CN113801020A - 一种用于核酸液相合成载体的化合物及其制备方法和用途 - Google Patents
一种用于核酸液相合成载体的化合物及其制备方法和用途 Download PDFInfo
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- CN113801020A CN113801020A CN202110658317.4A CN202110658317A CN113801020A CN 113801020 A CN113801020 A CN 113801020A CN 202110658317 A CN202110658317 A CN 202110658317A CN 113801020 A CN113801020 A CN 113801020A
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- 102000039446 nucleic acids Human genes 0.000 title claims abstract description 17
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- 125000000217 alkyl group Chemical group 0.000 claims description 22
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- 238000000034 method Methods 0.000 claims description 22
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- 239000001257 hydrogen Substances 0.000 claims description 10
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- 229930195733 hydrocarbon Natural products 0.000 description 1
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- BGXZIBSLBRKDTP-UHFFFAOYSA-N methyl 9-(4-chloroanilino)-[1,3]thiazolo[5,4-f]quinazoline-2-carboximidate Chemical compound C12=C3SC(C(=N)OC)=NC3=CC=C2N=CN=C1NC1=CC=C(Cl)C=C1 BGXZIBSLBRKDTP-UHFFFAOYSA-N 0.000 description 1
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- FHZQVUQHQIUSPM-PKZQBKLLSA-N n-[1-[(2r,4s,5r)-5-[[bis(4-methoxyphenyl)-phenylmethoxy]methyl]-4-hydroxyoxolan-2-yl]-2-oxopyrimidin-4-yl]acetamide Chemical compound C1=CC(OC)=CC=C1C(C=1C=CC(OC)=CC=1)(C=1C=CC=CC=1)OC[C@@H]1[C@@H](O)C[C@H](N2C(N=C(NC(C)=O)C=C2)=O)O1 FHZQVUQHQIUSPM-PKZQBKLLSA-N 0.000 description 1
- MUJNAWXXOJRNGK-UHFFFAOYSA-N n-[3-(6-methyl-1,2,3,4-tetrahydrocarbazol-9-yl)propyl]cyclohexanamine Chemical compound C1=2CCCCC=2C2=CC(C)=CC=C2N1CCCNC1CCCCC1 MUJNAWXXOJRNGK-UHFFFAOYSA-N 0.000 description 1
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 1
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- PFGVNLZDWRZPJW-OPAMFIHVSA-N otamixaban Chemical compound C([C@@H](C(=O)OC)[C@@H](C)NC(=O)C=1C=CC(=CC=1)C=1C=C[N+]([O-])=CC=1)C1=CC=CC(C(N)=N)=C1 PFGVNLZDWRZPJW-OPAMFIHVSA-N 0.000 description 1
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- 239000002243 precursor Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
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- 239000002904 solvent Substances 0.000 description 1
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- 238000001308 synthesis method Methods 0.000 description 1
- FRACPXUHUTXLCX-BELIEFIBSA-N tert-butyl N-{1-[(1S)-1-{[(1R,2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2-cyclopropylethyl]-2-oxopyridin-3-yl}carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CN(C1=O)[C@@H](CC2CC2)C(=O)N[C@@H](C[C@@H]3CCNC3=O)[C@H](C(=O)NCC4=CC=CC=C4)O FRACPXUHUTXLCX-BELIEFIBSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
- C07C69/40—Succinic acid esters
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/23—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
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Abstract
Description
技术领域
本发明属于核酸合成技术领域,具体涉及一种用于核酸液相合成载体的化合物及其制备方法和用途。
背景技术
化学合成寡核苷酸是指通过促使核苷酸单体间形成5’-3’磷酸二酯键,从而将多个核苷酸单元连接为寡核苷酸链的过程,其中涉及保护的核苷酸的合成。主要合成方法包括:磷酸三酯法、H-膦酸酯法、亚磷酰胺法等等。
目前通用的寡核苷酸合成方法是使用亚磷酰胺法的固相合成法,首先将核苷酸上的5’-OH用二对甲氧三苯甲基(DMT)保护,碱基上的氨基用苯甲酰基保护,3’-OH用氨基亚磷酸化合物进行活化。将第一个核苷酸的3’-OH与固相树脂结合在一起,并脱去5’-OH上的保护基,使裸露的5’-OH与第二个核苷酸的用氨基亚磷酸化合物进行活化的3’-OH之间形成一个亚磷酸三酯,亚磷酸三酯经碘氧化形成磷酸三酯,再加入三氯乙酸除去第二个核苷酸的5’-OH上的保护基。至此,寡核苷酸链已经延伸了一个核苷酸单元,并可投入下一轮延伸反应。经过若干轮的延伸反应,整个寡核苷酸片段合成完毕之后,用浓氢氧化铵将寡核苷酸片段从固相树脂上洗脱下来,经过脱保护和纯化得到寡核苷酸。
固相方法从速度方面看具有优势,这是由于该方法已经达到最佳化,并且已经发展了自动化。然而,它的缺陷在于:由于设备限制而限制了规模放大,使用过量的试剂和起始材料,并且在中间步骤中确定反应进展状态、分析中间体结构等等都有困难。
近些年为了改进传统固相合成方法的缺点,科学家们发明了一类采用液相合成和液相载体相结合的方法进行核苷酸化合物合成,通过设计具有特定结构的液相载体,在液相合成中进行核苷酸偶联,结合固相合成和液相合成中间体纯化和后处理方法进行核酸的合成,这类方法可以大大提高固相合成的生产规模和中间体的纯度,实现核酸合成规模的放大,大大提高生产效率。
发明内容
为了改进固相合成方法的缺点,本发明公开了一种可以作为核酸液相载体的稠环化合物,其具有如下式(I)所示:
R2、R3各自独立地选自氢或C1~C10的烷基,或R2、R3相连形成5~8元芳环;和/或,所述的5~8元芳环被0~5个R4取代;R1为0~4个;
R1、R4各自独立地选自氢或-OR5,所述的R5选自C1~C100烷基、C2~C100烯基、C2~C100炔基、C3~C100环烷基、C1~C100烷基取代的C3~C100环烷基、C1~C50烷氧基取代的C3~C100环烷基、取代C1~C100烷基;
取代C1~C100烷基的取代基的数量为一个或多个;取代烷基的取代基是相互独立的选自C1~C50烷氧基、C3~C100环烷基、C1~C50烷氧基取代的C3~C100环烷基、5~8元芳基、C1~C50烷氧基取代的5~8元芳基。
作为优选地;所述的式I化合物为:
其中,X选自O、NH或-(CH2)nO-或化学键;Y选自CH或N;n的取值为1或2,R1、R4分别为0~4个;
每个R1、R4各自独立地选自氢或-OR5,所述的R5选自C1~C100烷基、C2~C100烯基、C2~C100炔基、C3~C100环烷基、C1~C100烷基取代的C3~C100环烷基、C1~C50烷氧基取代的C3~C100环烷基、取代C1~C100烷基;
取代C1~C100烷基的取代基的数量为一个或多个;取代烷基的取代基是相互独立的选自C1~C50烷氧基、C3~C100环烷基、C1~C50烷氧基取代的C3~C100环烷基、5~8元芳基、C1~C50烷氧基取代的5~8元芳基。
进一步地,所述的式I化合物为:
作为优选地,所述的式I化合物为:
其中,X选自O、NH或-(CH2)nO-;m的取值为1或2;n的取值为1或2,Y选自CH或N;R1为0~4个;
每个R1各自独立地选自氢或-OR5,所述的R5选自C1~C100烷基、C2~C100烯基、C2~C100炔基、C3~C100环烷基、C1~C100烷基取代的C3~C100环烷基、C1~C50烷氧基取代的C3~C100环烷基、取代C1~C100烷基;
取代C1~C100烷基的取代基的数量为一个或多个;取代烷基的取代基是相互独立的选自C1~C50烷氧基、C3~C100环烷基、C1~C50烷氧基取代的C3~C100环烷基、5~8元芳基、C1~C50烷氧基取代的5~8元芳基。
进一步地,所述的式I化合物为:
作为优选地,所述的式I化合物为:
X选自O、NH或-(CH2)nO-;n的取值为1或2,Y选自CH或N;R1为0~4个;
每个R1各自独立地选自氢或-OR5,所述的R5选自C1~C100烷基、C2~C100烯基、C2~C100炔基、C3~C100环烷基、C1~C100烷基取代的C3~C100环烷基、C1~C50烷氧基取代的C3~C100环烷基、取代C1~C100烷基;
取代C1~C100烷基的取代基的数量为一个或多个;取代烷基的取代基是相互独立的选自C1~C50烷氧基、C3~C100环烷基、C1~C50烷氧基取代的C3~C100环烷基、5~8元芳基、C1~C50烷氧基取代的5~8元芳基。
进一步地,所述的式I化合物为:
本发明另一个方面提供了式1所述的稠环化合物作为液相合成载体的用途。
本发明另一个方面提供了式1所述的稠环化合物用于在液相合成核酸的用途。
本发明再一个方面提供了一种核酸的合成方法,其以权利要求1所示的化合物作为液相合成载体,在式I所示化合物的官能团上依次偶联不同的核苷单体片段。
本发明提供了一种核酸的合成方法,其以式I所示化合物作为液相合成载体,在式I所示化合物的官能团上与5’-DMTr(4,4’-二甲氧基三苯基甲基)保护的核苷或者核苷聚合物的偶合前体作为起始物料,经过脱保护、与核酸单体或者聚合物(例如二聚体、三聚体)化合物进行偶合生产核酸聚合物,或使核酸聚合物进行氧化或者硫代反应,然后进一步重复类似的循环直至完成最后一个核酸的合成,最后通过液相合成载体的切除,保护基的脱除得到相应的目标核酸聚合物化合物或者盐。
有益效果:
1、本发明制备的液相载体用于核酸合成,操作较传统液相合成简便,不需要特制的反应设备,如:DNA合成仪等;
2、本发明制备的液相载体用于核酸合成,合成规模大于传统的固相合成;
3、本发明制备的液相载体用于核酸合成,反应效果更好,而且易于回收,重复使用;
4、本发明制备的液相载体用于核酸合成,可以有效减少的杂质,提高核酸产品质量;
5、本发明制备的液相载体用于核酸合成,可以大大降低单体材料、试剂和溶剂的使用,与固相合成相比具有成本优势,产生更少的废物,工艺更加绿色环保。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀(Ca~Cb)烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,C1~C20烷基是指包含1~20个碳原子的直链或支链的烷基。
烷基是指烷烃分子中直链或支链的烃基,例如甲基-CH3、乙基-CH2CH3、亚甲基-CH2-;烷基基团也可以是其他基团的一部分,所述其他基团例如为C1~C6烷氧基,C1~C6烷基氨基。
烷氧基:是指烷基与氧原子连接形成取代基,例如甲氧基为-OCH3。
环烷基:是指具有多个碳原子且没有环杂原子且具有单个环或多个环(包括稠合、桥连和螺环体系)的饱和或部分饱和的环状基团。
5~8元芳环/基:是指不含杂原子,由C原子构成的芳香性单一环或多个环状基团。
烯基:包括直链或支化烯基。
炔基:包括直链或支化炔基。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明所用原料与设备均为已知产品,通过购买市售产品所得。
本发明中,“室温”指20~25℃。
本发明实施例中的简写或英文如下:DMF:N,N-二甲基甲酰胺;DMAP:4-二甲氨基吡啶;DCM:二氯甲烷;Cholesterol:胆固醇;DIAD:偶氮二甲酸二异丙酯;THF:四氢呋喃;2-Bromoethanol:溴乙醇;1-Bromooctadecane:1-溴十八烷;Succinic anhydride:丁二酸酐。
文中的%指质量百分比。
实施例1,化合物1的合成
步骤1:化合物1b的合成
室温下将1a(7.0g,35.7mmol)溶解在N,N-二甲基甲酰胺(140.0mL)中,加入碳酸钾(9.8g,71.4mmol),1-溴十八烷(23.7g,71.4mmol),反应混合液在80℃搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到1b(11.2g,24.5mmol)白色固体,70%收率。1H-NMR(400MHz,CDCl3)δ=8.44(d,J=4.0Hz,1H),8.34(d,J=4.0Hz,1H),7.78-7.24(m,5H),4.06(m,2H),1.76(m,2H),1.43-1.31(m,30H),0.88(m,3H);MS(ESI)m/z=448.4。
步骤2:化合物1c的合成
室温下将1b(11.2g,24.5mmol)溶解在甲醇(112.0mL)中,冰浴下加入硼氢化钠(1.4g,36.7mmol),反应混合液在0℃搅拌0.5小时,向反应液中加入饱和氯化铵水溶液,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到1c(9.9g,22.05mmol)白色固体,90%收率。1H-NMR(400MHz,CDCl3)δ=8.44(d,J=4.0Hz,1H),8.34(d,J=4.0Hz,1H),7.78-7.24(m,5H),6.43(s,1H),5.60(s,1H),4.06(m,2H),1.76(m,2H),1.43-1.31(m,30H),0.88(m,3H);MS(ESI)m/z=450.4。
步骤3:化合物1的合成
室温下将1c(9.9g,22.05mmol)溶解在无水二氯甲烷(100.0mL)中,加入三乙胺(5.5g,55.1mmol),4-二甲氨基吡啶(6.7g,55.1mmol),丁二酸酐(3.3g,33.1mmol),反应混合液在室温搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到1(10.3g,18.7mmol)白色固体,85%收率。1H-NMR(400MHz,CDCl3)δ=11.01(s,1H),8.44(d,J=4.0Hz,1H),8.34(d,J=4.0Hz,1H),7.78-7.24(m,5H),6.43(s,1H),5.60(s,1H),4.06(m,2H),2.83-2.52(m,4H),1.76(m,2H),1.43-1.31(m,30H),0.88(m,3H);MS(ESI)m/z=551.3。
按照上述相同步骤,保持其它条件不变,在步骤1中加入对应的不同烷基溴代物,可以得到不同R取代的化合物1。R=-OC18H33,-OC19H39,-OC27H45,-OC37H67,-OC59H119,-OC61H115,-OC61H121。
实施例2,化合物2的合成
步骤1:化合物2c的合成
室温下将2b(5.0g,11.1mmol)溶解在甲醇(100.0mL)中,加入甲酸铵(7.0g,111mmol),10%钯碳(700mg),反应混合液在氮气保护下室温搅拌15小时,将反应液过滤并用二氯甲烷洗3次,母液浓缩得到粗品,粗品加入甲醇过滤得到2c(2.99g,6.66mmol)白色固体,60%收率。1H-NMR(400MHz,CDCl3)δ=8.44(d,J=4.0Hz,1H),8.34(d,J=4.0Hz,1H),7.78-7.24(m,5H),5.11(s,1H),5.01(s,1H),4.06(m,2H),1.76(m,2H),1.43-1.31(m,30H),0.88(m,3H);MS(ESI)m/z=450.4。
步骤2:化合物2的合成
室温下将2c(2.99g,6.66mmol)溶解在无水二氯甲烷(50.0mL)中,加入三乙胺(1.3g,13.3mmol),4-二甲氨基吡啶1.6g,13.3mmol),丁二酸酐(9.9g,9.99mmol),反应混合液在室温搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到2(2.9g,5.3mmol)白色固体,80%收率。1H-NMR(400MHz,CDCl3)δ=11.12(s,1H),8.44(d,J=4.0Hz,1H),8.34(d,J=4.0Hz,1H),7.78-7.24(m,5H),5.11(s,1H),5.01(s,1H),4.06(m,2H),2.83-2.52(m,4H),1.76(m,2H),1.43-1.31(m,30H),0.88(m,3H);MS(ESI)m/z=550.3。
按照上述相同步骤,保持其它条件不变,通过不同R的化合物2b,可以得到不同R取代的化合物2。R=-OC18H33,-OC19H39,-OC27H45,-OC37H67,-OC59H119,-OC61H115,-OC61H121。
实施例3,化合物3的合成
步骤1:化合物3b的合成
室温下将3a(5.0g,27.3mmol)溶解在N,N-二甲基甲酰胺(100.0mL)中,加入碳酸钾(7.5g,54.6mmol),1-溴十八烷(13.6g,40.95mmol),反应混合液在50℃搅拌8小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到3b(5.9g,13.6mmol)白色固体,50%收率。1H-NMR(400MHz,CDCl3)δ=10.01(s,1H),8.44(d,J=4.0Hz,1H),8.34(d,J=4.0Hz,1H),7.78-7.24(m,5H),4.06(m,2H),1.76(m,2H),1.43-1.31(m,30H),0.88(m,3H);MS(ESI)m/z=436.3。
步骤2:化合物3c的合成
室温下将3b(5.9g,13.6mmol)溶解在N,N-二甲基甲酰胺(120.0mL)中,加入氢氧化钾(2.1g,38.2mmol),溴乙醇(4.7g,38.2mmol),反应混合液,50℃搅拌6小时;向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到3c(4.5g,9.5mmol)白色固体,70%收率。1H-NMR(400MHz,CDCl3)δ=10.01(s,1H),8.44(d,J=4.0Hz,1H),8.34(d,J=4.0Hz,1H),7.78-7.24(m,5H),4.47(m,2H),4.06(m,2H),3.63(m,2H),3.62(s,1H),1.76(m,2H),1.43-1.31(m,30H),0.88(m,3H);MS(ESI)m/z=480.4。
步骤3:化合物3的合成
室温下将3c(4.5g,9.5mmol)溶解在无水二氯甲烷(90.0mL)中,加入三乙胺(1.9g,19.0mmol),4-二甲氨基吡啶(2.3g,19.0mmol),丁二酸酐(1.4g,14.2mmol),反应混合液在室温搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到3(4.4g,7.6mmol)白色固体,80%收率。1H-NMR(400MHz,CDCl3)δ=10.01(s,1H),8.44(d,J=4.0Hz,1H),8.34(d,J=4.0Hz,1H),7.78-7.24(m,5H),4.47(m,2H),4.06(m,2H),3.63(m,2H),3.62(s,1H),2.83-2.52(m,4H),1.76(m,2H),1.43-1.31(m,30H),0.88(m,3H);MS(ESI)m/z=580.4。
按照上述相同步骤,保持其它条件不变,在步骤1中加入对应的不同烷基溴代物,可以得到不同R取代的化合物3。R=-OC37H67。
实施例4,化合物4的合成
步骤1:化合物4b的合成
室温下将4a(5.0g,23.5mmol)溶解在N,N-二甲基甲酰胺(150.0mL)中,加入碳酸钾(16.5g,117.5mmol),1-溴十八烷(11.7g,35.2mmol),反应混合液在80℃搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到4b(10.1g,14.1mmol)白色固体,60%收率。1H-NMR(400MHz,CDCl3)δ=7.76(d,J=4.0Hz,2H),7.06(d,J=4.0Hz,2H),6.89(d,J=4.0Hz,2H),4.06(m,4H),1.76(m,4H),1.43-1.31(m,60H),0.88(m,6H);MS(ESI)m/z=717.6。
步骤2:化合物4c的合成
室温下将4b(10.1g,14.1mmol)溶解在甲醇(200.0mL)中,冰浴下加入硼氢化钠(803mg,21.1mmol),反应混合液在0℃搅拌0.5小时,向反应液中加入饱和氯化铵水溶液,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到4c(9.1g,12.6mmol)白色固体,90%收率。1H-NMR(400MHz,CDCl3)δ=7.76(d,J=4.0Hz,2H),7.06(d,J=4.0Hz,2H),6.89(d,J=4.0Hz,2H),6.43(s,1H),5.60(s,1H),4.06(m,4H),1.76(m,4H),1.43-1.31(m,60H),0.88(m,6H);MS(ESI)m/z=719.6。
步骤3:化合物4的合成
室温下将4c(9.1g,12.6mmol)溶解在无水二氯甲烷(180.0mL)中,加入三乙胺(2.5g,25.2mmol),4-二甲氨基吡啶(3.1g,25.2mmol),丁二酸酐(1.9g,18.9mmol),反应混合液在室温搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到4(8.7g,10.7mmol)白色固体,85%收率。1H-NMR(400MHz,CDCl3)δ=11.12(s,1H),7.76(d,J=4.0Hz,2H),7.06(d,J=4.0Hz,2H),6.89(d,J=4.0Hz,2H),6.43(s,1H),5.60(s,1H),4.06(m,4H),2.83-2.52(m,4H),1.76(m,4H),1.43-1.31(m,60H),0.88(m,6H);MS(ESI)m/z=819.6。
按照上述相同步骤,保持其它条件不变,在步骤1中加入对应的不同烷基溴代物,可以得到不同R取代的化合物4。R=-OC27H45,-OC37H67,-OC61H115。
实施例5,化合物5的合成
步骤1:化合物5c的合成
室温下将4b1(10.5g,11.1mmol)溶解在甲醇(200.0mL)中,加入甲酸铵(7.0g,111mmol),10%钯碳(1.05g),反应混合液在氮气保护下室温搅拌15小时,反应液过滤并用二氯甲烷洗3次,母液浓缩得到粗品,粗品加入甲醇过滤得到5c(6.3g,6.66mmol)白色固体,60%收率。1H-NMR(400MHz,CDCl3)δ=7.76(d,J=4.0Hz,2H),7.06(d,J=4.0Hz,2H),6.89(d,J=4.0Hz,2H),5.11(s,1H),5.01(s,1H),4.06(m,4H),1.76(m,4H),1.43-1.31(m,100H),0.88(m,6H);MS(ESI)m/z=950.7。
步骤2:化合物5的合成
室温下将5c(6.3g,6.66mmol)溶解在无水二氯甲烷(120.0mL)中,加入三乙胺(1.3g,13.3mmol),4-二甲氨基吡啶(1.6g,13.3mmol),丁二酸酐(9.9g,9.99mmol),反应混合液在室温搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到5(5.5g,5.3mmol)白色固体,80%收率。1H-NMR(400MHz,CDCl3)δ=7.76(d,J=4.0Hz,2H),7.06(d,J=4.0Hz,2H),6.89(d,J=4.0Hz,2H),5.11(s,1H),5.01(s,1H),4.06(m,4H),2.83-2.52(m,4H),1.76(m,4H),1.43-1.31(m,100H),0.88(m,6H);MS(ESI)m/z=1050.7。
实施例6,化合物6的合成
步骤1:化合物6b的合成
室温下将6a(2.2g,11.1mmol)溶解在四氢呋喃(50.0mL)中,加入三苯基膦(5.8g,22.2mmol),胆固醇(4.2g,11.1mmol),冰浴下加入偶氮二甲酸二异丙酯(4.5g,22.2mmol),反应混合液在氮气保护下室温搅拌15小时,向反应液中加入水,二氯甲烷萃取浓缩得到粗品,粗品加入甲醇过滤得到6b(6.2g,6.66mmol)白色固体,60%收率。1H-NMR(400MHz,CDCl3)δ=10.01(s,1H),7.76(d,J=4.0Hz,2H),7.06(d,J=4.0Hz,2H),6.89(d,J=4.0Hz,2H),4.06(m,4H),1.76(m,4H),1.43-1.31(m,100H),0.88(m,6H);MS(ESI)m/z=936.7。
步骤2:化合物6的合成
室温下将6b(6.2g,6.66mmol)溶解在无水二氯甲烷(120.0mL)中,加入三乙胺(1.3g,13.3mmol),4-二甲氨基吡啶(1.6g,13.3mmol),丁二酸酐(9.9g,9.99mmol),反应混合液在室温搅拌15小时,向反应液加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到6(5.5g,5.3mmol)白色固体,80%收率。1H-NMR(400MHz,CDCl3)δ=10.01(s,1H),7.76(d,J=4.0Hz,2H),7.06(d,J=4.0Hz,2H),6.89(d,J=4.0Hz,2H),4.06(m,4H),2.83-2.52(m,4H),1.76(m,4H),1.43-1.31(m,100H),0.88(m,6H);MS(ESI)m/z=1036.7。
实施例7,化合物7的合成
步骤1:化合物7c的合成
室温下将6b(17.8g,19.11mmol)溶解在N,N-二甲基甲酰胺(356.0mL)中,加入氢氧化钾(2.1g,38.2mmol),溴乙醇(4.7g,38.2mmol),反应混合液在50℃搅拌6小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到7c(13.1g,13.3mmol)白色固体,70%收率。1H-NMR(400MHz,CDCl3)δ=7.76(d,J=4.0Hz,2H),7.06(d,J=4.0Hz,2H),6.89(d,J=4.0Hz,2H),4.47(m,2H),4.06(m,2H),3.63(m,2H),3.62(s,1H),1.76(m,4H),1.43-1.31(m,100H),0.88(m,6H);MS(ESI)m/z=980.7。
步骤2:化合物7的合成
室温下将7c(13.1g,13.3mmol)溶解在无水二氯甲烷(260.0mL)中,加入三乙胺(2.6g,26.6mmol),4-二甲氨基吡啶(3.2g,26.6mmol),丁二酸酐(1.9g,19.9mmol),反应混合液在室温搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到7(11.4g,10.6mmol)白色固体,80%收率。1H-NMR(400MHz,CDCl3)δ=11.12(s,1H),7.76(d,J=4.0Hz,2H),7.06(d,J=4.0Hz,2H),6.89(d,J=4.0Hz,2H),4.47(m,2H),4.06(m,2H),3.63(m,2H),3.62(s,1H),2.83-2.52(m,4H),1.76(m,4H),1.43-1.31(m,100H),0.88(m,6H);MS(ESI)m/z=1080.7。
实施例8,化合物8的合成
步骤1:化合物8b的合成
室温下将8a(5.2g,35.7mmol)溶解在N,N-二甲基甲酰胺(50.0mL)中,加入碳酸钾(24.6g,178.5mmol),1-溴十八烷(17.8g,53.5mmol),反应混合液在50℃搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到8b(9.8g,24.5mmol)白色固体,70%收率。1H-NMR(400MHz,CDCl3)δ=7.09(d,J=4.0Hz,1H),6.71(m,2H),2.86(m,2H),2.31(m,2H),1.76(m,2H),1.43-1.31(m,30H),0.88(m,3H);MS(ESI)m/z=401.3。
步骤2:化合物8c的合成
室温下将8b(9.8g,24.5mmol)溶解在甲醇(200.0mL)中,冰浴下加入硼氢化钠(1.4g,36.7mmol),反应混合液在0℃搅拌0.5小时,反应液加入饱和氯化铵水溶液,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到8c(8.9g,22.05mmol)白色固体,90%收率。1H-NMR(400MHz,CDCl3)δ=7.09(d,J=4.0Hz,1H),6.71(m,2H),4.64(m,1H),4.06(m,2H),2.86(m,2H),2.31(m,2H),1.76(m,2H),1.43-1.31(m,30H),0.88(m,3H);MS(ESI)m/z=403.3。
步骤3:化合物8的合成
室温下将8c(8.9g,22.05mmol)溶解在无水二氯甲烷(180.0mL)中,加入三乙胺(5.5g,55.1mmol),4-二甲氨基吡啶(6.7g,55.1mmol),丁二酸酐(3.3g,33.1mmol),反应混合液在室温搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到8(9.4g,18.7mmol)白色固体,85%收率。1H-NMR(400MHz,CDCl3)δ=11.12(s,1H),7.09(d,J=4.0Hz,1H),6.71(m,2H),4.64(m,1H),4.06(m,2H),3.65(m,1H),2.86(m,2H),2.83-2.52(m,4H),2.31(m,2H),1.76(m,2H),1.43-1.31(m,30H),0.88(m,3H);MS(ESI)m/z=503.3。
按照上述相同步骤,保持其它条件不变,在步骤1中加入对应的不同烷基溴代物,可以得到不同R取代的化合物8。R=-OC27H45,-OC37H67,-OC61H115。
实施例9,化合物9的合成
步骤1:化合物9b的合成
室温下将9a(1.8g,11.1mmol)溶解在四氢呋喃(40.0mL)中,加入三苯基膦(5.8g,22.2mmol),(6Z,9Z,28Z,31Z)-庚三十碳-6,9,28,31-四烯-19-甲醇(6.3g,11.1mmol),冰浴下加入偶氮二甲酸二异丙酯(4.5g,22.2mmol),反应混合液在氮气保护下室温搅拌15小时,向反应液中加入水,二氯甲烷萃取浓缩得到粗品,粗品加入甲醇过滤得到9b(4.5g,6.66mmol)白色固体,60%收率。1H-NMR(400MHz,CDCl3)δ=7.09(d,J=4.0Hz,1H),6.71(m,2H),5.43(m,8H),2.86(m,2H),2.83-2.52(m,4H),2.50(m,2H),2.31(m,2H),1.76-1.31(m,54H),0.88(m,6H);MS(ESI)m/z=673.5。
步骤2:化合物9c的合成
室温下将9b(4.5g,6.66mmol)溶解在甲醇(90.0mL)中,冰浴下加入硼氢化钠(303mg,7.9mmol),反应混合液在0℃搅拌0.5小时,向反应液中加入饱和氯化铵水溶液,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到9c(4.0g,6.0mmol)白色固体,90%收率。MS(ESI)m/z=675.6。
步骤3:化合物9的合成
室温下将9c(4.0g,6.0mmol)溶解在无水二氯甲烷(80.0mL)中,加入三乙胺(1.2g,12.0mmol),4-二甲氨基吡啶(1.5g,12.0mmol),丁二酸酐(900mg,9.0mmol),反应混合液在室温搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到9(3.9g,5.1mmol)白色固体,85%收率。1H-NMR(400MHz,CDCl3)δ=11.12(s,1H),7.09(d,J=4.0Hz,1H),6.71(m,2H),5.43(m,8H),3.65(m,1H),2.86(m,2H),2.83-2.52(m,4H),2.50(m,2H),2.31(m,2H),1.76-1.31(m,54H),0.88(m,6H);MS(ESI)m/z=775.6。
实施例10,化合物10的合成
步骤1:化合物10b的合成
室温下将10a(5.8g,35.7mmol)溶解在N,N-二甲基甲酰胺(110.0mL)中,加入碳酸钾(24.6g,178.5mmol),1-溴十八烷(23.7g,71.4mmol),反应混合液在50℃搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到10b(14.3g,21.4mmol)白色固体,60%收率。1H-NMR(400MHz,CDCl3)δ=7.09(d,J=4.0Hz,2H),2.86(m,2H),2.31(m,2H),1.76(m,4H),1.43-1.31(m,60H),0.88(m,6H);MS(ESI)m/z=669.6。
步骤2:化合物10c的合成
室温下将10b(14.3g,21.4mmol)溶解在甲醇(280.0mL)中,冰浴下加入硼氢化钠(1.2g,32.1mmol),反应混合液在0℃搅拌0.5小时,向反应液中加入饱和氯化铵水溶液,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到10c(12.9g,19.2mmol)白色固体,90%收率。1H-NMR(400MHz,CDCl3)δ=7.09(d,J=4.0Hz,2H),4.64(m,1H),4.04(m,1H),2.86(m,2H),2.31(m,2H),1.76(m,4H),1.43-1.31(m,60H),0.88(m,6H);MS(ESI)m/z=671.6。
步骤3:化合物10的合成
室温下将10c(12.9g,19.2mmol)溶解在无水二氯甲烷(200.0mL)中,加入三乙胺(3.8g,38.4mmol),4-二甲氨基吡啶(4.6g,38.4mmol),丁二酸酐(2.8g,28.8mmol),反应混合液在室温搅拌15小时,反应液加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到10(14.8g,16.3mmol)白色固体,85%收率。1H-NMR(400MHz,CDCl3)δ=11.12(s,1H),7.09(d,J=4.0Hz,2H),4.64(m,1H),2.86(m,2H),2.83-2.52(m,4H),2.31(m,2H),1.76(m,4H),1.43-1.31(m,60H),0.88(m,6H);MS(ESI)m/z=771.6。
实施例11,化合物11的合成
步骤1:化合物11b的合成
室温下将11a(6.3g,35.7mmol)溶解在N,N-二甲基甲酰胺(120.0mL)中,加入碳酸钾(24.6g,178.5mmol),1-溴十八烷(23.7g,71.4mmol),反应混合液在50℃搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到11b(16.5g,24.5mmol)白色固体,70%收率。1H-NMR(400MHz,CDCl3)δ=7.09(d,J=4.0Hz,2H),2.86(m,2H),2.83-2.52(m,4H),2.50(m,2H),2.31(m,2H),1.76(m,4H),1.43-1.31(m,60H),0.88(m,6H);MS(ESI)m/z=683.6。
步骤2:化合物11c的合成
室温下将11b(16.5g,24.5mmol)溶解在甲醇(240.0mL)中,冰浴下加入硼氢化钠(1.4g,36.7mmol),反应混合液在0℃搅拌0.5小时。向反应液中加入饱和氯化铵水溶液,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到11c(15.1g,22.05mmol)白色固体,90%收率。1H-NMR(400MHz,CDCl3)δ=7.09(d,J=4.0Hz,2H),4.64(m,1H),4.01(m,1H),2.86(m,2H),2.83-2.52(m,4H),2.50(m,2H),2.31(m,2H),1.76(m,4H),1.43-1.31(m,60H),0.88(m,6H);MS(ESI)m/z=685.6。
步骤3:化合物11的合成
室温下将11c(15.1g,22.05mmol)溶解在无水二氯甲烷(300.0mL)中,加入三乙胺(5.5g,55.1mmol),4-二甲氨基吡啶(6.7g,55.1mmol),丁二酸酐(3.3g,33.1mmol),反应混合液在室温搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到11(14.6g,18.7mmol)白色固体,85%收率。1H-NMR(400MHz,CDCl3)δ=11.12(s,1H),7.09(d,J=4.0Hz,2H),4.64(m,1H),2.86(m,2H),2.83-2.52(m,4H),2.50(m,2H),2.31(m,2H),1.76(m,4H),1.43-1.31(m,60H),0.88(m,6H);MS(ESI)m/z=785.6。
实施例12,化合物12的合成
步骤1:化合物12b的合成
室温下将12a(5.0g,22.5mmol)溶解在无水二氯甲烷(50.0mL)中,三溴化硼的二氯甲烷溶液(78.8mL,78.8mmol,1M/DCM)在-30℃下缓慢加入,反应混合液在-30℃搅拌2小时,缓慢加入饱和的碳酸氢钠水溶液中和至中性,二氯甲烷萃取,干燥浓缩得到粗品12b(2.8g,15.7mmol)白色固体,70%收率。1H-NMR(400MHz,CDCl3)δ=7.09(s,1H),5.35(m,3H),2.86(m,2H),2.31(m,2H);MS(ESI)m/z=181.0。
步骤2:化合物12c的合成
室温下将12b(2.8g,15.7mmol)溶解在N,N-二甲基甲酰胺(100.0mL)中,加入碳酸钾(31g,225.0mmol),1-溴十八烷(18.2g,54.9mmol),反应混合液在50℃搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到12c(8.8g,9.4mmol)白色固体,60%收率。1H-NMR(400MHz,CDCl3)δ=7.09(s,1H),2.86(m,2H),2.31(m,2H),1.76(m,6H),1.43-1.31(m,90H),0.88(m,9H);MS(ESI)m/z=937.8。
步骤3:化合物12d的合成
室温下将12c(8.8g,9.4mmol)溶解在甲醇(163.0mL)中,冰浴下加入硼氢化钠(535mg,14.1mmol),反应混合液在0℃搅拌0.5小时,加入饱和氯化铵水溶液,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到12d(7.9g,8.46mmol)白色固体,90%收率。1H-NMR(400MHz,CDCl3)δ=7.09(s,1H),4.64(m,1H),4.01(m,1H),2.86(m,2H),2.31(m,2H),1.76(m,6H),1.43-1.31(m,90H),0.88(m,9H);MS(ESI)m/z=939.9。
步骤4:化合物12的合成
室温下将12d(7.9g,8.46mmol)溶解在无水二氯甲烷(160.0mL)中,加入三乙胺(1.7g,16.9mmol),4-二甲氨基吡啶(2.1g,55.1mmol),丁二酸酐(1.2g,12.6mmol),反应混合液在室温搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到12(7.1g,6.7mmol)白色固体,80%收率。1H-NMR(400MHz,CDCl3)δ=11.12(s,1H),7.09(s,1H),4.64(m,1H),2.86(m,2H),2.83-2.52(m,4H),2.31(m,2H),1.76(m,6H),1.43-1.31(m,90H),0.88(m,9H);MS(ESI)m/z=1039.9。
实施例13,化合物13的合成
步骤1:化合物13b的合成
室温下将13a(2.0g,15.0mmol)溶解在N,N-二甲基甲酰胺(50.0mL)中,加入碳酸钾(10.3g,75.1mmol),1-溴十八烷(7.5g,22.5mmol),反应混合液在50℃搅拌15小时,反应液加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到13b(2.9g,7.5mmol)白色固体,50%收率。1H-NMR(400MHz,CDCl3)δ=10.1(m,1H),7.78-7.24(m,5H),4.06(m,2H),1.76(m,2H),1.43-1.31(m,30H),0.88(m,3H);MS(ESI)m/z=386.3。
步骤2:化合物13c的合成
室温下将13b(2.9g,7.5mmol)溶解在N,N-二甲基甲酰胺(50.0mL)中,加入氢氧化钾(3.1g,22.5mmol),溴乙醇(2.8g,22.5mmol),反应混合液在50℃搅拌6小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到13c(2.2g,5.2mmol)白色固体,70%收率。1H-NMR(400MHz,CDCl3)δ=7.78-7.24(m,5H),4.47(m,2H),4.06(m,2H),3.63(m,2H),3.61(m,1H),1.76(m,2H),1.43-1.31(m,30H),0.88(m,3H);MS(ESI)m/z=430.3。
步骤3:化合物13的合成
室温下将13c(2.2g,5.2mmol)溶解在无水二氯甲烷(50.0mL)中,加入三乙胺(1.0g,10.4mmol),4-二甲氨基吡啶(1.2g,10.4mmol),丁二酸酐(0.78g,7.8mmol),反应混合液在室温搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到13(2.2g,4.16mmol)白色固体,80%收率。1H-NMR(400MHz,CDCl3)δ=11.01(s,1H),7.78-7.24(m,5H),4.47(m,2H),4.06(m,2H),3.63(m,2H),2.83-2.53(m,4H),1.76(m,2H),1.43-1.31(m,30H),0.88(m,3H);MS(ESI)m/z=530.3。
实施例14,化合物14的合成
步骤1:化合物14b的合成
室温下将14a(3.0g,20.1mmol)溶解在N,N-二甲基甲酰胺(60.0mL)中,加入碳酸钾(13.9g,100.5mmol),1-溴十八烷(13.6g,40.95mmol),反应混合液在50℃搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到14b(6.5g,10.0mmol)白色固体,50%收率。1H-NMR(400MHz,CDCl3)δ=10.1(m,1H),7.78-7.24(m,4H),4.06(m,4H),1.76(m,4H),1.43-1.31(m,60H),0.88(m,6H);MS(ESI)m/z=654.6。
步骤2:化合物14c的合成
室温下将14b(6.5g,10.0mmol)溶解在N,N-二甲基甲酰胺(130.0mL)中,加入氢氧化钾(2.1g,38.2mmol),溴乙醇(4.7g,38.2mmol),反应混合液在50℃搅拌6小时。向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到14c(4.9g,7.0mmol)白色固体,70%收率。1H-NMR(400MHz,CDCl3)δ=7.78-7.24(m,4H),4.06(m,4H),4.06(m,2H),3.63(m,2H),3.61(m,1H),1.76(m,4H),1.43-1.31(m,60H),0.88(m,6H);MS(ESI)m/z=698.6。
步骤3:化合物14的合成
室温下将14c(4.9g,7.0mmol)溶解在无水二氯甲烷(100.0mL)中,加入三乙胺(1.4g,14.0mmol),4-二甲氨基吡啶(1.7g,14.0mmol),丁二酸酐(1.1g,10.5mmol),反应混合液在室温搅拌15小时,向反应液中加入水,二氯甲烷萃取,干燥浓缩得到粗品,粗品加入甲醇过滤得到14(8.5g,10.6mmol)白色固体,80%收率。1H-NMR(400MHz,CDCl3)δ=11.01(s,1H),7.78-7.24(m,4H),4.06(m,4H),4.06(m,2H),3.63(m,2H),3.61(m,1H),2.83-2.53(m,4H),1.76(m,4H),1.43-1.31(m,60H),0.88(m,6H);MS(ESI)m/z=798.6。
实施例15,化合物15的合成
室温下将化合物4(5.0g,6.1mmol)溶解在二氯甲烷(50.0mL)中,加入4-二甲氨基吡啶(1.1g,9.1mmol),二异丙基乙胺(1.1g,9.1mmol),苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(3.4g,9.1mmol),N-乙酰基-5'-O-(4,4'-二甲氧基三苯甲基)-2'-脱氧胞苷(4.2g,7.3mmol),反应混合液在室温搅拌15小时,向反应液中加入200.0mL的甲醇析出固体,过滤得到化合物15(7.5g,5.5mmol)白色固体,90%收率。1H-NMR(400MHz,CDCl3)δ=10.12(s,1H),7.76(d,J=4.0Hz,2H),7.80-7.12(m,15H),7.06(d,J=4.0Hz,2H),6.89(d,J=4.0Hz,2H),6.52(m,1H),6.43(s,1H),5.60(s,1H),4.56(m,1H),4.06(m,4H),3.89(m,1H),3.63(s,6H),3.01-2.89(m,2H),2.45-2.41(m,2H),2.83-2.52(m,4H),1.76(m,4H),1.43-1.31(m,60H),0.88(m,6H);MS(ESI)m/z=1372.8。
实施例16,化合物16的合成
室温下将化合物15(7.5g,5.5mmol)溶解在3%(v/v)的二氯乙酸/二氯甲烷溶液(75.0mL)中,加入吡咯(3.6g,55.0mmol),反应混合液在室温搅拌30分钟,吡啶(2.1mL,27.0mmol)加入反应液中和,然后加入7.5g分子筛,N-乙酰基-5'-O-(4,4'-二甲氧基三苯甲基)-2'-脱氧胞苷-3'-[O-(2-氰乙基)-(N,N-二异丙基)]-亚磷酰胺(8.5g,11.0mmol)的二氯甲烷溶液加入反应液,反应混合液在室温搅拌15分钟,加入0.25M 5-乙硫基四氮唑/乙腈(88.0mL,22.0mmol),反应混合液在室温搅拌1小时,加入0.2M碘/吡啶(50.0mL)/水(5.0mL)溶液室温搅拌10分钟,再加入饱和的亚硫酸钠甲醇溶液室温搅拌10分钟;向反应液中加入500.0mL的二氯甲烷,过滤得到滤液,浓缩后加入甲醇析出固体,过滤得到16(8.7g,4.95mmol)白色固体,90%收率。1H-NMR(400MHz,CDCl3)δ=10.12(s,2H),7.76(d,J=4.0Hz,2H),7.80-7.12(m,17H),7.06(d,J=4.0Hz,2H),6.89(d,J=4.0Hz,2H),6.52(m,2H),6.43(s,1H),5.60(s,1H),4.56(m,2H),4.06(m,4H),3.89(m,2H),3.63(s,12H),3.01-2.89(m,4H),2.45-2.41(m,8H),2.83-2.52(m,4H),1.76(m,4H),1.43-1.31(m,60H),0.88(m,6H);MS(ESI)m/z=1756.9。
实施例17,化合物17的合成
将N-乙酰基-5'-O-(4,4'-二甲氧基三苯甲基)-2'-脱氧胞苷-3'-[O-(2-氰乙基)-(N,N-二异丙基)]-亚磷酰胺替换为对应的不同原料,重复实施例16的操作15次得到化合物17(7.4g)。
实施例18,化合物18的合成
室温下将化合物17(7.4g)加入50.0mL乙醇中,加入100.0mL 37%(wt%)甲胺水溶液,反应混合物在45℃下反应1小时,加入二氯甲烷萃取3次,水相冻干得到化合物粗品化合物18,用GE Source 15Q离子交换柱色谱法(1.5M NaBr/40mM Tris-HBr缓冲液pH 8.0)对化合物18粗品原料进行HPLC精制,将精制后合格的产品段混合后进行脱盐处理并冷冻干燥,获得目标化合物。MS(ESI)m/z=4841.9。
Claims (10)
1.一种用于核酸液相合成载体的化合物,其特征在于:
R2、R3各自独立地选自氢或C1~C10的烷基,或R2、R3相连形成5~8元芳环;和/或,所述的5~8元芳环被0~5个R4取代;R1为0~4个;
每个R1、R4各自独立地选自氢或-OR5,所述的R5选自C1~C100烷基、C2~C100烯基、C2~C100炔基、C3~C100环烷基、C1~C100烷基取代的C3~C100环烷基、C1~C50烷氧基取代的C3~C100环烷基、取代C1~C100烷基;
取代C1~C100烷基的取代基的数量为一个或多个;取代烷基的取代基是相互独立的选自C1~C50烷氧基、C3~C100环烷基、C1~C50烷氧基取代的C3~C100环烷基、5~8元芳基、C1~C50烷氧基取代的5~8元芳基。
2.根据权利要求1所述的化合物,其特征在于:所述的式I化合物为:
其中,X选自O、NH、-(CH2)nO-或化学键;Y选自CH或N;n的取值为1或2;R1、R4分别为0~4个;
每个R1、R4各自独立地选自氢或-OR5,所述的R5选自C1~C100烷基、C2~C100烯基、C2~C100炔基、C3~C100环烷基、C1~C100烷基取代的C3~C100环烷基、C1~C50烷氧基取代的C3~C100环烷基、取代C1~C100烷基;
取代C1~C100烷基的取代基的数量为一个或多个;取代烷基的取代基是相互独立的选自C1~C50烷氧基、C3~C100环烷基、C1~C50烷氧基取代的C3~C100环烷基、5~8元芳基、C1~C50烷氧基取代的5~8元芳基。
4.根据权利要求1所述的化合物,其特征在于:所述的式I化合物为:
其中,X选自O、NH或-(CH2)nO-;m的取值为1或2;n的取值为1或2,Y选自CH或N;R1为0~4个;
每个R1各自独立地选自氢或-OR5,所述的R5选自C1~C100烷基、C2~C100烯基、C2~C100炔基、C3~C100环烷基、C1~C100烷基取代的C3~C100环烷基、C1~C50烷氧基取代的C3~C100环烷基、取代C1~C100烷基;
取代C1~C100烷基的取代基的数量为一个或多个;取代烷基的取代基是相互独立的选自C1~C50烷氧基、C3~C100环烷基、C1~C50烷氧基取代的C3~C100环烷基、5~8元芳基、C1~C50烷氧基取代的5~8元芳基。
6.根据权利要求1所述的化合物,其特征在于:所述的式I化合物为:
X选自O、NH或-(CH2)nO-;n的取值为1或2,Y选自CH或N;R1为0~4个;
R1各自独立地选自氢或-OR5,所述的R5选自C1~C100烷基、C2~C100烯基、C2~C100炔基、C3~C100环烷基、C1~C100烷基取代的C3~C100环烷基、C1~C50烷氧基取代的C3~C100环烷基、取代C1~C100烷基;
取代C1~C100烷基的取代基的数量为一个或多个;取代烷基的取代基是相互独立的选自C1~C50烷氧基、C3~C100环烷基、C1~C50烷氧基取代的C3~C100环烷基、5~8元芳基、C1~C50烷氧基取代的5~8元芳基。
8.权利要求1所述的化合物作为液相合成载体的用途。
9.权利要求1所述的化合物用于在液相合成核酸的用途。
10.一种核酸的合成方法,其以权利要求1所示的化合物作为液相合成载体,在式I所示化合物的官能团上依次偶联不同的核苷单体片段。
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