CN110452213B - 一种胡椒碱的合成方法 - Google Patents
一种胡椒碱的合成方法 Download PDFInfo
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- MXXWOMGUGJBKIW-YPCIICBESA-N piperine Chemical compound C=1C=C2OCOC2=CC=1/C=C/C=C/C(=O)N1CCCCC1 MXXWOMGUGJBKIW-YPCIICBESA-N 0.000 title claims abstract description 30
- 229940075559 piperine Drugs 0.000 title claims abstract description 29
- WVWHRXVVAYXKDE-UHFFFAOYSA-N piperine Natural products O=C(C=CC=Cc1ccc2OCOc2c1)C3CCCCN3 WVWHRXVVAYXKDE-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 235000019100 piperine Nutrition 0.000 title claims abstract description 29
- 238000010189 synthetic method Methods 0.000 title description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 20
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 18
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 17
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 13
- 239000003495 polar organic solvent Substances 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 claims abstract description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000001590 oxidative effect Effects 0.000 claims abstract description 7
- 239000001301 oxygen Substances 0.000 claims abstract description 7
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 27
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 4
- 238000005580 one pot reaction Methods 0.000 claims description 4
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- -1 1, 2-methylenedioxyphenyl Chemical group 0.000 abstract description 2
- UPFOWRZRKRILHH-UHFFFAOYSA-N 5-(7aH-1,3-benzodioxol-3a-yl)pent-2-enal Chemical compound C1OC2(C(C=CC=C2)O1)CCC=CC=O UPFOWRZRKRILHH-UHFFFAOYSA-N 0.000 abstract 1
- 230000009435 amidation Effects 0.000 abstract 1
- 238000007112 amidation reaction Methods 0.000 abstract 1
- 230000003197 catalytic effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- JGTLDSRAUATRLK-ZPUQHVIOSA-N (2e,4e)-5-(1,3-benzodioxol-5-yl)penta-2,4-dienal Chemical compound O=C\C=C\C=C\C1=CC=C2OCOC2=C1 JGTLDSRAUATRLK-ZPUQHVIOSA-N 0.000 description 3
- RHBGITBPARBDPH-ZPUQHVIOSA-N (E,E)-piperic acid Chemical compound OC(=O)\C=C\C=C\C1=CC=C2OCOC2=C1 RHBGITBPARBDPH-ZPUQHVIOSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
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- 239000000047 product Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229910002666 PdCl2 Inorganic materials 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- JEDHEXUPBRMUMB-UHFFFAOYSA-N n,n-dimethylpyridin-3-amine Chemical compound CN(C)C1=CC=CN=C1 JEDHEXUPBRMUMB-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 235000002566 Capsicum Nutrition 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000006002 Pepper Substances 0.000 description 1
- 241000722363 Piper Species 0.000 description 1
- 235000016761 Piper aduncum Nutrition 0.000 description 1
- 235000017804 Piper guineense Nutrition 0.000 description 1
- 235000008184 Piper nigrum Nutrition 0.000 description 1
- 241000758706 Piperaceae Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000001361 allenes Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000002113 chemopreventative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
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- 235000013399 edible fruits Nutrition 0.000 description 1
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- 239000000706 filtrate Substances 0.000 description 1
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- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
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- 229910052723 transition metal Inorganic materials 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
本发明公开了一种胡椒碱的合成方法,其合成步骤是以5‑(1,2‑亚甲二氧基苯基)‑2‑戊烯醛为起始原料,使用钯催化剂,氧气为氧化剂,三氟乙酸为添加剂,在极性有机溶剂中,经一步氧化脱氢得到5‑(1,2‑亚甲二氧基苯基)‑2,4‑二戊烯醛,再经氧化,酰胺化,高收率的合成胡椒碱。本发明方法实现了通过钯催化氧化脱氢作为合成胡椒碱的关键步骤,高效,简洁的合成胡椒碱。其与传统方法相比操作简单,反应收率更高,环境友好,产率高,原子利用率高。
Description
技术领域
本发明涉及一种胡椒碱的合成方法,属于有机合成技术领域。
背景技术
胡椒科植物广泛分布于热带和亚热带地区,在传统医药系统中(如:中印医学体系)的应用已有数千年之久,其中胡椒碱Piperine是由成熟的胡椒果实中提取出的一类广谱类药物。最近的研究表明,胡椒碱具有多种生物活性,包括化学预防,抗氧化,免疫调节,抗癌,刺激,保护,抗炎,抗微生物和抗溃疡活性。目前胡椒碱Piperine主要从植物中提取分离,步骤冗长,效率低下,因此寻求用有机合成的方式取代天然提取将成为一种趋势。
目前已有的胡椒碱的合成路径多存在产率较低,需要剧烈的反应条件,所需试剂价格高等缺点,因此,寻找简易高效的合成胡椒碱的方法,具有非常重要的意义(J. Nutr. Biochem.2013, 24, 231–239;Compr. Rev. Food Sci. F.2017, 16, 124–140;Tetrahedron Lett.2000, 41, 2667–2670)。
近年来,利用过渡金属氧化脱氢策略构建碳碳双键的反应取得了很大发展,这类方法是直接通过切断连续的 C-H 键而构建碳碳双键,然而利用便宜易得的烯醛通过γ,δ-氧化脱氢的方法构建联烯还没有被人们报道。本发明报道了一种利用烯醛通过γ,δ-氧化脱氢的构建不饱和二烯的方法。这种方法用于制备不饱和二烯醛、酮不仅合成步骤非常简洁,而且节能环保,具有很好的经济效益和应用价值。本发明用γ,δ-氧化脱氢构建不饱和二烯醛,并以此作为关键步骤来合成胡椒碱。由于胡椒碱类化合物在药物分子中的重要性,对其合成显得尤为重要。
发明内容
本发明的目的在于提供一种简洁,高效,反应效率更高、环境友好、符合绿色化学要求的胡椒碱的合成方法。
本发明实现过程如下:
一种胡椒碱的合成方法,化合物II经过氧化和缩合得到,所述化合物II通过如下方法合成得到:以化合物I为起始原料,使用钯催化剂,氧气为氧化剂,三氟乙酸为添加剂,在极性有机溶剂中,经一步γ,δ-氧化脱氢得到化合物II,
上述钯催化剂选自Pd(OAc)2,Pd(TFA)2,Pd(PPh3)4,Pd2(dba)3,PdCl2,优选为Pd(OAc)2。
上述极性有机溶剂选自DMF、DMSO、CH3CN、THF,优选为DMSO。
上述胡椒碱的合成方法,包括以下步骤:
(1)以化合物I为起始原料,使用钯催化剂,氧气为氧化剂,三氟乙酸为添加剂,在极性有机溶剂中,经一步γ,δ-氧化脱氢得到化合物II,
(2)化合物II经琼斯试剂氧化得到化合物III,
(3)化合物III与哌啶缩合得到目标化合物胡椒碱,
上述钯催化剂选自Pd(OAc)2,Pd(TFA)2,Pd(PPh3)4,Pd2(dba)3,PdCl2,优选为Pd(OAc)2。
上述极性有机溶剂选自DMF、DMSO、CH3CN、THF,优选为DMSO。
本发明的优点:(1)本发明实现了γ,δ-氧化脱氢反应,此方法与传统方法相比原料易得,操作简单,底物适应范围更广,反应效率更高,环境友好,产率高,原子利用率高。(2)本发明应用于胡椒碱化合物的合成,高效的合成Piperine。具体实施方式
实施例1
化合物II合成
在一个100 mL的圆底烧瓶中,加入原料I(612 mg, 3 mmol),醋酸钯(6 mol%,0.18 mmol, 40.3 mg),将圆底烧瓶密封并抽成真空状态,用氧气求将圆底烧瓶填充。接下来,依次加入7.5 mL 处理好的DMSO,三氟乙酸(6.0 mmol,456 uL),所有物质添加完毕后,在氧气氛围中充分搅拌。反应混合液在80 ℃搅拌至TLC(薄层色谱)监测反应不再进行。反应完毕后,冷却至室温,混合液用100 mL乙酸乙酯分散,用5 mL水萃取有机相3次,再用5 mL饱和食盐水萃取有机相3次,接下来,有机相用无水硫酸钠干燥大于30 min。过滤,浓缩,柱色谱分离得到目标化合物II(产率91%)。
(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienal (II)产物为黄色固体。熔点77 – 78 oC。 R f = 0.45 (EtOAc / hexanes 1 : 10).1H NMR (400 MHz, CDCl3):δ= 9.59 (d, J = 8.0 Hz, 1H), 7.24 (dd, J = 14.9, 10.4 Hz, 1H), 7.08 – 6.75(m, 5H), 6.23 (dd, J = 15.1, 8.0 Hz, 1H), 6.01 (s, 2H). 13C NMR (100 MHz,CDCl3) : δ= 193.7, 152.5, 149.3, 148.5, 142.4, 131.0, 130.2, 124.6, 123.8,108.8, 106.2, 101.7.HRMS (ESI) for C12H10O3Na [M+Na+]: Calcd: 225.0522; Found:225.0506.IR (KBr): 2914, 1675,1599, 1495, 1444, 1359, 1296,1253, 1195,1154,1035, 983, 797 cm-1。
化合物III的合成
在一个50 mL的圆底烧瓶中,加入原料II(606 mg, 3 mmol),丙酮(15mL),在0 ℃加入1 mL琼斯试剂,反应体系搅拌至反应不再进行,加入异丙醇搅拌大于1小时,加入100mL乙酸乙酯分散,用每次20 mL水洗涤三次,饱和食盐水洗涤,有机相用无水硫酸钠干燥大于30 min。过滤,浓缩,柱色谱分离得到目标化合物III(产率83%)。
(2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienoic acid (III)产物为黄色固体。熔点194 – 195 oC。 R f = 0.40 (EtOAc / hexanes 1 : 4).1H NMR (400 MHz,DMSO-d 6 ): δ= 12.29 (s, 1H), 7.31 (ddd, J = 15.2, 6.6, 3.7 Hz, 1H), 7.24 (d, J= 1.2 Hz, 1H), 7.05 – 6.88 (m, 4H), 6.06 (s, 2H), 5.93 (d, J = 15.2 Hz, 1H).13C NMR (100 MHz, DMSO-d 6 ) : δ= 168.1, 148.6, 148.5, 145.1, 140.3, 131.0,125.3, 123.6, 121.6, 109.0, 106.2, 101.8.HRMS (ESI) for C12H10O4Na [M+Na+]:Calcd: 241.0471; Found: 241.0482.IR (KBr): 2921, 2544, 1679, 1601, 1459,1449, 1368, 1309, 1257, 1193, 1148, 1104, 1035, 998, 930, 851, 797, 607 cm-1。
化合物Piperine的合成
在一个无水无氧处理后的圆底烧瓶中准确称取III(218 mg,1 mmol)、六氢吡啶(102 mg,1.2 mmol),加入二氯甲烷使其完全溶解。氩气保护下,将二环己基碳二亚胺(DCC)(226 mg,1.1 mmol)和3-二甲氨基吡啶(DMAP)(13.2 mg, 0.11 mmol)溶于二氯甲烷后滴加到反应体系中,氮气保护下反应18 h,薄层色谱监测(至反应完毕。反应完毕后,抽滤多次,保留滤液,有机相用饱和氯化钠洗涤,无水硫酸钠干燥,浓缩,柱色谱分离得到目标化合物Piperine(产率71%)。
Piperine。产物为淡黄色固体。熔点121 – 122 oC。 R f = 0.42 (EtOAc / hexanes1 : 10)。1H NMR (400 MHz, CDCl3): δ= 7.40 (ddd, J = 14.6, 7.3, 2.9 Hz, 1H),6.97 (s, 1H), 6.88 (dd, J = 8.0, 0.9 Hz, 1H), 6.81 – 6.71 (m, 3H), 6.44 (d, J= 14.7 Hz, 1H), 5.96 (s, 2H), 3.57 (d, J = 44.1 Hz, 4H), 1.62 (dd, J = 28.2,4.5 Hz, 6H). 13C NMR (100 MHz, CDCl3) : δ= 165.4, 148.2, 148.1, 142.5, 138.2,131.0, 125.4, 122.5, 120.1, 108.5, 105.7, 101.3, 46.9, 43.3, 26.8, 25.7,24.7.HRMS (ESI) for C17H20NO3 [M+H+]: Calcd: 286.1438; Found: 286.1447.IR(KBr): 3007, 2938, 1634, 1583, 1489, 1444, 1363, 1252, 1194, 1132, 1027, 926,850 cm-1。
实施例2
发明人使用不同的钯催化剂、三氟乙酸添加剂和极性有机溶剂合成化合物II,化合物II收率
Claims (8)
2.根据权利要求1所述胡椒碱的合成方法,其特征在于:所述的钯催化剂为Pd(OAc)2。
3.根据权利要求1所述胡椒碱的合成方法,其特征在于:所述的极性有机溶剂选自DMF、DMSO、CH3CN、THF。
4.根据权利要求3所述胡椒碱的合成方法,其特征在于:所述的极性有机溶剂为DMSO。
6.根据权利要求5所述胡椒碱的合成方法,其特征在于:所述的钯催化剂为Pd(OAc)2。
7.根据权利要求5所述胡椒碱的合成方法,其特征在于:所述的极性有机溶剂选自DMF、DMSO、CH3CN、THF。
8.根据权利要求7所述胡椒碱的合成方法,其特征在于:所述的极性有机溶剂为DMSO。
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