CN110590839A - 一种乐伐替尼衍生物及制备方法和用途 - Google Patents
一种乐伐替尼衍生物及制备方法和用途 Download PDFInfo
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- CN110590839A CN110590839A CN201910461438.2A CN201910461438A CN110590839A CN 110590839 A CN110590839 A CN 110590839A CN 201910461438 A CN201910461438 A CN 201910461438A CN 110590839 A CN110590839 A CN 110590839A
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- amino
- alkyl
- isopropyl
- compound
- phosphoryl
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- 238000002360 preparation method Methods 0.000 title description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 124
- 150000003839 salts Chemical class 0.000 claims abstract description 18
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- 239000000203 mixture Substances 0.000 claims description 67
- 229910052739 hydrogen Inorganic materials 0.000 claims description 43
- 229910052794 bromium Inorganic materials 0.000 claims description 41
- 229910052801 chlorine Inorganic materials 0.000 claims description 41
- 229910052731 fluorine Inorganic materials 0.000 claims description 41
- 229910052740 iodine Inorganic materials 0.000 claims description 40
- -1 methoxy, ethoxy Chemical group 0.000 claims description 39
- 125000001424 substituent group Chemical group 0.000 claims description 37
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 32
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
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- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 12
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 11
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
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- 125000003118 aryl group Chemical group 0.000 claims description 6
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
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- CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 description 25
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- YAQKNCSWDMGPOY-JEDNCBNOSA-N propan-2-yl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.CC(C)OC(=O)[C@H](C)N YAQKNCSWDMGPOY-JEDNCBNOSA-N 0.000 description 19
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- SLPZENBDISBDFV-ABGKOZRJSA-N propan-2-yl (2S)-2-[[butoxy-(4-nitrophenoxy)phosphoryl]amino]propanoate Chemical compound CCCCOP(=O)(N[C@@H](C)C(=O)OC(C)C)OC1=CC=C(C=C1)[N+](=O)[O-] SLPZENBDISBDFV-ABGKOZRJSA-N 0.000 description 1
- AQGLXUCLKKBJOP-DCXKMBIZSA-N propan-2-yl (2S)-2-[[cyclohexyloxy-(4-nitrophenoxy)phosphoryl]amino]propanoate Chemical compound C[C@@H](C(=O)OC(C)C)NP(=O)(OC1CCCCC1)OC2=CC=C(C=C2)[N+](=O)[O-] AQGLXUCLKKBJOP-DCXKMBIZSA-N 0.000 description 1
- ZLWMZQLAVVLBDG-GKIKDSKJSA-N propan-2-yl (2S)-2-[[hexoxy-(4-nitrophenoxy)phosphoryl]amino]propanoate Chemical compound CCCCCCOP(=O)(N[C@@H](C)C(=O)OC(C)C)OC1=CC=C(C=C1)[N+](=O)[O-] ZLWMZQLAVVLBDG-GKIKDSKJSA-N 0.000 description 1
- UBKCIXXGQRZHRO-UHFFFAOYSA-N propan-2-yl 2-aminoacetate;hydrochloride Chemical compound Cl.CC(C)OC(=O)CN UBKCIXXGQRZHRO-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009885 systemic effect Effects 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
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- LQUPKVMEAATBSL-UHFFFAOYSA-L zinc;2,3,4-trichlorophenolate Chemical compound [Zn+2].[O-]C1=CC=C(Cl)C(Cl)=C1Cl.[O-]C1=CC=C(Cl)C(Cl)=C1Cl LQUPKVMEAATBSL-UHFFFAOYSA-L 0.000 description 1
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- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
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Abstract
本发明涉及一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,以及在制备用于抗肿瘤的药物中的应用,通式(I)化合物的结构为Q‑L‑R1,其基团定义与说明书定义一致。
Description
技术领域
本发明涉及一种乐伐替尼衍生物及其制备方法,以及在制备抗肿瘤药物中的用途。
背景技术
乐伐替尼(Lenvatinib)是由日本卫材公司研制的口服多靶点酪氨酸激酶抑制剂(TKI),于2015年2月获FDA批准上市,适用于有局部地复发或转移、进展性、放射性碘-难治性分化型甲状腺癌患者的治疗。
但是乐伐替尼具有严重的副作用,包括心衰、血栓形成(动脉血栓栓塞事件)、肾损伤(肾衰竭及损伤)、胃肠道穿孔或胃或肠之间异常连接、心电图活动发生变化(QT间隔延长)、低血钙、伴随性头痛、癫痫发作和视觉变化(可逆性白质脑病综合征)、严重出血(大出血)、如果患者妊娠期间治疗会出现未出生儿风险及促甲状腺激素产生出现损伤性抑制(Oncotarget.2016,7:44545-44557)。王凌霄等2015年报道了乐伐替尼常见的副作用还有高血压、蛋白尿等(临床药物治疗杂志,13(5):11)。靳雨辰等2017年报道了乐伐替尼的严重不良反应包括高血压(43%)、蛋白尿(10%)和血栓栓塞(6.5%);其他不良反应包括QTc间期延长(8%)、肾衰竭(4.2%)和胃肠瘘(1.5%)(《中国癌症杂志》,27(6):451)。
上述副作用限制了乐伐替尼在临床上的应用,因此迫切需要对乐伐替尼进一步研究以改善药效及安全性,造福更多患者。
发明内容
本发明人经过大量创造性劳动,令人惊讶的得到了一种乐伐替尼的衍生物,显著改善了乐伐替尼的药效及安全性。
具体的,本发明涉及一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,
Q-L-R1 (I)
其中:
Q选自
R1选自 优选地,R1选自
Ar选自C6-10芳基或5至10元杂芳基,所述的芳基或杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-6烷氧基的取代基所取代,所述的杂芳基含有1至4个选自O、S、N的杂原子;
X1、X2、X4、X5各自独立的选自O或S;
X3选自O或N;
R1a、R1a`、R1c、R1c`、R1e、R1e`各自独立的选自H、C1-6烷基或C3-8碳环基,所述的C1-6烷基或C3-8碳环基任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-6烷氧基的取代基所取代;
R1b、R1d、R1f各自独立的选自C1-6烷基、苄基或C3-8碳环基,所述的C1-6烷基、苄基或C3-8碳环基任选进一步被0至4个选自H、F、Cl、Br、I、C1-6烷基或C1-6烷氧基的取代基所取代;
R1g选自C1-6烷基、-C1-6烷基-C3-8碳环基、C3-8碳环基或C5-10杂环基,所述的C1-6烷基、-C1-6烷基-C3-8碳环基、C3-8碳环基或C5-10杂环基任选进一步被0至4个选自H、F、Cl、Br、I、苯基、C1-6烷基或C1-6烷氧基的取代基所取代,所述的杂环基含有1至4个选自O、S、N的杂原子;
L选自键、其中L的左边与Q连接,右边与R1连接;
T选自C1-6烷基、C3-8碳环基、-C1-6烷基-C3-8碳环基,所述的C1-6烷基、C3-8碳环基、-C1-6烷基-C3-8碳环基任选进一步被0至4个选自H、F、Cl、Br、I、苯基、C1-6烷基、C3-6环烷基或C1-6烷氧基的取代基所取代;
优选地,L选自其中L的左边与Q连接,右边与R1连接;
RL1选自H、C1-6烷基、C1-6烷氧基或C3-6环烷基,所述的C1-6烷基、C1-6烷氧基或C3-6环烷基任选进一步被0至4个选自H、F、Cl、Br、I、C1-6烷基、C1-6烷氧基或C3-6环烷基的取代基所取代;
RL2选自H、F、Cl、Br、I、C1-6烷基、C1-6烷氧基或C3-6环烷基,所述的C1-6烷基、C1-6烷氧基或C3-6环烷基任选进一步被0至4个选自H、F、Cl、Br、I、C1-6烷基、C1-6烷氧基或C3-6环烷基的取代基所取代;
n选自0、1、2或3;m选自0、1、2、3或4;p选自0或1;r选自1、2、3、4、5或6。
本发明的一些实施例中,Ar选自C6-10芳基或5至10元杂芳基,优选苯基或5至6元杂芳基,进一步优选苯基或吡啶基;所述的芳基、杂芳基、苯基、吡啶基任选进一步被0、1、2、3或4个选自H、F、Cl、Br、I、C1-4烷基或C1-6烷氧基的取代基所取代,优选所述的芳基、杂芳基、苯基、吡啶基任选进一步被0、1、2、3或4个选自H、F、Cl、Br、I、甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基的取代基所取代;所述的杂芳基含有1、2、3或4个选自O、S、N的杂原子;
R1a、R1a`、R1c、R1c`、R1e、R1e`各自独立的选自H、C1-6烷基或C3-8碳环基,优选H或C1-4烷基,进一步优选H、甲基、乙基、丙基或异丙基;所述的C1-6烷基、C3-8碳环基、烷基或碳环基任选进一步被0、1、2、3或4个选自H、F、Cl、Br、I、C1-4烷基或C1-6烷氧基的取代基所取代,优选任选进一步被0、1、2、3或4个选自H、F、Cl、Br、I、甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基的取代基所取代;
R1b、R1d、R1f各自独立的选自C1-6烷基、苄基或C3-8碳环基,优选C1-4烷基或苄基,进一步优选甲基、乙基、丙基、异丙基或苄基;所述的C1-6烷基、C3-8碳环基、烷基、苄基或碳环基任选进一步被0、1、2、3或4个选自H、F、Cl、Br、I、C1-6烷基或C1-6烷氧基的取代基所取代,优选任选进一步被0、1、2、3或4个选自H、F、Cl、Br、I、甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基的取代基所取代,;
R1g选自C1-6烷基、-C1-6烷基-C3-8碳环基、C3-8碳环基或C5-10杂环基,优选C1-6烷基、-C1-4烷基-C3-6碳环基、C3-6碳环基、苯基或苄基,进一步优选取代或未取代的甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、己基、环戊基、环己基、苯基、苄基、亚甲基环丙基或亚甲基环丁基;所述的甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、己基、环戊基、环己基、苯基、苄基、亚甲基环丙基、亚甲基环丁基、苯基、苄基、C1-6烷基、C3-8碳环基、C5-10杂环基、烷基、碳环基或杂环基任选进一步被0、1、2、3或4个选自H、F、Cl、Br、I、苯基、C1-6烷基或C1-6烷氧基的取代基所取代,优选任选进一步被0、1、2、3或4个选自H、F、Cl、Br、I、甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基的取代基所取代;所述的杂环基含有1至4个选自O、S、N的杂原子;
L选自键、其中L的左边与Q连接,右边与R1连接;
RL1选自H、C1-6烷基、C1-6烷氧基或C3-6环烷基,优选H、C1-6烷基、,进一步优选H或甲基;所述的C1-6烷基、C1-6烷氧基、C3-6环烷基、烷基、烷氧基或环烷基任选进一步被0、1、2、3或4个选自H、F、Cl、Br、I、C1-6烷基、C1-6烷氧基或C3-6环烷基的取代基所取代,优选所述的烷基、烷氧基或环烷基任选进一步被0、1、2、3或4个选自H、F、Cl、Br、I、甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基的取代基所取代;
RL2选自H、F、Cl、Br、I、C1-6烷基、C1-6烷氧基或C3-6环烷基,优选H、F、Cl、Br、I、C1-6烷基、C1-6烷氧基,进一步优选H、F、Cl、Br、I、甲基或甲氧基;所述的烷基、烷氧基或环烷基任选进一步被0至4个选自H、F、Cl、Br、I、C1-6烷基、C1-6烷氧基或C3-6环烷基的取代基所取代,优选所述的烷基、烷氧基或环烷基任选进一步被0至4个选自H、F、Cl、Br、I、甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基的取代基所取代。
本发明的一些实施例中,R1a、R1a`、R1c、R1c`、R1e、R1e`各自独立的选自H或C1-4烷基;R1b、R1d、R1f各自独立的选自C1-4烷基或苄基;R1g选自C1-4烷基、苯基或苄基;RL1选自H或C1-4烷基;RL2选自H、F、Cl、Br、I、C1-4烷基或C1-4烷氧基。
本发明的一些实施例中,R1a、R1a`、R1c、R1c`、R1e、R1e`各自独立的选自H、甲基、乙基、丙基或异丙基;R1b、R1d、R1f各自独立的选自甲基、乙基、丙基、异丙基或苄基;R1g选自甲基、乙基、丙基、异丙基、苯基、苄基、亚甲基环丙基或亚甲基环丁基,所述的苯基或苄基任选进一步被0、1、2、3或4个选自H、F、Cl、Br、I、甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基的取代基所取代;L选自键、其中L的左边与Q连接,右边与R1连接;RL1选自H或甲基;RL2选自H、F、Cl、Br、I、甲基或甲氧基;n为1;m选自0、1、2、3或4;p为1;r为2或3。
本发明所述的化合物及其立体异构体或药学上可接受的盐,选自如下结构之一:
本发明的一些实施例中,所述的化合物及其立体异构体或药学上可接受的盐,为与选自下述的酸所成的盐:三氟乙酸、盐酸等。例如,所述的盐为
本发明还涉及一种药物组合物,所述药物组合物含有治疗有效剂量的上述的化合物或其立体异构体或药学上可接受的盐,以及药学上可接受的载体和赋形剂。
本发明还涉及上述的化合物及其立体异构体或药学上可接受的盐,以及上述的药物组合物在制备抗肿瘤药物中的应用。
本发明所述的肿瘤包括但不限于胰脏癌、胃癌、大肠癌、乳癌、前列腺癌、肺癌、肾癌、脑肿瘤、血液癌、卵巢癌、肝癌或甲状腺癌。
为了完成本发明的目的,本发明化合物可以由以下方案制备而得:
方法一:
通式I-A与三氯氧磷(或(甲氧基甲基)膦酰二氯或二氯磷酸R1g酯)反应,再与相应的氨基酸酯(例如)反应得到通式I-B的化合物,再经过硼氢化钠还原得到通式I-D的化合物;或者由通式I-C与三氯氧磷(或(甲氧基甲基)膦酰二氯或二氯磷酸R1g酯)反应,再与相应的氨基酸酯(例如)反应得到通式I-D的化合物。原料SM-1与草酰氯反应成活性中间态,再与通式I-D生成通式I-E的化合物,最后与环丙胺反应生成通式I-1的化合物。
方法二:
通式IIA与三氯氧磷(或(甲氧基甲基)膦酰二氯或二氯磷酸R1g酯)反应,再与相应的氨基酸酯(例如)反应得到通式IIB的化合物。通式IIB与通式IIC在叔丁基氯化镁的作用下生成通式IID的化合物,原料SM-1与草酰氯反应成活性中间态,再与通式IID生成通式IIE的化合物,最后与环丙胺反应生成通式II的化合物。
乐伐替尼与通式IIB在叔丁基氯化镁的作用下直接生成通式III化合物。
方法三:
X’选自O或N;
R1g、Ar、Q、L、R1与通式(I)的定义一致;
通式IA与三氯氧磷生成中间体IB(部分可商业购买),中间体IB(无须纯化)依次与氨基酸酯和通式IC反应生成通式IE;或者由4-硝基苯二氯化磷依次与通式IA和氨基酸酯反应生成通式IE;或者由4-硝基苯二氯化磷与通式ID反应生成通式IE;或者由(甲氧基甲基)膦酰二氯依次与氨基酸酯和通式IC反应生成通式IE。通式IE与乐伐替尼在叔丁基氯化镁的作用下直接生成通式I化合物。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明中,C3-8碳环基表示C3-8的环烷基或C6-8芳基,C3-8的环烷基表示碳原子数为3-8的环状烷基,例如环丙基、环丁基、环戊基、环己基;C6-8芳基表示碳原子数是为6-8的芳香族环状基团,例如苯基、苄基。C1-6烷基表示碳原子数1-6的支链或直链烷基,例如甲基、乙基、丙基、异丙基、丁基、叔丁基。C1-6烷氧基表示氧原子与C1-6烷基结合形成的基团,例如甲氧基、乙氧基。C3-6环烷基表示碳原子数为3-6的环状烷基,例如环丙基、环丁基、环戊基。C5-10杂环基表示环的原子数为5-10的芳香族或非芳香族杂环基团,环的原子种类包括一个或以上的杂原子(例如N、O、S),例如吗啉基、氮杂环丁烷、哌啶基、哌嗪基、吡咯烷基。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又称为重氢)、氚(T,又称为超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生,该说明包括该事件或环境发生或不发生的场合。如:“任选被F取代的烷基”指烷基可以但不必须被F取代,说明包括烷基被F取代的情形和烷基不被F取代的情形。
“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐与其他组成成分的混合物,其中其它组分包含生理学/药学上可接受的载体和赋形剂。
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。
“赋形剂”指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和不同类型的淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。
“前药”是指可以在生理条件下或通过溶剂解转化为具有生物活性的本发明化合物的化合物。本发明的前药通过修饰本发明化合物中的功能基团来制备,该修饰可以通过常规的操作或者在体内被除去,而得到母体化合物。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“有效剂量”指引起组织、系统或受试者生理或医学反应的化合物的量,此量是所寻求的,包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。
与乐伐替尼相比,本发明显著提高了对靶部位作用的特异性,特别是对肝靶向。并发现具有此类结构的化合物表现出优异的效果和作用,具有良好口服生物利用度、降低毒副作用、提高安全性、延长半衰期、延长作用时间等优点。
具体实施方式
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果,旨在帮助阅读者更好地理解本发明的实质和特点,不作为对本案可实施范围的限定。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的,超临界流体色谱法(SFC)拆分手性结构。
NMR位移(δ)以10-6(ppm)的单位给出。
NMR的测定是用(Bruker ADVANCE III 400)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS),1HNMR信息以下列格式来列表:化学位移(多重峰(s,单峰;d,双重峰;t,三重峰;q,四重峰;m,多重峰),质子数)。
MS的测定用(Agilent 6120B(ESI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(ZorbaxSB-C18 100x4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.20mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
本发明的已知的起始原料及阳性对照乐伐替尼可以采用或按照本领域已知的方法来合成,或购买于成都科龙化工,成都西陇化工,成都效佳,安耐吉化学,成都叮当化学,爱斯特(成都)医药技术有限公司,韶远化学科技(上海)有限公司,国药集团药业股份有限公司,百灵威科技有限公司等公司。
本发明中,DCM:二氯甲烷;DMF:N,N-二甲基甲酰胺;TFA:三氟乙酸;THF:四氢呋喃。
实施例1:
异丙基(2S)-2-[[[4-[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基甲酰氧基甲基]苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯2,2,2-三氟乙酸盐(化合物1);
isopropyl
(2S)-2-[[[4-[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]carbamoyloxymethyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate 2,2,2-trifluoroacetate.
(1)第一步:
异丙基(2S)-2-[[[4-(羟甲基)苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯;
isopropyl
(2S)-2-[[[4-(hydroxymethyl)phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate.
氮气保护下,将二氯甲烷(90mL)加入反应瓶中,搅拌下加入甲氧基甲基)膦酰二氯(8.96g,55mmol),冷却至-30℃。加入L-丙氨酸异丙酯盐酸盐(9.22g,55mmol),缓慢滴入三乙胺(11.11g,110mmol)和二氯甲烷(5mL)的混合溶液,加完后于-30℃反应30min。然后依次加入1A(6.21g,50mmol)和三乙胺(5.05g,50mmol),加完后升至室温搅拌反应4h,然后加入水(100mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)1/1),得到异丙基(2S)-2-[[[4-(羟甲基)苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(1B),淡黄色透明油状物6.12g,收率:33.66%。
MS m/z(ESI):346.2[M+H]+
1H NMR(400MHz,CDCl3)δ7.39–7.08(m,4H),5.11–4.90(m,1H),4.68–4.50(m,2H),4.16–4.00(m,1H),3.85–3.54(m,3H),3.49–3.34(m,3H),2.87(s,1H),1.33–1.17(m,9H).
(2)第二步:
异丙基(2S)-2-[[[4-[[4-[3-氯-4-苯氧基羰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基甲酰氧基甲基]苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯盐酸盐;
isopropyl
(2S)-2-[[[4-[[4-[3-chloro-4-(phenoxycarbonylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]carbamoyloxymethyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate hydrochloride.
将化合物1C(1g,2.16mmol)溶于20mL THF中,加入草酰氯(0.55g,4.32mmol),升温至回流反应1h,冷却至室温减压除去溶剂,加入20mL DCM溶解后,加入1B(1.12g,3.24mmol),搅拌1h。减压除去溶剂,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇=(v/v)100/1-20/1),得到目标化合物1D,淡黄色固体(1.2g,63.8%yield)。
MS m/z(ESI):835.2[M+H]+
(3)第三步:
异丙基(2S)-2-[[[4-[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基甲酰氧基甲基]苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯;2,2,2-三氟乙酸盐(化合物1);
isopropyl
(2S)-2-[[[4-[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]carbamoyloxymethyl]phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate;2,2,2-trifluoroacetate.
将1D(0.9g,1.07mmol)溶于20mL四氢呋喃中,加入环丙胺(0.6g,10.5mmol)室温下搅拌2h。减压除去溶剂,残留物通过制备液相(制备条件:仪器:WATERS 2767;柱:XbridgeC18,5μm,19mm*250mm;流动相:乙腈/水(含0.1%TFA);梯度洗脱方法:乙腈由10%梯度洗脱70%,洗脱时间15min;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;样品制备:化合物溶解于12mL DMF中;注射:0.9mL/针)进一步分离纯化得到目标化合物1,淡黄色固体(0.22g,23.3%yield)。
MS m/z(ESI):798.2[M+H]+
1H NMR(400MHz,DMSO-d6)11.15(s,1H),8.71(d,1H),8.29(d,2H),7.98(s,1H),7.52-7.45(m,2H),7.40-7.33(m,2H),7.28-7.23(m,1H),7.21-7.13(m,3H),6.61(d,1H),5.72-5.62(m,1H),5.10(s,2H),4.95-4.75(m,1H),3.93(s,3H),3.89-3.82(m,1H),3.80-3.71(m,2H),3.40-3.34(m,3H),2.63-2.54(m,1H),1.20-1.11(m,9H),0.70-0.62(m,2H),0.47-0.40(m,2H).
实施例2:
异丙基(2S)-2-[[[5-[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基甲酰氧基甲基]-2-甲氧基-苯氧基]-[[(1S)-2-异丙氧基-1-甲基-2-氧-乙基]氨基]磷酰基]氨基]丙酸酯(化合物2);
isopropyl
(2S)-2-[[[5-[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]carbamoyloxymethyl]-2-methoxy-phenoxy]-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate;
(1)第一步:
异丙基(2S)-2-[[(5-甲酰-2-甲氧基-苯氧基)-[[(1S)-2-异丙氧基-1-甲基-2-氧-乙基]氨基]磷酰基]氨基]丙酸酯;
isopropyl
(2S)-2-[[(5-formyl-2-methoxy-phenoxy)-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate;
将2A(5g,32.86mmol)溶于200mL二氯甲烷中,-78摄氏度下加入三氯氧磷(5g,32.86mmol),再缓慢滴加三乙胺(3.4g,33.60mmol),此温度下搅拌20min,加入L-丙氨酸异丙酯盐酸盐(11g,65.48mmol),再缓慢加入三乙胺(13.6g,134.4mmol),缓慢升温至室温搅拌2h。依次用100mL饱和磷酸二氢钠水溶液和100mL饱和食盐水洗涤,有机层用无水硫酸钠干燥后浓缩,得化合物2B,黄色油状物(13g,86.3%yield),直接用于下一步。
MS m/z(ESI):459.2[M+H]+
1H NMR(400MHz,CDCl3)δ9.85(d,1H),7.89-7.75(m,1H),7.74-7.64(m,
1H),7.15-7.00(m,1H),5.10-4.90(m,2H),4.21-3.85(m,6H),3.77-3.68(m,1H),1.47-1.33(m,6H),1.28-1.22(m,12H).
(2)第二步:
异丙基(2S)-2-[[[5-(羟甲基)-2-甲氧基-苯氧基)-[[(1S)-2-异丙氧基-1-甲基-2-氧-乙基]氨基]磷酰基]氨基]丙酸酯;
isopropyl
(2S)-2-[[[5-(hydroxymethyl)-2-methoxy-phenoxy]-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate.
将化合物2B(5g,10.91mmol)溶于20mL THF中,降温至-10℃,缓慢加入硼氢化钠(0.29g,7.64mmol),升温至室温搅拌20min。加入40mL乙酸乙酯和40mL饱和氯化钠水溶液,萃取后,有机层用无水硫酸钠干燥,浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)1/1~0/1),得化合物2C,淡黄色油状物(2.5g,50%yield)。
MS m/z(ESI):461.2[M+H]+
1H NMR(400MHz,CDCl3)δ7.25(t,1H),7.10(d,1H),6.89(d,1H),5.10-4.90(m,2H),4.52(d,2H),4.13-3.94(m,2H),3.88(s,3H),3.87-3.74(m,2H),2.66(s,1H),1.45-1.32(m,6H),1.28-1.17(m,12H).
(3)第三步:
异丙基(2S)-2-[[[5-[[4-[3-氯-4-(苯氧基羰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基甲酰氧基甲基]-2-甲氧基-苯氧基]-[[(1S)-2-异丙氧基-1-甲基-2-氧-乙基]氨基]磷酰基]氨基]丙酸酯盐酸盐;
isopropyl
(2S)-2-[[[5-[[4-[3-chloro-4-(phenoxycarbonylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]carbamoyloxymethyl]-2-methoxy-phenoxy]-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoatehydrochloride;
将化合物1C(1g,2.16mmol)溶于20mL THF中,加入草酰氯(0.55g,4.32mmol),升温至回流反应1h,冷却至室温减压除去溶剂,加入20mL DCM溶解后,加入2C(1.49g,3.24mmol),搅拌1h。减压除去溶剂,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇=(v/v)100/1-20/1),得到目标化合物2D,淡黄色固体(1.4g,56.5%yield)。
MS m/z(ESI):950.3[M+H]+
(4)第四步:
异丙基(2S)-2-[[[5-[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基甲酰氧基甲基]-2-甲氧基-苯氧基]-[[(1S)-2-异丙氧基-1-甲基-2-氧-乙基]氨基]磷酰基]氨基]丙酸酯(化合物2);
isopropyl
(2S)-2-[[[5-[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]carbamoyloxymethyl]-2-methoxy-phenoxy]-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate;
将2D(1.4g,1.42mmol)溶于20mL四氢呋喃中,加入环丙胺(1.2g,21.0mmol),室温下搅拌2h。减压除去溶剂,残留物通过制备液相(制备条件:仪器:WATERS 2767;柱:XbridgeC18,5μm,19mm*250mm;流动相:乙腈/水(含0.1%TFA);梯度洗脱方法:乙腈由10%梯度洗脱70%,洗脱时间15min;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;样品制备:化合物溶解于12mL DMF中;注射:0.9mL/针)进一步分离纯化得到目标化合物2,淡黄色固体(0.5g,38.6%yield)。
MS m/z(ESI):913.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.67(d,1H),8.32-8.20(m,2H),7.97(s,1H),7.47(s,2H),7.30(s,1H),7.27-7.17(m,2H),7.14-7.09(m,1H),7.07-7.02(m,1H),6.55(d,1H),5.03(s,2H),4.99-4.92(m,2H),4.91-4.84(m,2H),3.93(s,3H),3.92-3.82(m,2H),3.78(d,3H),2.63-2.53(m,1H),1.29-1.23(m,6H),1.19-1.14(m,12H),0.70-0.62(m,2H),0.47-0.38(m,2H).
实施例3:
异丙基(2S)-2[[[5-[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基甲酰氧基甲基]-2-甲氧基-苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物3)
isopropyl
(2S)-2-[[[5-[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]carbamoyloxymethyl]-2-methoxy-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate.
(1)第一步:
氮气保护下,将二氯甲烷(90mL)加入反应瓶中,搅拌下加入甲氧基甲基)膦酰二氯(8.96g,55mmol),冷却至-30℃。加入L-丙氨酸异丙酯盐酸盐(9.22g,55mmol),缓慢滴入三乙胺(11.11g,110mmol)和二氯甲烷(5mL)的混合溶液,加完后-30℃反应30min。然后依次加入3A(7.50g,50mmol)和三乙胺(5.05g,50mmol)加完后升至室温搅拌反应4h,然后加入水(100mL),搅拌5min,静置分层。有机层用无水硫酸钠干燥,过滤,减压浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)1/1),得到目标化合物3B,淡黄色透明油状物(6.51g,35.64%)。
MS m/z(ESI):376.1[M+H]+
1H NMR(400MHz,CDCl3)δ7.33–7.25(m,1H),7.20–7.05(m,1H),6.95–6.84(m,1H),5.06–4.90(m,1H),4.59–4.49(m,2H),4.09–3.98(m,1H),3.91–3.75(m,6H),3.53–3.44(m,3H),3.27(s,1H),1.41–1.17(m,9H).
(2)第二步:
异丙基(2S)-2-[[[5-[[4-[3-氯-4-苯氧基羰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基甲酰氧基甲基]-2甲氧基-苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯盐酸盐;
isopropyl
(2S)-2-[[[5-[[4-[3-chloro-4-(phenoxycarbonylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]carbamoyloxymethyl]-2-methoxy-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate hydrochloride.
将化合物1C(1g,2.16mmol)溶于20mL THF中,加入草酰氯(0.55g,4.32mmol),升温至回流反应1h,冷却至室温减压除去溶剂,加入20mL DCM溶解后,加入3B(1.6g,4.24mmol),搅拌1h。减压除去溶剂,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇=(v/v)100/1-20/1),得到目标化合物3C,淡黄色固体(1.2g,61.7%yield)。
MS m/z(ESI):865.2[M+H]+
(3)第三步:
异丙基(2S)-2-[[[5-[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基甲酰氧基甲基]-2甲氧基-苯氧基]-(甲氧基甲基)磷酰基]氨基]丙酸酯;
isopropyl
(2S)-2-[[[5-[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]carbamoyloxymethyl]-2-methoxy-phenoxy]-(methoxymethyl)phosphoryl]amino]propanoate.
将3C(1.2g,1.33mmol)溶于20mL四氢呋喃中,加入环丙胺(1.2g,21.0mmol),室温下搅拌2h。减压除去溶剂,残留物通过制备液相(制备条件:仪器:WATERS 2767;柱:XbridgeC18,5μm,19mm*250mm;流动相:乙腈/水(含0.1%TFA);梯度洗脱方法:乙腈由10%梯度洗脱70%,洗脱时间15min;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;样品制备:化合物溶解于12mL DMF中;注射:0.9mL/针)进一步分离纯化得到目标化合物3,淡黄色固体(0.1g,9.1%yield)。
MS m/z(ESI):828.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),8.67(d,1H),8.40-8.17(m,2H),7.97(s,1H),7.47(d,2H),7.33-7.10(m,5H),6.54(d,1H),5.51(s,1H),5.04(d,2H),4.93-4.79(m,1H),3.93(s,4H),3.84-3.75(m,5H),3.36(d,3H),2.62-2.53(m,1H),1.20-1.12(m,9H),0.70-0.64(m,2H),0.47-0.39(m,2H).
实施例4:
异丙基(2S)-2-[[3-[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]]丙氧基-[[(1S)-2-异丙氧基-1-甲基-2-氧-乙基]氨基]磷酰基]氨基丙酸酯(化合物4);
isopropyl
(2S)-2-[[3-[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]carbamoyloxy]propoxy-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate.
(1)第一步:
异丙基(2S)-2-[[[[(1S)-2-异丙氧基-1-甲基-2-氧代-乙基]氨基]-(2,3,4,5,6-五氟苯氧基)磷酰基]氨基]丙酸酯;
isopropyl
(2S)-2-[[[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino]propanoate。
将化合物4A(5g,27.17mmol)溶于二氯甲烷(200mL)中,降温至-78℃,加入三氯氧磷(4.57g,29.88mol),再滴加三乙胺(3g,29.66mmol)。此温度下搅拌20分钟后,加入L-丙氨酸异丙酯盐酸盐(10g,59.52mmol),再加入三乙胺(12g,118.66mmol),升温至室温继续搅拌30min。减压除去溶剂,加入甲基叔丁基醚(100mL),过滤,滤液浓缩后,用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)20/1~4/1),得化合物4B,淡黄色固体(5g,37.53%yield)。
MS m/z(ESI):491.2[M+H]+
(2)第二步:
异丙基(2S)-2-[[3-羟丙氧基-[[(1S)-2-异丙基-1-甲基-2-氧-乙基]氨基]磷酰基]氨基]丙酸酯;
isopropyl
(2S)-2-[[3-hydroxypropoxy-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate.
将1,3-丙二醇(1g,13.14mmol)溶于10mL THF中,室温下缓慢滴加叔丁基氯化镁四氢呋喃溶液(1N,26mL),搅拌20min后,降温至0℃,加入4B(1.9g,3.87mmol),缓慢升温至室温,搅拌2h。减压除去溶剂,加入20mL DCM,用20mL饱和氯化钠水溶液洗涤有机相,有机层干燥后浓缩,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇=(v/v)100/1-30/1),得目标化合物4C,淡黄色油状物(0.7g,50%yield)。
MS m/z(ESI):383.2[M+H]+
1H NMR(400MHz,CDCl3)δ5.10-4.92(m,2H),4.20-4.05(m,2H),4.00-3.82(m,2H),3.72(t,2H),3.37(s,3H),1.90-1.75(m,2H),1.43-1.32(m,6H),1.30-1.20(m,12H).
(3)第三步:
异丙基(2S)-2-[[3-[[4-[3-氯-4-(苯氧基羰基氨基苯氧基]-7-甲氧基-喹啉-6-羰基]氨基甲酰氧基甲基]丙氧基-[[(1S)-2-异丙氧基-1-甲基-2-氧-乙基]氨基]磷酰基]氨基]丙酸酯盐酸盐;
isopropyl
(2S)-2-[[3-[[4-[3-chloro-4-(phenoxycarbonylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]carbamoyloxy]propoxy-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate hydrochloride.
将化合物1C(0.6g,1.29mmol)溶于20mL THF中,加入草酰氯(0.3g,2.36mmol),升温至80℃搅拌1h。减压除去溶剂,加入4C(0.7g,1.82mmol)的DCM溶液10mL,继续搅拌1h。减压除去溶剂,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇=(v/v)100/1-20/1),得目标化合物4D,淡黄色固体(0.9g,76.6%yield)。
MS m/z(ESI):872.2[M+H]+
(4)第四步:
异丙基(2S)-2-[[3-[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]]丙氧基-[[(1S)-2-异丙氧基-1-甲基-2-氧-乙基]氨基]磷酰基]氨基丙酸酯;
isopropyl
(2S)-2-[[3-[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]carbamoyloxy]propoxy-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate.
将4D(0.9g,1.00mmol)溶于20mL四氢呋喃中,加入环丙胺(0.6g,10.5mmol),室温下搅拌2h。减压除去溶剂,残留物通过制备液相(制备条件:仪器:WATERS 2767;柱:XbridgeC18,5μm,19mm*250mm;流动相:乙腈/水(含0.1%TFA);梯度洗脱方法:乙腈由10%梯度洗脱70%,洗脱时间15min;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;样品制备:化合物溶解于12mL DMF中;注射:0.9mL/针)进一步分离纯化得到目标化合物4,淡黄色固体(0.2g,24.0%yield)。
MS m/z(ESI):835.3[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.67(d,1H),8.35-8.20(m,2H),7.97(s,1H),7.60-7.40(m,2H),7.30-7.10(m,2H),6.55(d,1H),4.95-4.80(m,2H),4.75-4.55(m,2H),4.13(t,2H),3.97(s,3H),3.90-3.81(m,2H),3.76-3.62(m,2H),2.65-2.53(m,1H),1.93-1.80(m,2H),1.26-1.12(m,18H),0.73-0.61(m,2H),0.47-0.38(m,2H).
实施例5:
异丙基(2S)-2-[[2-[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基甲酰氧基]乙氧基-(甲氧甲基)磷酰基]氨基]丙酸酯(化合物5);
isopropyl
(2S)-2-[[2-[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]carbamoyloxy]ethoxy-(methoxymethyl)phosphoryl]amino]propanoate.
(1)第一步:
异丙基(2S)-2-[[甲氧甲基-(4-硝基苯氧基)磷酰基]氨基]丙酸酯;
isopropyl
(2S)-2-[[methoxymethyl-(4-nitrophenoxy)phosphoryl]amino]propanoate。
-20℃下,将化合物5A(2g,14.38mmol)和(甲氧基甲基)膦酰二氯(2.34g,14.38mmol)溶于二氯甲烷(50mL)中,向此混合物中缓慢滴加三乙胺(1.45g,14.38mmol),此温度下继续搅拌20min后,依次加入L-丙氨酸异丙酯盐酸盐(2.42g,14.39mmol)和三乙胺(2.91g,28.78mmol),自然升温至室温继续搅拌30min。加入二氯甲烷(50mL),依次用饱和磷酸二氢钠溶液和食盐水洗涤,有机层用无水硫酸钠干燥后浓缩,残留物用硅胶柱层析分离提纯(石油醚/乙酸乙酯=(v/v)10/1~4/1),得化合物5B,淡黄色粘稠半固体(3g,57.90%yield)。
MS m/z(ESI):359.2[M-H]-
(2)第二步:
异丙基(2S)-2-[[2-羟乙氧基(甲氧基甲基l)磷酰基]氨基]丙酸酯;
isopropyl
(2S)-2-[[2-hydroxyethoxy(methoxymethyl)phosphoryl]amino]propanoate.
将乙二醇(2.8g,45.2mmol)溶于四氢呋喃(10mL)中,冰浴下,滴加叔丁基氯化镁四氢呋喃溶液(1N,45.2mL),升温至室温继续搅拌30min后降温至0℃。向此混合液中加入5B(8g,8.88mol),自然升温至室温,加入二氯甲烷(100mL),用饱和食盐水(100mL×2)洗涤,有机层干燥浓缩,残留物用硅胶柱层析分离提纯(甲醇/二氯甲烷=(v/v)100/1~20/1),得化合物5C,淡黄色油状物(0.9g,35.78%yield)。
MS m/z(ESI):284.2[M+H]+
(3)第三步:
异丙基(2S)-2-[[2-[[4-[3-氯-4-(苯氧羰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基甲酰氧基]乙氧基-(甲氧甲基)磷酰基]氨基]丙酸酯盐酸盐;
isopropyl
(2S)-2-[[2-[[4-[3-chloro-4-(phenoxycarbonylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]carbamoyloxy]ethoxy-(methoxymethyl)phosphoryl]amino]propanoatehydrochloride;
将化合物1C(0.6g,1.29mmol)溶于20mL THF中,加入草酰氯(0.3g,2.36mmol),升温至80℃搅拌1h。减压除去溶剂,加入5C(0.7g,2.46mmol)的DCM溶液10mL,继续搅拌1h。减压除去溶剂,残留物用硅胶柱层析分离提纯(二氯甲烷/甲醇=(v/v)100/1-20/1),得目标化合物5D,淡黄色固体(0.8g,76.7%yield)。
MS m/z(ESI):773.2[M+H]+
(4)第四步:
异丙基(2S)-2-[[2-[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基甲酰氧基]乙氧基-(甲氧甲基)磷酰基]氨基]丙酸酯(化合物5);
isopropyl
(2S)-2-[[2-[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]carbamoyloxy]ethoxy-(methoxymethyl)phosphoryl]amino]propanoate.
将5D(0.8g,0.99mmol)溶于20mL四氢呋喃中,加入环丙胺(0.6g,10.5mmol),室温下搅拌2h。减压除去溶剂,残留物通过制备液相(制备条件:仪器:WATERS 2767;柱:XbridgeC18,5μm,19mm*250mm;流动相:乙腈/水(含0.1%TFA);梯度洗脱方法:乙腈由10%梯度洗脱70%,洗脱时间15min;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;样品制备:化合物溶解于12mL DMF中;注射:0.9mL/针)进一步分离纯化得到目标化合物5,淡黄色固体(0.19g,26.1%yield)。
MS m/z(ESI):736.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.11(d,1H),8.68(d,1H),8.28(d,2H),7.97(s,1H),7.51-7.44(m,2H),7.26-7.16(m,2H),6.55(d,1H),5.25-5.14(m,1H),4.95-4.80(m,1H),4.34-4.18(m,2H),4.16-4.02(m,2H),3.97(s,3H),3.84-3.72(m,1H),3.68-3.52(m,2H),3.34-3.30(m,3H),2.62-2.54(m,1H),1.28-1.24(m,3H),1.21-1.15(m,6H),0.71-0.62(m,2H),0.48-0.38(m,2H).
实施例6:
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(甲氧甲基)磷酰基]氨基]丙酸酯(化合物6);
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(methoxymethyl)phosphoryl]amino]propanoate.
(1)第一步:
异丙基(2S)-2-[[(3-氰基苯氧基)-(甲氧基甲基)磷酰基]氨基]丙酸酯:
isopropyl
(2S)-2-[[(3-cyanophenoxy)-(methoxymethyl)phosphoryl]amino]propanoate.
将(甲氧基甲基)膦酰二氯(4.9g,30.2mmol)溶于200mL的DCM中,加入6A(3g,25.2mmol),降温至-20℃,加入三乙胺(9.2g,90.9mmol),搅拌20min后加入L-丙氨酸异丙酯盐酸盐(5.1g,30.4mmol),缓慢升温至室温搅拌20min。分别用200mL饱和磷酸氢二钠溶液和200mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/2~1/1),得目标化合物6B,黄色固体(4g,46.7%yield)。
MS m/z(ESI):341.2[M+H]+
1H NMR(400MHz,CDCl3)δ7.57-7.39(m,4H),5.06-4.94(m,1H),4.16-4.03(m,1H),3.88-3.76(m,2H),3.74-3.60(m,1H),3.52-3.40(m,3H),1.37-1.31(m,3H),1.26-1.22(m,6H).
(2)第二步:
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(甲氧甲基)磷酰基]氨基]丙酸酯(化合物6);
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(methoxymethyl)phosphoryl]amino]propanoate.
将6B(0.72g,2.11mmol)溶于4mL DMF中,加入乐伐替尼(0.3g,0.70mmol),室温下缓慢滴加叔丁基氯化镁THF溶液(1N,2.8mmol)。加毕后搅拌10min,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mL×3)洗涤,无水硫酸钠干燥,减压浓缩,残留物通过制备液相(制备条件:仪器:WATERS 2767;柱:Xbridge C18,5μm,19mm*250mm;流动相:乙腈/水(含5mM乙酸铵);梯度洗脱方法:乙腈由25%梯度洗脱50%,洗脱时间15min;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;样品制备:化合物溶解于5mL DMF中;注射:0.9mL/针)进一步分离纯化得到目标化合物6,白色固体(150mg,33%yield)。
MS m/z(ESI):648.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.36-9.26(m,1H),8.75-8.60(m,2H),8.29(d,1H),7.98(s,1H),7.58(d,1H),7.49(d,1H),7.28-7.25(m,1H),7.19(d,1H),6.59-6.54(m,1H),5.42-5.24(m,1H),4.95-4.80(m,1H),4.13-4.02(m,3H),4.01-3.95(m,1H),3.95-3.90(m,2H),3.40-3.37(m,3H),2.63-2.54(m,1H),1.32(d,3H),1.21-1.14(m,6H),0.72-0.60(m,2H),0.48-0.38(m,2H).
实施例7
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-[[(1S)-2-异丙氧基-1-甲基-2-氧-乙基]氨基]磷酰基]氨基]丙酸酯(化合物9);
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate.
(1)第一步:
异丙基(2S)-2-[[(3-氰基苯氧基)-[[(1S)-2-异丙氧基-1-甲基-2-氧-乙基]氨基]磷酰基]氨基]丙酸酯;
isopropyl
(2S)-2-[[(3-cyanophenoxy)-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate.
将(甲氧基甲基)膦酰二氯(5g,32.3mmol)溶于200mL的DCM中,加入6A(3.5g,29.4mmol),降温至-20℃,加入三乙胺(14.9g,146.9mmol),搅拌20min后加入L-丙氨酸异丙酯盐酸盐(9.9g,58.8mmol),缓慢升温至室温搅拌20min。分别用200mL饱和磷酸氢二钠溶液和200mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/2~1/1),得目标化合物9B,淡黄色油状物(3g,24.0%yield)。
MS m/z(ESI):426.2[M+H]+
1H NMR(400MHz,CDCl3)7.55-7.47(m,2H),7.45-7.37(m,2H),5.10-4.95(m,2H),4.06-3.92(m,2H),3.69(s,2H),1.44-1.36(m,6H),1.27-1.22(m,12H).
(2)第二步:
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-[[(1S)-2-异丙氧基-1-甲基-2-氧-乙基]氨基]磷酰基]氨基]丙酸酯(化合物9);
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-[[(1S)-2-isopropoxy-1-methyl-2-oxo-ethyl]amino]phosphoryl]amino]propanoate.
将9B(0.90g,2.11mmol)溶于4mL DMF中,加入乐伐替尼(0.3g,0.70mmol),室温下缓慢滴加叔丁基氯化镁THF溶液(1N,2.8mmol)。加毕后搅拌10min,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mL×3)洗涤,无水硫酸钠干燥,减压浓缩,残留物通过硅胶柱层析进一步纯化(二氯甲烷/甲醇=(v/v)100/1~10/1),得目标化合物9,白色固体(0.12g,23.3%yield)。
MS m/z(ESI):733.3[M+H]+
1H NMR(400MHz,DMSO-d6)9.20(d,1H),8.69(d,1H),8.59(s,1H),8.28(d,1H),7.98(s,1H),7.55(s,1H),7.47(d,1H),7.26-7.21(m,1H),7.19(d,1H),6.56(d,1H),4.99-4.82(m,4H),4.05(s,3H),3.99-3.83(m,2H),2.65-2.53(m,1H),1.30(d,6H),1.22-1.14(m,12H),0.71-0.64(m,2H),0.47-0.40(m,2H).
实施例8
(S)-异丙基(2R)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-苯氧基-磷酰基]氨基]丙酸酯(化合物10-a);
(S)-isopropyl
(2R)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-phenoxy-phosphoryl]amino]propanoate.
(1)第一步:
异丙基(2S)-2-[[(3-氰基苯氧基)-苯氧基-磷酰基]氨基]丙酸酯;
isopropyl(2S)-2-[[(3-cyanophenoxy)-phenoxy-phosphoryl]amino]propanoate.
将二氯磷酸苯酯(6.8g,32.3mmol)溶于200mL的DCM中,加入L-丙氨酸异丙酯盐酸盐(4.9g,29.3mmol),降温至-20℃,加入三乙胺(9.2g,90.9mmol),搅拌20min后加入6A(3.5g,29.38mmol),缓慢升温至室温搅拌20min。分别用200mL饱和磷酸氢二钠溶液和200mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/3~1/1),得目标化合物10B,淡黄色油状物(7g,61.3%yield)。
MS m/z(ESI):389.2[M+H]+
(2)第二步:
(S)-异丙基(2R)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-苯氧基-磷酰基]氨基]丙酸酯(化合物10-a)
(S)-isopropyl
(2R)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-phenoxy-phosphoryl]amino]propanoate.
将10B(0.96g,2.46mmol)溶于4mL DMF中,加入乐伐替尼(0.35g,0.82mmol),室温下缓慢滴加叔丁基氯化镁THF溶液(1N,2.5mmol)。加毕后搅拌10min,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mL×3)洗涤,无水硫酸钠干燥,减压浓缩,残留物通过硅胶柱层析进一步纯化(二氯甲烷/甲醇=(v/v)100/1~20/1),得目标化合物10-a,白色固体(0.05g,8.8%yield,保留时间:31.305min)。
分析条件:
设备:安捷伦1260DAD高压液相色谱仪
色谱柱:大赛璐ChiralPak IC,5μm,4.6×250mm.
流动相:A for n-hexane and B for Ethanol.
梯度:B 50%
流速:0.7mL/min
柱温:35℃
波长:210nm
时间:50min
MS m/z(ESI):696.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.79(d,1H),8.69(d,1H),8.45(s,1H),8.29(d,1H),7.98(s,1H),7.53(s,1H),7.48(d,1H),7.43-7.33(m,2H),7.32-7.12(m,5H),6.56(d,1H),5.95-5.83(m,1H),4.94-4.81(m,1H),4.17-4.04(m,1H),4.03-3.90(m,3H),2.63-2.55(m,1H),1.35-1.26(m,3H),1.14(d,6H),0.74-0.62(m,2H),0.50-0.38(m,2H).
31P NMR(162MHz,DMSO-d6)δ1.91.
实施例9
(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(甲氧基甲基)磷酰基]氨基]丙酸乙酯(化合物7)。
ethyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(methoxymethyl)phosphoryl]amino]propanoate.
第一步:
(2S)-2-[[(3-氰基苯氧基)-(甲氧基甲基)磷酰基]氨基]丙酸乙酯(7B)
ethyl(2S)-2-[[(3-cyanophenoxy)-(methoxymethyl)phosphoryl]amino]propanoate.
将(甲氧基甲基)膦酰二氯(4.5g,27.6mmol)溶于200mL的DCM中,加入6A(3g,25.2mmol),降温至-20℃,加入三乙胺(9.2g,90.9mmol),搅拌20min后加入L-丙氨酸乙酯盐酸盐(4.2g,25.2mmol),缓慢升温至室温搅拌20min。分别用200mL饱和磷酸氢二钠溶液和200mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/2~1/1),得目标化合物7B,淡黄色固体(4g,48.7%yield)。
MS m/z(ESI):327.1[M+H]+
第二步:
(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(甲氧基甲基)磷酰基]氨基]丙酸乙酯(化合物7)
ethyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(methoxymethyl)phosphoryl]amino]propanoate.
将7B(0.9g,2.75mmol)溶于4mL DMF中,加入乐伐替尼(0.4g,0.94mmol),室温下缓慢滴加叔丁基氯化镁THF溶液(1N,2.8mmol)。加毕后搅拌10min,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mL×3)洗涤,无水硫酸钠干燥,减压浓缩,残留物通过制备液相(制备条件:仪器:WATERS 2767;柱:Xbridge C18,5μm,19mm*250mm;流动相:乙腈/水(含5mM乙酸铵);梯度洗脱方法:乙腈由25%梯度洗脱50%,洗脱时间15min;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;样品制备:化合物溶解于5mL DMF中;注射:0.9mL/针)进一步分离纯化得到目标化合物7,白色固体(120mg,20%yield)。
MS m/z(ESI):634.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.33(d,1H),8.70(d,1H),8.62(s,1H),8.28(d,1H),7.98(s,1H),7.57(s,1H),7.50(d,1H),7.28-7.22(m,1H),7.19(d,1H),6.56(d,1H),5.38-5.29(m,1H),4.14-4.08(m,2H),4.07(s,3H),4.04-3.96(m,1H),3.91(d,2H),3.40(s,3H),2.61-2.56(m,1H),1.33(d,3H),1.20(t,3H),0.72-0.62(m,2H),0.48-0.38(m,2H).
实施例10
苄基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(甲氧基甲基)磷酰基]氨基]丙酸酯(化合物8)
benzyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(methoxymethyl)phosphoryl]amino]propanoate.
第一步:
苄基(2S)-2-[[(3-氰基苯氧基)-(甲氧基甲基)磷酰基]氨基]丙酸酯(8B)
benzyl
(2S)-2-[[(3-cyanophenoxy)-(methoxymethyl)phosphoryl]amino]propanoate.
将(甲氧基甲基)膦酰二氯(4.1g,25.2mmol)溶于200mL的DCM中,加入6A(2.5g,21.0mmol),降温至-20℃,加入三乙胺(6.4g,63.2mmol),搅拌20min后加入L-丙氨酸苄酯盐酸盐(4.5g,21.0mmol),缓慢升温至室温搅拌20min。分别用200mL饱和磷酸氢二钠溶液和200mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/2~1/1),得目标化合物8B,淡黄色油状物(3g,36.8%yield)。
MS m/z(ESI):389.1[M+H]+
第二步:
将8B(1.1g,2.82mmol)溶于4mL DMF中,加入乐伐替尼(0.4g,0.94mmol),室温下缓慢滴加叔丁基氯化镁THF溶液(1N,2.8mmol)。加毕后搅拌10min,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mL×3)洗涤,无水硫酸钠干燥,减压浓缩,残留物通过制备液相(制备条件:仪器:WATERS 2767;柱:Xbridge C18,5μm,19mm*250mm;流动相:乙腈/水(含5mM乙酸铵);梯度洗脱方法:乙腈由25%梯度洗脱50%,洗脱时间15min;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;样品制备:化合物溶解于5mL DMF中;注射:0.9mL/针)进一步分离纯化得到目标化合物8,白色固体(150mg,23%yield)。
MS m/z(ESI):696.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.36-9.30(m,1H),8.73-8.61(m,2H),8.28(d,1H),7.98(s,1H),7.57(d,1H),7.49(t,1H),7.38-7.18(m,7H),6.56(d,1H),5.54-5.38(m,1H),5.20-5.06(m,2H),4.16-4.07(m,1H),4.06(d,4H),3.95-3.86(m,2H),3.36(d,3H),2.63-2.54(m,1H),1.36(d,3H),0.72-0.62(m,2H),0.48-0.39(m,2H).
实施例11
(S)-异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-苯氧基-磷酰基]氨基]丙酸酯(化合物10-b);
(S)-isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-phenoxy-phosphoryl]amino]propanoate.
第一步:
(S)-异丙基(2S)-2-[[(2,3,4,5,6-五氟苯氧基)-苯氧基-磷酰基]氨基]丙酸酯(10C);
(S)-isopropyl
(2S)-2-[[(2,3,4,5,6-pentafluorophenoxy)-phenoxy-phosphoryl]amino]propanoate.
参考文献J.Org.Chem.2011,76,8311–8319,将二氯磷酸苯酯(5.0g,23.9mmol)溶于200mL的DCM中,加入L-丙氨酸异丙酯盐酸盐(4.0g,23.9mmol),降温至-20℃,加入三乙胺(7.3g,72.1mmol),搅拌20min后加入4A(4.4g,23.9mmol),缓慢升温至室温搅拌20min。分别用200mL饱和磷酸二氢钠溶液和200mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物加入乙酸乙酯/正己烷(60mL,1/5)的混合液打浆,过滤,得目标化合物10C,白色固体(3g,27.7%yield)。
MS m/z(ESI):454.1[M+H]+
第二步:化合物10-b
将10C(2g,4.41mmol)溶于4mL DMF中,加入乐伐替尼(0.4g,0.94mmol),氮气保护下升温至60℃,然后缓慢滴加叔丁基氯化镁THF溶液(1N,5.0mmol)。加毕后搅拌10min,冷却至室温,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mL×3)洗涤,无水硫酸钠干燥,减压浓缩,残留物通过硅胶柱层析进一步纯化(二氯甲烷/甲醇=(v/v)100/1~20/1),得目标化合物10-b,白色固体(0.24g,40%yield,保留时间:36.434min)。
分析条件:
设备:安捷伦1260DAD高压液相色谱仪
色谱柱:大赛璐ChiralPak IC,5μm,4.6×250mm.
流动相:A for n-hexane and B for Ethanol.
梯度:B 50%
流速:0.7mL/min
柱温:35℃
波长:210nm
时间:50min
MS m/z(ESI):696.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.69(d,1H),8.43(s,1H),8.29(d,1H),7.98(s,1H),7.52(s,1H),7.47(d,1H),7.42-7.35(m,2H),7.30-7.15(m,5H),6.56(d,1H),5.93-5.82(m,1H),4.94-4.81(m,1H),4.17-4.02(m,1H),3.99(s,3H),2.63-2.55(m,1H),1.29(d,3H),1.16-1.12(m,6H),0.71-0.63(m,2H),0.47-0.40(m,2H).
31P NMR(162MHz,DMSO-d6)δ1.43.
实施例12
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-甲氧基-磷酰基]氨基]丙酸酯(化合物11);
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-methoxy-phosphoryl]amino]propanoate.
第一步:
异丙基(2S)-2-[[(3-氰基苯氧基)-甲氧基-磷酰基]氨基]丙酸酯(11B);
isopropyl(2S)-2-[[(3-cyanophenoxy)-methoxy-phosphoryl]amino]propanoate.
将二氯磷酸甲酯(5.3g,35.6mmol)溶于200mL的DCM中,加入L-丙氨酸异丙酯盐酸盐(4.9g,29.3mmol),降温至-20℃,加入三乙胺(9.2g,90.9mmol),搅拌20min后加入6A(3.5g,29.38mmol),缓慢升温至室温搅拌20min。分别用200mL饱和磷酸氢二钠溶液和200mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/3~1/1),得目标化合物11B,淡黄色油状物(3.5g,37%yield)。
MS m/z(ESI):327.2[M+H]+
第二步:
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-甲氧基-磷酰基]氨基]丙酸酯(化合物11);
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-methoxy-phosphoryl]amino]propanoate.
将11B(0.92g,2.82mmol)溶于4mL DMF中,加入乐伐替尼(0.4g,0.94mmol),室温下缓慢滴加叔丁基氯化镁THF溶液(1N,2.8mmol)。加毕后搅拌10min,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mL×3)洗涤,无水硫酸钠干燥,减压浓缩,残留物通过制备液相(制备条件:仪器:WATERS 2767;柱:Xbridge C18,5μm,19mm*250mm;流动相:乙腈/水(含5mM乙酸铵);梯度洗脱方法:乙腈由25%梯度洗脱50%,洗脱时间15min;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;样品制备:化合物溶解于5mL DMF中;注射:0.9mL/针)进一步分离纯化得到目标化合物11,白色固体(150mg,25.2%yield)。
MS m/z(ESI):634.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.52-9.40(m,1H),8.72-8.66(m,1H),8.52(d,1H),8.28(d,1H),7.98(s,1H),7.55(d,1H),7.48(d,1H),7.27-7.15(m,2H),6.58-6.54(m,1H),5.52-5.38(m,1H),4.95-4.83(m,1H),4.04(d,3H),3.99-3.89(m,1H),3.70-3.62(m,3H),2.62-2.54(m,1H),1.30(d,3H),1.19-1.14(m,6H),0.71-0.63(m,2H),0.46-0.40(m,2H).
实施例13:
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-乙氧基-磷酰基]氨基]丙酸酯(化合物12)
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-ethoxy-phosphoryl]amino]propanoate
第一步:
异丙基(2S)-2-[[(3-氰基苯氧基)-乙氧基-磷酰基]氨基]丙酸酯(12B);
isopropyl(2S)-2-[[(3-cyanophenoxy)-ethoxy-phosphoryl]amino]propanoate.
将二氯磷酸乙酯(4.5g,27.7mmol)溶于200mL的DCM中,加入L-丙氨酸异丙酯盐酸盐(4.2g,25.1mmol),降温至-20℃,加入三乙胺(7.6g,75.5mmol),搅拌20min后加入6A(3g,25.2mmol),缓慢升温至室温搅拌20min。分别用200mL饱和磷酸氢二钠溶液和200mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/3~1/1),得目标化合物12B,淡黄色固体(3g,35%yield)。
MS m/z(ESI):341.1[M+H]+
第二步:
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-乙氧基-磷酰基]氨基]丙酸酯(化合物12)
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-ethoxy-phosphoryl]amino]propanoate
将12B(1g,2.92mmol)溶于4mL DMF中,加入乐伐替尼(0.5g,1.17mmol),室温下缓慢滴加叔丁基氯化镁THF溶液(1N,3mmol)。加毕后搅拌10min,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mL×3)洗涤,无水硫酸钠干燥,减压浓缩,残留物通过制备液相(制备条件:仪器:WATERS 2767;柱:Xbridge C18,5μm,19mm*250mm;流动相:乙腈/水(含5mM乙酸铵);梯度洗脱方法:乙腈由25%梯度洗脱50%,洗脱时间15min;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;样品制备:化合物溶解于5mL DMF中;注射:0.9mL/针)进一步分离纯化得到目标化合物12,白色固体(200mg,26.3%yield)。
MS m/z(ESI):648.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.46-9.38(m,1H),8.71-8.68(m,1H),8.53(d,1H),8.28(d,1H),7.98(s,1H),7.55(d,1H),7.48(d,1H),7.26-7.22(m,1H),7.19(d,1H),6.58-6.54(m,1H),5.45-5.31(m,1H),4.92-4.81(m,1H),4.10-3.90(m,6H),2.62-2.54(m,1H),1.32-1.23(m,6H),1.19-1.13(m,6H),0.71-0.64(m,2H),0.46-0.40(m,2H).
取化合物12(200mg)用于拆分,得到两个光学异构体化合物12-a(0.15g,保留时间6.074min,白色固体,ee%=100%),化合物12-b(0.03g,保留时间8.288min,白色固体,ee%=99%)。
制备条件:
仪器:MGⅡpreparative SFC(SFC-1)
色谱柱:ChiralPak AD,250×30mm I.D.,5μm
流动相:A for CO2and B for Ethanol
梯度:B 45%
流速:50mL/min
背压:100bar
柱温:38℃
波长:254nm
周期:~9min
样品制备:Compound was dissolved in~10mL methanol
注射:1.5mL per injection.
化合物12-a
1H NMR(400MHz,DMSO-d6)δ9.43(d,1H),8.70(d,1H),8.55(s,1H),8.29(d,1H),7.98(s,1H),7.55(s,1H),7.48(d,1H),7.26-7.22(m,1H),7.19(d,1H),6.56(d,1H),5.41(t,1H),4.94-4.85(m,1H),4.05(s,3H),4.04-3.91(m,3H),2.62-2.55(m,1H),1.30(d,3H),1.25(t,3H),1.18-1.13(m,6H),0.70-0.64(m,2H),0.47-0.41(m,2H).
31P NMR(162MHz,DMSO-d6)δ5.02。
化合物12-b
1H NMR(400MHz,DMSO-d6)δ9.42(d,1H),8.69(d,1H),8.52(s,1H),8.28(d,1H),7.98(s,1H),7.54(s,1H),7.48(d,1H),7.26-7.22(m,1H),7.19(d,1H),6.56(d,1H),5.35(t,1H),4.94-4.85(m,1H),4.12-3.93(m,3H),4.04(s,3H),2.62-2.55(m,1H),1.33-1.25(m,6H),1.20-1.15(m,6H),0.70-0.64(m,2H),0.47-0.40(m,2H).
31P NMR(162MHz,DMSO-d6)δ4.74。
实施例14:
苄基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-苯氧基-磷酰基]氨基]丙酸酯(化合物13)
benzyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-phenoxy-phosphoryl]amino]propanoate.
第一步:
苄基(2S)-2-[[(4-硝基苯氧基)-苯氧基-磷酰基]氨基]丙酸酯(13B);
benzyl(2S)-2-[[(4-nitrophenoxy)-phenoxy-phosphoryl]amino]propanoate.
将二氯磷酸苯酯(4.5g,21.3mmol)溶于200mL的DCM中,加入L-丙氨酸苄酯盐酸盐(3.9g,18.1mmol),降温至-20℃,加入三乙胺(5.5g,54.3mmol),搅拌20min后加入5A(2.5g,18.0mmol),缓慢升温至室温搅拌20min。分别用200mL饱和磷酸氢二钠溶液和200mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/3~1/1),得目标化合物13B,淡黄色油状物(5g,60.5%yield)。
MS m/z(ESI):457.1[M+H]+
第二步:
苄基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-苯氧基-磷酰基]氨基]丙酸酯(化合物13)
benzyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-phenoxy-phosphoryl]amino]propanoate.
将13B(2.6g,5.68mmol)溶于4mL DMF中,加入乐伐替尼(0.5g,1.17mmol),室温下缓慢滴加叔丁基氯化镁THF溶液(1N,6mmol)。加毕后搅拌10min,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mL×3)洗涤,无水硫酸钠干燥,减压浓缩,残留物通过硅胶柱层析进一步纯化(二氯甲烷/甲醇=(v/v)100/1~20/1),得目标化合物13,黄色固体(0.13g,15%yield)。
MS m/z(ESI):744.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.79(d,1H),8.69(d,1H),8.44(d,1H),8.28(d,1H),7.98(s,1H),7.51(s,1H),7.46(t,1H),7.38-7.16(m,12H),6.58-6.52(m,1H),6.10-5.99(m,1H),5.10(d,2H),4.29-4.18(m,1H),3.97(s,3H),2.62-2.55(m,1H),1.33(d,3H),0.71-0.64(m,2H),0.46-0.40(m,2H).
实施例15
2-[[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-苯氧基-磷酰基]氨基]乙酸异丙酯(化合物14)
isopropyl
2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-phenoxy-phosphoryl]amino]acetate.
第一步:
2-[[(3-氰基苯氧基)-苯氧基-磷酰基]氨基]乙酸异丙酯(14B)
isopropyl 2-[[(3-cyanophenoxy)-phenoxy-phosphoryl]amino]acetate.
将二氯磷酸苯酯(4.9g,23.2mmol)溶于200mL的DCM中,加入甘氨酸异丙酯盐酸盐(3.2g,20.8mmol),降温至-20℃,加入三乙胺(6.4g,63.2mmol),搅拌20min后加入6A(2.5g,20.8mmol),缓慢升温至室温搅拌20min。分别用200ml饱和磷酸氢二钠溶液和200ml饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/3~1/1),得目标化合物14B,淡黄色油状物(2g,25%yield)。
MS m/z(ESI):375.1[M+H]+
第二步:
将14B(1.05g,2.81mmol)溶于4mL DMF中,加入乐伐替尼(0.4g,0.94mmol),室温下缓慢滴加叔丁基氯化镁THF溶液(1N,5mmol)。加毕后搅拌10min,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mL×3)洗涤,无水硫酸钠干燥,减压浓缩,残留物通过硅胶柱层析进一步纯化(二氯甲烷/甲醇=(v/v)100/1~20/1),得目标化合物14,淡黄色固体(0.16g,25%yield)。
MS m/z(ESI):682.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.79(s,1H),8.69(d,1H),8.45(s,1H),8.28(d,1H),7.98(s,1H),7.52(s,1H),7.47(d,1H),7.39(t,2H),7.30-7.14(m,5H),6.56(d,1H),5.88-5.78(m,1H),4.96-4.85(m,1H),3.99(s,3H),3.85-3.77(m,2H),2.63-2.54(m,1H),1.16(d,6H),0.70-0.64(m,2H),0.47-0.40(m,2H).
实施例16
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(邻甲苯基甲氧基)磷酰基]氨基]丙酸酯(化合物15)
Isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(o-tolylmethoxy)phosphoryl]amino]propanoate.
第一步:
异丙基(2S)-2-[[邻甲苯基甲氧基-(2,3,4,5,6-五氟苯氧基)磷酰基]氨基]丙酸酯(15B)
Isopropyl
(2S)-2-[[o-tolylmethoxy-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino]propanoate
合成方案参考Peng等,J.Med.Chem.,59,8,3661-3670,操作如下:
将三氯氧磷(6g,39.1mmol)溶于200mL的DCM中,-78℃下滴加2-甲基苄醇(4.8,39.1mmol)和三乙胺的混合物(4g,39.1mmol),此温度下反应1h后,加入L-丙氨酸异丙酯盐酸盐(5.2g,31.3mmol),加毕,缓慢滴加三乙胺(6.4g,63.2mmol),此温度下继续搅拌30min后加入4A(6.5g,35.2mmol),加毕,缓慢滴加三乙胺(3.6g,35.2mmol),缓慢升温至室温搅拌30min。分别用200mL饱和磷酸氢二钠溶液和200mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用MTBE/正己烷混合液(45mL,1/2)打浆,过滤,滤饼减压干燥得目标化合物15B,白色固体(2g,10.6%yield)。
第二步:
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(邻甲苯基甲氧基)磷酰基]氨基]丙酸酯(化合物15)
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(o-tolylmethoxy)phosphoryl]amino]propanoate.
将15B(1.02g,2.11mmol)溶于4mL DMF中,加入乐伐替尼(0.3g,0.70mmol),氮气保护下升温至60℃后,缓慢滴加叔丁基氯化镁THF溶液(1N,2.8mmol)。加毕后搅拌10min,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mL×3)洗涤,无水硫酸钠干燥,减压浓缩,残留物通过硅胶柱层析进一步纯化(二氯甲烷/甲醇=(v/v)100/1~20/1),得目标化合物15,淡黄色固体(70mg,14%yield)。
MS m/z(ESI):724.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.56(d,1H),8.69(d,1H),8.51(d,1H),8.28(d,1H),7.98(s,1H),7.54(s,1H),7.48(d,1H),7.45-7.36(m,1H),7.29-7.14(m,5H),6.56(d,1H),5.61-5.36(m,1H),5.14-5.00(m,2H),4.94-4.82(m,1H),4.06-3.95(m,4H),2.61-2.55(m,1H),2.33(d,3H),1.34-1.28(m,3H),1.18-1.10(m,6H),0.71-0.63(m,2H),0.47-0.39(s,2H).
实施例17
2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(甲氧基甲基)磷酰基]氨基]-2-甲基丙酸乙酯(化合物16)
ethyl
2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(methoxymethyl)phosphoryl]amino]-2-methyl-propanoate.
第一步:
2-[[(3-氰基苯氧基)-(甲氧基甲基)磷酰基]氨基]-2-甲基丙酸乙酯(16B).
ethyl
2-[[(3-cyanophenoxy)-(methoxymethyl)phosphoryl]amino]-2-methyl-propanoate.
将(甲氧基甲基)膦酰二氯(4.5g,27.6mmol)溶于200mL的DCM中,加入6A(3g,25.2mmol),降温至-20℃,加入三乙胺(9.2g,90.9mmol),搅拌20min后加入2-氨基异丁酸乙酯盐酸盐(4.5g,26.8mmol),缓慢升温至室温搅拌20min。分别用200mL饱和磷酸二氢钠溶液和200mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/3~1/1),得目标化合物16B,黄色固体(3g,40%yield)。
MS m/z(ESI):341.1[M+H]+
第二步:
2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(甲氧基甲基)磷酰基]氨基]-2-甲基丙酸乙酯(化合物16)
ethyl
2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(methoxymethyl)phosphoryl]amino]-2-methyl-propanoate.
将16B(0.72g,2.11mmol)溶于4mL DMF中,加入乐伐替尼(0.3g,0.70mmol),室温下缓慢滴加叔丁基氯化镁THF溶液(1N,2.8mmol)。加毕后搅拌10min,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mLx3)洗涤,无水硫酸钠干燥,减压浓缩,残留物通过制备液相(制备条件:仪器:WATERS 2767;柱:Xbridge C18,5μm,19mm*250mm;流动相:乙腈/水(含5mM乙酸铵);梯度洗脱方法:乙腈由25%梯度洗脱50%,洗脱时间15min;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;样品制备:化合物溶解于5mL DMF中;注射:0.9mL/针)进一步分离纯化得到目标化合物16,白色固体(220mg,48%yield)。
MS m/z(ESI):648.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.33(d,1H),8.71(d,1H),8.63(s,1H),8.29(d,1H),7.98(s,1H),7.57(s,1H),7.50(d,1H),7.28-7.22(m,1H),7.19(d,1H),6.56(d,1H),5.16(d,1H),4.17-4.03(m,5H),3.90(d,2H),3.40(d,3H),2.63-2.54(m,1H),1.49(d,6H),1.19(t,3H),0.71-0.64(m,2H),0.47-0.41(m,2H).
实施例18
S-异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(甲氧基甲基)磷酰基]氨基]硫代丙酸酯(化合物17)。
S-isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(methoxymethyl)phosphoryl]amino]propanethioate.
第一步:
S-异丙基(2S)-2-[[(3-氰基苯氧基)-(甲氧基甲基)磷酰基]氨基]硫代丙酸酯(17B)
S-isopropyl
(2S)-2-[[(3-cyanophenoxy)-(methoxymethyl)phosphoryl]amino]propanethioate;
将(甲氧基甲基)膦酰二氯(4.1g,25.2mmol)溶于200mL的DCM中,加入6A(3g,25.2mmol),降温至-20℃,加入三乙胺(7.6g,75.5mmol),搅拌20min后加入S-异丙基(2S)-2-氨基硫代丙酸酯盐酸盐(合成详见WO2017/133517A1)(4.6g,25.2mmol),缓慢升温至室温搅拌20min。分别用200mL饱和磷酸二氢钠溶液和200mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/3~1/1),得目标化合物17B,黄色固体(4g,45%yield)。
MS m/z(ESI):357.1[M+H]+
第二步:
S-异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(甲氧基甲基)磷酰基]氨基]硫代丙酸酯(化合物17)。
S-isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(methoxymethyl)phosphoryl]amino]propanethioate.
将17B(0.75g,2.11mmol)溶于4mL DMF中,加入乐伐替尼(0.3g,0.70mmol),室温下缓慢滴加叔丁基氯化镁THF溶液(1N,2.8mmol)。加毕后搅拌10min,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mLx3)洗涤,无水硫酸钠干燥,减压浓缩,残留物通过制备液相(制备条件:仪器:WATERS 2767;柱:Xbridge C18,5μm,19mm*250mm;流动相:乙腈/水(含5mM乙酸铵);梯度洗脱方法:乙腈由25%梯度洗脱50%,洗脱时间15min;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;样品制备:化合物溶解于5mL DMF中;注射:0.9mL/针)进一步分离纯化得到目标化合物17,白色固体(80mg,17%yield)。
MS m/z(ESI):664.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.43-9.30(m,1H),8.71(d,1H),8.65(d,1H),8.29(d,1H),7.98(s,1H),7.58(d,1H),7.52-7.46(m,1H),7.28-7.22(m,1H),7.19(d,1H),6.56(d,1H),5.77-5.62(m,1H),4.07(d,3H),4.04-3.82(m,3H),3.46-3.38(m,4H),2.62-2.55(m,1H),1.31(d,3H),1.25(d,3H),1.18(d,3H),0.72-0.62(m,2H),0.48-0.39(m,2H).
实施例19
4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-N-[(4S)-4-(3-氯苯基)-2-氧代-1,3,2-二氧杂膦-2-基]-7-甲氧基-喹啉-6-甲酰胺(化合物18)
4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-N-[(4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphinan-2-yl]-7-methoxy-quinoline-6-carboxamide.
第一步:
(4S)-4-(3-氯苯基)-2-(4-硝基苯氧基)-1,3,2-二氧杂膦-2-氧化物(18B)
(4S)-4-(3-chlorophenyl)-2-(4-nitrophenoxy)-1,3,2-dioxaphosphinane-2-oxide.
将化合物18A(1.3g,6.97mmol)溶于10mL四氢呋喃中,加入三乙胺(2.1g,20.8mmol),室温下缓慢加入二氯膦酸对硝基苯酯(2.1g,8.20mmol),室温下搅拌1h。加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mLx3)洗涤,无水硫酸钠干燥,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/1~1/0),得目标化合物18B,淡黄色油状物(2.5g,97%yield)。
MS m/z(ESI):739.0[2M+H]+
1H NMR(400MHz,CDCl3)δ8.25(d,2H),7.47-7.17(m,6H),5.80-5.55(m,1H),4.82-4.50(m,2H),2.49-2.06(m,2H).
第二步:
4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-N-[(4S)-4-(3-氯苯基)-2-氧代-1,3,2-二氧杂膦-2-基]-7-甲氧基-喹啉-6-甲酰胺(化合物18)
4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-N-[(4S)-4-(3-chlorophenyl)-2-oxo-1,3,2-dioxaphosphinan-2-yl]-7-methoxy-quinoline-6-carboxamide.
将18B(1.04g,2.81mmol)溶于4mL DMF中,加入乐伐替尼(0.3g,0.70mmol),升温至60℃,缓慢滴加叔丁基氯化镁THF溶液(1N,2.8mmol)。加毕后此温度下搅拌1h,冷却至室温,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mLx3)洗涤,无水硫酸钠干燥,减压浓缩,残留物通过制备液相(制备条件:仪器:WATERS 2767;柱:XbridgeC18,5μm,19mm*250mm;流动相:乙腈/水(含5mM乙酸铵);梯度洗脱方法:乙腈由25%梯度洗脱50%,洗脱时间15min;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;样品制备:化合物溶解于5mL DMF中;注射:0.9mL/针)进一步分离纯化得到目标化合物18,黄色固体(70mg,15%yield)。
MS m/z(ESI):657.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ10.15-10.05(m,1H),8.70(d,1H),8.42(d,1H),8.28(d,1H),7.98(s,1H),7.61-7.38(m,6H),7.27-7.22(m,1H),7.19(d,1H),6.59-6.55(m,1H),5.85-5.68(m,1H),4.70-4.40(m,2H),4.03(d,3H),2.63-2.54(m,1H),2.34-2.07(m,2H),0.70-0.62(m,2H),0.47-0.40(m,2H).
实施例20
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(环丙基甲氧基)磷酰基]氨基]丙酸酯(化合物19)
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(cyclopropylmethoxy)phosphoryl]amino]propanoate.
第一步:
异丙基(2S)-2-[[环丙基甲氧基-(4-硝基苯氧基)磷酰基]氨基]丙酸酯(19B);
Isopropyl
(2S)-2-[[cyclopropylmethoxy-(4-nitrophenoxy)phosphoryl]amino]propanoate.
将19A(2g,7.81mmol)溶于100mL的DCM中,0℃下滴加环丙基甲醇(0.56g,7.81mmol)和三乙胺的混合物(0.79g,7.81mmol),此温度下反应0.5h后,加入L-丙氨酸异丙酯盐酸盐(1.31g,7.81mmol),加毕,缓慢滴加三乙胺(1.58,15.62mmol),加毕,缓慢升温至室温搅拌30min。分别用100mL饱和磷酸二氢钠溶液和100mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/3~1/1),得目标化合物19B,无色透明油状物(2g,66%yield)。
MS m/z(ESI):387.1[M+H]+
第二步:
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(环丙基甲氧基)磷酰基]氨基]丙酸酯(化合物19)
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(cyclopropylmethoxy)phosphoryl]amino]propanoate
将19B(0.90g,2.34mmol)溶于4mL DMF中,加入乐伐替尼(0.5g,1.17mmol),升温至50℃,缓慢滴加叔丁基氯化镁THF溶液(1N,3.51mmol)。加毕后此温度下搅拌0.5h,冷却至室温,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mLx3)洗涤,无水硫酸钠干燥,减压浓缩,残留物用硅胶柱层析进一步纯化(二氯甲烷/甲醇=(v/v)50/1~20/1),得到目标化合物19,淡黄色固体(200mg,25%yield)。
MS m/z(ESI):674.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.47-9.40(m,1H),8.70(d,1H),8.54(d,1H),8.29(d,1H),7.98(s,1H),7.55(d,1H),7.48(d,1H),7.27-7.22(m,1H),7.19(d,1H),6.58-6.54(m,1H),5.44-5.30(m,1H),4.93-4.83(m,1H),4.04(d,3H),4.01-3.94(m,1H),3.88-3.78(m,2H),2.62-2.55(m,1H),1.33-1.27(m,3H),1.18-1.14(m,7H),0.70-0.64(m,2H),0.56-0.49(m,2H),0.46-0.40(m,2H),0.33-0.26(m,2H).
实施例21
异丙基(2S)-2-[[(苄基氨基)-[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]磷酰基]氨基]丙酸酯(化合物20)
isopropyl(2S)-2-[[(benzylamino)-[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]phosphoryl]amino]propanoate.
第一步:
异丙基(2S)-2-[[(苄基氨基)-(4-硝基苯氧基)磷酰基]氨基]丙酸酯(20B);
isopropyl(2S)-2-[[(benzylamino)-(4-nitrophenoxy)phosphoryl]amino]propanoate.
将19A(2g,7.81mmol)溶于100mL的DCM中,0℃下滴加苄胺(0.84g,7.81mmol)和三乙胺的混合物(0.79g,7.81mmol),此温度下反应0.5h后,加入L-丙氨酸异丙酯盐酸盐(1.31g,7.81mmol),加毕,缓慢滴加三乙胺(1.58,15.62mmol),加毕,缓慢升温至室温搅拌30min。分别用100mL饱和磷酸二氢钠溶液和100mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/3~1/1),得目标化合物20B,淡黄色透明油状物(1.2g,36%yield)。
MSm/z(ESI):422.2[M+H]+
第二步:
异丙基(2S)-2-[[(苄基氨基)-[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]磷酰基]氨基]丙酸酯(化合物20)
isopropyl(2S)-2-[[(benzylamino)-[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]phosphoryl]amino]propanoate.
将20B(0.99g,2.34mmol)溶于4mLDMF中,加入乐伐替尼(0.5g,1.17mmol),升温至50℃,缓慢滴加叔丁基氯化镁THF溶液(1N,3.51mmol)。加毕后此温度下搅拌0.5h,冷却至室温,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mLx3)洗涤,无水硫酸钠干燥,减压浓缩,残留物用硅胶柱层析进一步纯化(二氯甲烷/甲醇=(v/v)50/1~20/1),得到目标化合物20,淡黄色固体(80mg,10%yield)。
MSm/z(ESI):709.2[M+H]+
1HNMR(400MHz,DMSO-d6)δ9.26-9.08(m,1H),8.73-8.66(m,1H),8.60-8.44(m,1H),8.28(d,1H),7.98(s,1H),7.56-7.50(m,1H),7.49-7.46(m,1H),7.43-7.36(m,2H),7.32-7.26(m,2H),7.26-7.22(m,1H),7.21-7.15(m,2H),6.57-6.53(m,1H),5.35-5.10(m,1H),4.95-4.80(m,2H),4.15-3.88(m,6H),2.62-2.55(m,1H),1.31-1.27(m,3H),1.18-1.13(m,6H),0.70-0.63(m,2H),0.47-0.40(m,2H).
实施例22
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-异丙氧基-磷酰基]氨基]丙酸酯(化合物21)
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-isopropoxy-phosphoryl]amino]propanoate.
第一步:
异丙基(2S)-2-[[(3-氰基苯氧基)-异丙氧基-磷酰基]氨基]丙酸酯(21B)
isopropyl(2S)-2-[[(3-cyanophenoxy)-isopropoxy-phosphoryl]amino]propanoate.
将三氯氧磷(9g,58.7mmol)溶于200mL的DCM中,-78℃下滴加异丙醇(3.5g,58.7mmol)和三乙胺的混合物(5.9g,58.7mmol),此温度下反应1h后,加入L-丙氨酸异丙酯盐酸盐(7.9g,47.1mmol),加毕,缓慢滴加三乙胺(9.6g,94.8mmol),此温度下继续搅拌30min后加入6A(5.6g,47.0mmol),加毕,缓慢滴加三乙胺(4.8g,47.4mmol),缓慢升温至室温搅拌30min。分别用200mL饱和磷酸二氢钠溶液和200mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/3~1/1),得目标化合物21B,淡黄色油状物(3.5g,17%yield)。
MS m/z(ESI):355.1[M+H]+
第二步:
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-异丙氧基-磷酰基]氨基]丙酸酯(化合物21)
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-isopropoxy-phosphoryl]amino]propanoate.
将21B(0.83g,2.34mmol)溶于4mL DMF中,加入乐伐替尼(0.5g,1.17mmol),升温至50℃,缓慢滴加叔丁基氯化镁THF溶液(1N,3.51mmol)。加毕后此温度下搅拌0.5h,冷却至室温,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mLx3)洗涤,无水硫酸钠干燥,减压浓缩,残留物通过制备液相(制备条件:仪器:WATERS 2767;柱:Xbridge C18,5μm,19mm*250mm;流动相:乙腈/水(含5mM乙酸铵);梯度洗脱方法:乙腈由25%梯度洗脱50%,洗脱时间15min;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;样品制备:化合物溶解于5mL DMF中;注射:0.9mL/针)进一步分离纯化得到目标化合物21,淡黄色固体(150mg,19%yield)。
MS m/z(ESI):662.3[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.42-9.35(m,1H),8.70(d,1H),8.54(d,1H),8.28(d,1H),7.97(s,1H),7.55(s,1H),7.48(d,1H),7.27-7.22(m,1H),7.19(d,1H),6.59-6.53(m,1H),5.35-5.21(m,1H),4.95-4.83(m,1H),4.73-4.55(m,1H),4.05(s,3H),4.03-3.93(m,1H),2.62-2.54(m,1H),1.32-1.25(m,9H),1.18-1.13(m,6H),0.71-0.64(m,2H),0.47-0.40(m,2H).
实施例23
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(2-甲氧基乙氧基)磷酰基]氨基]丙酸酯(化合物22)
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(2-methoxyethoxy)phosphoryl]amino]propanoate.
第一步:
异丙基(2S)-2-[[2-甲氧基乙氧基-(4-硝基苯氧基)磷酰基]氨基]丙酸酯(22B)
isopropyl
(2S)-2-[[2-methoxyethoxy-(4-nitrophenoxy)phosphoryl]amino]propanoate.
将19A(2g,7.81mmol)溶于100mL的DCM中,0℃下滴加乙二醇单甲醚(0.59g,7.81mmol)和三乙胺的混合物(0.79g,7.81mmol),此温度下反应0.5h后,加入L-丙氨酸异丙酯盐酸盐(1.31g,7.81mmol),加毕,缓慢滴加三乙胺(1.58,15.62mmol),加毕,缓慢升温至室温搅拌30min。分别用100mL饱和磷酸二氢钠溶液和100mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/3~1/1),得目标化合物22B,无色透明油状物(1.4g,46%yield)。
MS m/z(ESI):391.2[M+H]+
第二步:
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(2-甲氧基乙氧基)磷酰基]氨基]丙酸酯(化合物22)
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(2-methoxyethoxy)phosphoryl]amino]propanoate.
将22B(0.91g,2.34mmol)溶于4mL DMF中,加入乐伐替尼(0.5g,1.17mmol),升温至50℃,缓慢滴加叔丁基氯化镁THF溶液(1N,3.51mmol)。加毕后此温度下搅拌0.5h,冷却至室温,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mLx3)洗涤,无水硫酸钠干燥,减压浓缩,残留物通过制备液相(制备条件:仪器:WATERS 2767;柱:Xbridge C18,5μm,19mm*250mm;流动相:乙腈/水(含5mM乙酸铵);梯度洗脱方法:乙腈由25%梯度洗脱50%,洗脱时间15min;流量:30mL/min;背压:1000PSI;柱温:30℃;波长:210nm;样品制备:化合物溶解于5mL DMF中;注射:0.9mL/针)进一步分离纯化得到目标化合物22,淡黄色固体(160mg,20%yield)。
MS m/z(ESI):678.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.50-9.40(m,1H),8.72-8.68(m,1H),8.54(d,1H),8.29(d,1H),7.98(s,1H),7.55(d,1H),7.48(d,1H),7.27-7.21(m,1H),7.19(d,1H),6.59-6.53(m,1H),5.51-5.36(m,1H),4.93-4.82(m,1H),4.16-4.07(m,2H),4.05(d,3H),4.01-3.93(m,1H),3.60-3.52(m,2H),3.28(d,3H),2.62-2.55(m,1H),1.31(d,3H),1.19-1.14(m,6H),0.71-0.64(m,2H),0.47-0.40(m,2H).
实施例24
异丙基(2S)-2-[[丁氧基-[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]磷酰基]氨基]丙酸酯(化合物23)
isopropyl
(2S)-2-[[butoxy-[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]phosphoryl]amino]propanoate.
第一步:
异丙基(2S)-2-[[丁氧基-(4-硝基苯氧基)磷酰基]氨基]丙酸酯(23B)
isopropyl(2S)-2-[[butoxy-(4-nitrophenoxy)phosphoryl]amino]propanoate.
将19A(5g,19.53mmol)溶于200mL的DCM中,0℃下滴加正丁醇(1.49g,19.53mmol)和三乙胺的混合物(2g,19.53mmol),此温度下反应0.5h后,加入L-丙氨酸异丙酯盐酸盐(3.27g,19.53mmol),加毕,缓慢滴加三乙胺(4g,39.06mmol),加毕,缓慢升温至室温搅拌30min。分别用200mL饱和磷酸二氢钠溶液和200mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/3~1/1),得目标化合物23B,无色透明油状物(5g,66%yield)。
MS m/z(ESI):389.2[M+H]+
第二步:
异丙基(2S)-2-[[丁氧基-[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]磷酰基]氨基]丙酸酯(化合物23)
isopropyl
(2S)-2-[[butoxy-[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]phosphoryl]amino]propanoate.
将23B(0.91g,2.34mmol)溶于4mL DMF中,加入乐伐替尼(0.5g,1.17mmol),升温至50℃,缓慢滴加叔丁基氯化镁THF溶液(1N,3.51mmol)。加毕后此温度下搅拌0.5h,冷却至室温,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mLx3)洗涤,无水硫酸钠干燥,减压浓缩,残留物用硅胶柱层析进一步纯化(二氯甲烷/甲醇=(v/v)50/1~20/1)得到目标化合物23,黄色固体(300mg,38%yield)。
MS m/z(ESI):676.3[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.46-9.39(m,1H),8.73-8.67(m,1H),8.53(d,1H),8.29(d,1H),7.98(s,1H),7.55(d,1H),7.48(d,1H),7.27-7.21(m,1H),7.19(d,1H),6.58-6.55(m,1H),5.45-5.30(m,1H),4.95-4.83(m,1H),4.04(d,3H),4.02-3.93(m,3H),2.63-2.55(m,1H),1.64-1.55(m,2H),1.41-1.34(m,2H),1.32-1.28(m,3H),1.18-1.14(m,6H),0.91-0.86(m,3H),0.70-0.64(m,2H),0.47-0.41(m,2H).
实施例25
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-己氧基-磷酰基]氨基]丙酸酯(化合物24)
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-hexoxy-phosphoryl]amino]propanoate.
第一步:
异丙基(2S)-2-[[己氧基-(4-硝基苯氧基)磷酰基]氨基]丙酸酯(24B)
isopropyl(2S)-2-[[hexoxy-(4-nitrophenoxy)phosphoryl]amino]propanoate.
将19A(3g,11.72mmol)溶于100mL的DCM中,0℃下滴加正己醇(1.20g,11.72mmol)和三乙胺的混合物(1.19g,11.72mmol),此温度下反应0.5h后,加入L-丙氨酸异丙酯盐酸盐(1.96g,11.72mmol),加毕,缓慢滴加三乙胺(2.37g,23.44mmol),加毕,缓慢升温至室温搅拌30min。分别用100mL饱和磷酸二氢钠溶液和100mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/3~1/1),得目标化合物24B,无色透明油状物(3g,61%yield)。
MS m/z(ESI):417.2[M+H]+
第二步:
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-己氧基-磷酰基]氨基]丙酸酯(化合物24)
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-hexoxy-phosphoryl]amino]propanoate.
将24B(1g,2.40mmol)溶于4mL DMF中,加入乐伐替尼(0.5g,1.17mmol),升温至50℃,缓慢滴加叔丁基氯化镁THF溶液(1N,3.51mmol)。加毕后此温度下搅拌0.5h,冷却至室温,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mLx3)洗涤,无水硫酸钠干燥,减压浓缩,残留物用硅胶柱层析进一步纯化(二氯甲烷/甲醇=(v/v)50/1~20/1)得到目标化合物24,黄色固体(400mg,50%yield)。
MS m/z(ESI):704.3[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.41(d,1H),8.70(d,1H),8.53(d,1H),8.29(d,1H),7.98(s,1H),7.55(s,1H),7.47(d,1H),7.26-7.21(m,1H),7.19(d,1H),6.58-6.54(m,1H),5.45-5.30(m,1H),4.95-4.83(m,1H),4.04(d,3H),4.02-3.90(m,3H),2.64-2.54(m,1H),1.64-1.54(m,2H),1.36-1.24(m,9H),1.18-1.13(m,6H),0.87-0.83(m,3H),0.71-0.64(m,2H),0.47-0.40(s,2H).
实施例26
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(环己氧基)磷酰基]氨基]丙酸酯(化合物25)
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(cyclohexoxy)phosphoryl]amino]propanoate.
第一步:
异丙基(2S)-2-[[环己氧基-(4-硝基苯氧基)磷酰基]氨基]丙酸酯(25B)
isopropyl(2S)-2-[[cyclohexoxy-(4-nitrophenoxy)phosphoryl]amino]propanoate.
将19A(2.25g,8.79mmol)溶于100mL的DCM中,0℃下滴加环己醇(0.84g,8.35mmol)和三乙胺的混合物(0.89g,8.80mmol),此温度下反应0.5h后,加入L-丙氨酸异丙酯盐酸盐(1.47g,8.79mmol),加毕,缓慢滴加三乙胺(1.78g,17.60mmol),加毕,缓慢升温至室温搅拌30min。分别用100mL饱和磷酸二氢钠溶液和100mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/3~1/1),得目标化合物25B,无色透明油状物(1.2g,33%yield)。
MS m/z(ESI):415.2[M+H]+
第二步:
异丙基(2S)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(环己氧基)磷酰基]氨基]丙酸酯(化合物25)
isopropyl
(2S)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(cyclohexoxy)phosphoryl]amino]propanoate.
将25B(0.97g,2.34mmol)溶于4mL DMF中,加入乐伐替尼(0.5g,1.17mmol),升温至50℃,缓慢滴加叔丁基氯化镁THF溶液(1N,3.51mmol)。加毕后此温度下搅拌0.5h,冷却至室温,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mLx3)洗涤,无水硫酸钠干燥,减压浓缩,残留物用硅胶柱层析进一步纯化(二氯甲烷/甲醇=(v/v)50/1~20/1)得到目标化合物25,黄色固体(100mg,12%yield)。
MS m/z(ESI):702.3[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.42-9.36(m,1H),8.69(d,1H),8.53(d,1H),8.28(d,1H),7.97(s,1H),7.55(s,1H),7.48(d,1H),7.26-7.20(m,1H),7.19(d,1H),6.58-6.54(m,1H),5.35-5.20(m,1H),4.92-4.83(m,1H),4.45-4.30(m,1H),4.04(s,3H),4.03-3.93(m,1H),2.61-2.55(m,1H),1.86(brs,2H),1.68(brs,2H),1.54-1.42(m,3H),1.36-1.25(m,6H),1.19-1.14(m,6H),0.70-0.63(m,2H),0.47-0.40(m,2H).
实施例27
异丙基(2SR)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(4-甲氧基苯氧基)磷酰基]氨基]丙酸酯(化合物26)
isopropyl
(2SR)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(4-methoxyphenoxy)phosphoryl]amino]propanoate.
第一步:
异丙基(2S)-2-[[(4-甲氧基苯氧基)-(2,3,4,5,6-五氟苯氧基)磷酰基]氨基]丙酸酯(26B)
isopropyl
(2S)-2-[[(4-methoxyphenoxy)-(2,3,4,5,6-pentafluorophenoxy)phosphoryl]amino]propanoate.
将三氯氧磷(10.38g,67.67mmol)溶于200mL的DCM中,-78℃下滴加4-甲氧基苯酚(8.0g,64.44mmol)和三乙胺的混合物(6.52g,64.44mmol),此温度下反应1h后,加入L-丙氨酸异丙酯盐酸盐(10.80g,64.44mmol),加毕,缓慢滴加三乙胺(13.04g,128.88mmol),此温度下继续搅拌30min后加入4A(11.86g,64.44mmol),加毕,缓慢滴加三乙胺(6.52g,64.44mmol),缓慢升温至室温搅拌30min。分别用200mL饱和磷酸二氢钠溶液和200mL饱和食盐水洗涤反应液,有机层用无水硫酸钠干燥后,减压浓缩,残留物用硅胶柱层析进一步纯化(乙酸乙酯/石油醚=(v/v)1/3~1/1),得目标化合物26B,淡黄色油状物(9g,29%yield)。
MS m/z(ESI):484.0[M+H]+
第二步:
异丙基(2SR)-2-[[[[4-[3-氯-4-(环丙基氨基甲酰基氨基)苯氧基]-7-甲氧基-喹啉-6-羰基]氨基]-(4-甲氧基苯氧基)磷酰基]氨基]丙酸酯(化合物26)
isopropyl
(2SR)-2-[[[[4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxy-quinoline-6-carbonyl]amino]-(4-methoxyphenoxy)phosphoryl]amino]propanoate.
将26B(1.13g,2.34mmol)溶于4mL DMF中,加入乐伐替尼(0.5g,1.17mmol),升温至50℃,缓慢滴加叔丁基氯化镁THF溶液(1N,3.51mmol)。加毕后此温度下搅拌0.5h,冷却至室温,加入20mL水和20mL乙酸乙酯萃取,分液后,有机层再用饱和氯化钠水溶液(20mLx3)洗涤,无水硫酸钠干燥,减压浓缩,残留物用硅胶柱层析进一步纯化(二氯甲烷/甲醇=(v/v)50/1~20/1)得到目标化合物26,浅黄色固体(200mg,24%yield)。
MS m/z(ESI):726.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.75-9.67(m,1H),8.69(d,1H),8.45(d,1H),8.29(d,1H),7.98(s,1H),7.52(d,1H),7.47(d,1H),7.26-7.22(m,1H),7.21-7.14(m,3H),6.96-6.90(m,2H),6.58-6.54(m,1H),5.84-5.76m,1H),4.92-4.82(m,1H),4.16-4.04(m,1H),4.00(d,3H),3.71(s,3H),2.62-2.55(m,1H),1.29(d,3H),1.17-1.13(m,6H),0.72-0.63(m,2H),0.46-0.41(m,2H).
生物测试例
化合物1大鼠药代动力学测试
1.试验材料
(1)试验动物:
雄性SD大鼠,200g左右,6~8周龄,共3只。购于成都达硕实验动物有限公司。
(2)受试化合物
准确称取一定量化合物1,用75%PEG400溶解。
2.试验方法
化合物1口服给药剂量(以游离碱计)为5.61mg/kg,给药体积灌胃为10ml/kg。
每只动物在给药前及给药后异氟烷麻醉经眼眶取血0.15ml,置于EDTAK2离心管中并放置冰浴上。5000rpm,4℃离心10min,收集血浆。灌胃给药取血时间点设:给药后5min,15min,30min,1h,2h,3h,4h,6h,8h,24h;所有血浆样品存于-80℃用于检测。用HPLC-MS/MS对样品进行检测,检测内容为化合物1。
表1化合物1大鼠药代动力学参数
*注:i.g.(灌胃)给予化合物1,检测原药乐伐替尼
结论:运用本发明技术所合成的乐伐替尼前药化合物1在大鼠中具有良好的口服生物利用度。
大鼠组织分布实验
1.试验材料
(1)试验动物:
雄性SD大鼠,200g左右,6~8周龄,共285只。购于成都达硕实验动物有限公司。
(2)受试化合物
准确称取一定量受试化合物,用75%PEG400+25%水溶解。
2.试验方法
受试化合物灌胃给药剂量(以游离碱计)为5.61mg/kg,给药体积灌胃为10ml/kg。每只动物在给药前及给药后异氟烷麻醉经眼眶取血0.5ml,置于EDTAK2离心管中并放置冰浴上。5000rpm,4℃离心10min,收集血浆。动物安乐死放血后取肝组织,清洗干净后用冰的50%甲醇水溶液按照1:1(m/v)匀浆获取组织匀浆液。采集时间点:给药后30min,1h,3h,4h,8h;所有样品存于-80℃用于检测。用HPLC-MS/MS对样品进行检测,检测内容为乐伐替尼。肝血比=AUC0-t(肝)/AUC0-t(血浆)。
表2大鼠组织分布参数
*注:i.g.(灌胃)给予各受试化合物,检测原药乐伐替尼
乐伐替尼是多重激酶抑制剂,已上市用于治疗分化型甲状腺癌(DTC)和晚期肾细胞癌(RCC),目前进行临床III期试验用于治疗晚期肝细胞肝癌(uHCC),同时2018年3月被日本推荐为uHCC一线用药。乐伐替尼在DTC患者为每日口服24mg,在RCC患者为每日口服乐伐替尼18mg与依维莫司5mg联用治疗。
值得注意的是,乐伐替尼在临床试验中表现出明显的剂量限制性毒性,随药物暴露量增加,不良反应(如高血压、蛋白尿、恶心,呕吐等)的发生率也增加。在乐伐替尼用于DTC患者每日口服24mg 28天周期的临床试验中,有97.3%患者出现不良反应,其中75.9%患者严重不良反应,67%患者因为不良反应需要降低剂量,82.4%患者也因为不良反应需要中断给药,这都对患者造成极大伤害。
出乎意料的,本发明所得到的乐伐替尼前药在大鼠组织分布中具有更高的肝血比,其肝血比较乐伐替尼提高了31%-694%,显示出显著优于乐伐替尼的肝靶向性,可在较低的剂量下即达到与乐伐替尼相当的肝组织浓度,同时降低系统暴露量。因此本发明所得到的乐伐替尼前药在运用于临床时将大大减少诸如高血压、蛋白尿、恶心,呕吐等不良反应的发生率,避免因不良反应降低剂量或中断给药的发生率,达到减毒增效的目的,造福广大患者。
Claims (9)
1.一种通式(I)所示化合物及其立体异构体或药学上可接受的盐,
Q-L-R1 (I)
其中:
Q选自
R1选自 优选地,所述R1选自
Ar选自C6-10芳基或5至10元杂芳基,所述的芳基或杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-6烷氧基的取代基所取代,所述的杂芳基含有1至4个选自O、S、N的杂原子;
X1、X2、X4、X5各自独立的选自O或S;
X3选自O或N;
R1a、R1a`、R1c、R1c`、R1e、R1e`各自独立的选自H、C1-6烷基或C3-8碳环基,所述的C1-6烷基或C3-8碳环基任选进一步被0至4个选自H、F、Cl、Br、I、C1-6烷基或C1-6烷氧基的取代基所取代;
R1b、R1d、R1f各自独立的选自C1-6烷基、苄基或C3-8碳环基,所述的C1-6烷基、苄基或C3-8碳环基任选进一步被0至4个选自H、F、Cl、Br、I、C1-6烷基或C1-6烷氧基的取代基所取代;
R1g选自C1-6烷基、-C1-6烷基-C3-8碳环基、C3-8碳环基或C5-10杂环基,所述的C1-6烷基、-C1-6烷基-C3-8碳环基、C3-8碳环基或C5-10杂环基任选进一步被0至4个选自H、F、Cl、Br、I、苯基、C1-6烷基或C1-6烷氧基的取代基所取代,所述的杂环基含有1至4个选自O、S、N的杂原子;
L选自键、其中L的左边与Q连接,右边与R1连接;
T选自C1-6烷基、C3-8碳环基、-C1-6烷基-C3-8碳环基,所述的C1-6烷基、C3-8碳环基、-C1-6烷基-C3-8碳环基任选进一步被0至4个选自H、F、Cl、Br、I、苯基、C1-6烷基、C3-6环烷基或C1-6烷氧基的取代基所取代;
优选地,L选自
RL1选自H、C1-6烷基、C1-6烷氧基或C3-6环烷基,所述的C1-6烷基、C1-6烷氧基或C3-6环烷基任选进一步被0至4个选自H、F、Cl、Br、I、C1-6烷基、C1-6烷氧基或C3-6环烷基的取代基所取代;
RL2选自H、F、Cl、Br、I、C1-6烷基、C1-6烷氧基或C3-6环烷基,所述的C1-6烷基、C1-6烷氧基或C3-6环烷基任选进一步被0至4个选自H、F、Cl、Br、I、C1-6烷基、C1-6烷氧基或C3-6环烷基的取代基所取代;
n选自0、1、2或3;m选自0、1、2、3或4;p选自0或1;r选自1、2、3、4、5或6。
2.根据权利要求1所述的化合物及其立体异构体或药学上可接受的盐,其中
Ar选自苯基或5至6元杂芳基,所述的苯基或杂芳基任选进一步被0至4个选自H、F、Cl、Br、I、C1-4烷基或C1-6烷氧基的取代基所取代,所述的杂芳基含有1至4个选自O、S、N的杂原子;
R1a、R1a`、R1c、R1c`、R1e、R1e`各自独立的选自H或C1-4烷基;
R1b、R1d、R1f各自独立的选自C1-4烷基或苄基;
R1g选自C1-6烷基、-C1-4烷基-C3-6碳环基、C3-6碳环基;优选地,R1g选自苯基或苄基,所述的苯基、苄基、烷基或碳环基任选进一步被0至4个选自H、F、Cl、Br、I、苯基、C1-4烷基或C1-4烷氧基的取代基所取代;
RL1选自H或C1-4烷基;
RL2选自H、F、Cl、Br、I、C1-4烷基或C1-4烷氧基。
3.根据权利要求2所述的化合物及其立体异构体或药学上可接受的盐,其中
Ar选自苯基或吡啶基,所述苯基或吡啶基任选进一步被0至4个选自H、F、Cl、Br、I、甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基的取代基所取代,
R1a、R1a`、R1c、R1c`、R1e、R1e`各自独立的选自H、甲基、乙基、丙基或异丙基;
R1b、R1d、R1f各自独立的选自甲基、乙基、丙基、异丙基或苄基;
R1g选自取代或未取代的甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、己基、环戊基、环己基、苯基、苄基、亚甲基环丙基或亚甲基环丁基,当被取代时,任选进一步被0、1、2、3或4个选自H、F、Cl、Br、I、甲基、乙基、异丙基、甲氧基、乙氧基或异丙氧基的取代基所取代;
L选自键、其中L的左边与Q连接,右边与R1连接;RL1选自H或甲基;
RL2选自H、F、Cl、Br、I、甲基或甲氧基;
n为1;m选自0、1、2、3或4;p为1;r为2或3。
4.根据权利要求1所述的化合物及其立体异构体或药学上可接受的盐,选自如下结构之一:
5.根据权利要求1-4任意一项所述的化合物及其立体异构体或药学上可接受的盐,为与选自下述的酸所成的盐:三氟乙酸、盐酸。
6.根据权利要求5所述的化合物及其立体异构体或药学上可接受的盐,为
7.一种药物组合物,所述药物组合物含有治疗有效剂量的权利要求1~6中任意一项所述的化合物或其立体异构体或药学上可接受的盐,以及药学上可接受的载体和赋形剂。
8.权利要求1~6中任意一项所述的化合物及其立体异构体或药学上可接受的盐,以及权利要求7所述的组合物在制备抗肿瘤药物中的应用。
9.根据权利要求8所述的用途,其中所述的肿瘤为胰脏癌、胃癌、大肠癌、乳癌、前列腺癌、肺癌、肾癌、脑肿瘤、血液癌、卵巢癌、肝癌或甲状腺癌。
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