL)滴入。然后反应在20度进行30min,用水淬灭反应,有机相用氯化钠溶液洗剂两次,干燥,过滤,浓缩后柱层析得到2.179g化合物V。
MS(ESI)m/z:461(M+Na+)
1H NMR(400MHz,Chloroform-d)δ7.85(d,J=8.3Hz,2H),7.43(d,J=8.3Hz,2H),5.70(ddt,J=17.3,10.3,7.1Hz,1H),5.08-4.91(m,2H),4.26-4.12(m,1H),4.08(dd,J=8.0,6.0Hz,1H),3.90-3.78(m,2H),3.64(dd,J=8.0,7.2Hz,1H),3.52(q,J=6.2Hz,1H),3.42(s,3H),3.14(dd,J=14.3,9.3Hz,1H),3.04(dd,J=14.3,4.6Hz,1H),2.78(q,J=7.6Hz,2H),2.55-2.25(m,3H),2.06-1.91(m,2H),1.42(s,3H),1.37(s,3H),1.30(t,J=7.6Hz,3H).
实施例8制备化合物IV
将化合物V(1.93g)溶解于10mL甲醇,缓慢加入5mL的1N盐酸水溶液,室温搅拌1h,饱和碳酸氢钠猝灭反应,50mL乙酸乙酯萃取,无水硫酸钠干燥,浓缩后柱层析得到1.92g化合物IV。
MS(ESI)m/z:399(M+H+)
1H NMR(400MHz,Chloroform-d)δ7.85(d,J=8.3Hz,2H),7.43(d,J=8.3Hz,2H),5.79-5.57(m,1H),5.08-4.92(m,2H),4.04-3.82(m,3H),3.72-3.49(m,3H),3.43(s,3H),3.38-3.29(m,1H),3.20-3.00(m,2H),2.78(q,J=7.6Hz,2H),2.59-2.21(m,4H),1.97(dt,J=14.7,9.1Hz,1H),1.80(dt,J=14.7,3.3Hz,1H),1.30(t,J=7.6Hz,3H).
实施例9制备化合物III
将化合物IV(1.726g)溶于8mL DMF,依次加入咪唑(1g)和TBSCI(1.63g),反应在室温进行2小时,MTBE稀释反应液,用水洗涤,有机相依次使用水和碳酸氢钠洗涤,干燥,浓缩后柱层析得到2.418g化合物III。
MS(ESI)m/z:627(M+H+)
1H NMR(400MHz,Chloroform-d)δ7.93-7.77(m,2H),7.42(d,J=8.2Hz,2H),5.07-4.89(m,2H),3.96-3.75(m,3H),3.59(dd,J=10.3,5.6Hz,1H),3.50(dd,J=10.3,5.2Hz,1H),3.42(s,4H),3.13-2.96(m,2H),2.78(q,J=7.6Hz,2H),2.53-2.21(m,3H),1.99(ddd,J=13.9,6.3,5.1Hz,1H),1.82(dt,J=13.7,6.8Hz,1H),1.30(t,J=7.6Hz,3H),0.90(d,J=2.9Hz,18H),0.10(s,6H),0.06(d,J=2.5Hz,6H).
实施例10制备化合物IIa
将化合物III(2g)溶解于20mL异丙醇,冷却到-40度后,通入臭氧,搅拌30min后,加入三苯基膦(20g)猝灭反应并搅拌2h,直接浓缩反应液,柱层析得到1.8g化合物IIa。
MS(ESI)m/z:629(M+H+)
1H NMR(400MHz,Chloroform-d)δ9.63(t,J=1.4Hz,1H),7.83-7.60(m,2H),7.39-7.25(m,2H),3.94-3.81(m,2H),3.78-3.63(m,2H),3.49(dd,J=10.2,5.5Hz,1H),3.38(dd,J=10.2,5.5Hz,1H),3.29(s,3H),3.22(dd,J=14.1,5.1Hz,1H),3.00(dd,J=14.1,8.9Hz,1H),2.81(ddd,J=17.5,6.5,1.8Hz,1H),2.78(q,J=7.6Hz,2H),2.70(ddd,J=17.5,5.9,1.2Hz,1H),2.42(ddd,J=8.9,5.0,1.2Hz,1H),1.89(ddd,J=13.9,6.3,5.1Hz,1H),1.30(t,J=7.6Hz,3H),0.81(d,J=3.3Hz,18H),0.00(s,6H),-0.03(s,3H),-0.04(s,3H).
由于已根据其特殊的实施方案描述了本发明,某些修饰和等价变化对于本领域普通技术人员是显而易见的且包括在本发明的范围内。
Claims (21)
1.一种如式II所示的化合物,
其中,Ar为C1-10烷基取代或烷基氧基取代的芳基;优选为对位被C1-10烷基取代的苯基,更优选为对位被乙基取代的苯基。
2.根据权利要求1所述的化合物,具有如式IIa所示的结构:
3.根据权利要求2所述的如式IIa所示的化合物的制备方法,其特征在于,通过如式III所示的化合物经过臭氧化反应后制得,
4.一种如式III所示的化合物,
5.根据权利要求4所述的如式III所示的化合物的制备方法,其特征在于,通过如式IV所示的化合物经过羟基硅保护反应制得,
6.一种如式IV所示的化合物,
7.根据权利要求6所述的如式IV所示的化合物的制备方法,其特征在于通过如式V所示的化合物经过羟基保护基水解反应制得,
8.一种如式V所示的化合物,
9.根据权利要求8所述的如式V示的化合物的制备方法,其特征在于通过如式VI所示的化合物经过羟基甲基化反应制得,
10.一种如式VI所示的化合物,
11.根据权利要求10所述的如式VI所示的化合物的制备方法,其特征在于,通过如式VII所示的化合物经过羟基保护反应后制得,
12.一种如式VII所示的化合物,
13.根据权利要求12所述的如式VII所示的化合物的制备方法,其特征在于,通过如式VIII所示的化合物经过去羟基保护反应后制得,
14.一种如式VIII所示的化合物,
15.根据权利要求14所述的如式VIII所示的化合物的制备方法,其特征在于,通过如式IX所示的化合物经过双键还原反应后制得,
16.一种如式IX所示的化合物,
17.根据权利要求16所述的如式IX所示的化合物的制备方法,其特征在于,通过如式X所示的化合物经过去羟基保护反应后制得,
18.一种如式X所示的化合物,
19.根据权利要求18所述的如式X所示的化合物的制备方法,其特征在于,通过如式XI所示的化合物和如式XII所示的化合物在碱性条件下反应后制得,
20.一种如式IIa所示的化合物的制备方法,其特征在于包括如下步骤,
21.一种艾日布林的制备方法,其特征在于包括经式IIa所示化合物制备艾日布林的步骤,所述式IIa所示的化合物由权利要求3或20中任意一项所述的制备方法而得。
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CN113214307A (zh) * | 2020-02-04 | 2021-08-06 | 上海时莱生物技术有限公司 | 一种用于制备艾日布林的中间体及其制备方法 |
CN113387850A (zh) * | 2020-03-12 | 2021-09-14 | 上海时莱生物技术有限公司 | 一种艾日布林中间体的制备方法 |
WO2021218041A1 (zh) * | 2020-04-26 | 2021-11-04 | 博瑞生物医药(苏州)股份有限公司 | 艾日布林及其中间体的制备方法 |
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CN113214307A (zh) * | 2020-02-04 | 2021-08-06 | 上海时莱生物技术有限公司 | 一种用于制备艾日布林的中间体及其制备方法 |
CN113387850A (zh) * | 2020-03-12 | 2021-09-14 | 上海时莱生物技术有限公司 | 一种艾日布林中间体的制备方法 |
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