CN114057793A - 一种坦西莫司衍生物 - Google Patents
一种坦西莫司衍生物 Download PDFInfo
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- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical class C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 69
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000007530 organic bases Chemical class 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical class C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 claims abstract description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 9
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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 8
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
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- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 102000018679 Tacrolimus Binding Proteins Human genes 0.000 description 1
- 108010027179 Tacrolimus Binding Proteins Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- 150000004291 polyenes Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems
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- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本发明属于医药化工领域,具体涉及一种坦西莫司衍生物;所述坦西莫司衍生物制备方法包括惰性气体保护,化合物VI和化合物VII加入有机溶剂中,加入有机碱,控温反应,TLC检测,反应完毕,加入溶液稀释,无水硫酸钠干燥,减压浓缩,得化合物I;提供一种新中间体化合物VI,可有效提高雷帕霉素酯化反应的区域选择性,有利于42位羟基的反应,可有效避免31位羟基的反应。
Description
技术领域
本发明属于医药化工领域,具体涉及一种坦西莫司衍生物。
背景技术
坦西莫司(Temsirolimus,商品名:)由原惠氏制药公司研发,于2007年 5月由美国FDA批准上市,用于治疗肾细胞癌。其作用机理与雷帕霉素作用机制类似,都是与FKBP、mTOR结合形成复合物,从而抑制细胞***。这说明雷帕霉素及其类似物具有抗肿瘤的潜在活性,基于此机理,雷帕霉素之后用于抗肿瘤研究,得到一系列衍生物并测试它们的抗肿瘤活性。
雷帕霉素的结构很复杂,在形成的大环中具有31个原子,有15个手性中心,且所有的烯基是全反式结构,因这些因素,其难以进行全合成或合成效率太低,不适合工业生产,且不经济环保。所以在合成雷帕霉素类似物时应用的方法是半合成法。主要包括对羟基、多烯基、哌啶酯基进行修饰,或者应用扩环反应使大环增大。有研究人员对雷帕霉素的三烯基进行修饰,利用路易斯酸(SnCl4,BF3–OEt2等作为催化剂)完成氢化反应,但是在这些反应中,反应的位点没有专一性,得到的是多种烯烃与烷烃的混合物。
另外,雷帕霉素在人体代谢之后发生开环反应,24位的氧与其连接的羰基发生水解,产生secorapamycins,由于secorapamycin几乎无活性,所以为了减少雷帕霉素在体内的消除,研究人员进行了多种设计,比如将27位的羰基转化成肟或腙、或者还原为羟基,但形成肟之后,化合物的毒性势必增加。。
从构效关系可知,修饰42位上的羟基可以使化合物的性质发生改变,可以增加药物的活性。一般而言,大多与42位羟基反应形成酯基、磺酸基、酰胺基之后活性较好。由于在31位上也有一个羟基,在反应的时候势必也会使31位的羟基发生反应,而得到二者的混合物,最终只能用色谱方法将它们分离开,而目前仍没有对42位的专一的反应。
鉴于上述问题,本发明的目的提供一种坦西莫司衍生物,此有利于42位羟基的反应,可有效避免31位羟基的反应,该制备方法得到的化合物无毒性,选择性高,适合工业化生产。
发明内容
本发明所要解决的技术问题是克服现有技术的不足,提供一种坦西莫司衍生物。
本发明的具体技术方案如下:
一种坦西莫司衍生物,为式I所示,结构式如下:
一种如式I所示的坦西莫司衍生物的制备方法,反应式如下:
其中,R1为-H,-OH,-C1-C4烷烃,-OCH3,-COCH3,-COCH2CH3,-OCH2COCH3; n=0,1,2,3,4。
R1优选为-H,丙基、-OH;n=0,3。
R1进一步优选为丙基;n=3。
具体包括以下步骤:
惰性气体保护,化合物VI和化合物VII加入有机溶剂A中,加入有机碱,控温反应,TLC检测,反应完毕,加入溶剂B稀释,无水硫酸钠干燥,减压浓缩,得化合物I。
优选地,所述有机碱选自N,N-二异丙基乙胺、三乙胺、2,6-二甲基吡啶、4-二甲胺基吡啶、N-甲基吗啉中的一种或其组合,进一步优选为4-二甲胺基吡啶。
优选地,所述有机溶剂A选自二氯甲烷、N,N-二甲基甲酰胺、三氯甲烷、四氢呋喃、甲苯、二氧六环中的一种或其组合,进一步优选为二氯甲烷。
优选地,所述的化合物VII和有机碱的投料摩尔比为1:3.0~6.0,进一步优选为1:4.0。
优选地,所述的化合物VII和化合物VI的投料摩尔比为1:1.0~2.0,进一步优选为1:1.2。
优选地,所述溶剂B为二氯甲烷、三氯甲烷、乙酸乙酯中的一种或其组合。
优选地,所述的控温反应温度为0~10℃,进一步优选为5℃。
化合物IV的制备
反应路线如下:
其中,R1为-H,-OH,-C1-C4烷烃,-OCH3,-COCH3,-COCH2CH3,-OCH2COCH3; n=0,1,2,3,4。
R1优选为-H,丙基、-OH;n=0,3。
R1进一步优选为丙基;n=3。
具体制备方法:
惰性气体保护,化合物III和化合物II加入有机溶剂C中,控温加入有机碱,加入完毕,室温下反应,TLC检测,反应完毕,抽滤,减压浓缩,得化合物IV。
优选地,所述的有机碱选自氢化钠、甲醇钠、叔丁醇钾,正丁基锂,二异丙基氨基锂中的一种或其组合,特别优选氢化钠。
优选地,所述的化合物II、化合物III的投料摩尔比为1:1.0~1.5,特别优选为1:1.2。
优选地,所述的化合物II和有机碱的投料摩尔比为1:2~2.5,特别优选为1:2.2。
优选地,所述的有机溶剂C为二氯甲烷、1,4-二氧六环、乙腈、三氯甲烷、四氢呋喃中的一种或其组合,特别优选为四氢呋喃。
优选地,所述的加入有机碱温度为-5~5℃,特别优选0℃。
化合物VI的制备
反应路线如下:
其中,R1为-H,-OH,-C1-C4烷烃,-OCH3,-COCH3,-COCH2CH3,-OCH2COCH3; n=0,1,2,3,4。
R1优选为-H,丙基、-OH;n=0,3。
R1进一步优选为丙基;n=3。
具体制备方法:
化合物IV和有机碱溶于有机溶液D中,加入化合物V,控温,TLC检测,反应完毕,过滤,减压浓缩,得化合物VI。
优选地,所述有机碱选自N,N-二异丙基乙胺、三乙胺、吡啶、4-二甲胺基吡啶、 N-甲基吗啉中的一种或其组合,特别优选N,N-二异丙基乙胺。
优选地,所述有机溶剂D选自二氯甲烷、N,N-二甲基甲酰胺、三氯甲烷、四氢呋喃、甲苯中的一种或其组合,进一步优选为二氯甲烷。
优选地,所述的化合物V与有机碱的投料摩尔比为1:1.0~4.0,进一步优选为1:2.0。
优选地,所述的化合物V与化合物IV的投料摩尔比为1:1.0~1.3.0,进一步优选为1:1.1。
优选地,所述的加入温度为25~40℃,进一步优选为30℃。
与现有技术相比,本发明取得的技术效果是:
1、提供了一种坦西莫司衍生物;
2、本发明提供的新中间体化合物VI在反应过程中因位阻大,可有效提高雷帕霉素酯化反应的区域选择性,有利于42位羟基的反应,可有效避免31位羟基的反应。
具体实施方式
下面通过实施例来进一步说明本发明。应该正确理解的是:本发明的实施例仅仅是用于说明本发明,而不是对本发明的限制,所以,在本发明的方法前提下对本发明的简单改进均属本发明要求保护的范围。
对本发明得到的新化合物结构确证:
当R1为H,n=0时,
实施例1
化合物IV的合成:
氮气保护,化合物II(16.62g,0.1mol)和化合物III(16.10g,0.12mol)加入30ml四氢呋喃中,控温0℃,加入甲醇钠(11.88g,0.22mol),加入完毕,升至室温反应,TLC 检测,反应完毕,抽滤,减压浓缩,得化合物IV,收率97.5%,纯度99.76%。
化合物VI的合成:
化合物IV(29.50g,0.1mol)和N,N-二异丙基乙胺(25.85g,0.2mol)溶于120mL二氯甲烷中,加入化合物V(24.39g,0.10mol),控温35℃,TLC检测,反应完毕,过滤,减压浓缩,得化合物VI,收率96.1%,纯度99.70%。
化合物I的合成:
氮气保护,化合物VII(45.74g,0.05mol)和化合物VI(27.46g,0.06mol)加入300mL甲苯中搅拌溶解,加入4-二甲胺基吡啶(24.44g,0.20mol),溶清后控温0℃, TLC检测,反应完毕,加入乙酸乙酯稀释,无水硫酸钠干燥,减压浓缩,得化合物I,收率95.5%,纯度99.89%。
化合物IV:
1H-NMR(400MHz,CDCl3)δ:1.31(s,3H),3.54~3,62(m,2H),3.69~3.91(m,6H),3.97~4.06(m,2H),4.23~4.47(m,2H),11.94(s,1H);
13CNMR(100MHz,CDCl3)δ:15.9,45.8,60.3,60.3,71.9,71.9,73.1,73.1,179.5
ESI-HRMS:m/z=269.2031[M+H]+;
化合物VI:
1H-NMR(400MHz,CDCl3)δ:1.27(s,3H),3.44~3,50(m,2H),3.64~3.88(m,6H),3.92~4.01(m,2H),4.20~4.37(m,2H),7.73(s,2H);
13CNMR(100MHz,CDCl3)δ:15.4,43.8,60.6,60.6,71.1,71.1,72.2,72.2,127.9,127.9,132.7,138.3,183.3,143.5,151.9,178.5
ESI-HRMS:m/z=475.1313[M+H]+;
化合物I:
1H-NMR(400MHz,DMSO-d6)δ:0.73(d,J=6.6Hz,3H),0.78(d,J=6.0Hz,3H),0.80(d,J=6.0Hz,3H),0.85(d,J=6.0Hz,3H),0.97(d,J=6.6Hz,3H),1.10(s,3H),1.11~1.18(m,2H),1.44(s,3H),1.52~1.59(m,6H),1.66(s,3H),1.75(s,3H),1.79(s,3H), 1.92~2.01(m,3H),2.14~2.21(m,2H),2.20~2.24(t,J=4.6Hz,2H),2.36~2.74(m,3H), 3.12(s,3H),3.17(s,3H),3.15~3.31(m,5H),3.39~3.51(m,6H),3.60(d,J=11.4Hz,1H),3.65(dd,J=12.4、10.2Hz,2H),3.73~3.77(m,4H),3.80~3.84(m,4H),3.96(d,J=3.6Hz,1H), 4.05~4.13(m,1H),4.17(dd,J=12.4、10.2Hz,2H),4.24(br s,1H),4.36~4.48(m,1H), 4.56(t,J=4.5Hz,2H),4.58~4.63(m,4H),4.93(d,J=3.6Hz,1H),4.97~5.09(m,1H), 5.13(d,J=10.2Hz,1H),5.32(d,J=4.2Hz,1H),5.44(dd,J=14.4、10.2Hz,1H),6.11~6.16 (m,2H),6.23(t,J=10.2Hz,1H),6.37(dd,J=13.8、11.4Hz,1H),6.62(s,1H);
13CNMR(100MHz,DMSO-d6)δ:10.6,12.9,14.2,15.0,15.6,16.7,17.3,20.8, 22.5,24.6,25.7,26.3,27.1,29.6,30.2,31.1,33.4,33.8,35.5,35.6,36.5,38.8, 39.6,40.1,40.3,40.5,45.0,45.4,50.3,51.1,56.6,57.9,58.1,60.6,60.6,64.2, 64.2,66.8,72.4,72.5,73.3,73.3,74.2,76.6,76.6,80.9,82.2,85.6,99.7,125.3, 127.7,131.1,132.8,137.4,138.0,139.6,167.1,169.6,174.6,175.8,199.4,208.2, 211.3.
ESI-HRMS:m/z=1178.6352[M+H]+;
当R1为H,n=3时
实施例2
化合物IV的合成:
氮气保护,化合物II(25.03g,0.10mol)和化合物III(20.13g,0.15mol)加入30ml乙腈中,控温2℃,加入氢化钠(24.69g,0.22mol),加入完毕,升至室温反应,TLC检测,反应完毕,抽滤,减压浓缩,得化合物IV,收率97.0%,纯度99.71%。
化合物VI的合成:
化合物IV(35.24g,0.10mol)和N,N-二异丙基乙胺(25.85g,0.2mol)溶于120mL N,N- 二甲基甲酰胺中,加入化合物V(24.39g,0.10mol),控温25℃,TLC检测,反应完毕,过滤,减压浓缩,得化合物VI,收率96.4%,纯度99.67%。
化合物I的合成:
氮气保护,化合物VII(45.74g,0.05mol)和化合物VI(33.59g,0.06mol)加入300mLN,N-二甲基甲酰胺中搅拌溶解,加入N,N-二异丙基乙胺(25.85g,0.20mol),溶清后控温10℃,TLC检测,反应完毕,加入三氯甲烷稀释,无水硫酸钠干燥,减压浓缩,得化合物I,收率95.0%,纯度99.84%。
化合物IV:
1H-NMR(400MHz,CDCl3)δ:1.52(s,3H),2.03~2.28(m,12H),3.50~3.63(m,6H),3.71~4.79(m,4H)3.99~4.14(m,2H),4.25(s,1H),12.06(s,1H);
13CNMR(100MHz,CDCl3)δ:15.4,20.9,20.9,29.6,29.6,31.1,31.1,45.2,57.9,57.9,72.4,72.4,73.6,73.6,179.2.
ESI-HRMS:m/z=353.1724[M+H]+;
化合物VI:
1H-NMR(400MHz,CDCl3)δ:1.53(s,3H),2.01~2.30(m,12H),3.56~3.64(m,6H),3.69~4.78(m,4H)3.95~4.11(m,2H),5.33(s,1H),7.81(s,2H);
13CNMR(100MHz,CDCl3)δ:15.1,20.5,20.5,29.7,29.7,30.9,30.9,44.4,57.6,57.6,72.2,72.2,73.4,73.4,127.7,127.7,131,8,138.2,138.2,142.4,153.0,179.2.
ESI-HRMS:m/z=559.0703[M+H]+;
化合物I:
1H-NMR(400MHz,DMSO-d6)δ:0.69(d,J=6.6Hz,3H),0.78(d,J=6.0Hz,3H),0.82(d,J=6.0Hz,3H),0.88(d,J=6.0Hz,3H),0.97(d,J=6.6Hz,3H),1.15(s,3H),1.09~1.16(m,2H),1.42(s,3H),1.54~1.59(m,6H),1.69(s,3H),1.76(s,3H),1.80(s,3H), 1.85~1.91(m,4H),1.94~1.99(m,4H),2.04~2.08(m,3H),2.11~216(m,4H),2.20~2.15 (m,4H),2.19~2.23(m,2H),2.27~2.32(t,J=4.6Hz,2H),2.47~2.78(m,3H),3.16(s,3H),3.21(s,3H),3.28~3.33(m,5H),3.39~3.50(m,6H),3.65(d,J=11.4Hz,1H),3.67~3.70(m,4H),3.74(dd,J=12.4、10.2Hz,2H),3.94(d,J=3.6Hz,1H),4.03~4.11(m,1H), 4.16(dd,J=12.4、10.2Hz,2H),4.25(br s,1H),4.38~4.49(m,1H),4.54(t,J=4.5Hz,2H),4.57~4.61(m,4H),4.95(d,J=3.6Hz,1H),4.99~5.11(m,1H),5.14(d,J=10.2Hz,1H),5.17(s,1H),5.33(d,J=4.2Hz,1H),5.45(dd,J=14.4、10.2Hz,1H),6.12~6.17(m,2H),6.24(t,J=10.2Hz,1H),6.39(dd,J=13.8、11.4Hz,1H),6.64(s,1H);
13CNMR(100MHz,DMSO-d6)δ:11.3,13.7,14.2,15.5,15.8,16.7,17.5,20.7, 20.8,21.0,22.9,24.9,26.7,27.4,28.6,28.7,29.4,29.5,30.0,30.7,31.4,33.8, 34.1,35.8,35.9,36.7,38.8,39.5,40.1,40.3,40.5,43.8,44.8,45.4,50.7,51.3, 56.4,57.8,58.0,64.2,64.3,66.9,70.5,70.6,73.1,73.2,74.1,75.5,75.6,76.7, 76.7,80.8,82.5,86.0,99.4,125.2,127.8,130.7,132.9,137.4,138.3,139.8,167.1, 169.8,174.5,175.7,199.7,208.2,211.3.
ESI-HRMS:m/z=1248.7115[M+H]+;
当R1为OH,n=0时
实施例3
化合物IV的合成:
氮气保护,化合物II(18.22g,0.10mol)和化合物III(17.45g,0.13mol)加入30ml无水1,4-二氧六环中,控温-2℃,加入正丁基锂(14.09g,0.22mol),加入完毕,控温-2℃反应,TLC检测,反应完毕,抽滤,减压浓缩,得化合物IV,收率97.1%,纯度99.72%。
化合物VI的合成:
化合物IV(28.42g,0.10mol)和N,N-二异丙基乙胺(25.85g,0.2mol)溶于120mL三氯甲烷中,加入化合物V(24.39g,0.10mol),控温40℃,TLC检测,反应完毕,过滤,减压浓缩,得化合物VI,收率97.0%,纯度99.70%。
化合物I的合成:
氮气保护,化合物VII(45.74g,0.05mol)和化合物VI(29.50g,0.06mol)加入300mL三氯甲烷中搅拌溶解,加入2,6-二甲基吡啶(21.43g,0.20mol),溶清后控温5℃, TLC检测,反应完毕,加入二氯甲烷稀释,无水硫酸钠干燥,减压浓缩,得化合物I,收率94.8%,纯度99.80%。
化合物IV:
1H-NMR(400MHz,CDCl3)δ:1.34(s,3H),3.44~3.56(m,2H),3.80~4.04(m,6H),4.16~4.23(m,2H),4.83~4.97(m,2H),5.34(s,1H),12.21(s,1H);
13CNMR(100MHz,CDCl3)δ:15.6,45.3,68.9,68.9,70.9,70.9,72.1,72.1,179.1
ESI-HRMS:m/z=285.0732[M+H]+;
化合物VI:
1H-NMR(400MHz,CDCl3)δ:1.42(s,3H),3.40~3.51(m,2H),3.83~4.08(m,6H),4.14~4.21(m,2H),4.79~4.95(m,2H),5.31(s,1H),7.70(s,2H);
13CNMR(100MHz,CDCl3)δ:15.7,42.9,60.3,60.3,71.6,71.6,72.7,72.7,128.2,128.2,133.0,138.8,183.8,143.3,151.4,177.9;
ESI-HRMS:m/z=491.1125[M+H]+;
化合物I:
1H-NMR(400MHz,DMSO-d6)δ:0.74(d,J=6.6Hz,3H),0.79(d,J=6.0Hz,3H),0.83(d,J=6.0Hz,3H),0.88(d,J=6.0Hz,3H),0.98(d,J=6.6Hz,3H),1.09(s,3H),1.12~1.21(m,2H),1.43(s,3H),1.49~1.59(m,6H),1.67(s,3H),1.75(s,3H),1.79(s,3H), 1.93~2.01(m,3H),2.12~2.18(m,2H),2.22~2.26(t,J=4.6Hz,2H),2.35~2.76(m,3H), 3.09(s,3H),3.17(s,3H),3.16~3.29(m,5H),3.38~3.48(m,6H),3.60(d,J=11.4Hz,1H),3.67(dd,J=12.4、10.2Hz,2H),3.73~3.82(m,4H),3.95(d,J=3.6Hz,1H),4.04~4.12(m,1H), 4.15(dd,J=12.4、10.2Hz,2H),4.24~4.32(m,4H),4.39(br s,1H),4.42~4.49(m,1H), 4.56(t,J=4.5Hz,2H),4.61~4.71(m,4H),4.94(d,J=3.6Hz,1H),4.96~5.05(m,1H), 5.14(d,J=10.2Hz,1H),5.33(d,J=4.2Hz,1H),5.46(dd,J=14.4、10.2Hz,1H),5.65(S,1H), 6.11~6.16(m,2H),6.25(t,J=10.2Hz,1H),6.39(dd,J=13.8、11.4Hz,1H),6.63(s,1H);
13CNMR(100MHz,DMSO-d6)δ:10.3,12.7,14.0,15.1,15.6,16.7,17.3,20.8, 22.4,24.7,25.7,26.3,27.1,29.6,30.2,31.1,33.4,33.8,35.5,35.6,36.5,38.8, 39.6,40.1,40.3,40.5,45.0,45.4,50.3,51.1,56.6,57.9,58.1,64.2,64.2,60.6, 60.6,66.8,70.4,70.5,73.3,73.3,74.2,76.7,76.7,80.9,82.2,85.6,99.7,125.3, 127.6,131.1,132.8,137.4,138.0,139.6,167.1,169.6,174.6,175.8,199.4,208.1, 211.2.
ESI-HRMS:m/z=1194.6351[M+H]+;
当R1为OH,n=3时
实施例4
化合物IV的合成:
氮气保护,化合物II(26.63g,0.10mol)和化合物III(16.11g,0.12mol)加入30ml三氯甲烷中,控温-5℃,加入二异丙基氨基锂(23.57g,0.22mol),加入完毕,升至室温反应,TLC检测,反应完毕,降温至0℃,抽滤,减压浓缩,得化合物IV,收率97.4%,纯度99.77%。
化合物VI的合成:
化合物IV(40.52g,0.11mol)和N,N-二异丙基乙胺(38.78g,0.3mol)溶于120mL四氢呋喃中,加入化合物V(24.39g,0.10mol),控温35℃,TLC检测,反应完毕,过滤,减压浓缩,得化合物VI,收率97.3%,纯度99.74%。
化合物I的合成:
氮气保护,化合物VII(45.74g,0.05mol)和化合物VI(34.55g,0.06mol)加入300mL四氢呋喃中搅拌溶解,加入N-甲基吗啉(20.23g,0.20mol),溶清后控温0℃, TLC检测,反应完毕,加入乙酸乙酯稀释,无水硫酸钠干燥,减压浓缩,得化合物I,收率95.3%,纯度99.85%。
化合物IV:
1H-NMR(400MHz,CDCl3)δ:1.35(s,3H),2.18~2.45(m,12H),3.59~3.72(m,6H),4.06~4.12(m,2H),4.55~4.67(m,4H),5.01(s,1H),11.95(s,1H);
13CNMR(100MHz,CDCl3)δ:15.1,19.9,19.9,28.2,28.2,28.7,28.7,45.0,65.9,65.9,70.8,70.8,73.6,73.6,178,3.
ESI-HRMS:m/z=369.3325[M+H]+;
化合物VI:
1H-NMR(400MHz,CDCl3)δ:1.32(s,3H),2.10~2.38(m,12H),3.64~3.76(m,6H),4.01~4.10(m,2H),4.54~4.66(m,4H),5.12(s,1H),7.71(s,2H);
13CNMR(100MHz,CDCl3)δ:15.5,20.3,20.3,29.9,29.9,31.7,31.7,45.1,56.9,56.9,72.6,72.6,73.8,73.8,128.2,128.2,132.5,132.5,138.7,141.9,153.3,179.7.
ESI-HRMS:m/z=575.0763[M+H]+;
化合物I:
1H-NMR(400MHz,DMSO-d6)δ:0.72(d,J=6.6Hz,3H),0.76(d,J=6.0Hz,3H),0.81(d,J=6.0Hz,3H),0.88(d,J=6.0Hz,3H),0.97(d,J=6.6Hz,3H),1.03(s,3H),1.09~1.17(m,2H),1.42(s,3H),1.51~1.59(m,6H),1.62(s,3H),1.74(s,3H),1.76(s,3H), 1.81~1.87(m,4H),1.91~1.95(m,4H),1.97~2.03(m,3H),2.05~2.08(m,4H),2.11~2.14 (m,4H),2.16~2.20(m,2H),2.23~2.26(t,J=4.6Hz,2H),2.34~2.69(m,3H),3.02(s,3H),3.12(s,3H),3.16~3.29(m,5H),3.37~3.48(m,6H),3.61(d,J=11.4Hz,1H),3.63~3.66(m,4H),3.69(dd,J=12.4、10.2Hz,2H),3.92(d,J=3.6Hz,1H),4.01~4.11(m,1H),4.15(dd,J=12.4、10.2Hz,2H),4.21(br s,1H),4.35~4.47(m,1H),4.55(t,J=4.5Hz,2H),4.58~4.66(m,4H),4.94(d,J=3.6Hz,1H),4.96~5.07(m,1H),5.11(d,J=10.2Hz,1H),5.31(d,J=4.2Hz,1H),5.44(dd,J=14.4、10.2Hz,1H),5.66(S,1H),6.10~6.15(m,2H),6.23(t,J=10.2Hz,1H),6.38(dd,J=13.8、11.4Hz,1H),6.62(s,1H);
13CNMR(100MHz,DMSO-d6)δ:11.2,13.7,14.2,15.6,15.9,16.8,17.4,20.7,20.8,21.0,22.9,24.9,26.6,27.4,28.6,28.7,29.54,29.6,30.1,30.7,31.3,33.8, 34.2,35.8,35.9,36.7,38.8,39.5,40.2,40.3,40.5,43.8,44.8,45.4,50.7,51.3, 56.4,57.7,58.0,64.3,64.4,66.9,70.5,70.6,73.1,73.2,74.1,75.4,75.5,76.7, 76.7,80.8,82.5,86.0,99.4,125.1,127.8,130.7,132.9,137.4,138.2,139.8,167.3, 169.6,174.6,175.7,199.4,208.3,211.5.
ESI-HRMS:m/z=1263.7126[M+H]+;
当R1为丙基,n=0时
实施例5
化合物IV的合成:
氮气保护,化合物II(20.82g,0.10mol)和化合物III(16.11g,0.12mol)加入30ml二氯甲烷中,控温5℃,加入氢化钠(5.28g,0.22mol),加入完毕,升至室温反应,TLC 检测,反应完毕,抽滤,减压浓缩,得化合物IV,收率97.1%,纯度99.75%。
化合物VI的合成:
化合物IV(34.13g,0.11mol)和N,N-二异丙基乙胺(38.78g,0.3mol)溶于120mL甲苯中,加入化合物V(24.39g,0.10mol),控温35℃,TLC检测,反应完毕,过滤,减压浓缩,得化合物VI,收率97.5%,纯度99.71%。
化合物I的合成:
氮气保护,化合物VII(45.74g,0.05mol)和化合物VI(31.06g,0.06mol)加入300mL二氯甲烷中搅拌溶解,加入三乙胺(20.24g,0.20mol),溶清后控温10℃,TLC 检测,反应完毕,加入三氯甲烷稀释,无水硫酸钠干燥,减压浓缩,得化合物I,收率 95.7%,纯度99.87%。
化合物IV:
1H-NMR(400MHz,CDCl3)δ:1.01(t,J=4.0Hz,3H),1.37(s,3H),1.54(m,2H),1.77(d,2H),3.22~3.41(m,2H),3.65~3.79(m,6H),4.27~4.40(m,4H),12.11(s,1H);
13CNMR(100MHz,CDCl3)δ:15.2,15.4,16.6,32.8,45.7,70.4,70.4,71.3,71.3,74.0,74.0,178.9.
ESI-HRMS:m/z=310.2836[M+H]+;
化合物VI:
1H-NMR(400MHz,CDCl3)δ:1.01(t,J=4.0Hz,3H),1.34(s,3H),1.57(m,2H),1.79(d,2H),3.23~3.38(m,2H),3.64~3.81(m,6H),4.23~4.37(m,4H),7.66(s,2H);
13CNMR(100MHz,CDCl3)δ:15.1,15.4,16.7,31.9,42.7,60.5,60.5,72.0,72.0,73.1,73.1,128.4,128.4,133.3,138.2,183.2,143.1,151.9,178.7;
ESI-HRMS:m/z=517.0324[M+H]+;
化合物I:
1H-NMR(400MHz,DMSO-d6)δ:0.71(d,J=6.6Hz,3H),0.79(d,J=6.0Hz,3H),0.81(d,J=6.0Hz,3H),0.86(d,J=6.0Hz,3H),0.93(t,J=4.0Hz,3H),0.97(d,J=6.6Hz,3H),1.10(s,3H),1.11~1.18(m,2H),1.32~1.37(m,2H),1.42(s,3H),1.52~1.59(m,6H),1.64(s,3H),1.71(d,J=4.2Hz,2H),1.75(s,3H),1.79(s,3H),1.92~2.02(m,3H), 2.14~2.21(m,2H),2.23~2.27(t,J=4.6Hz,2H),2.36~2.74(m,3H),3.06(s,3H),3.12 (s,3H),3.15~3.33(m,5H),3.38~3.50(m,6H),3.60(d,J=11.4Hz,1H),3.66(dd,J=12.4、10.2Hz,2H),3.71~3.77(m,4H),3.80~3.84(m,4H),3.96(d,J=3.6Hz,1H),4.05~4.12(m,1H),4.17(dd,J=12.4、10.2Hz,2H),4.22(br s,1H),4.36~4.45(m,1H),4.53 (t,J=4.5Hz,2H),4.58~4.64(m,4H),4.93(d,J=3.6Hz,1H),4.97~5.08(m,1H),5.15 (d,J=10.2Hz,1H),5.31(d,J=4.2Hz,1H),5.44(dd,J=14.4、10.2Hz,1H),6.11~6.16(m,2H),6.23(t,J=10.2Hz,1H),6.37(dd,J=13.8、11.4Hz,1H),6.61(s,1H);
13CNMR(100MHz,DMSO-d6)δ:10.4,12.7,14.1,15.0,15.3,15.8,16.7,16.9, 17.3,20.6,22.4,24.5,25.7,26.3,27.1,29.6,30.2,31.1,32.8,33.4,33.8,35.5, 35.6,36.5,38.8,39.6,40.1,40.3,40.5,45.0,45.4,50.3,51.1,56.6,57.9,58.1, 60.6,60.6,64.3,64.3,66.8,72.6,72.5,73.2,73.2,74.4,76.7,76.7,80.9,82.2, 85.6,99.5,125.3,127.7,131.1,132.9,137.4,138.0,139.6,167.1,169.6,174.6, 175.7,199.4,208.1,211.3.
ESI-HRMS:m/z=1219.6831[M+H]+
当R1为丙基,n=3时
实施例6
化合物IV的合成:
氮气保护,化合物II(29.24g,0.10mol)和化合物III(16.11g,0.12mol)加入30ml四氢呋喃中,控温0℃,加入氢化钠(5.28g,0.22mol),加入完毕,升至室温反应,TLC 检测,反应完毕,抽滤,减压浓缩,得化合物IV,收率98.1%,纯度99.80%。
化合物VI的合成:
化合物IV(43.38,0.11mol)和N,N-二异丙基乙胺(38.78g,0.3mol)溶于120mL二氯甲烷中,加入化合物V(24.39g,0.10mol),控温30℃,TLC检测,反应完毕,过滤,减压浓缩,得化合物VI,收率98.5%,纯度99.78%。
化合物I的合成:
氮气保护,化合物VII(45.74g,0.05mol)和化合物VI(36.11g,0.06mol)加入300mL二氯甲烷中搅拌溶解,加入4-二甲胺基吡啶(24.44g,0.20mol),溶清后控温5℃, TLC检测,反应完毕,加入二氯甲烷稀释,无水硫酸钠干燥,减压浓缩,得化合物I,收率96.5%,纯度99.91%。
化合物IV:
1H-NMR(400MHz,CDCl3)δ:0.98(t,J=4.0Hz,3H),1.52(s,3H),1.76(d,2H),2.13~2.39 (m,14H),3.61~3.70(m,6H),3.96~4.03(m,2H),4.68~4.77(m,4H),11.86(s,1H);
13CNMR(100MHz,CDCl3)δ:15.1,15.6,16.9,20.8,20.8,29.1,29.1,29.5,29.5,33.4,45.6,71.2,71.2,74.3,74.3,75.9,75.9,180.4;
ESI-HRMS:m/z=395.3115[M+H]+。
化合物VI:
1H-NMR(400MHz,CDCl3)δ:0.94(t,J=4.0Hz,3H),1.37(s,3H),1.69(d,2H),1.77~1.84 (m,4H),1.99~2.05(m,4H),2.17~2.22(m,4H),2.24~2.35(t,J=4.2Hz,2H),3.63~3.71 (m,6H),3.87~3.99(m,2H),4.55~4.62(m,4H),7.82(s,2H);
13CNMR(100MHz,CDCl3)δ:15.3,15.7,16.6,20.6,20.7,28.8,28.9,29.1,29.3,33.6,44.9,70.6,70.7,73.2,73.3,75.4,75.5,127.3,127.4,132.3,137.5,137.6, 142.9,153.4,175.5;
ESI-HRMS:m/z=602.4172[M+H]+。
化合物I:
1H-NMR(400MHz,DMSO-d6)δ:0.71(d,J=6.6Hz,3H),0.77(d,J=6.0Hz,3H),0.81(d,J=6.0Hz,3H),0.87(d,J=6.0Hz,3H),0.92(t,J=4.0Hz,3H),0.96(d,J=6.6Hz,3H),1.06(s,3H),1.09~1.17(m,2H),1.33~1.36(m,2H),1.41(s,3H),1.51~1.57(m,6H),1.65(s,3H),1.69(d,J=4.2Hz,2H),1.73(s,3H),1.78(s,3H),1.80~1.86(m,4H), 1.89~1.92(m,4H),1.95~2.03(m,3H),2.04~2.07(m,4H),2.09~2.11(m,4H),2.13~2.20 (m,2H),2.23~2.26(t,J=4.6Hz,2H),2.34~2.73(m,3H),3.10(s,3H),3.19(s,3H), 3.16~3.29(m,5H),3.37~3.49(m,6H),3.62(d,J=11.4Hz,1H),3.63~3.66(m,4H),3.69 (dd,J=12.4、10.2Hz,2H),3.93(d,J=3.6Hz,1H),4.01~4.11(m,1H),4.14(dd,J=12.4、10.2Hz,2H),4.22(br s,1H),4.35~4.47(m,1H),4.55(t,J=4.5Hz,2H),4.58~4.62(m,4H),4.94(d,J=3.6Hz,1H),4.96~5.07(m,1H),5.10(d,J=10.2Hz,1H),5.31(d,J=4.2Hz,1H), 5.44(dd,J=14.4、10.2Hz,1H),6.10~6.15(m,2H),6.22(t,J=10.2Hz,1H),6.38(dd,J=13.8、 11.4Hz,1H),6.61(s,1H);
13CNMR(100MHz,DMSO-d6)δ:11.1,13.6,14.1,15.2,15.3,15.7,16.6,16.7, 17.4,20.6,20.7,20.9,22.7,24.9,26.9,27.1,28.8,28.9,29.3,29.4,29.9,30.6, 31.3,32.8,33.6,33.9,35.7,35.8,36.6,38.7,39.6,40.0,40.2,40.4,43.9,44.9, 45.5,50.6,51.4,56.3,57.6,57.8,64.1,64.2,66.7,70.6,70.7,73.2,73.3,74.0, 75.4,75.5,76.5,76.6,80.7,82.4,85.9,99.5,125.1,127.9,130.9,132.7,137.6, 138.2,139.9,167.2,169.7,174.4,175.5,199.6,208.0,211.0;
ESI-HRMS:m/z=1291.5603[M+H]+。
Claims (10)
3.根据权利要求2所述的制备方法,其特征在于,该方法具体步骤如下,
惰性气体保护,化合物VI和化合物VII加入有机溶剂A中,加入有机碱,控温反应,TLC检测,反应完毕,加入溶剂B稀释,无水硫酸钠干燥,减压浓缩,得化合物I。
4.根据权利要求3所述的制备方法,其特征在于,所述有机碱选自N,N-二异丙基乙胺、三乙胺、2,6-二甲基吡啶、4-二甲胺基吡啶、N-甲基吗啉中的一种或其组合。
5.根据权利要求3所述的制备方法,其特征在于,所述有机溶剂A选自二氯甲烷、N,N-二甲基甲酰胺、三氯甲烷、四氢呋喃、甲苯、二氧六环中的一种或其组合。
6.根据权利要求3所述的制备方法,其特征在于,所述的化合物VII和有机碱的投料摩尔比为1:3.0~6.0。
7.根据权利要求3所述的制备方法,其特征在于,所述的化合物VII和化合物VI的投料摩尔比为1:1.0~2.0。
8.根据权利要求3所述的制备方法,其特征在于,所述溶剂B为二氯甲烷、三氯甲烷、乙酸乙酯中的一种或其组合。
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