CN107312168A - The monomer initiator and its synthetic method of hydroxyl synthesis are protected with 3,4 dihydro 2H pyrans - Google Patents
The monomer initiator and its synthetic method of hydroxyl synthesis are protected with 3,4 dihydro 2H pyrans Download PDFInfo
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 title claims abstract description 26
- 239000003999 initiator Substances 0.000 title claims abstract description 18
- 239000000178 monomer Substances 0.000 title claims abstract description 16
- 238000010189 synthetic method Methods 0.000 title claims abstract description 5
- 150000004880 oxines Chemical class 0.000 title claims abstract 4
- 238000003786 synthesis reaction Methods 0.000 title abstract description 5
- 230000015572 biosynthetic process Effects 0.000 title abstract description 4
- 239000005457 ice water Substances 0.000 claims abstract description 9
- -1 pyrans forms acetal Chemical class 0.000 claims abstract description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000524 functional group Chemical group 0.000 abstract description 6
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 239000002253 acid Substances 0.000 abstract 1
- 230000000903 blocking effect Effects 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 229920001223 polyethylene glycol Polymers 0.000 description 25
- 239000002202 Polyethylene glycol Substances 0.000 description 22
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 20
- 238000003756 stirring Methods 0.000 description 18
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 13
- 239000003814 drug Substances 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- ZJCCRDAZUWHFQH-UHFFFAOYSA-N Trimethylolpropane Chemical compound CCC(CO)(CO)CO ZJCCRDAZUWHFQH-UHFFFAOYSA-N 0.000 description 4
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 3
- LZDXRPVSAKWYDH-UHFFFAOYSA-N 2-ethyl-2-(prop-2-enoxymethyl)propane-1,3-diol Chemical compound CCC(CO)(CO)COCC=C LZDXRPVSAKWYDH-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000006320 pegylation Effects 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- GXEDVNCPTFKBGI-PCMKAUBLSA-N CCC(CO[C@@H]1COC=CC1)(COC1OCCCC1)/C=[O]\C1OCCCC1 Chemical compound CCC(CO[C@@H]1COC=CC1)(COC1OCCCC1)/C=[O]\C1OCCCC1 GXEDVNCPTFKBGI-PCMKAUBLSA-N 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 108091006006 PEGylated Proteins Proteins 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000002715 modification method Methods 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 108020001775 protein parts Proteins 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 238000010526 radical polymerization reaction Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229920006305 unsaturated polyester Polymers 0.000 description 1
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/26—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds
- C08G65/2603—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen
- C08G65/2606—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen containing hydroxyl groups
- C08G65/2609—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen containing hydroxyl groups containing aliphatic hydroxyl groups
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
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Abstract
Description
技术领域technical field
本发明涉及有机化学合成领域，具体是指以3,4-二氢-2H-吡喃保护羟基合成的单体引发剂及其合成方法。The invention relates to the field of organic chemical synthesis, in particular to a monomer initiator synthesized by protecting a hydroxyl group with 3,4-dihydro-2H-pyran and a synthesis method thereof.
背景技术Background technique
近年来，随着蛋白质药物的聚乙二醇修饰技术的发展，聚乙二醇化药物得到了广泛的应用。目前已有十余种聚乙二醇修饰的蛋白药物上市，临床医疗效果优异，市场上也表现出了良好的业绩。同时还有数十种聚乙二醇化蛋白质药物处在临床或临床前研究阶段。In recent years, with the development of PEG modification technology for protein drugs, PEGylated drugs have been widely used. At present, there are more than ten kinds of polyethylene glycol-modified protein drugs on the market, with excellent clinical and medical effects, and good performance in the market. At the same time, dozens of PEGylated protein drugs are in the clinical or preclinical research stage.
聚乙二醇(poly(ethylene glycol))是一类聚醚类聚合物。随着平均分子量的不同，性质也产生差异。当分子量小于1000Da时，聚乙二醇是无色无臭粘稠的液体，高分子量的聚乙二醇则是白色固体。固体聚乙二醇的熔点正比于分子量，逐渐接近67℃的极限。Polyethylene glycol (poly(ethylene glycol)) is a class of polyether polymers. As the average molecular weight is different, the properties are also different. When the molecular weight is less than 1000Da, polyethylene glycol is a colorless, odorless, viscous liquid, while high molecular weight polyethylene glycol is a white solid. The melting point of solid polyethylene glycol is proportional to the molecular weight, gradually approaching the limit of 67 °C.
聚乙二醇分子中含有大量乙氧基，能够与水形成氢键，具有高度的亲水性，在水溶液中有较大的水动力学体积，能改变药物在水溶液中的生物分配行为和溶解性，在其修饰的药物周围产生空间屏障，减少药物的酶解，避免在肾脏的代谢中很快被消除，并使药物能被免疫系统的细胞识别。聚乙二醇修饰的蛋白质一般构象不会改变，其结合物的生物学活性主要由结合物的蛋白质部分产生。聚乙二醇具有免疫学惰性，即使分子量高达5.9×106Da，本身的免疫原性也很低。临床上使用聚乙二醇修饰蛋白治疗时，未发现抗聚乙二醇抗体产生。聚乙二醇是经美国食品药品管理局(FDA)批准的极少数能作为体内注射药用的合成聚合物之一。聚乙二醇修饰又称分子的PEG化(pegylation)，是20世纪70年代后期发展起来的修饰方法。将活化的聚乙二醇与蛋白质分子相偶联，影响蛋白质的空间结构，最终导致蛋白质各种生物化学性质的改变：化学稳定性增加，抵抗蛋白酶水解的能力提高，免疫原性和毒性降低或消失，体内半衰期延长，血浆清除率降低等。Polyethylene glycol molecules contain a large number of ethoxy groups, which can form hydrogen bonds with water, have a high degree of hydrophilicity, and have a large hydrodynamic volume in aqueous solution, which can change the biodistribution behavior and dissolution of drugs in aqueous solution Sex, create a space barrier around the modified drug, reduce the enzymatic hydrolysis of the drug, avoid being quickly eliminated in the metabolism of the kidney, and enable the drug to be recognized by the cells of the immune system. The general conformation of the protein modified by polyethylene glycol will not change, and the biological activity of the conjugate is mainly produced by the protein part of the conjugate. Polyethylene glycol is immunologically inert, and its immunogenicity is very low even though its molecular weight is as high as 5.9×106Da. No anti-polyethylene glycol antibody was found when the polyethylene glycol-modified protein was used clinically for treatment. Polyethylene glycol is one of the very few synthetic polymers approved by the U.S. Food and Drug Administration (FDA) for intracorporeal drug use. Polyethylene glycol modification, also known as molecular PEGylation (pegylation), is a modification method developed in the late 1970s. Coupling activated polyethylene glycol with protein molecules affects the spatial structure of the protein, and ultimately leads to changes in various biochemical properties of the protein: increased chemical stability, improved ability to resist protease hydrolysis, reduced immunogenicity and toxicity or Disappeared, prolonged half-life in vivo, decreased plasma clearance, etc.
引发剂英文为initiator，又称自由基引发剂，指一类容易受热分解成自由基(即初级自由基)的化合物，可用于引发烯类、双烯类单体的自由基聚合和共聚合反应，也可用于不饱和聚酯的交联固化和高分子交联反应。合成聚乙二醇的小分子引发剂很多，但是具备合成末端不同官能团的引发剂却是很少。从而限制了聚乙二醇修饰的药物载体的应用空间，因此有必要对此进行改进。Initiator is initiator in English, also known as free radical initiator, which refers to a class of compounds that are easily decomposed into free radicals (ie primary free radicals) by heat, and can be used to initiate free radical polymerization and copolymerization reactions of olefinic and diene monomers , It can also be used for cross-linking curing of unsaturated polyester and polymer cross-linking reaction. There are many small molecule initiators for the synthesis of polyethylene glycol, but there are very few initiators with different functional groups at the end of the synthesis. Thereby the application space of the drug carrier modified by polyethylene glycol is limited, so it is necessary to improve this.
发明内容Contents of the invention
本发明实施例所要解决的技术问题在于，提供一种以3,4-二氢-2H-吡喃保护羟基合成的单体引发剂。The technical problem to be solved in the embodiments of the present invention is to provide a monomer initiator synthesized by protecting hydroxyl groups with 3,4-dihydro-2H-pyran.
本发明的第二个目的是提供一种上述单体引发剂的合成方法。The second object of the present invention is to provide a kind of synthetic method of above-mentioned monomeric initiator.
为实现上述目的，本发明的技术方案是学结构式为：For realizing above-mentioned object, technical scheme of the present invention is to learn structural formula to be:
进一步设置是包括以下步骤：Further settings include the following steps:
⑴以乙醚或者四氢呋喃为溶剂，以对甲苯磺酸一水为催化剂，反应温度是冰水浴，带两个或三个或四个羟基的烷烃与3,4-二氢-2H-吡喃反应，反⑴Using diethyl ether or tetrahydrofuran as a solvent, p-toluenesulfonic acid monowater as a catalyst, the reaction temperature is an ice-water bath, and an alkane with two or three or four hydroxyl groups reacts with 3,4-dihydro-2H-pyran, opposite
应时间4～6小时，得到一种以3,4-二氢-2H-吡喃保护羟基的单体引发剂。After a reaction time of 4-6 hours, a monomeric initiator in which a hydroxyl group is protected with 3,4-dihydro-2H-pyran is obtained.
进一步设置是单体的羟基与3,4-二氢-2H-吡喃摩尔比为羟基个数：吡喃环数＝2:1料。The further setting is that the molar ratio of the hydroxyl group of the monomer to the 3,4-dihydro-2H-pyran is the number of hydroxyl groups: the number of pyran rings = 2:1.
本发明的有益效果是：The beneficial effects of the present invention are:
本发明的是一种以3,4-二氢-2H-吡喃保护羟基合成新型单体引发剂是合成双官能化聚乙二醇、异端官能化聚乙二醇、官能化两臂聚乙二醇、官能化四臂聚乙二醇、主链官能化聚乙二醇、新型官能化两臂聚乙二醇、官能化Y型聚乙二醇、官能化环状聚乙二醇、官能化支化聚乙二醇的引发剂。本发明的一种3,4-二氢-2H-吡喃保护羟基制备的新型单体引发剂合成聚乙二醇高分子能很好解决制备末端不同官能团高分子聚乙二醇药物载体。The present invention is a novel monomer initiator for synthesizing a hydroxyl group with 3,4-dihydro-2H-pyran, which is used for synthesizing bifunctional polyethylene glycol, hetero-functionalized polyethylene glycol, and functionalized two-armed polyethylene glycol. Diol, functionalized four-armed polyethylene glycol, main chain functionalized polyethylene glycol, new functionalized two-armed polyethylene glycol, functionalized Y-type polyethylene glycol, functionalized cyclic polyethylene glycol, functionalized Initiator for branched polyethylene glycol. The novel monomer initiator prepared by protecting the hydroxyl group of 3,4-dihydro-2H-pyran of the present invention can well solve the problem of preparing macromolecule polyethylene glycol drug carriers with different functional groups at the end.
本发明的特点是这种以缩醛键形式存在的3,4-二氢-2H-吡喃保护羟基的产物在碱性试剂中能够稳定存在，在酸性条件下保护基团会断裂还原成羟基，具有合成末端带不同官能团单体及末端不同官能团高分子化合物的优势。The present invention is characterized in that the 3,4-dihydro-2H-pyran protected hydroxyl product in the form of an acetal bond can exist stably in alkaline reagents, and the protective group will be broken and reduced to hydroxyl under acidic conditions , has the advantage of synthesizing monomers with different functional groups at the end and polymer compounds with different functional groups at the end.
具体实施方式detailed description
为使本发明的目的、技术方案和优点更加清楚，下面将结合对本发明作进一步地详细描述。In order to make the object, technical solution and advantages of the present invention clearer, the present invention will be further described in detail below.
实施例1Example 1
乙二醇与3,4-二氢-2H-吡喃反应保护一个羟基的制备Preparation of a hydroxyl group protected by the reaction of ethylene glycol with 3,4-dihydro-2H-pyran
将1.0g(0.016mol)乙二醇、1.34g(0.016mol)3,4-二氢-2H-吡喃、10ml乙醚依次加入一带搅拌磁子的干燥洁净的50ml圆底烧瓶中并搅拌均匀，然后在冰水浴中，分批加入对甲苯磺酸一水70mg。之后继续搅拌反应4～6小时。反应方程式如下：Add 1.0g (0.016mol) of ethylene glycol, 1.34g (0.016mol) of 3,4-dihydro-2H-pyran, and 10ml of diethyl ether into a dry and clean 50ml round-bottomed flask with a stirring magnet in sequence and stir evenly. Then, in an ice-water bath, 70 mg of p-toluenesulfonic acid monohydrate was added in batches. After that, the stirring reaction was continued for 4-6 hours. The reaction equation is as follows:
实施例2Example 2
三羟甲基丙烷与3,4-二氢-2H-吡喃反应保护一个羟基的制备Preparation of a hydroxyl group protected by the reaction of trimethylolpropane with 3,4-dihydro-2H-pyran
将1.0g(7.45mmol)三羟甲基丙烷、0.63g(7.45mmol)3,4-二氢-2H-吡喃、10ml乙醚依次加入一带搅拌磁子的干燥洁净的50ml圆底烧瓶中并搅拌均匀，然后在冰水浴中，分批加入对甲苯磺酸一水49mg。之后继续搅拌反应4～6小时。反应方程式如下：Add 1.0g (7.45mmol) of trimethylolpropane, 0.63g (7.45mmol) of 3,4-dihydro-2H-pyran, and 10ml of diethyl ether into a dry and clean 50ml round-bottomed flask with a stirring magnet in sequence and stir homogeneously, and then in an ice-water bath, add 49 mg of p-toluenesulfonic acid monohydrate in batches. After that, the stirring reaction was continued for 4-6 hours. The reaction equation is as follows:
实施例3Example 3
三羟甲基丙烷与3,4-二氢-2H-吡喃反应保护两个羟基的制备Preparation of two hydroxyl groups protected by reaction of trimethylolpropane with 3,4-dihydro-2H-pyran
将1.0g(7.45mmol)三羟甲基丙烷、1.25g(14.9mmol)3,4-二氢-2H-吡喃、10ml乙醚依次加入一带搅拌磁子的干燥洁净的50ml圆底烧瓶中并搅拌均匀，然后在冰水浴中，分批加入对甲苯磺酸一水68mg。之后继续搅拌反应4～6小时。反应方程式如下：Add 1.0g (7.45mmol) trimethylolpropane, 1.25g (14.9mmol) 3,4-dihydro-2H-pyran, and 10ml ether into a dry and clean 50ml round-bottomed flask with a stirring magnet in sequence and stir homogeneously, and then in an ice-water bath, 68 mg of p-toluenesulfonic acid monohydrate was added in batches. After that, the stirring reaction was continued for 4-6 hours. The reaction equation is as follows:
实施例4Example 4
三羟甲基丙烷烯丙醚与3,4-二氢-2H-吡喃反应保护一个羟基的制备Preparation of a hydroxyl group protected by the reaction of trimethylolpropane allyl ether with 3,4-dihydro-2H-pyran
将1.0g(5.7mmol)三羟甲基丙烷烯丙醚、0.48g(14.9mmol)3,4-二氢-2H-吡喃、10ml乙醚依次加入一带搅拌磁子的干燥洁净的50ml圆底烧瓶中并搅拌均匀，然后在冰水浴中，分批加入对甲苯磺酸一水44mg。之后继续搅拌反应4～6小时。反应方程式如下：Add 1.0g (5.7mmol) trimethylolpropane allyl ether, 0.48g (14.9mmol) 3,4-dihydro-2H-pyran, and 10ml diethyl ether into a dry and clean 50ml round bottom flask with a stirring magnet and stir evenly, and then in an ice-water bath, add 44 mg of p-toluenesulfonic acid monohydrate in batches. After that, the stirring reaction was continued for 4-6 hours. The reaction equation is as follows:
实施例5Example 5
季戊四醇与3,4-二氢-2H-吡喃反应保护三个羟基的制备Preparation of three hydroxyl groups protected by reaction of pentaerythritol with 3,4-dihydro-2H-pyran
将1.0g(7.3mmol)季戊四醇、1.84g(22.0mmol)3,4-二氢-2H-吡喃、10ml乙醚依次加入一带搅拌磁子的干燥洁净的50ml圆底烧瓶中并搅拌均匀，然后在冰水浴中，分批加入对甲苯磺酸一水85mg。之后继续搅拌反应4～6小时。反应方程式如下：Add 1.0g (7.3mmol) of pentaerythritol, 1.84g (22.0mmol) of 3,4-dihydro-2H-pyran, and 10ml of diethyl ether into a dry and clean 50ml round-bottomed flask with a stirring magnet in sequence and stir evenly, then in In an ice-water bath, 85 mg of p-toluenesulfonic acid monohydrate was added in batches. After that, the stirring reaction was continued for 4-6 hours. The reaction equation is as follows:
实施例6Example 6
季戊四醇与3,4-二氢-2H-吡喃反应保护一个羟基的制备Preparation of a hydroxyl group protected by reaction of pentaerythritol with 3,4-dihydro-2H-pyran
将1.0g(7.3mmol)季戊四醇、0.61g(7.3mmol)3,4-二氢-2H-吡喃、10ml乙醚依次加入一带搅拌磁子的干燥洁净的50ml圆底烧瓶中并搅拌均匀，然后在冰水浴中，分批加入对甲苯磺酸一水48mg。之后继续搅拌反应4～6小时。反应方程式如下：Add 1.0g (7.3mmol) of pentaerythritol, 0.61g (7.3mmol) of 3,4-dihydro-2H-pyran, and 10ml of diethyl ether into a dry and clean 50ml round-bottomed flask with a stirring magnet in sequence and stir evenly, then in In an ice-water bath, 48 mg of p-toluenesulfonic acid monohydrate was added in batches. After that, the stirring reaction was continued for 4-6 hours. The reaction equation is as follows:
以上所揭露的仅为本发明较佳实施例而已，当然不能以此来限定本发明之权利范围，因此依本发明权利要求所作的等同变化，仍属本发明所涵盖的范围。The above disclosures are only preferred embodiments of the present invention, and certainly cannot limit the scope of rights of the present invention. Therefore, equivalent changes made according to the claims of the present invention still fall within the scope of the present invention.
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| WO1995022330A1 (en) * | 1994-02-17 | 1995-08-24 | Commonwealth Scientific And Industrial Research Organisation | Antiviral agents |
| TW201213301A (en) * | 2010-09-09 | 2012-04-01 | Jsr Corp | Radiation-sensitive resin composition, polymer, and compound |
| CN104781245A (en) * | 2012-10-12 | 2015-07-15 | 学校法人冲绳科学技术大学院大学学园 | Process for producing dihydro-2H-pyran derivatives |
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