CN105566166A - Preparation method of tert-butyl (3R, 4S, 5S)-5-hydroxy-3-methyl-7-ocentyl-4-carbamate - Google Patents
Preparation method of tert-butyl (3R, 4S, 5S)-5-hydroxy-3-methyl-7-ocentyl-4-carbamate Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 15
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- 238000004440 column chromatography Methods 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 claims description 16
- -1 tert-butyl (3R, 4S, 5S)-5-hydroxyl-3-methyl-7-octene-4-carbamate Chemical compound 0.000 claims description 13
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 11
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- RHJPBGWFGOAEID-BEDNPZBZSA-N chembl1256416 Chemical compound C1([C@H](CC[C@H](C)[C@@H]2[C@H]([C@@H]3C[C@@]4(O[C@@](O)(CC(=O)O[C@H](CC(=O)O3)[C@@H](C)O)[C@H](C)CC4(C)C)O2)C)OC)=CC(O)=CC=C1Br RHJPBGWFGOAEID-BEDNPZBZSA-N 0.000 abstract description 2
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- 238000003756 stirring Methods 0.000 description 8
- OFDNQWIFNXBECV-UHFFFAOYSA-N Dolastatin 10 Natural products CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)CC)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-UHFFFAOYSA-N 0.000 description 5
- OFDNQWIFNXBECV-VFSYNPLYSA-N dolastatin 10 Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-VFSYNPLYSA-N 0.000 description 5
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 3
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- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- GHCBYDBRCQYPPL-XKSSXDPKSA-N (3r,4s,5s)-3-methoxy-5-methyl-4-(methylamino)heptanoic acid Chemical compound CC[C@H](C)[C@H](NC)[C@H](OC)CC(O)=O GHCBYDBRCQYPPL-XKSSXDPKSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
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- 150000001299 aldehydes Chemical class 0.000 description 1
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- PBZROIMXDZTJDF-UHFFFAOYSA-N hepta-1,6-dien-4-one Chemical compound C=CCC(=O)CC=C PBZROIMXDZTJDF-UHFFFAOYSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
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Abstract
Description
技术领域 technical field
本发明涉及一种具有抗肿瘤活性的天然产物的中间体的合成方法，具体涉及一种叔丁基(3R，4S，5S)-5-羟基-3-甲基-7-辛烯-4-氨基甲酸酯即海兔毒素10的关键合成子(dolaisoleuine)Dil的中间体的制备方法。 The invention relates to a synthetic method of an intermediate of a natural product with antitumor activity, in particular to a tert-butyl (3R, 4S, 5S)-5-hydroxyl-3-methyl-7-octene-4- A method for preparing carbamate, the intermediate of Dil, the key synthon (dolaisoleuine) Dil of dolastatin 10.
背景技术 Background technique
海兔毒素是高活性的抗癌活性肽，主要用于小细胞肺癌、卵巢癌、黑素瘤和前列腺等实体瘤的治疗，尤其是D-10已进入II期临床。由于具有确切的作用机制及温和的毒性反应，D-10很有可能成为联合用药的首选药物之一。天然的D-10产量极小，而现有的合成方法和路线仅限于实验室规模，无法满足日益增长的需求。其中一个原因在于无法高效立体选择性地合成D-10中最复杂的组分，即具有三个手性中心的Dil。 Aplysia toxin is a highly active anti-cancer active peptide, which is mainly used for the treatment of solid tumors such as small cell lung cancer, ovarian cancer, melanoma and prostate, especially D-10 has entered phase II clinical trials. Due to its definite mechanism of action and mild toxicity, D-10 is likely to become one of the preferred drugs for combination therapy. The yield of natural D-10 is extremely small, and the existing synthetic methods and routes are limited to laboratory scale, which cannot meet the growing demand. One of the reasons is that the most complex component in D-10, Dil with three chiral centers, could not be synthesized efficiently and stereoselectively.
TetrahedronLetters，1991，32(7)第931-934页，报道了先生成β-羰基酯，再通过硼氢化钠还原的方法，该方法选立体选择性不高。Tetrahedron，1994，50(18)，第5345-5360页，报道了先通过格氏试剂形成烯丙基酮，再利用硼氢化钠还原酮的方法，但是该反应要求溶剂无水，而且还原反应立体选择性差。J.Org.Chem.2012，77，第733-738页应用Reformatsky反应进行立体选择性的合成β-羟基-γ-氨基酸，通过引入空间位阻大的基团来控制3位手性，该反应需要在超低温-78℃下进行，操作不方便。WO2013072813A2，US20130129753A1等公布了通过Aldol缩合反应得到β-羟基酯，该方法同样需要在超低温进行，同时反应收率也很低。 Tetrahedron Letters, 1991, 32 (7) pages 931-934, reported the method of generating β-carbonyl ester first, and then reducing it by sodium borohydride. The stereoselectivity of this method is not high. Tetrahedron, 1994,50 (18), the 5345-5360 page, has reported to form allyl ketone by Grignard reagent earlier, utilizes the method for sodium borohydride reduction ketone again, but this reaction requires solvent anhydrous, and reduction reaction stereo Poor selectivity. J.Org.Chem.2012, 77, pages 733-738 apply the Reformatsky reaction for stereoselective synthesis of β-hydroxy-γ-amino acids, and control the 3-position chirality by introducing groups with large steric hindrance. This reaction It needs to be carried out at an ultra-low temperature of -78°C, which is inconvenient to operate. WO2013072813A2, US20130129753A1, etc. have disclosed that β-hydroxy esters are obtained through Aldol condensation reaction. This method also needs to be carried out at ultra-low temperature, and the reaction yield is also very low.
发明内容 Contents of the invention
本发明旨在提供一种成本低廉、后处理简单的制备海兔毒素10的关键合成子Dil的中间体的新方法，所要解决的技术问题是遴选新的简单的合成方法。本发明合成路线通过进行甲基化、双键的氧化两步反应就能合成叔丁基(3R，4S，5S)-5-羟基-3-甲基-7-辛烯-4-氨基甲酸酯即海兔毒素10的关键合成子Dil。 The present invention aims to provide a new method for preparing the intermediate of the key synthon Dil of dolastatin 10 with low cost and simple post-treatment. The technical problem to be solved is to select a new and simple synthetic method. The synthetic route of the present invention can synthesize tert-butyl (3R, 4S, 5S)-5-hydroxyl-3-methyl-7-octene-4-carbamic acid through two-step reactions of methylation and double bond oxidation The ester is the key synthon Dil of dolastatin 10.
为实现上述目的，本发明以N-叔丁氧羰基-L-异亮氨醛和烯丙基溴为原料，再加入二水合氯化亚锡以及锌粉，以二氯甲烷为溶剂，在0～5℃温度条件下，通过Barbier反应，得到顺式与反式比例为4∶1的烯丙基化产物，通过柱层析分离纯化得到顺式结构产物即叔丁基(3R，4S，5S)-5-羟基-3-甲基-7-辛烯-4-氨基甲酸酯。 In order to achieve the above object, the present invention takes N-tert-butoxycarbonyl-L-isoleucinaldehyde and allyl bromide as raw materials, then adds tin protochloride dihydrate and zinc powder, takes dichloromethane as solvent, at 0 At a temperature of ~5°C, the allylated product with a cis-to-trans ratio of 4:1 was obtained through Barbier reaction, and the cis-structure product, namely tert-butyl (3R, 4S, 5S )-5-hydroxy-3-methyl-7-octene-4-carbamate.
本发明制备方法的反应如下式(I)所示： The reaction of preparation method of the present invention is shown in following formula (I):
本发明中，原料N-叔丁氧羰基-L-异亮氨醛和烯丙基溴的用量为1∶1.75～2.25。优选地，烯丙基溴的用量为原料N-叔丁氧羰基-L-异亮氨醛的2倍摩尔数。 In the present invention, the amount of raw materials N-tert-butoxycarbonyl-L-isoleucinaldehyde and allyl bromide is 1:1.75-2.25. Preferably, the amount of allyl bromide used is twice the mole number of the raw material N-tert-butoxycarbonyl-L-isoleucinaldehyde.
本发明中，所述金属盐二水合氯化亚锡的用量为原料N-叔丁氧羰基-L-异亮氨醛的1.75～2.25倍摩尔数。优选地，二水合氯化亚锡的用量为原料N-叔丁氧羰基-L-异亮氨醛的2倍摩尔数。 In the present invention, the amount of the metal salt dihydrate stannous chloride is 1.75-2.25 times the mole of the raw material N-tert-butoxycarbonyl-L-isoleucinaldehyde. Preferably, the amount of stannous chloride dihydrate used is twice the mole number of the raw material N-tert-butoxycarbonyl-L-isoleucinaldehyde.
本发明中，所述还原剂金属锌粉的用量为N-叔丁氧羰基-L-异亮氨醛的1.75～2.25倍摩尔数。优选地，锌粉的用量为原料N-叔丁氧羰基-L-异亮氨醛的2倍摩尔数。 In the present invention, the amount of the reducing agent metal zinc powder is 1.75-2.25 times the mole of N-tert-butoxycarbonyl-L-isoleucinaldehyde. Preferably, the amount of zinc powder used is twice the mole number of the raw material N-tert-butoxycarbonyl-L-isoleucinaldehyde.
本发明中，N-叔丁氧羰基-L-异亮氨醛∶烯丙基溴∶二水合氯化亚锡∶锌粉的摩尔比＝1∶1.75～2.25∶1.75～2.25∶1.75～2.25。 In the present invention, the molar ratio of N-tert-butoxycarbonyl-L-isoleucinaldehyde: allyl bromide: stannous chloride dihydrate: zinc powder is 1: 1.75-2.25: 1.75-2.25: 1.75-2.25.
本发明中，反应在0～5℃温度条件下进行。优选地，反应温度为0℃。 In the present invention, the reaction is carried out at a temperature of 0-5°C. Preferably, the reaction temperature is 0°C.
本发明中，反应时间为0.5～1小时。优选地，反应时间为0.5小时。 In the present invention, the reaction time is 0.5 to 1 hour. Preferably, the reaction time is 0.5 hours.
本发明中，通过Barbier反应得到顺式与反式的比例为4∶1的烯丙基化产物，然后，通过柱层析分离纯化得到顺式结构的产物即叔丁基(3R，4S，5S)-5-羟基-3-甲基-7-辛烯-4-氨基甲酸酯。 In the present invention, the ratio of cis and trans is 4:1 through the Barbier reaction to obtain the allylated product, and then the product of the cis structure is separated and purified by column chromatography, that is, tert-butyl (3R, 4S, 5S )-5-hydroxy-3-methyl-7-octene-4-carbamate.
在一个具体实施方案中，本发明制备方法包括如下步骤： In a specific embodiment, the preparation method of the present invention comprises the following steps:
先量取N-叔丁氧羰基-L-异亮氨醛：烯丙基溴摩尔比＝1∶1.75～2.25，然后在搅拌下分别溶解到十倍体积的二氯甲烷中，冰水浴冷却至0～5℃。再量取二水合氯化亚锡的量为N-叔丁氧羰基-L-异亮氨醛的1.75～2.25倍摩尔数加入上述溶液中，再量取还原剂金属锌粉的量为N-叔丁氧羰基-L-异亮氨醛的1.75～2.25倍摩尔数加入上述溶液中，维持0～5℃搅拌约半个小时，直至TLC显示N-叔丁氧羰基-L-异亮氨醛消耗完全。 First measure N-tert-butoxycarbonyl-L-isoleucinaldehyde: allyl bromide molar ratio = 1: 1.75 ~ 2.25, then dissolve them in ten times the volume of dichloromethane under stirring, and cool in an ice-water bath to 0～5℃. Then measure the amount of tin protochloride dihydrate to add 1.75 to 2.25 times the molar number of N-tert-butoxycarbonyl-L-isoleucinaldehyde in the above solution, and then measure the amount of reducing agent metal zinc powder as N- Add 1.75-2.25 times mole of tert-butoxycarbonyl-L-isoleucinaldehyde to the above solution, keep stirring at 0-5°C for about half an hour, until TLC shows N-tert-butoxycarbonyl-L-isoleucinaldehyde Consumed completely.
移除冰水浴，使体系升温至室温，过滤除去反应液中的不溶物，减压旋蒸除去滤液中的二氯甲烷及少量的水，残留物用体积比为5∶1的石油醚和乙酸乙酯混合溶剂通过柱层析分离纯化，得到叔丁基(3R，4S，5S)-5-羟基-3-甲基-7-辛烯-4-氨基甲酸酯即海兔毒素10的关键合成子Dil的中间体。 Remove the ice-water bath, warm the system to room temperature, filter to remove the insoluble matter in the reaction solution, remove dichloromethane and a small amount of water in the filtrate by rotary evaporation under reduced pressure, and use petroleum ether and acetic acid with a volume ratio of 5:1 to remove the residue The ethyl ester mixed solvent was separated and purified by column chromatography to obtain tert-butyl (3R, 4S, 5S)-5-hydroxy-3-methyl-7-octene-4-carbamate, the key to dolastatin 10 Intermediate of the synthon Dil.
本发明还提出了一种上述方法制备得到的叔丁基(3R，4S，5S)-5-羟基-3-甲基-7-辛烯-4-氨基甲酸酯即海兔毒素10的关键合成子Dil的中间体。 The present invention also proposes a tert-butyl (3R, 4S, 5S)-5-hydroxyl-3-methyl-7-octene-4-carbamate prepared by the above method, the key to dolastatin 10. Intermediate of the synthon Dil.
本发明有益效果包括：本发明利用Barbier反应进行醛的烯丙基化反应，烯丙基化试剂为烯丙基溴，还原剂为二水合氯化亚锡以及锌粉，原料便宜易得，节约成本。本发明使用的底物及试剂对水不敏感，反应溶剂不需要专门进行无水处理，反应也不需要在无水条件下进行，简化了实验操作流程。本发明利用Barbier反应，反应时间只需要0.5h左右，相比现有技术中的合成方法，大大减少了反应时间。 The beneficial effects of the present invention include: the present invention utilizes the Barbier reaction to carry out the allylation reaction of aldehydes, the allylation reagent is allyl bromide, the reducing agent is stannous chloride dihydrate and zinc powder, the raw materials are cheap and easy to obtain, saving cost. The substrates and reagents used in the present invention are not sensitive to water, the reaction solvent does not need to be specially anhydrous treated, and the reaction does not need to be carried out under anhydrous conditions, which simplifies the experimental operation process. The present invention utilizes the Barbier reaction, and the reaction time only needs about 0.5h, which greatly reduces the reaction time compared with the synthesis method in the prior art.
具体实施方式 detailed description
结合以下具体实施例，对本发明作进一步的详细说明，本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。 In conjunction with the following specific examples, the present invention will be further described in detail, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, changes and advantages conceivable by those skilled in the art are all included in the present invention, and the appended claims are the protection scope. The process, conditions, reagents, experimental methods, etc. for implementing the present invention are general knowledge and common knowledge in the art except for the content specifically mentioned below, and the present invention has no special limitation content.
实施例1 Example 1
室温下，量取N-叔丁氧羰基-L-异亮氨醛(3.22g，15mmol)，烯丙基溴(3.64g，30mmol)，在均匀搅拌下溶解在二氯甲烷(35mL)中，冰水浴冷却至0℃，再分别加入二水合二氯亚锡(6.78g，30mmol)，锌粉(1.96g，30mmol)，加完之后维持冰水浴，搅拌反应0.5小时，TLC监测确定反应终点。反应完成后，撤去冰水浴，过滤除去反应瓶中的固体，减压浓缩滤液，残余物直接通过柱层析分离纯化，洗脱剂为石油醚与乙酸乙酯体积比为5∶1的混合溶剂，得到顺式叔丁基(3R，4S，5S)-5-羟基-3-甲基-7-辛烯-4-氨基甲酸酯2.73g，其收率71％。 At room temperature, measure N-tert-butoxycarbonyl-L-isoleucinaldehyde (3.22g, 15mmol), allyl bromide (3.64g, 30mmol), dissolve in dichloromethane (35mL) under uniform stirring, Cool in an ice-water bath to 0°C, then add stannous dichloride dihydrate (6.78g, 30mmol) and zinc powder (1.96g, 30mmol) respectively. After the addition, keep the ice-water bath, stir and react for 0.5 hours, and monitor by TLC to determine the end point of the reaction. After the reaction was completed, the ice-water bath was removed, the solid in the reaction flask was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was directly separated and purified by column chromatography, and the eluent was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 5:1. , 2.73 g of cis-tert-butyl (3R, 4S, 5S)-5-hydroxy-3-methyl-7-octene-4-carbamate was obtained, and the yield was 71%.
1HNMR(400MHz，CDCl3)δ5.80-5.90(m，1H)，4.98-5.15(m，3H)，3.82-3.85(m，1H)，3.23-3.29(m，1H)，2.62(s，1H)，2.21-2.28(m，2H)，1.61-1.64(m，2H)，1.44(s，9H)，0.98-1.02(m，1H)，0.87-0.95(m，5H)。 1 HNMR (400MHz, CDCl 3 ) δ5.80-5.90(m, 1H), 4.98-5.15(m, 3H), 3.82-3.85(m, 1H), 3.23-3.29(m, 1H), 2.62(s, 1H), 2.21-2.28 (m, 2H), 1.61-1.64 (m, 2H), 1.44 (s, 9H), 0.98-1.02 (m, 1H), 0.87-0.95 (m, 5H).
实施例2 Example 2
室温下，量取N-叔丁氧羰基-L-异亮氨醛(3.22g，15mmol)，烯丙基溴(3.28g，27mmol)，在均匀搅拌下溶解在二氯甲烷(32mL)中，冰水浴冷却至0℃，再分别加入二水合二氯亚锡(6.10g，27mmol)，锌粉(1.76g，27mmol)，加完之后维持冰水浴，搅拌反应0.5小时，TLC监测确定反应终点。反应完成后，撤去冰水浴，过滤除去反应瓶中的固体，减压浓缩滤液，残余物直接通过柱层析分离纯化，洗脱剂为石油醚与乙酸乙酯体积比为5∶1的混合溶剂，得到顺式叔丁基(3R，4S，5S)-5-羟基-3-甲基-7-辛烯-4-氨基甲酸酯2.65g，其收率69％。 At room temperature, measure N-tert-butoxycarbonyl-L-isoleucinaldehyde (3.22g, 15mmol), allyl bromide (3.28g, 27mmol), dissolve in dichloromethane (32mL) under uniform stirring, Cool in an ice-water bath to 0°C, then add stannous dichloride dihydrate (6.10g, 27mmol) and zinc powder (1.76g, 27mmol) respectively. After the addition, keep the ice-water bath, stir and react for 0.5 hours, and monitor by TLC to determine the end point of the reaction. After the reaction was completed, the ice-water bath was removed, the solid in the reaction flask was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was directly separated and purified by column chromatography, and the eluent was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 5:1. , 2.65 g of cis-tert-butyl (3R, 4S, 5S)-5-hydroxy-3-methyl-7-octene-4-carbamate was obtained, and the yield was 69%.
1HNMR(400MHz，CDCl3)δ5.80-5.90(m，1H)，4.98-5.15(m，3H)，3.82-3.85(m，1H)，3.23-3.29(m，1H)，2.62(s，1H)，2.21-2.28(m，2H)，1.61-1.64(m，2H)，1.44(s，9H)，0.98-1.02(m，1H)，0.87-0.95(m，5H)。 1 HNMR (400MHz, CDCl 3 ) δ5.80-5.90(m, 1H), 4.98-5.15(m, 3H), 3.82-3.85(m, 1H), 3.23-3.29(m, 1H), 2.62(s, 1H), 2.21-2.28 (m, 2H), 1.61-1.64 (m, 2H), 1.44 (s, 9H), 0.98-1.02 (m, 1H), 0.87-0.95 (m, 5H).
实施例3 Example 3
室温下，量取N-叔丁氧羰基-L-异亮氨醛(3.22g，15mmol)，烯丙基溴(4.0g，33mmol)，在均匀搅拌下溶解在二氯甲烷(35mL)中，冰水浴冷却至0℃，再分别加入二水合二氯亚锡(7.46g，33mmol)，锌粉(2.16g，33mmol)，加完之后维持冰水浴，搅拌反应0.5小时，TLC监测确定反应终点。反应完成后，撤去冰水浴，过滤除去反应瓶中的固体，减压浓缩滤液，残余物直接通过柱层析分离纯化，洗脱剂为石油醚与乙酸乙酯体积比为5∶1的混合溶剂，得到顺式叔丁基(3R，4S，5S)-5-羟基-3-甲基-7-辛烯-4-氨基甲酸酯2.69g，其收率70％。 At room temperature, measure N-tert-butoxycarbonyl-L-isoleucinaldehyde (3.22g, 15mmol), allyl bromide (4.0g, 33mmol), dissolve in dichloromethane (35mL) under uniform stirring, Cool in an ice-water bath to 0°C, then add stannous dichloride dihydrate (7.46g, 33mmol) and zinc powder (2.16g, 33mmol) respectively. After the addition, keep the ice-water bath, stir and react for 0.5 hours, and monitor by TLC to determine the end point of the reaction. After the reaction was completed, the ice-water bath was removed, the solid in the reaction flask was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was directly separated and purified by column chromatography, and the eluent was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 5:1. , 2.69 g of cis-tert-butyl (3R, 4S, 5S)-5-hydroxy-3-methyl-7-octene-4-carbamate was obtained, and the yield was 70%.
1HNMR(400MHz，CDCl3)δ5.80-5.90(m，1H)，4.98-5.15(m，3H)，3.82-3.85(m，1H)，3.23-3.29(m，1H)，2.62(s，1H)，2.21-2.28(m，2H)，1.61-1.64(m，2H)，1.44(s，9H)，0.98-1.02(m，1H)，0.87-0.95(m，5H)。 1 HNMR (400MHz, CDCl 3 ) δ5.80-5.90(m, 1H), 4.98-5.15(m, 3H), 3.82-3.85(m, 1H), 3.23-3.29(m, 1H), 2.62(s, 1H), 2.21-2.28 (m, 2H), 1.61-1.64 (m, 2H), 1.44 (s, 9H), 0.98-1.02 (m, 1H), 0.87-0.95 (m, 5H).
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187820A (en) * | 2016-07-02 | 2016-12-07 | 深圳市康立生生物科技有限公司 | A kind of preparation method of bambuterol impurity B |
| CN106632998A (en) * | 2016-12-30 | 2017-05-10 | 中国石油大学(华东) | Barbier-reaction-based method for preparing high molecules |
| CN106700036A (en) * | 2016-12-30 | 2017-05-24 | 中国石油大学(华东) | Macromolecule with aggregation-induced luminescence effect, and preparation method of macromolecule |
| CN107954904A (en) * | 2016-10-14 | 2018-04-24 | 复旦大学 | The preparation method of active compound for anti tumor aplysiatoxin Dil fragments |
| CN109021065A (en) * | 2017-06-08 | 2018-12-18 | 复旦大学 | A method of preparing high anti-cancer activity peptide aplysiatoxin Dolastatin10 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102020589A (en) * | 2009-09-19 | 2011-04-20 | 浙江九洲药业股份有限公司 | Tert-butyl carbamate derivative and preparation method and application thereof |
| CN102146048A (en) * | 2010-02-06 | 2011-08-10 | 浙江九洲药业股份有限公司 | Lacosamide intermediate compound and preparation method and application thereof |
| WO2013072813A2 (en) * | 2011-11-17 | 2013-05-23 | Pfizer Inc. | Cytotoxic peptides and antibody drug conjugates thereof |
-
2014
- 2014-11-11 CN CN201410632877.2A patent/CN105566166A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102020589A (en) * | 2009-09-19 | 2011-04-20 | 浙江九洲药业股份有限公司 | Tert-butyl carbamate derivative and preparation method and application thereof |
| CN102146048A (en) * | 2010-02-06 | 2011-08-10 | 浙江九洲药业股份有限公司 | Lacosamide intermediate compound and preparation method and application thereof |
| WO2013072813A2 (en) * | 2011-11-17 | 2013-05-23 | Pfizer Inc. | Cytotoxic peptides and antibody drug conjugates thereof |
Non-Patent Citations (3)
| Title |
|---|
| CELLA, RODRIGO等: "Stereoselective synthesis of the dolastatin units by organotrifluoroborates additions to α-amino aldehydes", 《TETRAHEDRON LETTERS 》 * |
| PAOLA CIAPETTI, MAURIZIO TADDEI等: "CrCl2 mediated allylation of N-protected α-amino aldehydes. A versatile synthesis of polypeptides containing a hydroxyethylene isostere", 《TETRAHEDRON LETTERS》 * |
| 夏铃洁: "绿色Barbier反应及西他列汀侧链合成工艺的研究", 《中国优秀硕士论文全文数据库 工程科技Ⅰ辑》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187820A (en) * | 2016-07-02 | 2016-12-07 | 深圳市康立生生物科技有限公司 | A kind of preparation method of bambuterol impurity B |
| CN106187820B (en) * | 2016-07-02 | 2017-09-19 | 深圳市康立生生物科技有限公司 | A kind of preparation method of bambuterol impurity B |
| CN107954904A (en) * | 2016-10-14 | 2018-04-24 | 复旦大学 | The preparation method of active compound for anti tumor aplysiatoxin Dil fragments |
| CN106632998A (en) * | 2016-12-30 | 2017-05-10 | 中国石油大学(华东) | Barbier-reaction-based method for preparing high molecules |
| CN106700036A (en) * | 2016-12-30 | 2017-05-24 | 中国石油大学(华东) | Macromolecule with aggregation-induced luminescence effect, and preparation method of macromolecule |
| CN106700036B (en) * | 2016-12-30 | 2019-02-19 | 中国石油大学(华东) | A kind of polymer with aggregation-induced luminescence effect and preparation method thereof |
| CN109021065A (en) * | 2017-06-08 | 2018-12-18 | 复旦大学 | A method of preparing high anti-cancer activity peptide aplysiatoxin Dolastatin10 |
| CN109021065B (en) * | 2017-06-08 | 2021-10-01 | 复旦大学 | A kind of method for preparing dolastatin Dolastatin10 |
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