CN111320664A - A kind of preparation method of ethyl 24-cholenoate - Google Patents
A kind of preparation method of ethyl 24-cholenoate Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 108
- 238000006243 chemical reaction Methods 0.000 claims abstract description 65
- 239000003960 organic solvent Substances 0.000 claims abstract description 40
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 26
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 11
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000011701 zinc Substances 0.000 claims abstract description 9
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 239000012445 acidic reagent Substances 0.000 claims abstract description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 238000006192 iodination reaction Methods 0.000 claims description 28
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 23
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 22
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000003446 ligand Substances 0.000 claims description 14
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical group O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 claims description 12
- 238000012805 post-processing Methods 0.000 claims description 11
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 8
- 150000004292 cyclic ethers Chemical class 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- 239000011630 iodine Substances 0.000 claims description 8
- 150000007530 organic bases Chemical group 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- -1 pyridine solvent Chemical class 0.000 claims description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 238000010009 beating Methods 0.000 claims description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims 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 description 3
- 238000011097 chromatography purification Methods 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 125000000532 dioxanyl group Chemical group 0.000 claims 1
- 125000002883 imidazolyl group Chemical group 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 239000012267 brine Substances 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 10
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 10
- 239000002994 raw material Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- INBGSXNNRGWLJU-ZHHJOTBYSA-N 25-hydroxycholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCCC(C)(C)O)C)[C@@]1(C)CC2 INBGSXNNRGWLJU-ZHHJOTBYSA-N 0.000 description 4
- INBGSXNNRGWLJU-UHFFFAOYSA-N 25epsilon-Hydroxycholesterin Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(CCCC(C)(C)O)C)C1(C)CC2 INBGSXNNRGWLJU-UHFFFAOYSA-N 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- FMGSKLZLMKYGDP-UHFFFAOYSA-N Dehydroepiandrosterone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CC=C21 FMGSKLZLMKYGDP-UHFFFAOYSA-N 0.000 description 1
- SMEROWZSTRWXGI-UHFFFAOYSA-N Lithocholsaeure Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 SMEROWZSTRWXGI-UHFFFAOYSA-N 0.000 description 1
- 241000288049 Perdix perdix Species 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- SMEROWZSTRWXGI-HVATVPOCSA-N lithocholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 SMEROWZSTRWXGI-HVATVPOCSA-N 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 125000005489 p-toluenesulfonic acid group Chemical group 0.000 description 1
- 229960002847 prasterone Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- 239000005544 vitamin D3 metabolite Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种24‑胆烯烯酸乙酯的制备方法。本发明提供了一种如式04所示的24‑胆烯烯酸乙酯的制备方法,其包括如下步骤:步骤(1)、在有机溶剂中,在锌、催化剂和碱性试剂存在下,将如式02所示的化合物与丙烯酸乙酯进行如下所示的烷基化反应,得到如式03所示的化合物即可;步骤(2)、在水和有机溶剂中,在酸性试剂存在下,将步骤(1)中所述的如式03所示的化合物进行如下所示的反应,得到如式04所示的化合物即可。该制备方法,反应步骤短,收率高(二步总收率可达80%~91%),反应条件温和,试剂价格便宜,实验设备要求低,适合较大规模的合成。 The invention discloses a preparation method of ethyl 24-cholenoate. The invention provides a preparation method of ethyl 24-cholenoate as shown in formula 04, which comprises the following steps: step (1), in an organic solvent, in the presence of zinc, a catalyst and an alkaline reagent, The compound shown in formula 02 is subjected to the alkylation reaction shown below with ethyl acrylate to obtain the compound shown in formula 03; step (2), in water and an organic solvent, in the presence of an acidic reagent , the compound shown in formula 03 described in step (1) is subjected to the reaction shown below to obtain the compound shown in formula 04. The preparation method has short reaction steps, high yield (two-step total yield can reach 80%-91%), mild reaction conditions, cheap reagents, low requirements for experimental equipment, and is suitable for large-scale synthesis.
Description
技术领域technical field
本发明涉及一种24-胆烯烯酸乙酯的制备方法。The present invention relates to a preparation method of ethyl 24-cholenoate.
背景技术Background technique
25-羟基胆固醇是维生素D3的代谢产物前体,24-胆烯烯酸乙酯作为合成25-羟基胆固醇的关键中间体,只需一步就可以合成25-羟基胆固醇。25-hydroxycholesterol is the metabolite precursor of vitamin D3 , and 24-cholenoate ethyl ester is a key intermediate in the synthesis of 25-hydroxycholesterol, and 25-hydroxycholesterol can be synthesized in one step.
文献报道的合成24-胆烯烯酸乙酯的路线主要有两条。路线一:There are two main routes for the synthesis of 24-cholenoic acid ethyl ester reported in the literature. Route one:
以石胆酸为起始原料,经过11步反应制备得到,存在路线长,收率低(总收率为11.13%),实验试剂较为昂贵等缺点(steroids 121(2017)22-31)。Using lithocholic acid as the starting material, it is prepared through 11 steps of reaction, and has the disadvantages of long route, low yield (total yield is 11.13%), and relatively expensive experimental reagents (steroids 121 (2017) 22-31).
路线二:Route two:
以脱氢表雄甾酮为原料,经5步反应得到产品,其中两次用到Wittig反应,需要无水无氧操作;三步反应需要在-78℃进行,多步反应所用试剂昂贵。不适合较大规模的合成(Tetrahedron letters Vol.23,NO.20,PP 2077-2080,1982)。Using dehydroepiandrosterone as raw material, the product is obtained through 5-step reaction, two of which are used in Wittig reaction, which requires anhydrous and oxygen-free operation; the three-step reaction needs to be carried out at -78 ℃, and the reagents used in multi-step reaction are expensive. Not suitable for larger scale synthesis (Tetrahedron letters Vol. 23, NO. 20, PP 2077-2080, 1982).
综上,两条路线均不适合较大规模的合成。In conclusion, both routes are not suitable for larger scale synthesis.
发明内容SUMMARY OF THE INVENTION
本发明所要解决的技术问题是为了克服现有的24-胆烯烯酸乙酯的制备方法存在路线长,收率低,试剂较为昂贵,或者操作条件苛刻,不适合较大规模的合成的技术缺陷,而提供了一种24-胆烯烯酸乙酯的制备方法。本发明提供的制备方法,反应步骤短,收率高,反应条件温和,试剂价格便宜,实验设备要求低,适合较大规模的合成。The technical problem to be solved by the present invention is to overcome the existing preparation methods of ethyl 24-cholenoate, which have long routes, low yields, relatively expensive reagents, or harsh operating conditions, which are not suitable for larger-scale synthesis techniques. However, a method for preparing ethyl 24-cholenoate is provided. The preparation method provided by the invention has the advantages of short reaction steps, high yield, mild reaction conditions, cheap reagents, low requirements for experimental equipment, and is suitable for large-scale synthesis.
本发明是通过下述技术方案来解决上述技术问题的。The present invention solves the above-mentioned technical problems through the following technical solutions.
本发明提供了一种如式04所示的24-胆烯烯酸乙酯的制备方法,其包括如下步骤:The invention provides a preparation method of 24-cholenoic acid ethyl ester shown in formula 04, which comprises the following steps:
步骤(1)、有机溶剂中,在锌、催化剂和碱性试剂存在下,将如式02所示的化合物与丙烯酸乙酯进行如下所示的烷基化反应,得到如式03所示的化合物即可;In step (1), in an organic solvent, in the presence of zinc, a catalyst and an alkaline reagent, the compound shown in formula 02 is subjected to the alkylation reaction shown below with ethyl acrylate to obtain a compound shown in formula 03 You can;
步骤(2)、在水和有机溶剂中,在酸性试剂存在下,将步骤(1)中所述的如式03所示的化合物进行如下所示的反应,得到如式04所示的化合物即可;In step (2), in water and an organic solvent, in the presence of an acidic reagent, the compound shown in formula 03 described in step (1) is subjected to the reaction shown below to obtain the compound shown in formula 04. Can;
所述的步骤(1)中,所述的有机溶剂可为本领域该类反应中常规的有机溶剂,例如吡啶类溶剂(例如吡啶)和/或环醚类溶剂(例如四氢呋喃);较佳地为吡啶。In the described step (1), the organic solvent can be a conventional organic solvent in this type of reaction in the field, such as a pyridine solvent (such as pyridine) and/or a cyclic ether solvent (such as tetrahydrofuran); preferably for pyridine.
所述的步骤(1)中,所述的催化剂可为本领域中该类反应中常规的催化剂,本发明中较佳地为六水合氯化镍。In the step (1), the catalyst can be a conventional catalyst in this type of reaction in the art, and in the present invention, it is preferably nickel chloride hexahydrate.
所述的步骤(1)中,所述的碱性试剂可为本领域该类反应中常规的碱性试剂,本发明中较佳地为有机碱(例如吡啶)。In the step (1), the alkaline reagent may be a conventional alkaline reagent in this type of reaction in the art, and preferably an organic base (eg, pyridine) in the present invention.
所述的步骤(1)中,所述的有机溶剂的用量可不做具体限定,以不影响反应即可;本发明中,所述的式02所示的化合物与所述的有机溶剂的质量体积比较佳地为0.01g/mL~1g/mL(例如0.25g/mL~0.4g/mL)。In the described step (1), the amount of the organic solvent can be not specifically limited, as long as it does not affect the reaction; in the present invention, the mass volume of the compound shown in the formula 02 and the organic solvent is More preferably, it is 0.01 g/mL to 1 g/mL (for example, 0.25 g/mL to 0.4 g/mL).
所述的步骤(1)中,所述的锌可为本领域该类反应中常规的锌,例如锌粉;所述的锌与所述的式02所示的化合物的摩尔比可为5:1~10:1,较佳地为6:1~8:1(例如7.5:1)。In the described step (1), the zinc can be conventional zinc in this type of reaction in this area, such as zinc powder; the mol ratio of the zinc and the compound shown in the formula O2 can be 5: 1-10:1, preferably 6:1-8:1 (eg 7.5:1).
所述的步骤(1)中,所述的催化剂与所述的式02所示的化合物的摩尔比较佳地为1:1~2:1(例如1:1)。In the step (1), the molar ratio of the catalyst to the compound represented by formula 02 is preferably 1:1 to 2:1 (for example, 1:1).
所述的步骤(1)中,所述的碱性试剂与所述的式02所示的化合物的摩尔比较佳地为7.5:1~25:1(例如22:1)。In the step (1), the molar ratio of the basic reagent to the compound represented by formula 02 is preferably 7.5:1 to 25:1 (for example, 22:1).
所述的步骤(1)中,所述的丙烯酸乙酯与所述的式02所示的化合物的摩尔比可为5:1~10:1,较佳地为6:1~8:1(例如7.5:1)。In the step (1), the molar ratio of the ethyl acrylate to the compound represented by the formula 02 may be 5:1 to 10:1, preferably 6:1 to 8:1 ( eg 7.5:1).
所述的步骤(1)中,所述的烷基化反应的温度较佳地为0℃~80℃(例如10℃~70℃,又例如10℃~30℃、40℃~70℃)。In the step (1), the temperature of the alkylation reaction is preferably 0°C to 80°C (eg, 10°C to 70°C, for example, 10°C to 30°C, 40°C to 70°C).
所述的步骤(1)中,所述烷基化反应的进程可以采用本领域中的常规监测方法(例如TLC或NMR)进行监测,一般以所述的如式02所示的化合物消失或不再反应时为反应终点。In the step (1), the progress of the alkylation reaction can be monitored by conventional monitoring methods in the art (such as TLC or NMR), and generally the compound shown in formula 02 disappears or does not. Re-reaction is the end of the reaction.
所述的步骤(1)中,还可包括后处理操作,所述的后处理操作包括如下步骤,将所述的烷基化反应结束后的反应体系进行过滤,洗涤,浓缩,柱层析纯化,得所述的如式03所示的化合物;所述的洗涤,浓缩,柱层析纯化可为本领域中常规的操作;例如所述的洗涤可为依次以乙二胺四乙酸钠水溶液、盐水分别洗涤;所述的柱层析纯化可为本领域常规的操作,例如采用正己烷:乙酸乙酯(体积比=20:1)进行洗脱。In the step (1), a post-processing operation may also be included. The post-processing operation includes the following steps: filtering, washing, concentrating, and purifying the reaction system after the alkylation reaction is completed. , to obtain the compound shown in formula 03; the washing, concentrating, and purification by column chromatography can be conventional operations in the field; The brine is washed separately; the column chromatography purification can be a conventional operation in the field, for example, n-hexane:ethyl acetate (volume ratio=20:1) is used for elution.
所述的步骤(2)中,所述的有机溶剂可为本领域该类反应中常规的有机溶剂,本发明中较佳地为环醚类溶剂(例如二氧六环和/或四氢呋喃)。In the step (2), the organic solvent can be a conventional organic solvent in this type of reaction in the art, preferably a cyclic ether solvent (eg dioxane and/or tetrahydrofuran) in the present invention.
所述的步骤(2)中,所述的酸可为本领域该类反应中常规的酸,本发明中较佳地为对甲苯磺酸和/或甲磺酸。In the step (2), the acid can be a conventional acid in this type of reaction in the art, and in the present invention, it is preferably p-toluenesulfonic acid and/or methanesulfonic acid.
所述的步骤(2)中,所述的水与所述的有机溶剂的体积比较佳地为2:1~1:2(例如1:1)。In the step (2), the volume ratio of the water and the organic solvent is preferably 2:1 to 1:2 (for example, 1:1).
所述的步骤(2)中,所述的有机溶剂的用量可不做具体限定,以不影响反应即可;本发明中,所述的式03化合物与所述的有机溶剂的质量体积比较佳地为0.01g/mL~0.5g/mL(例如0.09g/mL~0.12g/mL)。In the described step (2), the amount of the described organic solvent may not be specifically limited, as long as it does not affect the reaction; in the present invention, the mass volume of the compound of formula 03 and the organic solvent is preferably It is 0.01 g/mL to 0.5 g/mL (for example, 0.09 g/mL to 0.12 g/mL).
所述的步骤(2)中,所述的酸与所述的式03所示的化合物的摩尔比较佳地为0.05:1~0.5:1(例如0.08:1~0.1:1)。In the step (2), the molar ratio of the acid to the compound represented by formula 03 is preferably 0.05:1 to 0.5:1 (for example, 0.08:1 to 0.1:1).
所述的步骤(2)中,所述反应的温度可为本领域该类反应中常规的温度,本发明中较佳地为80℃~100℃。In the step (2), the temperature of the reaction can be a conventional temperature in this type of reaction in the art, and in the present invention, it is preferably 80°C to 100°C.
所述的步骤(2)中,所述反应的进程可以采用本领域中的常规监测方法(例如TLC或NMR)进行监测,一般以所述的如式03所示的化合物消失或不再反应时为反应终点。In the described step (2), the progress of the reaction can be monitored by conventional monitoring methods (such as TLC or NMR) in the art, generally when the compound shown in Formula 03 disappears or no longer reacts. is the end point of the reaction.
所述的步骤(2)中,还可包括后处理操作,所述的后处理操作包括如下步骤,将所述反应结束后的反应体系进行萃取,洗涤,浓缩,得所述的如式04所示的化合物;所述的萃取,洗涤,浓缩可为本领域中常规的操作;例如所述萃取可采用乙酸乙酯进行萃取。In the described step (2), a post-processing operation may also be included, and the post-processing operation includes the following steps: extracting, washing, and concentrating the reaction system after the reaction ends to obtain the described formula as shown in formula 04. The compound shown; the extraction, washing, and concentration can be conventional operations in the field; for example, the extraction can be performed with ethyl acetate.
所述的制备方法,还可包括如下步骤,在有机溶剂中,在碱性试剂和配体存在下,将如式01所示的化合物与碘进行如下所示的碘化反应,得到所述的如式02所示的化合物即可;The preparation method may further include the following steps: in an organic solvent, in the presence of an alkaline reagent and a ligand, the compound shown in formula 01 is subjected to the iodination reaction shown below with iodine to obtain the Compounds as shown in formula 02 can be;
所述的碘化反应中,所述的有机溶剂可为本领域该类反应中常规的有机溶剂,例如卤代烷类溶剂(例如二氯甲烷)。In the iodination reaction, the organic solvent can be a conventional organic solvent in this type of reaction in the art, such as a halogenated alkane solvent (eg, dichloromethane).
所述的碘化反应中,所述的配体可为本领域该类反应中常规的配体,例如膦配体,本发明中较佳地为三苯基膦。In the iodination reaction, the ligand can be a conventional ligand in this type of reaction in the art, such as a phosphine ligand, preferably triphenylphosphine in the present invention.
所述的碘化反应中,所述的碱性试剂可为本领域该类反应中常规的碱性试剂,本发明中较佳地为有机碱(例如咪唑)。In the iodination reaction, the alkaline reagent may be a conventional alkaline reagent in this type of reaction in the art, and in the present invention, it is preferably an organic base (eg, imidazole).
所述的碘化反应中,所述的有机溶剂的用量可不做具体限定,以不影响反应即可;本发明中,所述的式01所示的化合物与所述的有机溶剂的质量体积比较佳地为0.01g/mL~0.2g/mL(例如0.07g/mL~0.09g/mL)。In the described iodination reaction, the amount of the organic solvent can be not specifically limited, as long as it does not affect the reaction; in the present invention, the compound shown in the formula 01 is compared with the mass volume of the organic solvent. Preferably, it is 0.01 g/mL to 0.2 g/mL (eg, 0.07 g/mL to 0.09 g/mL).
所述的碘化反应中,所述的碘与所述的式01所示的化合物的摩尔比可为2.3:1~1.5:1,本发明中较佳地为2.3:1~2:1。In the iodination reaction, the molar ratio of the iodine to the compound represented by the formula 01 may be 2.3:1-1.5:1, preferably 2.3:1-2:1 in the present invention.
所述的碘化反应中,所述的配体与所述的式01所示的化合物的摩尔比可为2.3:1~1.5:1,本发明中较佳地为2.3:1~2:1。In the iodination reaction, the molar ratio of the ligand to the compound represented by the formula 01 may be 2.3:1-1.5:1, preferably 2.3:1-2:1 in the present invention .
所述的碘化反应中,所述的碱性试剂与所述的式01所示的化合物的摩尔比可为3:1~6:1,本发明中较佳地为4:1~6:1。In the iodination reaction, the molar ratio of the alkaline reagent to the compound represented by the formula 01 may be 3:1 to 6:1, and preferably 4:1 to 6:1 in the present invention. 1.
所述的碘化反应的温度较佳地为室温(例如10℃~30℃)。The temperature of the iodination reaction is preferably room temperature (for example, 10°C to 30°C).
所述碘化反应的进程可以采用本领域中的常规监测方法(例如TLC或NMR)进行监测,一般以所述的如式01所示的化合物消失或不再反应时为反应终点。The progress of the iodination reaction can be monitored by conventional monitoring methods in the art (eg TLC or NMR), and generally the reaction end point is when the compound represented by formula 01 disappears or no longer reacts.
所述的如式02所示的化合物的制备方法还可包括后处理操作,所述的后处理操作包括如下步骤,将所述的碘化反应结束后的反应体系进行洗涤,浓缩,有机溶剂打浆,得所述的如式02所示的化合物;所述的洗涤,浓缩,打浆可为本领域中常规的操作;例如所述的洗涤可为依次以Na2S2O4水溶液、纯水、盐水分别洗涤;所述的打浆可为本领域常规的,以除去配体等不溶物;所述的打浆中,所述的有机溶剂可为本领域该类操作中常规的有机溶剂,较佳地为卤代烷类溶剂(例如二氯甲烷)和/或醚类溶剂(例如乙醚和/或甲基叔丁基醚)。The preparation method of the compound shown in formula 02 can also include post-processing operations, and the post-processing operations include the following steps, the reaction system after the iodination reaction is washed, concentrated, and beaten with an organic solvent. , to obtain the compound shown in formula 02 ; the washing, concentrating, and beating can be conventional operations in the field ; The brine is washed separately; the beating can be conventional in the field to remove insolubles such as ligands; in the beating, the organic solvent can be a conventional organic solvent in this type of operation in the field, preferably It is a halogenated alkane solvent (such as dichloromethane) and/or an ether solvent (such as diethyl ether and/or methyl tert-butyl ether).
所述的如式02所示的化合物的制备方法还可包括如下步骤,经如上所述的后处理操作后,较佳地不经纯化,将所述的如式02所示的化合物直接用于所述的烷基化反应,制备所述的化合物03。The preparation method of the compound shown in formula 02 may further include the following steps, after the post-processing operation as described above, preferably without purification, the compound shown in formula 02 is directly used for The alkylation reaction is performed to prepare the compound 03.
所述的如式01所示的化合物可参照文献《Vitamin D3Metabolites I.Synthesisof 25hydroxycholesterol John J.Partridge Stephanie Faber Milan R.》制备得到。The compound shown in the formula 01 can refer to the document "Vitamin D3Metabolites I.Synthesisof 25hydroxycholesterol John J.Partridge Stephanie Faber Milan R. "Prepared.
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明的积极进步效果在于:本发明提供的制备方法,反应步骤短,收率高(二步总收率可达80%~91%),反应条件温和,试剂价格便宜,实验设备要求低,适合较大规模的合成。The positive improvement effects of the present invention are: the preparation method provided by the present invention has short reaction steps, high yield (the total yield of two steps can reach 80% to 91%), mild reaction conditions, cheap reagents, and low requirements for experimental equipment, Suitable for larger scale synthesis.
具体实施方式Detailed ways
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.
下述实施例中,HPLC方法:In the following examples, the HPLC method:
色谱柱:Thermo C18 4.6*150mmChromatographic column: Thermo C18 4.6*150mm
进样量:15μLInjection volume: 15μL
波长:205nmWavelength: 205nm
柱温:30℃Column temperature: 30℃
流速:1mL/minFlow rate: 1mL/min
流动相:A:甲醇;B:10%的甲醇水溶液;A:B=87:13。Mobile phase: A: methanol; B: 10% methanol in water; A:B=87:13.
化合物02的制备Preparation of compound 02
实施例1Example 1
将三苯基膦36.17g,咪唑24.51g溶于300ml二氯甲烷,加入碘35.03g,反应一段时间后滴加化合物01的二氯甲烷溶液(化合物01 20.78g,二氯甲烷150ml),室温反应。TLC板显示反应完全,原料基本上全转化成化合物02;反应液用Na2S2O4水溶液、纯水、盐水分别洗涤,干燥、过滤、旋干得类白色固体,固体用150ml正己烷打浆,滤液旋干后得化合物02粗品29.9g,(化合物01:三苯基膦:咪唑:碘=1:2.3:6:2.3;由于粗品中含有三苯基膦,物料收率109.22%),不做进一步纯化直接投下一步反应。Dissolve 36.17 g of triphenylphosphine and 24.51 g of imidazole in 300 ml of dichloromethane, add 35.03 g of iodine, and after reacting for a period of time, dropwise add the dichloromethane solution of compound 01 (20.78 g of compound 01, 150 ml of dichloromethane), and react at room temperature . The TLC plate showed that the reaction was complete, and the raw materials were basically converted into compound 02; the reaction solution was washed with Na 2 S 2 O 4 aqueous solution, pure water, and brine respectively, dried, filtered, and spin-dried to obtain an off-white solid, which was slurried with 150 ml of n-hexane. , the filtrate was spin-dried to obtain 29.9 g of crude compound 02, (compound 01: triphenylphosphine: imidazole: iodine=1:2.3:6:2.3; since the crude product contained triphenylphosphine, the material yield was 109.22%), no For further purification, it was directly put into the next reaction.
实施例2Example 2
将三苯基膦131.05g,咪唑68.08g溶于1000ml二氯甲烷,加入碘126.9g,反应一段时间后滴加化合物01的二氯甲烷溶液(化合物01 86.67g,二氯甲烷500ml),室温反应。TLC板显示反应完全,原料基本上全转化成化合物02;反应液用Na2S2O4水溶液、纯水、盐水分别洗涤,干燥、过滤、旋干得类白色固体,固体用500ml正己烷打浆,滤液旋干后得化合物02粗品125.6g,(化合物01:三苯基膦:咪唑:碘=1:2:4:2;由于粗品中含有三苯基膦,物料收率110.0%),不做进一步纯化直接投下一步反应。Dissolve 131.05 g of triphenylphosphine and 68.08 g of imidazole in 1000 ml of dichloromethane, add 126.9 g of iodine, and after reacting for a period of time, add the dichloromethane solution of compound 01 dropwise (86.67 g of compound 01, 500 ml of dichloromethane), and react at room temperature . The TLC plate showed that the reaction was complete, and the raw materials were basically converted into compound 02; the reaction solution was washed with Na 2 S 2 O 4 aqueous solution, pure water, and brine respectively, dried, filtered, and spin-dried to obtain an off-white solid, and the solid was slurried with 500 ml of n-hexane. , the filtrate was spin-dried to obtain 125.6 g of a crude product of compound 02, (compound 01: triphenylphosphine: imidazole: iodine=1:2:4:2; since the crude product contained triphenylphosphine, the material yield was 110.0%), no For further purification, it was directly put into the next reaction.
实施例3Example 3
将三苯基膦23.59g,咪唑12.25g溶于300ml二氯甲烷,加入碘22.84g,反应一段时间后滴加化合物01的二氯甲烷溶液(化合物01 20.78g,二氯甲烷150ml),室温反应。TLC板显示有原料剩余,反应液用Na2S2O4水溶液、纯水、盐水分别洗涤,干燥、过滤、旋干得类白色固体,固体用150ml正己烷打浆,滤液旋干后得化合物02粗品27.3g。(化合物01:三苯基膦:咪唑:碘=1:1.5:3:1.5;粗品中含有三苯基膦,物料收率99.73%),不做进一步纯化直接投下一步反应。Dissolve 23.59 g of triphenylphosphine and 12.25 g of imidazole in 300 ml of dichloromethane, add 22.84 g of iodine, and after reacting for a period of time, dropwise add the dichloromethane solution of compound 01 (20.78 g of compound 01, 150 ml of dichloromethane), and react at room temperature . The TLC plate showed that the raw materials remained. The reaction solution was washed with Na 2 S 2 O 4 aqueous solution, pure water, and brine respectively, dried, filtered, and spin-dried to obtain an off-white solid. The solid was slurried with 150 ml of n-hexane, and the filtrate was spin-dried to obtain compound 02. Crude product 27.3g. (Compound 01: triphenylphosphine: imidazole: iodine = 1: 1.5: 3: 1.5; the crude product contains triphenylphosphine, the material yield is 99.73%), and it was directly put into the next reaction without further purification.
化合物03的制备Preparation of compound 03
实施例4Example 4
将8.17g锌粉,5.94g氯化镍六水合物,13.31ml丙烯酸乙酯混悬于30ml吡啶中,加热引发(40℃~70℃),降温到室温滴加化合物02(实施例2得到)的吡啶溶液(化合物0212.54g(按上步100%计算,约合化合物02 11.4g),吡啶15ml),滴毕后搅拌。TLC板显示有较多原料剩余,有少量杂质,反应液过滤,滤液用50ml EDTA液(EDTA:4g,NaHCO3:4g,H2O:50ml)、盐水洗涤,干燥,过滤,旋干,柱层析纯化得油状物约8.47g。(02:锌粉:乙烯酸乙酯:氯化镍六水合物=1:5:5:1;两步收率78.76%)8.17g of zinc powder, 5.94g of nickel chloride hexahydrate, 13.31ml of ethyl acrylate were suspended in 30ml of pyridine, heated to initiate (40°C ~ 70°C), cooled to room temperature and added dropwise to compound 02 (obtained in Example 2) 12.54g of the pyridine solution (compound 0212.54g (calculated according to 100% in the previous step, about 11.4g of compound 02), 15ml of pyridine), and stirred after completion of dropping. TLC plate showed that there were more raw materials remaining and a small amount of impurities. The reaction solution was filtered, and the filtrate was washed with 50ml EDTA solution (EDTA: 4g, NaHCO 3 : 4g, H 2 O: 50ml), brine, dried, filtered, spin-dried, column Chromatographic purification yielded about 8.47 g of an oil. (02: zinc powder: ethyl ethyl acetate: nickel chloride hexahydrate = 1:5:5:1; two-step yield 78.76%)
MS:453.34[M+Na]+,399.33[M-CH3O]+;1HNMR(400MHz,CD3Cl)δ:4.01(2H,q),3.41(3H,s),3.04(1H,t),2.35(2H,t),1.90(4H,m),1.60(8H,m),1.50(2H,m),1.38(6H,m),1.19(2H,m),1.07(7H,m),0.85(9H,m)。MS: 453.34 [M+Na] + , 399.33 [M-CH 3 O] + ; 1 HNMR (400 MHz, CD 3 Cl) δ: 4.01(2H,q), 3.41(3H,s), 3.04(1H,t ),2.35(2H,t),1.90(4H,m),1.60(8H,m),1.50(2H,m),1.38(6H,m),1.19(2H,m),1.07(7H,m) ,0.85(9H,m).
实施例5Example 5
将8.17g锌粉,5.94g氯化镍六水合物,13.31ml丙烯酸乙酯混悬于15ml吡啶+15ml四氢呋喃中,加热引发(40℃~70℃),降温到室温滴加化合物02(实施例2得到)的混合溶液(化合物02 12.54g(按上步100%计算,约合化合物02 11.4g),吡啶15ml,四氢呋喃15ml),滴毕后搅拌。TLC板显示有较多原料剩余,杂质较实施例4稍多,反应液过滤,滤液用EDTA水溶液、盐水洗涤,干燥,过滤,旋干,柱层析纯化得油状物约7.92g。(02:锌粉:乙烯酸乙酯:氯化镍六水合物=1:5:5:1;两步收率73.65%)8.17g of zinc powder, 5.94g of nickel chloride hexahydrate, 13.31ml of ethyl acrylate were suspended in 15ml of pyridine+15ml of tetrahydrofuran, heated to initiate (40 ° C ~ 70 ° C), cooled to room temperature and added dropwise to compound 02 (Example 2) mixed solution (compound 02 12.54g (calculated according to the 100% of the previous step, about compound 02 11.4g), pyridine 15ml, tetrahydrofuran 15ml), stir after completion of dropping. The TLC plate showed that there were more raw materials remaining, and the impurities were slightly more than that of Example 4. The reaction solution was filtered, and the filtrate was washed with EDTA aqueous solution and brine, dried, filtered, spin-dried, and purified by column chromatography to obtain about 7.92 g of an oily substance. (02: zinc powder: ethyl ethyl acetate: nickel chloride hexahydrate = 1:5:5:1; two-step yield 73.65%)
实施例6Example 6
将12.26g锌粉,5.94g氯化镍六水合物,13.31ml丙烯酸乙酯混悬于30ml吡啶中,加热引发(40℃~70℃),降温到室温滴加化合物02(实施例2得到)的吡啶溶液(化合物0212.54g(按上步100%计算,约合化合物0211.4g),吡啶15ml),滴毕后搅拌。TLC板显示有少量原料剩余,杂质较实施例4少,反应液过滤,滤液用EDTA水溶液、盐水洗涤,干燥,过滤,旋干,柱层析纯化得油状物约9.79g。(02:锌粉:乙烯酸乙酯:氯化镍六水合物=1:7.5:5:1;两步收率91.04%)12.26g of zinc powder, 5.94g of nickel chloride hexahydrate, 13.31ml of ethyl acrylate were suspended in 30ml of pyridine, heated to initiate (40°C ~ 70°C), cooled to room temperature and added dropwise to compound 02 (obtained in Example 2) The pyridine solution (compound 0212.54g (calculated according to 100% of the previous step, about compound 0211.4g), pyridine 15ml), was stirred after the dropping. The TLC plate showed that a small amount of raw material remained, and the impurities were less than that of Example 4. The reaction solution was filtered, and the filtrate was washed with EDTA aqueous solution and brine, dried, filtered, spin-dried, and purified by column chromatography to obtain about 9.79 g of an oily substance. (02: zinc powder: ethyl ethyl acetate: nickel chloride hexahydrate = 1:7.5:5:1; two-step yield 91.04%)
实施例7Example 7
将98.09g锌粉,47.54g氯化镍六水合物,159.69ml丙烯酸乙酯混悬于300ml吡啶中,加热引发(40℃~70℃),降温到室温滴加化合物02(实施例2得到)的吡啶溶液(化合物02 100.36g(按上步100%计算,约合化合物0291.24g),吡啶100ml),滴毕后搅拌。TLC板显示原料基本反应完全,只有痕量杂质,反应液过滤,滤液用EDTA水溶液、盐水洗涤,干燥,过滤,旋干,柱层析纯化得油状物约86.13g。(02:锌粉:乙烯酸乙酯:氯化镍六水合物=1:7.5:7.5:1;两步收率100.08%)98.09g of zinc powder, 47.54g of nickel chloride hexahydrate, and 159.69ml of ethyl acrylate were suspended in 300ml of pyridine, heated to initiate (40°C to 70°C), cooled to room temperature and added dropwise to compound 02 (obtained in Example 2) The pyridine solution (100.36 g of compound 02 (calculated according to the 100% of the previous step, about compound 0291.24 g), 100 ml of pyridine) was stirred after dropping. The TLC plate showed that the reaction of the raw materials was basically complete, with only trace impurities. The reaction solution was filtered, and the filtrate was washed with EDTA aqueous solution and brine, dried, filtered, spin-dried, and purified by column chromatography to obtain about 86.13 g of an oily substance. (02: zinc powder: ethyl ethyl acetate: nickel chloride hexahydrate = 1:7.5:7.5:1; two-step yield 100.08%)
实施例8Example 8
将24.52g锌粉,11.88g氯化镍六水合物,39.92ml丙烯酸乙酯混悬于30ml吡啶+30ml四氢呋喃中,加热引发(40℃~70℃),降温到室温滴加化合物02(实施例2得到)的混合溶液(化合物02 25.08g(按上步100%计算,约合化合物02 22.8g),吡啶15ml,四氢呋喃15ml),滴毕后搅拌。TLC板显示原料基本反应完全,反应液过滤,滤液用EDTA水溶液、盐水洗涤,干燥,过滤,旋干,柱层析纯化得油状物约21.17g。(02:锌粉:乙烯酸乙酯:氯化镍六水合物=1:7.5:7.5:1;两步收率98.45%)24.52g of zinc powder, 11.88g of nickel chloride hexahydrate, 39.92ml of ethyl acrylate were suspended in 30ml of pyridine+30ml of tetrahydrofuran, heated to initiate (40℃~70℃), cooled to room temperature and added dropwise to compound 02 (Example 2) mixed solution (compound 02 25.08g (calculated according to the 100% of the previous step, about compound 02 22.8g), pyridine 15ml, tetrahydrofuran 15ml), stirred after the drop was completed. TLC plate showed that the reaction of the raw materials was basically complete, the reaction solution was filtered, the filtrate was washed with EDTA aqueous solution and brine, dried, filtered, spin-dried, and purified by column chromatography to obtain about 21.17 g of oil. (02: zinc powder: ethyl ethyl acetate: nickel chloride hexahydrate = 1:7.5:7.5:1; two-step yield 98.45%)
化合物04的制备Preparation of compound 04
实施例9Example 9
将实施例4得到的化合物03油状物约8.47g溶于80ml 1,4-二氧六环和80ml水的混合溶剂中,加入0.34g对甲苯磺酸一水合物,加热回流(80℃~100℃)反应。TLC板显示反应完全,用EA提取,合并有机层,有机层用盐水洗涤,干燥,过滤,旋干,得白色固体7.29g,收率89.0%(03制备04的单步收率)(化合物02为100%理论收率计,两步收率70%;HPLC纯度96.5%)。About 8.47 g of the oily substance of compound 03 obtained in Example 4 was dissolved in a mixed solvent of 80 ml of 1,4-dioxane and 80 ml of water, 0.34 g of p-toluenesulfonic acid monohydrate was added, and the mixture was heated to reflux (80 ℃~100 ℃). °C) reaction. TLC plate showed that the reaction was complete, extracted with EA, the organic layers were combined, the organic layers were washed with brine, dried, filtered, and spin-dried to obtain 7.29 g of a white solid with a yield of 89.0% (the single-step yield of 03 to prepare 04) (Compound 02 For 100% theoretical yield, the two-step yield is 70%; the HPLC purity is 96.5%).
实施例10Example 10
将实施例5得到的化合物03油状物约7.92g溶于80ml 1,4-二氧六环和80ml水的混合溶剂中,加入0.32g对甲苯磺酸一水合物,加热回流反应。TLC板显示反应完全,用EA提取,合并有机层,有机层用盐水洗涤,干燥,过滤,旋干,得白色固体6.73g,收率87.86%(03制备04的单步收率)(以化合物02为100%理论收率计,两步收率65%;HPLC纯度96.0%)。About 7.92 g of the oily compound 03 obtained in Example 5 was dissolved in a mixed solvent of 80 ml of 1,4-dioxane and 80 ml of water, 0.32 g of p-toluenesulfonic acid monohydrate was added, and the reaction was heated under reflux. TLC plate showed that the reaction was complete, extracted with EA, combined the organic layers, washed the organic layers with brine, dried, filtered, and spin-dried to obtain 6.73 g of white solid, yield 87.86% (the single-step yield of 03 to prepare 04) (with compound 02 is 100% theoretical yield, two-step yield is 65%; HPLC purity is 96.0%).
实施例11Example 11
将实施例6得到的化合物03油状物约9.79g溶于90ml 1,4-二氧六环和90ml水的混合溶剂中,加入0.39g对甲苯磺酸一水合物,加热回流反应。TLC板显示反应完全,用EA提取,合并有机层,有机层用盐水洗涤,干燥,过滤,旋干,得白色固体8.57g,收率90.48%(03制备04的单步收率)(以化合物02为100%理论收率计,两步收率82.4%;HPLC纯度97.5%)。About 9.79 g of the oily substance of compound 03 obtained in Example 6 was dissolved in a mixed solvent of 90 ml of 1,4-dioxane and 90 ml of water, 0.39 g of p-toluenesulfonic acid monohydrate was added, and the reaction was heated and refluxed. TLC plate showed that the reaction was complete, extract with EA, combine the organic layers, wash the organic layers with brine, dry, filter, and spin dry to obtain 8.57 g of white solid, yield 90.48% (the single-step yield of 03 to prepare 04) (with compound 02 is 100% theoretical yield, two-step yield is 82.4%; HPLC purity is 97.5%).
实施例12Example 12
将实施例7得到的化合物03油状物约86.13g溶于800ml 1,4-二氧六环和800ml水的混合溶剂中,加入3.46g对甲苯磺酸一水合物,加热回流反应。TLC板显示反应完全,用EA提取,合并有机层,有机层用盐水洗涤,干燥,过滤,旋干,得白色固体75.74g,收率90.9%(03制备04的单步收率)(以化合物02为100%理论收率计,两步收率90.9%;HPLC纯度99.1%)。About 86.13 g of the oily substance of compound 03 obtained in Example 7 was dissolved in a mixed solvent of 800 ml of 1,4-dioxane and 800 ml of water, 3.46 g of p-toluenesulfonic acid monohydrate was added, and the reaction was heated and refluxed. The TLC plate showed that the reaction was complete, extracted with EA, combined the organic layers, washed the organic layers with brine, dried, filtered, and spin-dried to obtain 75.74 g of white solid, the yield was 90.9% (the single-step yield of 03 to prepare 04) (compound 02 is 100% theoretical yield, two-step yield 90.9%; HPLC purity 99.1%).
实施例13Example 13
将实施例8得到的化合物03油状物约21.17g溶于180ml 1,4-二氧六环和180ml水的混合溶剂中,加入0.83g对甲苯磺酸一水合物,加热回流反应。TLC板显示反应完全,用EA提取,合并有机层,有机层用盐水洗涤,干燥,过滤,旋干,得白色固体18.48g,收率90.21%(03制备04的单步收率)(以化合物02为100%理论收率计,两步收率88.8%;HPLC纯度98.7%)。About 21.17 g of the oily substance of compound 03 obtained in Example 8 was dissolved in a mixed solvent of 180 ml of 1,4-dioxane and 180 ml of water, 0.83 g of p-toluenesulfonic acid monohydrate was added, and the reaction was heated and refluxed. TLC plate showed that the reaction was complete, extract with EA, combine the organic layers, wash the organic layers with brine, dry, filter, spin dry to obtain 18.48 g of white solid, yield 90.21% (the single-step yield of 03 to prepare 04) (compound 02 is 100% theoretical yield, the two-step yield is 88.8%; the HPLC purity is 98.7%).
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