TWI666211B - Method for preparation of quibetin and the intermediate thereof - Google Patents
Method for preparation of quibetin and the intermediate thereof Download PDFInfo
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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- C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D497/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
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Abstract
本發明提供了一種曲貝替定的新的製備方法，該方法由蕃紅菌素(safracin B)為起始原料經過一系列反應合成曲貝替定，該方法原料易得，合成步驟少，並且不使用劇毒的有機錫試劑，安全，低廉，具有較大的工業化應用價值。 The present invention provides a new preparation method of trabectedin. The method uses safracin B as a starting material to synthesize trabectedin through a series of reactions. The method is easy to obtain raw materials and has few synthesis steps. And it does not use highly toxic organotin reagents, which is safe, inexpensive, and has great industrial application value.
Description
本發明涉及化學領域，尤其涉及曲貝替定的製備方法及其合成中間體。 The present invention relates to the field of chemistry, in particular to a method for preparing trabectedin and its synthetic intermediate.
曲貝替定又名海鞘素743、Ecteinascidin 743、ET-743，是1969年從加勒比海鞘中分離得到的一種具有較高抗腫瘤活性的四氫異喹啉衍生物，於2007年在歐洲上市用於治療卵巢癌和軟組織肉瘤，2015年10月作為治療卵巢癌的孤兒藥在美國上市，屬於首個海洋來源的抗腫瘤藥物。 Trabectedin, also known as ascidin 743, Ecteinascidin 743, and ET-743, is a tetrahydroisoquinoline derivative with high antitumor activity isolated from the Caribbean ascidian in 1969. It was marketed in Europe in 2007. For the treatment of ovarian cancer and soft tissue sarcoma, it was marketed in the United States in October 2015 as an orphan drug for ovarian cancer and is the first marine-derived antitumor drug.
目前曲貝替定的製備方法主要有以下幾種： At present, the preparation methods of trabectedin mainly include the following:
1、生物提取：曲貝替定的最高獲取量為0.0001%(ACS Chem.Biol.2011,6,1244)，不利於曲貝替定的大量製備。 1. Biological extraction: The highest amount of trabectedin is 0.0001% (ACS Chem. Biol. 2011, 6, 1244), which is not conducive to the large-scale preparation of trabectedin.
2、全合成：全合成的合成路線主要有以下幾條：1)Corey等報導的全合成經36步反應合成曲貝替定，產率0.5%，該路線需要採用昂貴的手性配體和貴金屬釕，以及在-78℃進行反應等苛刻的反應條件(J.Am.Chem.Soc.1996,118,9202-9203)；2)Fukuyama等報導的全合成經50步反應，產率0.56%，也需要採用昂貴的手性配體和貴金屬釕，此外，多次使用正丁基鋰這種易燃的危險試劑(J.Am.Chem.Soc.2002,124,6552-6554)；3)Zhu等報導的全合成路線經31步反應，產率1.7%，需要使用劇毒的氫氟酸以及危險的正丁基鋰(J.Am.Chem.Soc.2006,128,87-89)；4)Fukuyama等再次報導的一種新的全合成路線，經過30步反應，總產率1.3%，該合成中反復使用醋酸碘苯，以及昂貴的四氧化鋨、鈀催化劑(J.Am.Chem.Soc.2013,135,13684-13687)。通過以上報導的路線可以看出目前全合成的路線太長，操作複雜，昂貴試劑大量使用，產率低，不利於ET-743的大量生產。 2. Total synthesis: There are mainly the following synthetic routes: 1) The total synthesis reported by Corey et al. Synthesizes trabectedin through a 36-step reaction with a yield of 0.5%. This route requires the use of expensive chiral ligands and Precious metal ruthenium, and harsh reaction conditions such as reaction at -78 ° C (J. Am. Chem. Soc. 1996, 118, 9202-9203); 2) The total synthesis reported by Fukuyama et al. Was reacted in 50 steps with a yield of 0.56% It also requires the use of expensive chiral ligands and precious metal ruthenium. In addition, n-butyllithium, a flammable and dangerous reagent, has been used many times (J.Am.Chem.Soc.2002,124,6552-6554); 3) The total synthetic route reported by Zhu et al. Has a 31-step reaction with a yield of 1.7%, requiring the use of highly toxic hydrofluoric acid and dangerous n-butyl lithium (J. Am. Chem. Soc. 2006, 128, 87-89); 4 A new fully synthetic route reported by Fukuyama et al., After a 30-step reaction, the total yield was 1.3%. In this synthesis, iodobenzene acetate was repeatedly used, and the expensive osmium tetroxide and palladium catalyst (J.Am.Chem.Soc) .2013,135,13684-13687). It can be seen from the above reported routes that the current total synthesis route is too long, the operation is complicated, expensive reagents are used in large quantities, and the yield is low, which is not conducive to the mass production of ET-743.
3、半合成：西班牙PharmaMar公司報導了以氰基蕃紅菌素B (Caynosafracin B)為起始原料，經21步反應合成曲貝替定(化合物I)， 產率為1%(Org.Lett.,2000,16,2545-2548)。該半合成相對全合成路線較短，是目前工業化的合成路線，但是路線仍然較長，產率低。 3. Semi-synthetic: Spanish PharmaMar company reported (Caynosafracin B) as the starting material, and trabidine (compound I) was synthesized in 21 steps. The yield is 1% (Org. Lett., 2000, 16, 2545-2548). The semi-synthetic route is relatively short, which is the current industrial route, but the route is still long and the yield is low.
在以上半合成中，存在著關鍵中間體Xa-1，由氰基蕃紅菌素B製備得到Xa-1需通過15步反應，該反應路線長，且產率僅有4.8%，並且在由V製備Ⅵ時，需要使用劇毒有機錫試劑，以上都為ET-743的工業化生產帶來了巨大挑戰。 In the above semi-synthesis, there is a key intermediate Xa-1. The preparation of Xa-1 from cyanomycin B requires 15 steps. The reaction route is long and the yield is only 4.8%. V requires the use of highly toxic organotin reagents for the preparation of Ⅵ, all of which have brought great challenges to the industrial production of ET-743.
本發明所要解決的技術問題是現有技術中曲貝替定的製備尤其是曲貝替定的關鍵中間體Xa-1製備中存在的路線長，產率低，成本高，反應條件苛刻，操作複雜等缺陷。 The technical problem to be solved by the present invention is that in the prior art, the preparation of trabectedin, especially the key intermediate Xa-1 of trabectedin, has a long route, low yield, high cost, harsh reaction conditions, and complicated operations. And other defects.
本發明提供了一種安全、簡便、低廉製備曲貝替定及其中間體Ⅱa、Va、Ⅵa、Ⅶa、Ⅷa、Xa-1的新方法，該方法不使用劇毒的有機錫試劑，由蕃紅菌素(safracin B)合成Xa-1只需通過九步反應，大大簡化了曲貝替定和Xa-1的合成，具有較大的工業化應用價值。 The invention provides a safe, convenient and low-cost method for preparing trabectedin and its intermediates IIa, Va, Ⅵa, Ⅷa, Xa, Xa-1. The method does not use highly toxic organotin reagents. The synthesis of Xa-1 by safracin B only needs nine steps, which greatly simplifies the synthesis of trabectedin and Xa-1, and has great industrial application value.
在本發明的第一方面中，提供了一種製備曲貝替定和Xa的方法，所述方法包括下列步驟：
其中，R1為O和S；R2、R3為羥基保護基。 Among them, R1 is O and S; R2 and R3 are hydroxyl protecting groups.
該合成方法包括以下步驟：(1)Safracin B和異氰酸酯衍生物反應得到如式Ⅱa所示化合物：
其中，R1為O或S。 Wherein, R1 is O or S.
在優選的實施方案中，在步驟(1)中，所述異氰酸酯衍生物優選為異硫氰酸苯酯、異氰酸苯酯，更優選為異硫氰酸苯酯；Safracin B與異氰酸酯衍生物的摩爾比優選為1：1~10，更優選為1：6；反應的溫度優選為0~40℃，更優選為25℃；反應時間優選為2~48h，更優選24h。 In a preferred embodiment, in step (1), the isocyanate derivative is preferably phenyl isothiocyanate, phenyl isocyanate, and more preferably phenyl isothiocyanate; Safracin B and the isocyanate derivative The molar ratio is preferably 1: 1 to 10, more preferably 1: 6; the reaction temperature is preferably 0 to 40 ° C, more preferably 25 ° C; the reaction time is preferably 2 to 48h, and more preferably 24h.
(2)將化合物Ⅱa與氰化物反應得到如式Ⅲa所示化合物：
在優選的實施方案中，在步驟(2)中，所述氰化物優選為氰化 鈉，氰化鉀，更優選為氰化鈉；化合物Ⅱa與氰化物的摩爾比優選為1：1~10，更優選為1：2.5；反應溫度優選為-20~20℃，更優選為-10~-5℃；反應溶劑優選為四氫呋喃/水(v/v)=4~2：1，更優選為四氫呋喃/水(v/v)=4：1。 In a preferred embodiment, in step (2), the cyanide is preferably cyanide Sodium and potassium cyanide are more preferably sodium cyanide; the molar ratio of compound IIa to cyanide is preferably 1: 1 to 10, more preferably 1: 2.5; the reaction temperature is preferably -20 to 20 ° C, and more preferably- 10 ~ -5 ° C; the reaction solvent is preferably tetrahydrofuran / water (v / v) = 4 ~ 2: 1, and more preferably tetrahydrofuran / water (v / v) = 4: 1.
(3)化合物Ⅲa與三甲基氯矽烷發生Edman降解反應得到如式Ⅳa-1所示化合物：
其中，R1為O或S。 Wherein, R1 is O or S.
在優選的實施方案中，在步驟(3)中，化合物Ⅲa與三甲基氯矽烷的摩爾比優選為1：3~20，更優選為1：5.5；反應溶劑優選為有機溶劑，所述有機溶劑可以是任何適當的，包括但不限於優選為甲醇、乙醇、1,4-二氧六環、四氫呋喃；反應溫度優選為-20~50℃，更優選為0~5℃。 In a preferred embodiment, in step (3), the molar ratio of compound IIIa to trimethylchlorosilane is preferably 1: 3-20, more preferably 1: 5.5; the reaction solvent is preferably an organic solvent, and the organic The solvent may be any suitable, including, but not limited to, methanol, ethanol, 1,4-dioxane, and tetrahydrofuran; the reaction temperature is preferably -20 to 50 ° C, and more preferably 0 to 5 ° C.
(4)化合物Ⅳa-1經過與亞硝酸鈉和親核試劑發生重氮化和親核反應得到如式Va所示化合物：
其中，R2為羥基保護基。 Among them, R2 is a hydroxy protecting group.
在優選的實施方案中，在步驟(4)中，所述親核試劑優選為乙酸鈉、甲酸鈉、丙酸鈉，更優選為乙酸鈉；化合物Ⅳa-1與亞硝酸鈉、所述親核試劑的摩爾比優選為1：1~20：1~2，更優選為1：7.9：1.4；反應溶劑優選為有機溶劑或混合的有機溶劑，所述有機溶劑或混合溶劑可以是任何適當的，包括但不限於優選為二氯甲烷、四氫呋喃、乙腈、乙酸乙酯、或甲醇 與水、乙醇與水、四氫呋喃與水的混合溶劑；反應溫度優選為-10~30℃，更優選為-5~0℃。 In a preferred embodiment, in step (4), the nucleophile is preferably sodium acetate, sodium formate, sodium propionate, and more preferably sodium acetate; compound IVa-1 and sodium nitrite, the nucleophile The molar ratio is preferably 1: 1 to 20: 1 to 2, more preferably 1: 7.9: 1.4; the reaction solvent is preferably an organic solvent or a mixed organic solvent, and the organic solvent or mixed solvent may be any suitable, including It is not limited to dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate, or methanol. A mixed solvent with water, ethanol and water, and tetrahydrofuran and water; the reaction temperature is preferably -10 to 30 ° C, and more preferably -5 to 0 ° C.
(5)化合物Va同羥基保護劑反應得到如式Ⅵa所示化合物：
其中，R2為羥基保護基；R3為羥基保護基。 Among them, R2 is a hydroxyl protecting group; R3 is a hydroxyl protecting group.
在優選的實施方案中，在步驟(5)中，所述羥基保護劑優選為溴甲基甲醚、氯甲基甲醚、2-甲氧基乙氧基甲基氯，更優選為溴甲基甲醚；Va與羥基保護劑的摩爾比優選為1：1~20，更優選1：15；反應所用的鹼優選為N,N-二異丙基乙胺，三乙胺，氫化鈉，更優選為N,N-二異丙基乙胺；化合物Va與鹼的摩爾比優選為1：1~30，更優選1：20；反應溫度優選為-20~60℃，更優選為0~5℃。 In a preferred embodiment, in step (5), the hydroxyl protecting agent is preferably bromomethyl methyl ether, chloromethyl methyl ether, 2-methoxyethoxymethyl chloride, and more preferably bromomethyl Methyl ether; the molar ratio of Va to the hydroxyl protecting agent is preferably 1: 1-20, more preferably 1:15; the base used in the reaction is preferably N, N-diisopropylethylamine, triethylamine, sodium hydride, More preferred is N, N-diisopropylethylamine; the molar ratio of compound Va to the base is preferably 1: 1 to 30, more preferably 1:20; the reaction temperature is preferably -20 to 60 ° C, and more preferably 0 to 5 ° C.
(6)化合物Ⅵa經水解得到如式Ⅶa所示化合物：
其中，R2為羥基保護基；R3為羥基保護基。 Among them, R2 is a hydroxyl protecting group; R3 is a hydroxyl protecting group.
在優選的實施方案中，在步驟(6)中，所述水解反應優選在鹼催化下進行，所述鹼優選為無機鹼，所述無機鹼可以是任何適當的，包括但不限於優選為氫氧化鋰、氫氧化鈉、氫氧化鉀、碳酸鈉、碳酸鉀、碳酸銫；化合物Ⅵa與鹼的摩爾比優選為1：1~20，更優選為1：5.5。 In a preferred embodiment, in step (6), the hydrolysis reaction is preferably performed under base catalysis, the base is preferably an inorganic base, and the inorganic base may be any suitable, including but not limited to preferably hydrogen Lithium oxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate; the molar ratio of the compound VIa to the base is preferably 1: 1 to 20, and more preferably 1: 5.5.
(7)化合物Ⅶa經還原和環化反應得到如式Ⅷa所示化合物：
其中，R3為羥基保護基。 Among them, R3 is a hydroxyl protecting group.
在優選的實施方案中，在步驟(7)中，所述還原反應優選在鈀碳催化下進行，其中化合物Ⅶa與鈀碳的品質比優選為1：0.1~1，更優選為1：0.2；所述還原反應溫度優選為10~30℃，更優選為20~25℃；所述環化反應優選採用鹼催化進行環化反應，其中所述鹼優選為碳酸銫、氟化銫、碳酸鈉、碳酸鉀，更優選為碳酸銫，Ⅶa與鹼的摩爾比優選1：：15~5，更優選1：3；環化反應的溶劑優選為N,N-二甲基甲醯胺、二甲基亞碸、N,N-二甲基乙醯胺、乙腈、N-甲基吡咯烷酮，更優選為N,N-二甲基甲醯胺；所述環化反應溫度優選為50~110℃，更優選為95~110℃。 In a preferred embodiment, in step (7), the reduction reaction is preferably performed under the catalysis of palladium carbon, wherein the mass ratio of compound Ⅶa to palladium carbon is preferably 1: 0.1 ~ 1, and more preferably 1: 0.2; The reduction reaction temperature is preferably 10 to 30 ° C, and more preferably 20 to 25 ° C. The cyclization reaction is preferably catalyzed by a base, wherein the base is preferably cesium carbonate, cesium fluoride, sodium carbonate, Potassium carbonate is more preferably cesium carbonate, and the molar ratio of rhenium a to the base is preferably 1:15 to 5, more preferably 1: 3; the solvent for the cyclization reaction is preferably N, N-dimethylformamide, dimethyl Methylene, N, N-dimethylacetamide, acetonitrile, N-methylpyrrolidone, more preferably N, N-dimethylformamide, and the cyclization reaction temperature is preferably 50 to 110 ° C, more preferably It is preferably 95 to 110 ° C.
(8)化合物Ⅷa經氧化反應得到如式Ⅸa所示化合物：
其中，R3為羥基保護基。 Among them, R3 is a hydroxyl protecting group.
在優選的實施方案中，在步驟(8)中，所述氧化反應的氧化劑優選為苯亞硒酸酐、2-碘醯基苯甲酸，更優選為苯亞硒酸酐，化合物Ⅷa與氧化劑的摩爾比優選為1：1~2，更優選為1：1；反應溶劑優選為有機溶劑，所述有機溶劑可以是任何適當的，包括但不限於優選為二氯甲烷、四氫呋喃、乙酸乙酯、甲醇、乙醇、乙腈。 In a preferred embodiment, in step (8), the oxidizing agent of the oxidation reaction is preferably benzoselenoic anhydride, 2-iodofluorenylbenzoic acid, and more preferably benzoselenoic anhydride. The molar ratio of compound IXa to the oxidant It is preferably 1: 1 to 2, more preferably 1: 1; the reaction solvent is preferably an organic solvent, and the organic solvent may be any appropriate, including but not limited to preferably dichloromethane, tetrahydrofuran, ethyl acetate, methanol, Ethanol, acetonitrile.
(9)化合物Ⅸa與化合物XV經酯縮合反應得到如式Xa所示化合物：
其中，R3為羥基保護基。 Among them, R3 is a hydroxyl protecting group.
該反應參考文獻J.Am.Chem.Soc.1996,118,9202-9203製備方法。 This reaction refers to the preparation method of J. Am. Chem. Soc. 1996, 118, 9202-9203.
(10)化合物Xa經環合反應得到如式XIa所示化合物：
其中，R3為羥基保護基。 Among them, R3 is a hydroxyl protecting group.
該反應參考文獻J.Am.Chem.Soc.1996,118,9202-9203製備方法。 This reaction refers to the preparation method of J. Am. Chem. Soc. 1996, 118, 9202-9203.
(11)化合物XIa經酸催化脫保護得到如式XIIa-1所示化合物：
其中，R3為羥基保護基。 Among them, R3 is a hydroxyl protecting group.
在優選的實施方案中，在步驟(11)中，所述酸優選為三氟乙 酸、甲磺酸、對甲苯磺酸、苯磺酸，更優選為對甲苯磺酸；反應溫度優選為-10~30℃，更優選為20~30℃；化合物XIa與酸的摩爾比優選為1：4~15，更優選為1：5。 In a preferred embodiment, in step (11), the acid is preferably trifluoroethyl Acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, more preferably p-toluenesulfonic acid; the reaction temperature is preferably -10 to 30 ° C, more preferably 20 to 30 ° C; the molar ratio of the compound XIa to the acid is preferably 1: 4 to 15, more preferably 1: 5.
(12)將化合物XIIa-1的氨基轉化為酮羰基得到如式X Ⅲa-1所示化合物：
該反應參考文獻J.Am.Chem.Soc.1996,118,9202-9203製備方法。 This reaction refers to the preparation method of J. Am. Chem. Soc. 1996, 118, 9202-9203.
(13)化合物X Ⅲa-1與如式X Ⅵ所示化合物反應得到如式X Ⅳa-1所示化合物：
該反應參考文獻J.Am.Chem.Soc.2006,128,87-89製備方法。 This reaction refers to the preparation method of J. Am. Chem. Soc. 2006, 128, 87-89.
(14)化合物X Ⅳa-1經銅鹽催化將氰基轉化為羥基得到如式I所示化合物：
在優選的實施方案中，在步驟(14)中，所述銅鹽催化劑優選為氯化亞銅、溴化亞銅、碘化亞銅，硫酸亞銅，更優選為氯化亞銅；反應溫度優選為0~45℃，更優選為25~30℃；反應溶劑優選為乙腈水溶液、四氫呋喃水溶液，甲醇水溶液、二氯甲烷水溶液，更優選為四氫呋喃水溶液。 In a preferred embodiment, in step (14), the copper salt catalyst is preferably cuprous chloride, cuprous bromide, cuprous iodide, cuprous sulfate, and more preferably cuprous chloride; reaction temperature The temperature is preferably 0 to 45 ° C, and more preferably 25 to 30 ° C. The reaction solvent is preferably an acetonitrile aqueous solution, an aqueous tetrahydrofuran solution, a methanol aqueous solution, or a dichloromethane aqueous solution, and more preferably an aqueous tetrahydrofuran solution.
在本發明的一個優選的實施案例方案中，R1優選為S，R2優選為乙醯基，R3優選為甲氧基甲基(MOM)。 In a preferred embodiment of the present invention, R1 is preferably S, R2 is preferably ethenyl, and R3 is preferably methoxymethyl (MOM).
本發明原料Safracin B可以通過文獻(JP59225189，J.Antibiot.1983,36,1279-1283)成熟的發酵技術製備得到，並且可以得到公斤級的原料；本發明所述的化合物XV可以通過參考文獻(synthesis，1990，119，119-122)的方法製備得到，本發明所述的化合物X Ⅵ來源於市售。 The raw material Safracin B of the present invention can be prepared by a mature fermentation technology in the literature (JP59225189, J. Antibiot. 1983, 36, 1279-1283), and can obtain raw materials in the kilogram class; the compound XV according to the present invention can be obtained by reference ( synthesis, 1990, 119, 119-122), and the compound X VI according to the present invention is commercially available.
在一個特別優選的實施案例中，本發明提供了如式I所示的化合物的如下合成路線：
本發明，還提供一種如式Ⅱa所示的化合物，
其中，R1為O或S，優選為S。 Among them, R1 is O or S, and preferably S.
本發明，還提供一種如式Va所示的化合物，
其中，R2為羥基保護基，優選為乙醯基。 Among them, R2 is a hydroxy-protecting group, and is preferably an acetamyl group.
本發明，還提供一種如式Ⅵa所示的化合物，
其中，R2為羥基保護基，優選為乙醯基；R3為羥基保護基，優選為甲氧基甲基(MOM)。 Among them, R2 is a hydroxy protecting group, preferably an acetamyl group; R3 is a hydroxy protecting group, preferably a methoxymethyl group (MOM).
本發明，還提供一種如式Ⅶa所示的化合物，
其中，R3為羥基保護基，優選為甲氧基甲基(MOM)。 Among them, R3 is a hydroxy-protecting group, and preferably methoxymethyl (MOM).
本發明還提供一種如式Ⅷa所示的化合物，
其中，R3為羥基保護基，優選為甲氧基甲基(MOM)。 Among them, R3 is a hydroxy-protecting group, and preferably methoxymethyl (MOM).
本發明的優點在於：本發明提供的合成工藝構思巧妙，Ⅳa-1通過與亞硝酸鈉和親核試劑反應一步將氨基轉化為羥基保護的Va，減少了反應的步驟，提高了酚羥基在Va進行保護時合成Ⅵa的選擇性。而在Ⅵa合成Ⅶa時，通過一步反應脫除甲基和羥基的保護基，減少了反應的操作。本發明中不使用劇毒的有機錫試劑，減少了保護基的使用，使反應安全性和簡便性都大大提高。本發明以Safracin B為起始原料通過十四步反應合成曲貝替定(化合物I)，相較文獻(Org.Lett.,2000,16,2545-2548)報導的以Canyosarcin B經過二十一步反應合成曲貝替定縮短了七步反應，具有較大的工業化應用價值。 The advantage of the present invention is that the synthetic process concept provided by the present invention is clever. IVa-1 converts the amino group into a hydroxyl-protected Va by one step reaction with sodium nitrite and a nucleophile, which reduces the reaction steps and improves the phenolic hydroxyl group in Va. Selectivity for synthesis of VIa when protected. In the synthesis of VIIa from VIa, the protective groups of methyl and hydroxyl groups are removed by one step reaction, which reduces the operation of the reaction. The invention does not use highly toxic organotin reagent, reduces the use of protective groups, and greatly improves the safety and convenience of the reaction. The present invention uses Safracin B as a starting material to synthesize trabectedin (compound I) through a fourteen-step reaction. Compared with the literature (Org. Lett., 2000, 16, 2545-2548), it takes 21 to 21 The one-step reaction to synthesize trabectedin shortens the seven-step reaction and has great industrial application value.
本發明所使用的術語，除有相反的表述外，具有如下的含義： The terms used in the present invention have the following meanings, except to the contrary:
“烷基”指飽和的脂肪族烴基團，包括1至10個碳原子的直鏈和支鏈基團，優選包括1至6個碳原子。非限制性實施例包括但不限於甲基、乙基、正丙基、異丙基、正丁基、異丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、 2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或未取代的，當被取代時，取代基可以在任何可使用的連接點上被取代，優選為一個或多個以下基團，獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、鹵素、硫醇、輕基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、氧代。 "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl , 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl, Alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, light, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, Heteroalkoxy, cycloalkylthio, heterocycloalkylthio, oxo.
“羥基保護基”是本領域已知的適當的用於羥基保護的基團，參見文獻 "Hydroxy protecting group" is a suitable group for protecting hydroxy groups known in the art, see literature
("Protective Groups in Organic Synthesis",5Th Ed.T.W.Greene& P.G.M.Wuts)中的羥基保護基團。作為示例，優選的所述的羥基保護基可以是C1-10烷基或取代烷基，例如：甲基，叔丁基，烯丙基，苄基，甲氧基甲基，乙氧基乙基，2-四氫吡喃基(THP)等；可以是(C1-10烷基或芳基)3矽烷基，例如：三乙基矽基，三異丙基矽基，叔丁基二甲基矽基，叔丁基二苯基矽基等；可以是(C1-10烷基或芳香基)醯基，例如：甲醯基，乙醯基，苯甲醯基等；可以是(C1-6烷基或C6-10芳基)磺醯基；也可以是(C1-6烷氧基或C6-10芳基氧基)羰基。 ("Protective Groups in Organic Synthesis", 5Th Ed.T.W.Greene & P.G.M.Wuts). As an example, the preferred hydroxyl protecting group may be a C1-10 alkyl group or a substituted alkyl group, such as: methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl , 2-tetrahydropyranyl (THP), etc .; may be (C1-10 alkyl or aryl) 3 silyl, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethyl Silyl, tert-butyldiphenylsilyl, etc .; may be (C1-10 alkyl or aromatic) fluorenyl, for example: methylfluorenyl, ethylfluorenyl, benzamidine, etc .; may be (C1-6 Alkyl or C6-10aryl) sulfofluorenyl; may also be (C1-6alkoxy or C6-10aryloxy) carbonyl.
以下將結合具體實例詳細地解釋本發明，使得本專業技術人員更全面地理解本發明，具體實例僅用於說明本發明的技術方案，並不以任何方式限定本發明。 The following will explain the present invention in detail with specific examples, so that those skilled in the art can more fully understand the present invention. The specific examples are only used to explain the technical solution of the present invention, and do not limit the present invention in any way.
實施例1：製備化合物Ⅱa-1
於室溫下將Safracin B(51g)加入反應瓶中，加入二氯甲烷(100ml)溶清，滴加入異硫氰酸苯酯(76g)，攪拌反應24h，濃縮除去二氯甲烷，得棕色油狀物150g。(不進行純化接著下一步反應) Safracin B (51g) was added to the reaction bottle at room temperature, and dichloromethane (100ml) was added to dissolve the solution. Phenyl isothiocyanate (76g) was added dropwise. The reaction was stirred for 24h. The dichloromethane was removed by concentration to obtain a brown oil. 150g. (No purification followed by next reaction)
1H NMR(400MHZ，DMSO)δ：9.94(s,1H)，8.66(s,1H) 7.46-7.40(m,3H),7.36(t,J=8Hz,3H),7.15(t,J=7.6Hz,1H),6.20(s,1H),4.47(s,1H),4.36(t,J=7.2Hz,1H),3.99-3.63(m,5H),3.52(s,1H),3.33(s,3H),2.99(d,J=2.8Hz,1H),2.96-2.73(m,4H),2.16(s,3H),1.98(s,3H),1.84(s,3H),1.59(m,1H),1.15(d,J=6.1Hz,2H),0.46(d,J=2.8Hz,3H).MS：m/z(675),Found：658(M-H2O+H) 1 H NMR (400MHZ, DMSO) δ : 9.94 (s, 1H), 8.66 (s, 1H) 7.46-7.40 (m, 3H), 7.36 (t, J = 8Hz, 3H), 7.15 (t, J = 7.6 Hz, 1H), 6.20 (s, 1H), 4.47 (s, 1H), 4.36 (t, J = 7.2Hz, 1H), 3.99-3.63 (m, 5H), 3.52 (s, 1H), 3.33 (s , 3H), 2.99 (d, J = 2.8Hz, 1H), 2.96-2.73 (m, 4H), 2.16 (s, 3H), 1.98 (s, 3H), 1.84 (s, 3H), 1.59 (m, 1H), 1.15 (d, J = 6.1Hz, 2H), 0.46 (d, J = 2.8Hz, 3H). MS: m / z (675), Found: 658 (M-H2O + H)
實施例2：製備化合物Ⅲa-1
向實施例1所得油狀物中加入四氫呋喃(250ml)，乙酸(56ml)，降溫至-10℃，攪拌下滴加氰化鈉的水溶液(12g氰化鈉，100ml水)，加畢，反應0.5h。加入飽和碳酸鈉調節pH至10，加入乙酸乙酯(200ml)，分液，飽和食鹽水洗滌有機層2次，無水硫酸鈉乾燥有機層，抽濾，濃縮得油狀物，柱層析(石油醚：乙酸乙酯=4：1、3：1、2：1、1：1)得黃色固體54.9g，產率85%。 To the oil obtained in Example 1, tetrahydrofuran (250 ml) and acetic acid (56 ml) were added. The temperature was lowered to -10 ° C, and an aqueous solution of sodium cyanide (12 g of sodium cyanide, 100 ml of water) was added dropwise with stirring. After the addition, the reaction was 0.5. h. Saturated sodium carbonate was added to adjust the pH to 10, ethyl acetate (200 ml) was added, the layers were separated, and the organic layer was washed twice with saturated brine. The organic layer was dried over anhydrous sodium sulfate, suction filtered, and concentrated to give an oil. Ether: ethyl acetate = 4: 1, 3: 1, 2: 1, 1: 1) 54.9 g of a yellow solid was obtained with a yield of 85%.
1H NMR(400MHZ，DMSO)δ：9.87(s，1H)，8.55(s,1H)7.45-7.43(m,3H),7.36-7.32(m,2H),7.15-7.05(m,2H),6.22(s,1H),4.88(d,J=5.2Hz 1H),4.42(m,1H),4.39(m,1H),4.28(m,1H),4.13(s,1H),3.90(d,J=2.4Hz,1H),3.89(s,3H),3.87(m,1H),3.53(m,4H),3.11-2.96(m,3H),2.85-2.55(m,3H),2.11(s,3H),2.02(s,3H),1.82(s,3H),1.70-1.52(m,1H),0.55(d,J=6.8Hz,3H).MS：m/z(684),Found：685(M+H) 1 H NMR (400MHZ, DMSO) δ : 9.87 (s, 1H), 8.55 (s, 1H) 7.45-7.43 (m, 3H), 7.36-7.32 (m, 2H), 7.15-7.05 (m, 2H), 6.22 (s, 1H), 4.88 (d, J = 5.2Hz 1H), 4.42 (m, 1H), 4.39 (m, 1H), 4.28 (m, 1H), 4.13 (s, 1H), 3.90 (d, J = 2.4Hz, 1H), 3.89 (s, 3H), 3.87 (m, 1H), 3.53 (m, 4H), 3.11-2.96 (m, 3H), 2.85-2.55 (m, 3H), 2.11 (s , 3H), 2.02 (s, 3H), 1.82 (s, 3H), 1.70-1.52 (m, 1H), 0.55 (d, J = 6.8Hz, 3H). MS: m / z (684), Found: 685 (M + H)
實施例3：製備化合物Ⅳa-1
取化合物Ⅲa-1(25g)，加入70ml甲醇，冰浴降溫至0℃，滴加三甲基氯矽烷(25ml)，加畢，保溫反應3h，抽濾濾餅用二氯甲烷(20ml×2)洗滌，乾燥，得黃色固體13.8g，產率92%。 Take compound IIIa-1 (25g), add 70ml of methanol, cool to 0 ° C in an ice bath, add trimethylchlorosilane (25ml) dropwise, add heat, and incubate for 3h, filter the cake with dichloromethane (20ml × 2) ) Washed and dried to give 13.8 g of yellow solid with a yield of 92%.
1H NMR(400MHz,DMSO)δ 9.35(s,1H),7.53(s,3H),6.52(s,1H),5.06(s,1H),4.53(s,2H),4.14(d,J=14.6Hz,3H),3.97(s,4H),3.64(s,3H),3.28(s,1H),3.19-2.84(m,5H),2.20(s,3H),1.85(s,3H),1.74(dt,J=23.8,11.9Hz,1H).MS：m/z(514),Found：479(M-Cl) 1 H NMR (400MHz, DMSO) δ 9.35 (s, 1H), 7.53 (s, 3H), 6.52 (s, 1H), 5.06 (s, 1H), 4.53 (s, 2H), 4.14 (d, J = 14.6Hz, 3H), 3.97 (s, 4H), 3.64 (s, 3H), 3.28 (s, 1H), 3.19-2.84 (m, 5H), 2.20 (s, 3H), 1.85 (s, 3H), 1.74 (dt, J = 23.8,11.9Hz, 1H). MS: m / z (514), Found: 479 (M-Cl)
實施例4：製備化合物Va-1
取乙酸鈉(15g)，乙酸(91ml)，二氯甲烷(245ml)，水(120ml)，化合物Ⅳa-1(15g)加入反應瓶中，冰浴降溫至0℃，氮氣保護，滴加亞硝酸鈉的水溶液(亞硝酸鈉2.9g，水200ml)，加畢，保溫反應3h，飽和碳酸氫鈉調節pH至8，分液，有機層有飽和食鹽水洗滌，無水硫酸鈉乾燥有機層，抽濾，柱層析(石油醚：乙酸乙酯=6：1、5：1、4：1)得化合物Va-1(7.3g)，產率48%。 Add sodium acetate (15g), acetic acid (91ml), dichloromethane (245ml), water (120ml), compound IVa-1 (15g) to the reaction flask, cool to 0 ° C in an ice bath, protect with nitrogen, and add nitrite dropwise Aqueous sodium solution (2.9 g of sodium nitrite, 200 ml of water). After the addition, the reaction was held for 3 hours. The pH was adjusted to 8 with saturated sodium bicarbonate. The layers were separated. The organic layer was washed with saturated brine. Column chromatography (petroleum ether: ethyl acetate = 6: 1, 5: 1, 4: 1) gave compound Va-1 (7.3 g) with a yield of 48%.
1H NMR(400MHz,CDCl3)δ 6.48(s,1H),4.71(dd,J=11.5,3.1Hz,1H),4.21(d,J=1.6Hz,1H),4.13(s,1H),4.01(s,3H),3.95(d,J=1.9Hz,1H),3.76(s,3H),3.71-3.65(m,1H),3.47(d,J=6.9Hz,1H),3.21(d,J=11.1Hz,1H),3.13(dd,J=17.6,2.2Hz,1H),3.03(dd,J=18.1,7.9Hz,1H),2.61(d, J=18.1Hz,1H),2.38(s,3H),2.26(s,3H),1.96(s,3H),1.63(m,1H),1.40(s,3H),1.15(d,J=6.1Hz,1H).MS：m/z(521),Found：522(M+H) 1 H NMR (400MHz, CDCl3) δ 6.48 (s, 1H), 4.71 (dd, J = 11.5, 3.1Hz, 1H), 4.21 (d, J = 1.6Hz, 1H), 4.13 (s, 1H), 4.01 (s, 3H), 3.95 (d, J = 1.9Hz, 1H), 3.76 (s, 3H), 3.71-3.65 (m, 1H), 3.47 (d, J = 6.9Hz, 1H), 3.21 (d, J = 11.1Hz, 1H), 3.13 (dd, J = 17.6, 2.2Hz, 1H), 3.03 (dd, J = 18.1, 7.9Hz, 1H), 2.61 (d, J = 18.1Hz, 1H), 2.38 ( s, 3H), 2.26 (s, 3H), 1.96 (s, 3H), 1.63 (m, 1H), 1.40 (s, 3H), 1.15 (d, J = 6.1Hz, 1H). MS: m / z (521), Found: 522 (M + H)
實施例5：製備化合物Ⅵa-1
取化合物Va-1(1g)，乙腈(10ml)，N,N-二異丙基乙胺(4.8g)，冰浴降溫至0℃，滴加溴甲基甲醚(3.6g)的乙腈溶液(10ml)，加畢，升溫至室溫反應24h，用1M鹽酸調節pH至1，二氯甲烷提取，無水硫酸鈉乾燥有機層，抽濾，濃縮，得1.1g，產率100%。 Take compound Va-1 (1g), acetonitrile (10ml), N, N-diisopropylethylamine (4.8g), cool to 0 ° C in an ice bath, and add bromomethyl methyl ether (3.6g) in acetonitrile solution dropwise. (10ml). After the addition, the temperature was raised to room temperature for 24h, the pH was adjusted to 1 with 1M hydrochloric acid, and extracted with dichloromethane. The organic layer was dried with anhydrous sodium sulfate, filtered with suction, and concentrated to obtain 1.1g with a yield of 100%.
1H NMR(400MHz,CDCl3)δ 6.73(s,1H),5.16(q,J=6.0Hz,2H),4.67(dd,J=11.5,3.0Hz,1H),4.42(d,J=2.3Hz,1H),4.19(s,1H),4.01(s,3H),3.96(d,J=1.9Hz,1H),3.77-3.69(m,3H),3.67(dd,J=7.4,5.0Hz,2H),3.59(s,3H),3.35-3.22(m,1H),3.19-3.01(m,2H),2.69(d,J=18.2Hz,1H),2.45(s,3H),2.24(d,J=8.4Hz,3H),1.97(s,3H),1.67-1.49(m,1H),1.47-1.38(m,3H),MS：m/z(565),Found：566(M+H) 1 H NMR (400MHz, CDCl3) δ 6.73 (s, 1H), 5.16 (q, J = 6.0Hz, 2H), 4.67 (dd, J = 11.5,3.0Hz, 1H), 4.42 (d, J = 2.3Hz , 1H), 4.19 (s, 1H), 4.01 (s, 3H), 3.96 (d, J = 1.9Hz, 1H), 3.77-3.69 (m, 3H), 3.67 (dd, J = 7.4, 5.0Hz, 2H), 3.59 (s, 3H), 3.35-3.22 (m, 1H), 3.19-3.01 (m, 2H), 2.69 (d, J = 18.2Hz, 1H), 2.45 (s, 3H), 2.24 (d , J = 8.4Hz, 3H), 1.97 (s, 3H), 1.67-1.49 (m, 1H), 1.47-1.38 (m, 3H), MS: m / z (565), Found: 566 (M + H )
實施例6：製備化合物Ⅶa-1
取化合物Ⅵa-1(1.1g)加入四氫呋喃(22ml)，降溫至0℃，滴加0.5M的氫氧化鋰水溶液22ml，加畢，保溫反應12h，用0.5M鹽酸調節pH 至2，二氯甲烷提取，分液，用無水硫酸鈉乾燥有機層，抽濾，濃縮，得化合物Ⅵ(0.94g)，產率100%。 Take compound VIa-1 (1.1g), add tetrahydrofuran (22ml), lower the temperature to 0 ° C, dropwise add 22ml of 0.5M lithium hydroxide aqueous solution, add the solution, and incubate for 12h, adjust the pH with 0.5M hydrochloric acid It was extracted with dichloromethane and separated. The organic layer was dried over anhydrous sodium sulfate, filtered with suction, and concentrated to obtain compound VI (0.94 g) in a yield of 100%.
1H NMR(400MHz,CDCl3)δ 6.72(s,1H),5.32-5.05(m,2H),4.31(d,J=2.1Hz,1H),4.08(d,J=2.1Hz,1H),3.85(s,1H),3.79-3.66(m,4H),3.60(s,3H),3.48(dd,J=11.6,1.4Hz,1H),3.42(d,J=7,0Hz,1H),3.29(dt,J=11.2,2.8Hz,1H),3.15(dt,J=18.1,5.8Hz,2H),2.50(d,J=18.1Hz,1H),2.38(s,3H),2.22(s,3H),1.92(s,3H),1.64(m,1H).MS：m/z(509),Found：510(M+H) 1 H NMR (400MHz, CDCl3) δ 6.72 (s, 1H), 5.32-5.05 (m, 2H), 4.31 (d, J = 2.1Hz, 1H), 4.08 (d, J = 2.1Hz, 1H), 3.85 (s, 1H), 3.79-3.66 (m, 4H), 3.60 (s, 3H), 3.48 (dd, J = 11.6, 1.4Hz, 1H), 3.42 (d, J = 7, 0Hz, 1H), 3.29 (dt, J = 11.2,2.8Hz, 1H), 3.15 (dt, J = 18.1,5.8Hz, 2H), 2.50 (d, J = 18.1Hz, 1H), 2.38 (s, 3H), 2.22 (s, 3H), 1.92 (s, 3H), 1.64 (m, 1H). MS: m / z (509), Found: 510 (M + H)
實施例7：製備化合物Ⅷa-1
取化合物Ⅶa-1(0.7g)，N,N-二甲基甲醯胺(14ml)，加入氫化釜中，加入10%鈀碳(0.14g)，室溫下於1M氫氣壓力下攪拌反應5h，抽濾，加入碳酸銫(0.5g)，溴氯甲烷(4ml)，氮氣保護下，升溫至100℃，反應1h，抽濾，加入飽和食鹽水(100ml)，乙酸乙酯(40ml)，分液，有機層用無水硫酸鈉乾燥，抽濾，濃縮，柱層析純化，得化合物Ⅷa-1(0.36g)，產率41%。 Take compound Ⅶa-1 (0.7g), N, N-dimethylformamide (14ml), add it to a hydrogenation kettle, add 10% palladium on carbon (0.14g), and stir the reaction at room temperature under 1M hydrogen pressure for 5h , Suction filtration, add cesium carbonate (0.5g), bromochloromethane (4ml), warm to 100 ° C under nitrogen protection, react for 1h, suction filter, add saturated brine (100ml), ethyl acetate (40ml), separate The organic layer was dried over anhydrous sodium sulfate, filtered with suction, concentrated, and purified by column chromatography to obtain compound VIIa-1 (0.36 g) in a yield of 41%.
1H NMR(400MHz,CDCl3)δ 6.71(s,1H),5.91(d,J=1.3Hz,1H),5.84(d,J=1.3Hz,1H),5.45(d,J=16.6Hz,1H),5.36-5.30(m,1H),5.19(t,J=6.5Hz,1H),4.28(d,J=2.3Hz,1H),4.10(d,J=2.5Hz,1H),4.05-3.98(m,1H),3.70(dd,J=15.8,5.3Hz,7H),3.56(m,1H),3.44-3.36(m,2H),3.18-3.07(m,2H),2.54(d,J=2.0Hz,1H),2.38(d,J=5.7Hz,3H),2.25(d,J=11.3Hz,3H),2.10(s,3H),1.84(dd,J=15.2,11.8Hz,2H).MS：m/z(523),Found：524(M+H) 1 H NMR (400MHz, CDCl3) δ 6.71 (s, 1H), 5.91 (d, J = 1.3Hz, 1H), 5.84 (d, J = 1.3Hz, 1H), 5.45 (d, J = 16.6Hz, 1H ), 5.36-5.30 (m, 1H), 5.19 (t, J = 6.5Hz, 1H), 4.28 (d, J = 2.3Hz, 1H), 4.10 (d, J = 2.5Hz, 1H), 4.05-3.98 (m, 1H), 3.70 (dd, J = 15.8,5.3Hz, 7H), 3.56 (m, 1H), 3.44-3.36 (m, 2H), 3.18-3.07 (m, 2H), 2.54 (d, J = 2.0Hz, 1H), 2.38 (d, J = 5.7Hz, 3H), 2.25 (d, J = 11.3Hz, 3H), 2.10 (s, 3H), 1.84 (dd, J = 15.2, 11.8Hz, 2H ) .MS: m / z (523), Found: 524 (M + H)
實施例8：製備化合物Ⅸa-1
取化合物Ⅷa-1(0.25g)，加入二氯甲烷(15ml)溶清，降溫至 -10℃，加入70%苯亞硒酸酐(0.25g)，攪拌0.5h，加入水(20ml)猝滅反應，分液，無水硫酸鈉乾燥有機層，濃縮至乾，柱層析純化得化合物Ⅸa-1(0.30g)，產率100%。 Take compound Ⅷa-1 (0.25g), add dichloromethane (15ml) to dissolve, and lower the temperature to At -10 ° C, add 70% benzoselenoic anhydride (0.25g), stir for 0.5h, quench the reaction with water (20ml), separate the layers, dry the organic layer over anhydrous sodium sulfate, concentrate to dryness, and purify by column chromatography to obtain compound Ⅸa -1 (0.30 g), yield 100%.
1H NMR(400MHz,CDCl3)δ6.71(s,1H),5.84(s,1H),5.16(s,2H),4.10(m,2H),3.92(s,3H),3.83(m,1H),3.75(m,1H),3.58(m,1H),3.52(s,3H),3.34(m,1H),3.04(m,1H),2.73-2.65(m,1H),2.62(d,J=18Hz,1H),2.32(s,3H),2.27(s,3H),2.25-2.19(m,1H),2.02(m,2H),1.80(s,3H).MS：m/z(539),Found：540(M+H) 1 H NMR (400MHz, CDCl3) δ 6.71 (s, 1H), 5.84 (s, 1H), 5.16 (s, 2H), 4.10 (m, 2H), 3.92 (s, 3H), 3.83 (m, 1H ), 3.75 (m, 1H), 3.58 (m, 1H), 3.52 (s, 3H), 3.34 (m, 1H), 3.04 (m, 1H), 2.73-2.65 (m, 1H), 2.62 (d, J = 18Hz, 1H), 2.32 (s, 3H), 2.27 (s, 3H), 2.25-2.19 (m, 1H), 2.02 (m, 2H), 1.80 (s, 3H). MS: m / z ( 539), Found: 540 (M + H)
實施例9：製備化合物Xa-1
取化合物Ⅸa-1(0.20g),X V(0.24g)加入二氯甲烷(10ml)中，1-(3-二甲氨基丙基)-3-乙基碳二亞胺鹽酸鹽(0.17g)，4-二甲氨基吡啶(0.11g)，於室溫下反應5h，停止反應，加入碳酸氫鈉洗滌，分液，無水硫酸鈉乾燥有機層，抽濾，濃縮，柱層析(石油醚：乙酸乙酯=5：1、4：1、3：1、2：1、1：1)得Xa-1(0.23g)，產率70%。 Take compound Ⅸa-1 (0.20g), XV (0.24g) and add to dichloromethane (10ml), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.17g ), 4-dimethylaminopyridine (0.11g), react at room temperature for 5h, stop the reaction, wash with sodium bicarbonate, separate the layers, dry the organic layer over anhydrous sodium sulfate, suction filter, concentrate, and column chromatography (petroleum ether) : Ethyl acetate = 5: 1, 4: 1, 3: 1, 2: 1, 1: 1) to obtain Xa-1 (0.23 g) with a yield of 70%.
1H NMR(400MHz,CDCl3)δ7.73-7.63(m,4H),7.42-7.30(m,4H),6.65-6.56(m,1H),5.74(s,1H),5.65(s,1H),5.31(s,1H),5.05(m,1H),4.70-4.30(m,2H),4.30-4.12(m,3H),4.08-3.70(m,3H),3.64(s,3H),3.52(m, 3H),3.34(s,1H),3.19(s,2H),3.17-2.90(m,3H),2.60-2.05(m,8H),2.38(d,J=5.7Hz,3H),1.79(s,3H),1.45(s,8H).MS：m/z(920),Found：921(M+H) 1 H NMR (400MHz, CDCl3) δ 7.73-7.63 (m, 4H), 7.42-7.30 (m, 4H), 6.65-6.56 (m, 1H), 5.74 (s, 1H), 5.65 (s, 1H) , 5.31 (s, 1H), 5.05 (m, 1H), 4.70-4.30 (m, 2H), 4.30-4.12 (m, 3H), 4.08-3.70 (m, 3H), 3.64 (s, 3H), 3.52 (m, 3H), 3.34 (s, 1H), 3.19 (s, 2H), 3.17-2.90 (m, 3H), 2.60-2.05 (m, 8H), 2.38 (d, J = 5.7Hz, 3H), 1.79 (s, 3H), 1.45 (s, 8H). MS: m / z (920), Found: 921 (M + H)
實施例10：製備化合物XIa-1
取二甲基亞碸(1.6ml)加入二氯甲烷(88ml)中，降內溫至-78℃，滴加三氟甲磺酸酐(1.53ml)與二氯甲烷(1ml)的混合溶液，控溫低於-74℃，加畢，保溫反應20min，滴加Xa-1(4.18g)的二氯甲烷溶液(58ml)，滴加過程中控溫小於-76℃，加畢，升溫至-40℃下反應，顏色由黃色變為墨綠色，反應40min，滴加N,N-二異丙基乙胺(6.3ml)與二氯甲烷(4ml)的混合溶液，加畢，緩慢升溫至0℃，反應液由墨綠色變為黃色，反應40min，加入叔丁醇(1.7ml)與二氯甲烷(1ml)的混合溶液，保溫反應20min，滴加1,1,3,3-四甲基-2-叔丁基胍(5.4ml)與二氯甲烷(4ml)的混合溶液，加畢升溫至23℃，反應40min，滴加入醋酐(4.2ml)與二氯甲烷(4ml)的混合溶液，加畢，室溫反應1h，TLC檢測反應完畢，停止反應，加入飽和氯化銨洗滌二次，飽和食鹽水洗滌二次，無水硫酸鈉乾燥，抽濾，濃縮，柱層析(乙酸乙酯：石油醚=10：1、8：1、6：1、5：1、4：1)，得產物1.54g，產率44%。 Dimethyl sulfene (1.6 ml) was added to dichloromethane (88 ml), the internal temperature was lowered to -78 ° C, and a mixed solution of trifluoromethanesulfonic anhydride (1.53 ml) and dichloromethane (1 ml) was added dropwise. When the temperature is lower than -74 ℃, the reaction temperature is kept constant for 20min after the addition, and the dichloromethane solution (58ml) of Xa-1 (4.18g) is added dropwise. During the dropwise addition, the temperature is controlled to be lower than -76 ℃. Reaction at ℃, the color changed from yellow to dark green, and the reaction was carried out for 40min. A mixed solution of N, N-diisopropylethylamine (6.3ml) and dichloromethane (4ml) was added dropwise. After the addition was completed, the temperature was slowly raised to 0 ° C. The reaction solution changed from dark green to yellow. The reaction was carried out for 40 minutes. A mixed solution of tert-butanol (1.7 ml) and dichloromethane (1 ml) was added, and the reaction was held for 20 minutes. 1,1,3,3-tetramethyl- The mixed solution of 2-tert-butylguanidine (5.4ml) and dichloromethane (4ml) was heated up to 23 ° C and reacted for 40min. A mixed solution of acetic anhydride (4.2ml) and dichloromethane (4ml) was added dropwise. After completion of the addition, the reaction was performed at room temperature for 1 hour. The reaction was detected by TLC. The reaction was stopped. The reaction was washed with saturated ammonium chloride twice, washed with saturated brine twice, dried over anhydrous sodium sulfate, filtered with suction, concentrated, and subjected to column chromatography (ethyl acetate: Petroleum ether = 10: 1, 8: 1 6: 1,5: 1,4: 1) to give 1.54 g product, 44% yield.
1H NMR(400MHz,CDCl3)δ 6.79(s,1H),6.09(s,1H),5.99(s,1H),5.20(d,J=5.2Hz,2H),5.14(d,J=5.2Hz,1H),5.02(d,J=11.6Hz,1H),4.63(d,J=9.1Hz,1H),4.49(s,1H),4.29(m,3H),4.16(t,J=12.6Hz,2H),3.78(s,3H),3.57(s,3H),3.42(s,2H),2.93(s,2H),2.80(s,1H),2.37-2.29(m,6H),2.25-2.14(m,4H),2.05(m,4H),1.45(s,9H).MS：m/z(766),Found：767(M+H) 1 H NMR (400MHz, CDCl3) δ 6.79 (s, 1H), 6.09 (s, 1H), 5.99 (s, 1H), 5.20 (d, J = 5.2Hz, 2H), 5.14 (d, J = 5.2Hz , 1H), 5.02 (d, J = 11.6Hz, 1H), 4.63 (d, J = 9.1Hz, 1H), 4.49 (s, 1H), 4.29 (m, 3H), 4.16 (t, J = 12.6Hz , 2H), 3.78 (s, 3H), 3.57 (s, 3H), 3.42 (s, 2H), 2.93 (s, 2H), 2.80 (s, 1H), 2.37-2.29 (m, 6H), 2.25- 2.14 (m, 4H), 2.05 (m, 4H), 1.45 (s, 9H). MS: m / z (766), Found: 767 (M + H)
實施例11：製備化合物XIIa-1
取XIa-1(0.34g)，加入對甲苯磺酸(0.68g)，二氯甲烷(18ml)於室溫下攪拌反應4h，停止反應，將反應液滴加入碳酸氫鈉的水溶液中，分液，水層用二氯甲烷(10ml×2)提取，合併有機層，無水硫酸鈉乾燥，抽濾，濃縮至乾，得XIIa-1(0.28g)，產率100%。 Take XIa-1 (0.34g), add p-toluenesulfonic acid (0.68g), and dichloromethane (18ml) stir the reaction at room temperature for 4h, stop the reaction, add the reaction drop to an aqueous solution of sodium bicarbonate, and separate the liquid. The aqueous layer was extracted with dichloromethane (10 ml × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered with suction, and concentrated to dryness to obtain XIIa-1 (0.28 g) in a yield of 100%.
1H NMR(400MHz,CDCl3)δ 6.51(s,1H),6.05(m,2H),5.75(s,1H),5.01(d,J=11.6Hz,2H),4.52(m,1H),4.27(m,2H),4.14(m,2H),3.78(s,3H),3.40(m,2H),3.24(t,J=6.4Hz,1H),2.89(s,2H),2.80(m,2H),2.30-2.10(m,2H),2.30(s,3H),2.28(s,3H),2.17(s,3H),2.02(s,3H).MS：m/z(622),Found：623(M+H) 1 H NMR (400MHz, CDCl3) δ 6.51 (s, 1H), 6.05 (m, 2H), 5.75 (s, 1H), 5.01 (d, J = 11.6Hz, 2H), 4.52 (m, 1H), 4.27 (m, 2H), 4.14 (m, 2H), 3.78 (s, 3H), 3.40 (m, 2H), 3.24 (t, J = 6.4Hz, 1H), 2.89 (s, 2H), 2.80 (m, 2H), 2.30-2.10 (m, 2H), 2.30 (s, 3H), 2.28 (s, 3H), 2.17 (s, 3H), 2.02 (s, 3H). MS: m / z (622), Found : 623 (M + H)
實施例12：製備化合物X Ⅲa-1
取XIIa-1(100mg)，加入無水吡啶鹽(450mg)，二氯甲烷(5ml)和N,N-二甲基甲醯胺(5ml)的混合溶劑，於室溫下攪拌反應1h，降溫至0℃，滴加DBU與二氯甲烷的混合溶液(5ml二氯甲烷)，加畢升溫至室溫反應0.5h，降溫至0℃，加入5ml的飽和草酸溶液，升溫至室溫攪拌1h，分層，用飽和食鹽水洗滌二氯甲烷，無水硫酸鈉乾燥，柱層析(乙酸乙酯：石油醚=6：1、5：1、4：1、3：1、2：1、1：1)，得X Ⅲa-150mg，產率50%。 Take XIIa-1 (100 mg), add anhydrous pyridine salt (450 mg), a mixed solvent of dichloromethane (5 ml) and N, N-dimethylformamide (5 ml), stir the reaction at room temperature for 1 h, and lower the temperature to At 0 ° C, a mixed solution of DBU and dichloromethane (5ml of dichloromethane) was added dropwise. After completion of the reaction, the temperature was raised to room temperature and reacted for 0.5h. The temperature was lowered to 0 ° C, and 5ml of a saturated oxalic acid solution was added. The layer was washed with saturated dichloromethane, dried over anhydrous sodium sulfate, and column chromatography (ethyl acetate: petroleum ether = 6: 1, 5: 1, 4: 1, 3: 1, 2: 1, 1: 1). ) To obtain X IIIa-150 mg, yield 50%.
1H NMR(400MHz,CDCl3)δ 6.49(s,1H),6.10(s,1H),6.03(s, 1H),5.70(s,1H),5.09(d,J=11.6Hz,1H),4.66(br,1H),4.39(s,1H),4.24(d,J=4.8Hz,1H),4.22(d,J=11.6Hz,1H),4.16(s,1H),3.76(s,3H),3.54(d,J=4.8Hz,1H),3.43-3.40(m,1H),2.90(m,1H),2.83-2.56(m,2H),2,33(s,3H),2.24(s,3H),2.13(s,3H),2.04(s,3H)MS：m/z(621),Found：622(M+H) 1 H NMR (400MHz, CDCl3) δ 6.49 (s, 1H), 6.10 (s, 1H), 6.03 (s, 1H), 5.70 (s, 1H), 5.09 (d, J = 11.6Hz, 1H), 4.66 (br, 1H), 4.39 (s, 1H), 4.24 (d, J = 4.8Hz, 1H), 4.22 (d, J = 11.6Hz, 1H), 4.16 (s, 1H), 3.76 (s, 3H) , 3.54 (d, J = 4.8Hz, 1H), 3.43-3.40 (m, 1H), 2.90 (m, 1H), 2.83-2.56 (m, 2H), 2,33 (s, 3H), 2.24 (s , 3H), 2.13 (s, 3H), 2.04 (s, 3H) MS: m / z (621), Found: 622 (M + H)
實施例13：製備化合物X Ⅳa-1
取X Ⅲa-1(30mg)加入反應瓶中，加入胺(75mg)，4.5ml無水乙醇於室溫下攪拌1h，加入乙酸鈉(39mg)，接著反應4h，停止反應加入20ml乙酸乙酯和10ml水，分液，有機層用水洗滌二次，有機層用無水硫酸鈉乾燥，抽濾，濃縮，得X Ⅳa-1(35mg)，產率92%。 Take X Ⅲa-1 (30mg) into the reaction flask, add amine (75mg), stir 4.5ml of absolute ethanol at room temperature for 1h, add sodium acetate (39mg), then react for 4h, stop the reaction and add 20ml of ethyl acetate and 10ml Water, liquid separation, the organic layer was washed twice with water, the organic layer was dried over anhydrous sodium sulfate, filtered with suction, and concentrated to obtain X IVa-1 (35 mg), yield 92%.
1H NMR(400MHz,CDCl3)δ 6.60(s,1H),6.48(s,1H),6.45(s,1H),6,05(s,1H),5.98(s,1H),5.70(s,1H),5.36(s,1H),5.02(d,J=11.2Hz,1H),4.58(s,1H),4.33(s,1H),4.28(d,J=5.6Hz,1H),4.19(d,J=2.8Hz,1H),4.12(m,1H),3.79(s,3H),3.63(s,3H),3.50(d,J=5.0Hz,1H),3.42(m,1H),3.10(m,1H),2.94(m,2H),2.78(m,1H),2.62(m,1H),2.46(m,1H),2.35(m,1H),2.32(s,3H),2.27(s,3H),2.20(s,3H),2.08(m,1H),2.04(s,3H)MS：m/z(784),Found：785(M+H) 1 H NMR (400MHz, CDCl3) δ 6.60 (s, 1H), 6.48 (s, 1H), 6.45 (s, 1H), 6,05 (s, 1H), 5.98 (s, 1H), 5.70 (s, 1H), 5.36 (s, 1H), 5.02 (d, J = 11.2Hz, 1H), 4.58 (s, 1H), 4.33 (s, 1H), 4.28 (d, J = 5.6Hz, 1H), 4.19 ( d, J = 2.8Hz, 1H), 4.12 (m, 1H), 3.79 (s, 3H), 3.63 (s, 3H), 3.50 (d, J = 5.0Hz, 1H), 3.42 (m, 1H), 3.10 (m, 1H), 2.94 (m, 2H), 2.78 (m, 1H), 2.62 (m, 1H), 2.46 (m, 1H), 2.35 (m, 1H), 2.32 (s, 3H), 2.27 (s, 3H), 2.20 (s, 3H), 2.08 (m, 1H), 2.04 (s, 3H) MS: m / z (784), Found: 785 (M + H)
實施例14：製備化合物I
取X Ⅳa-1(30mg)加入反應瓶中，加入四氫呋喃(1.5ml)與水(0.5ml)的溶液，氯化亞銅(38mg)，氮氣保護、避光，於室溫下攪拌過夜，次日TLC檢測原料已反應完畢，加入氯化銨的飽和水溶液(20ml)、乙酸乙酯(20ml)，分液，有機層用飽和氯化銨洗滌二次，無水硫酸鈉乾燥，抽濾，濃縮得30mg，產率100%。 Take X Ⅳa-1 (30mg) into the reaction flask, add a solution of tetrahydrofuran (1.5ml) and water (0.5ml), cuprous chloride (38mg), protected by nitrogen and protected from light, and stir at room temperature overnight. Daily TLC tests that the raw materials have been reacted. Add a saturated aqueous solution of ammonium chloride (20 ml) and ethyl acetate (20 ml), and separate the layers. The organic layer is washed twice with saturated ammonium chloride, dried over anhydrous sodium sulfate, filtered with suction, and concentrated to obtain 30 mg, yield 100%.
1H NMR(400MHz,CDCl3)δ 6.60(s,1H),6.47(s,1H),6.44(s,1H),6.02(s,1H),5.93(s,1H),5.70(br,1H),5.39(br,1H),5.13(d,J=11.2Hz,1H),4.80(s,1H),4.48(s,1H),4.46(br,1H),4.16(d,J=4.2Hz,1H),4.05(dd,J=11.2,2.2Hz,1H),3.79(s,3H),3.61(s,3H),3.57(d,J=4.9Hz,1H),3.22(s,1H),3.12(m,1H),2.82-2.95(m,2H),2.80(m,1H),2.60(m,1H),2.48(m,1H),2.33(br,1H),2.32(s,3H),2.25(s,3H),2.20(s,3H),2.19(br,1H),2.03(s,3H)MS：m/z(761),Found：744(M-H2O+H) 1 H NMR (400MHz, CDCl3) δ 6.60 (s, 1H), 6.47 (s, 1H), 6.44 (s, 1H), 6.02 (s, 1H), 5.93 (s, 1H), 5.70 (br, 1H) , 5.39 (br, 1H), 5.13 (d, J = 11.2Hz, 1H), 4.80 (s, 1H), 4.48 (s, 1H), 4.46 (br, 1H), 4.16 (d, J = 4.2Hz, 1H), 4.05 (dd, J = 11.2, 2.2Hz, 1H), 3.79 (s, 3H), 3.61 (s, 3H), 3.57 (d, J = 4.9Hz, 1H), 3.22 (s, 1H), 3.12 (m, 1H), 2.82-2.95 (m, 2H), 2.80 (m, 1H), 2.60 (m, 1H), 2.48 (m, 1H), 2.33 (br, 1H), 2.32 (s, 3H) , 2.25 (s, 3H), 2.20 (s, 3H), 2.19 (br, 1H), 2.03 (s, 3H) MS: m / z (761), Found: 744 (M-H2O + H)
由於已根據其特殊的實施方案描述了本發明，某些修飾和等價變化對於熟習此領域的技術入員是顯而易見的且包括在本發明的範圍內。 Since the invention has been described in terms of its particular embodiments, certain modifications and equivalent variations will be apparent to those skilled in the art and are included within the scope of the invention.
本申請要求於2016年6月20日提交中國專利局、申請號為201610446335.5、發明名稱為“一種曲貝替定的製備方法及其中間體”的中國專利申請的優先權，其全部內容通過引用結合在本申請中。 This application claims priority from a Chinese patent application filed on June 20, 2016 with the Chinese Patent Office, application number 201610446335.5, and the invention name is "A Preparation Method of Trabectedin and Its Intermediate", the entire contents of which are incorporated by reference. Incorporated in this application.
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