CN104262229B - A kind of 2-phenyl replaces the preparation method of-3-benzoyl substituted indole - Google Patents

A kind of 2-phenyl replaces the preparation method of-3-benzoyl substituted indole Download PDF

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CN104262229B
CN104262229B CN201410417908.2A CN201410417908A CN104262229B CN 104262229 B CN104262229 B CN 104262229B CN 201410417908 A CN201410417908 A CN 201410417908A CN 104262229 B CN104262229 B CN 104262229B
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isopropoxy
methoxybenzene
methoxyl group
benzene
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CN104262229A (en
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孙青*
孙青�
张卫东
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Shandong Yi Tatsu Medical Technology Co Ltd
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Guangdong Yi Zhengda Pharmaceutical Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms

Abstract

The present invention relates to 2 phenyl and replace the preparation method of 3 benzoyl substituted indoles; specifically disclose a kind of 2 (3 ' hydroxyl 4 ' methoxyphenyl) 3 (3 "; 4 ", 5 " and trimethoxybenzoy) preparation method of 6 methoxy-Indoles (OXi8006).OXi8006 structural formula is as followsOXi8006 can produce good anti-tumor activity (IC by suppressing tubulin polymerization50=1.1 μMs), it is the clinical candidate compound of a critically important treatment tumor.The method synthesis OXi8006 using the present invention has that condition is simple, easily operation, reactions steps are short and the higher feature of total recovery.

Description

A kind of 2-phenyl replaces the preparation method of-3-benzoyl substituted indole
[technical field]
The present invention relates to compound field, specifically, be a kind of 2-(3 '-hydroxyl-4 '-methoxybenzene Base) preparation method of-3-(3 ", 4 ", 5 "-trimethoxybenzoy)-6-methoxy-Indole (OXi8006).
[background technology]
The discovery of the Antitumor Natural Products such as vinblastine, camptothecine makes people focus more on anti-tumor small molecular sky So compound structural modification, design and synthesize, especially there is the compound of indole core framing structure. 2-(3 '-hydroxyl-4 '-methoxyphenyl)-3-(3 ", 4 ", 5 " and-trimethoxybenzoy)-6-methoxy-Indole (OXi8006) it is one by suppression tubulin polymerization thus produce good anti-tumor activity and have 2,3- The small molecule, anti-tumor compound (IC50=1.1 μM) of disubstituted indole mother nucleus structure, with OXi8006 as elder generation Leading compound, Pharmaceutical Chemist has designed and synthesized a series of derivant with good anti-tumor activity, bag Including can the multiple people of Selective depression for the water-soluble phosphoric acid salt predrug OXi8007 that precursor synthesizes with OXi8006 Quasi-cancer cell strain and activity are better than precursor OXi8006 (GI50=36nM).
The synthetic method of the OXi8006 of document report mainly has two kinds at present:
Method one: with isovanillin as initiation material, reacts through five steps and obtains a bromoacetophenone, then with Aniline reaction constructs indole ring, introduces 3-position with trimethoxy-benzoyl chloride by friedel-crafts acylation the most again Benzoyl, finally obtains OXi8006.But eight step overall yield of reaction are only in about 10%, and its route There is two-step reaction need to carry out at 170 DEG C of high temperature.Main literature includes: 1. WO 2001019794A2；②US 20070082872A1；3. Bioorganic&medicinal chemistry, 2013,21,6831～6843；④ Journal of natural products, 2013,76,1668～1378.
Method two: first prepare 4-methoxyl group-3-isopropoxy benzene ethyl-acetylene, then with adjacent iodobenzene amide Et3N, Generate tolan under CuI, Pd (PPh3) 2Cl2 effect, add iodo trimethoxy-benzene, potassium carbonate subsequently Under carbon monoxide atmosphere, construct indole parent nucleus skeleton, then take off isopropyl protecting group and i.e. can get targeted Compound OXi8006 (J.Med.Chem.2002,45,2670～2673).
Although both the above method achieves the synthesis of OXi8006, but comprises following shortcoming: 1. route length step Rapid many, total recovery is low, and cost is high, is not suitable for constant and prepares；2. indivedual reactions need under 170 DEG C of high temperature anti- Should, reagent acyl chlorides to be used, condition is harsh, is corrosive and energy consumption is high；3. some reaction is used inflammable Explosive toxic gas CO, is unfavorable for preparing in a large number and security protection requirement height.
Therefore, the route that efficiently synthesizes finding compound OXi8006 for carrying out further with OXi8006 is Guide structure performs the derivatization modification and activity research is inquired into and is particularly important.
[summary of the invention]
It is an object of the invention to for deficiency of the prior art, it is provided that a kind of 2-(3 '-hydroxyl-4 '-methoxybenzene Base) preparation method of-3-(3 ", 4 ", 5 "-trimethoxybenzoy)-6-methoxy-Indole.
For achieving the above object, the present invention adopts the technical scheme that:
A kind of 2-(3 '-hydroxyl-4 '-methoxyphenyl)-3-(3 ", 4 ", 5 " and-trimethoxybenzoy)-6-methoxyl group Yin The preparation method of diindyl, comprises the following steps:
The first step: the synthesis of intermediate 3-isopropoxy-4-methoxybenzene ethyl-acetylene (1).
Second step: intermediate (1) and intermediate 3,4,5-Trimethoxybenzaldehyde (2) successively through nucleophilic addition and Oxidation reaction prepares arylalkyne ketone intermediate 3-(3-isopropoxy-4-methoxybenzene)-1-(3,4,5-trimethoxies Benzene)-2-alkynyl acetone (3).
3rd step: arylalkyne ketone intermediate (3) occurs cyclization anti-with 3-methoxyl group-6-iodo aniline (4) further Should, prepared compound 2-(4 '-methoxyl group-3 '-isopropyl phenyl)-3-(3 ", 4 ", 5 " and-trimethoxybenzoy)-6- Methoxy-Indole (5).
4th step: compound (5) selectivity is sloughed protection group isopropyl and realized the synthesis of OXi8006.
Described second step nucleophilic addition refers under solvent condition, intermediate 3-isopropoxy-4-methoxyl group The reaction that phenylacetylene (1) is occurred by base catalysis and compound 3,4,5-Trimethoxybenzaldehyde (2).
Described second step oxidation reaction refers to oxidized dose of the product of nucleophilic addition oxidation under solvent condition Anti-for intermediate 3-(3-isopropoxy-4-methoxybenzene)-1-(3,4,5-trimethoxy-benzene)-2-alkynyl acetone (3) Should.
Described 3rd step ring-closure reaction refers to intermediate 3-(3-isopropoxy-4-methoxybenzene)-1-(3,4,5-front threes Epoxide benzene)-2-alkynyl acetone (3) first occurs miscellaneous Michael's addition anti-with intermediate 3-methoxyl group-6-iodo aniline (4) Again through intramolecular Heck reaction cyclization, thus 2-aryl-3-aroyl indole ring mother nucleus structure should be constructed.
Described miscellaneous Michael addition reaction refers to intermediate 3-(3-isopropoxy-4-methoxybenzene)-1-(3,4,5-tri- Methoxybenzene)-2-alkynyl acetone (3) and intermediate 3-methoxyl group-6-iodo aniline (4) be under solvent and temperature conditions Generate the reaction of aryl amine propenone intermediate.
Described intramolecular Heck reaction refer to aryl amine propenone intermediate under solvent condition, via palladium-catalyzed dose And alkali effect generation coupling reaction generation 2-(4 '-methoxyl group-3 '-isopropyl phenyl)-3-(3 ", 4 ", 5 "-trimethoxies Base benzoyl)-6-methoxy-Indole (5).
Described 4th step selectivity deprotection reaction refers under solvent condition, and under reagent effect, selectivity takes off Go the reaction of isopropyl.
Concrete synthetic route chart is as shown in Figure 1.
Described second step nucleophilic addition use solvent be selected from: acetonitrile, benzene, toluene, dioxane, Oxolane, DMF and/or dimethyl sulfoxide, preferably dioxane and/or oxolane, Particularly preferably oxolane；Alkali used is selected from: sodium hydrogen, Sodamide., potassium tert-butoxide, n-BuLi, uncle Butyl lithium or diisopropylamine lithium, preferably n-BuLi, tert-butyl lithium or diisopropylamine Lithamide., the most excellent Select n-BuLi.
Described second step oxidation reaction use solvent be selected from: dichloromethane, acetonitrile, toluene, dioxane, Oxolane, DMF or dimethyl sulfoxide, preferably dichloromethane, dioxane or tetrahydrochysene Furan, particularly preferred oxolane；Oxidant used is selected from: manganese dioxide, sulfur trioxide pyridine, three Chromium oxide pyridine, pyridinium chlorochromate, selenium dioxide or Dess-Martin oxidant, preferably manganese dioxide or Dess-Martin oxidant, particularly preferred manganese dioxide.
Solvent used by the described 3rd miscellaneous Michael addition reaction of step is selected from: absolute methanol, N, N-dimethyl methyl Amide, dimethyl sulfoxide, DMF and water mixed solvent or absolute methanol and dimethyl sulfoxide Mixed solvent, preferably absolute methanol, dimethyl sulfoxide or absolute methanol and dimethyl sulfoxide mixed solvent, special Not preferably absolute methanol and dimethyl sulfoxide mixed solvent；Described absolute methanol mixes molten with dimethyl sulfoxide The volume proportion of agent is 1: 1～5: 1, preferably 1: 1～3: 1, particularly preferred 1.5: 1；Reaction temperature is 80～150 DEG C, Preferably 100 DEG C～130 DEG C, particularly preferred 115 DEG C～120 DEG C；Response time is 40～80 hours, preferably 50～70 Hour, particularly preferred 55～60 hours.
Solvent used by described 3rd step intramolecular Heck reaction is: acetonitrile, dioxane, oxolane, DMF or dimethyl sulfoxide, preferably acetonitrile, oxolane or DMF, Particularly preferably DMF；Palladium catalyst used is: Palladous chloride., palladium bromide, palladium, Tetra-triphenylphosphine palladium or three (dibenzalacetone) two palladium, preferably palladium or tetra-triphenylphosphine palladium, especially Preferably palladium；Alkali used is: Disilver carbonate, sodium acetate, potassium acetate or triethylamine, preferably potassium acetate or Triethylamine, particularly preferred triethylamine；Reaction temperature is 80～150 DEG C, preferably 100 DEG C～130 DEG C, the most excellent Select 115 DEG C～120 DEG C；Response time is 10～18 hours, preferably 12～16 hours, particularly preferred 13～14 Hour.
Solvent used by described 4th step selectivity deprotection reaction is: ether, acetonitrile, dioxane, two Chloromethanes, toluene, DMF or dimethyl sulfoxide, preferably dichloromethane or toluene, especially Preferably dichloromethane；Reagent used is: boron chloride, Boron tribromide, hydrobromic acid or hydrochloric acid, preferably Hydrochloric acid or boron chloride, particularly preferred boron chloride；Reaction temperature is-50～30 DEG C, preferably-30～0 DEG C, Particularly preferably-20～-15 DEG C；Response time is 1～5 hour preferably 1～3 hour, particularly preferred 1.5～2 hours.
The synthesis step of described intermediate 3-isopropoxy-4-methoxybenzene ethyl-acetylene (1) is:
1) by isovanillin, K2CO3It is dissolved in acetone, is stirred at room temperature, and be dividedly in some parts isopropyl bromide, Reaction is stirred at room temperature, it is thus achieved that oily liquids 3-isopropoxy-4-methoxybenzaldehyde；
2) by zinc powder, PPh3, CBr4It is dissolved in anhydrous methylene chloride, argon shield, stirs lower in 0 DEG C Add 3-isopropoxy-4-methoxybenzaldehyde, drip the complete room temperature that is warming up to again and continue stirring.React complete, Treated 4-(2,2-bis-bromo vinyl)-3-isopropoxy-1-methoxybenzene；
3) 4-(2,2-bis-bromo vinyl)-3-isopropoxy-1-methoxybenzene being dissolved in anhydrous THF, argon is protected Protect, stirring, drip n-BuLi THF solution, drip this temperature of complete holding and continue stirring, then be warming up to Room temperature continues stirring, reacts complete addition H2O, Et2O extracts, and saturated common salt is washed, and anhydrous sodium sulfate is done Dry, concentrate, chromatographic column obtains 3-isopropoxy-4-methoxybenzene ethyl-acetylene.
The invention has the advantages that: compared with prior art, the present invention has condition operation simple, easy, reaction Step is short and the higher feature of total recovery, is more suitable for laboratory and high-volume prepares target compound OXi8006 And analog.
[accompanying drawing explanation]
Accompanying drawing 1 is the synthetic route chart of OXi8006 of the present invention.
[detailed description of the invention]
The detailed description of the invention provided the present invention below elaborates.
Embodiment 1:
The first step: the synthesis of intermediate 3-isopropoxy-4-methoxybenzene ethyl-acetylene (1)
1) by isovanillin (5.0g, 32.86mmol), K2CO3(6.8g, 49.29mmol) is dissolved in acetone, It is stirred at room temperature, and is dividedly in some parts isopropyl bromide (8.1g, 65.72mmol).React after 48h is stirred at room temperature Finish.Treated acquisition oily liquids is 3-isopropoxy-4-methoxybenzaldehyde (5.8g, 91%yield).
2) by zinc powder (2.69g, 41.2mmol), PPh3(8.1g, 30.9mmol), CBr4(13.7g, 41.2 Mmol) it is dissolved in anhydrous methylene chloride, argon shield, in the lower dropping 3-isopropoxy-4-methoxy of 0 DEG C of stirring Benzaldehyde (2.0g, 10.3mmol), drips the complete room temperature that is warming up to again and continues stirring 4h.React complete, Treated greenish yellow solid be 4-(2,2-bis-bromo vinyl)-3-isopropoxy-1-methoxybenzene (3.24g, 90%yield).
3) 4-(2,2-bis-bromo vinyl)-3-isopropoxy-1-methoxybenzene (1.00g, 2.86mmol) is dissolved in Anhydrous THF, argon shield, in-78 DEG C of stirrings, slowly drip the n-BuLi THF solution of 1.6mol/L (5.34ml, 8.55mmol).Drip this temperature of complete holding and continue stirring 1h, then be warming up to room temperature and continue to stir Mix 1h.React complete addition 15ml H2O, Et2O extracts, and saturated common salt is washed, and anhydrous sodium sulfate is dried, Concentrate, chromatographic column (Pe/EtOAc=40: 1) white crystalline solid 3-isopropoxy-4-methoxybenzene ethyl-acetylene (1, 0.42g, 78%yield).1H NMR (500MHz, CDCl3) δ 7.09 (dd, J=8.3,1.9Hz, 1H), 7.01 (d, J=1.9Hz, 1H), 6.80 (d, J=8.3Hz, 1H), 4.51 (dt, J=12.2,6.1Hz, 1H), 3.85 (s, 3H), 2.98 (s, 1H), 1.36 (d, J=6.1Hz, 6H)；13C NMR (126MHz, CDCl3)δ 151.4,147.0,125.9,119.2,114.2,111.8,84.0,75.6,71.7,56.1,22.1.ESI-MS:[M+H]+ 191.1[M+Na]+213.2。
Second step: intermediate 3-(3-isopropoxy-4-methoxybenzene)-1-(3,4,5-trimethoxy-benzene)-2-alkynyl third The synthesis of ketone (3)
Intermediate 3-isopropoxy-4 methoxybenzene ethyl-acetylene (1) (0.40g, 2.10mmol) is dissolved in anhydrous THF, argon shield ,-78 DEG C of stirrings, slowly dropping 1.6mol/L n-BuLi THF solution (1.31ml, 2.10mmol), drip to drip again after this temperature of complete holding continues stirring 1h and be dissolved in the 3,4,5-of THF in advance TMB (2) (0.41g, 2.10mmol), is warming up to room temperature after this temperature stirring 0.5h and continues to stir Mix 2h.React complete, add H2O, EtOAc extract, and saturated common salt is washed, and anhydrous sodium sulfate is dried, Concentrating, chromatographic column (Pe/EtOAc=5: 1) obtains 0.71g solid chemical compound, and this solid is soluble in anhydrous CH2Cl2, Add MnO2(0.64g, 7.35mmol), 30 DEG C of stirring 10h.React complete, filter, concentrate, heavily tie The brilliant white solid that obtains is 3-(3-isopropoxy-4-methoxybenzene)-1-(3,4,5-trimethoxy-benzene)-2-alkynyl third Ketone (3) (0.65g, 80%yield).1H NMR (500MHz, CDCl3) δ 7.50 (s, 2H), 7.29 (d, J=1.8 Hz, 1H), 7.27 (d, J=1.8Hz, 1H), 7.17 (d, J=1.7Hz, 1H), 6.89 (d, J=8.4Hz, 1H), 4.54 (dt, J=12.1,6.1Hz, 1H), 3.96 (d, J=4.4Hz, 9H), 3.90 (s, 3H), 1.39 (d, J=6.1 Hz, 6H)；13C NMR (126MHz, CDCl3) δ 177.0,153.3,153.2,147.4,143.6,132.5, 127.5,119.7,111.98,111.9,107.0,94.5,86.5,71.9,61.2,56.4,56.2,22.1. ESI-MS:[M+H]+385.2[M+Na]+407.4.HRMS (ESI): m/z calcd for C22H24O6 [M+H]+: 385.1676, found 385.1689.
3rd step: compound 2-(4 '-methoxyl group-3 '-isopropyl phenyl)-3-(3 ", 4 ", 5 "-trimethoxybenzoyl Base) synthesis of-6-methoxy-Indole (5)
By intermediate 3-(3-isopropoxy-4-methoxybenzene)-1-(3,4,5-trimethoxy-benzene)-2-alkynyl acetone (3) (0.20g, 0.52mmol), 2-iodo-5-aminoanisole (4) (0.16g, 0.62mmol) are dissolved in absolute methanol With the mixed liquor (1.5: 1) of anhydrous DMSO, argon shield, at 120 DEG C, stir 60h.React complete, post layer Analysis (Pe/EtOAc=7: 1) obtains yellow solid intermediate.This intermediate is dissolved in dry DMF, adds palladium (11.6mg, 0.052mmol), triethylamine (0.21g, 2.08mmol), argon shield 120 DEG C stirring 14h. Reacting complete, column chromatography (Pe/EtOAc=5: 1) obtains yellow solid and is 2-(4 '-methoxyl group-3 '-isopropoxy benzene Base) and-3-(3 ", 4 ", 5 " and-trimethoxybenzoy)-6-methoxy-Indole (5) (131.4mg, 50%yield).1H NMR (500MHz, CDCl3) δ 8.61 (s, 1H), 7.93 (d, J=9.3Hz, 1H), 6.99 (s, 3H), 6.91 (dd, J=4.7,2.4Hz, 2H), 6.75 (dd, J=5.0,3.1Hz, 2H), 4.17 (dt, J=12.2,6.1Hz, 1H), 3.86 (s, 3H), 3.79 (s, 6H), 3.67 (s, 6H), 1.20 (d, J=6.1Hz, 6H).；13C NMR(126 MHz, CDCl3) δ 191.9,157.5,152.7,151.2,147.4,142.4,141.4,136.5,134.7,125.0, 123.4,122.6,121.1,117.5,112.9,111.8,107.5,94.7,71.9,60.9,56.1,55.9,29.8,22.1. ESI-MS:[M+H]+506.2[M+Na]+528.4.HRMS (ESI): m/z calcd for C29H31NO7 [M+H]+: 506.2173, found506.2158.
4th step: 2-(3 '-hydroxyl-4 '-methoxyphenyl)-3-(3 ", 4 ", 5 " and-trimethoxybenzoy)-6-methoxyl group The synthesis of indole (OXi8006)
By intermediate 2-(4 '-methoxyl group-3 '-isopropyl phenyl)-3-(3 ", 4 ", 5 "-trimethoxybenzoy)-6- Methoxy-Indole (5) (40mg, 0.079mmol) is dissolved in anhydrous methylene chloride, argon shield, stirs in-20 DEG C Mix, be slowly added dropwise the BCl of 1mol/L3Dichloromethane solution (0.316ml, 0.316mmol), drips complete Being warming up to room temperature and continue stirring 2h, react complete, add saturated aqueous common salt cancellation, dichloromethane extracts, anhydrous Sodium sulfate is dried, and thickness is prepared plate and obtained yellow solid OXi8006 (29mg, 78%yield).1H NMR(500 MHz, Acetone-d6) δ 7.89 (d, J=8.7Hz, 1H), 7.02 (d, J=2.3Hz, 1H), 6.92 (d, J=3.2 Hz, 3H), 6.86 (dd, J=8.7,2.3Hz, 1H), 6.83-6.81 (m, 1H), 6.79 (d, J=8.3Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.68 (s, 6H), 3.67 (s, 3H)；13C NMR (126MHz, Acetone) δ 192.1,158.2,153.7,148.8,147.3,143.9,142.1,137.9,136.5,126.6,124.2,122.9, 122.3,117.1,113.3,112.1,108.23 (s), 95.5,60.6,56.4,55.9 (2 × C) .ESI-MS:[M+H]+ 464.2[M+Na]+486.4.HRMS (ESI): m/z calcd for C26H25NO7[M+H]+: 464.1704, found 464.1716.
Embodiment 2:
The first step: with the synthesis of embodiment 1 intermediate (1).
Second step: intermediate 3-(3-isopropoxy-4-methoxybenzene)-1-(3,4,5-trimethoxy-benzene)-2-alkynyl third The synthesis of ketone (3)
Intermediate 3-isopropoxy-4-methoxybenzene ethyl-acetylene (1) (0.40g, 2.10mmol) is dissolved in anhydrous Dioxane, argon shield ,-78 DEG C of stirrings, slowly dropping 1.6mol/L diisopropylamine Lithamide. THF is molten Liquid (1.31ml, 2.10mmol), drips after dripping this temperature of complete holding continuation stirring 1h again and is dissolved in THF in advance 3,4,5-Trimethoxybenzaldehyde (2) (0.41g, 2.10mmol), this temperature stirring 0.5h after be warming up to room Temperature continues stirring 2h.React complete, add H2O, EtOAc extract, and saturated common salt is washed, anhydrous slufuric acid Sodium is dried, and concentrates, and chromatographic column (Pe/EtOAc=5: 1) obtains 0.71g solid chemical compound, and this solid is soluble in anhydrous Dioxane, adds Dess-Martin oxidant (3.12g, 7.35mmol), 30 DEG C of stirring 10h.React Finishing, filter, concentrate, recrystallization obtains white solid and is 3-(3-isopropoxy-4-methoxybenzene)-1-(3,4,5- Trimethoxy-benzene)-2-alkynyl acetone (3) (0.62g).1H NMR (500MHz, CDCl3) δ 7.50 (s, 2H), 7.29 (d, J=1.8Hz, 1H), 7.27 (d, J=1.8Hz, 1H), 7.17 (d, J=1.7Hz, 1H), 6.89 (d, J =8.4Hz, 1H), 4.54 (dt, J=12.1,6.1Hz, 1H), 3.96 (d, J=4.4Hz, 9H), 3.90 (s, 3H), 1.39 (d, J=6.1Hz, 6H)；13C NMR (126MHz, CDCl3) δ 177.0,153.3,153.2,147.4, 143.6,132.5,127.5,119.7,111.98,111.9,107.0,94.5,86.5,71.9,61.2,56.4,56.2, 22.1.ESI-MS:[M+H]+385.2[M+Na]+407.4.HRMS (ESI): m/z calcd for C22H24O6 [M+H]+: 385.1676, found 385.1689.
3rd step: 2-(4 '-methoxyl group-3 '-isopropyl phenyl)-3-(3 ", 4 ", 5 " and-trimethoxybenzoy)-6-first The synthesis of epoxide indole (5)
By intermediate 3-(3-isopropoxy-4-methoxybenzene)-1-(3,4,5-trimethoxy-benzene)-2-alkynyl acetone (3) (0.20g, 0.52mmol), 2-iodo-5-aminoanisole (4) (0.16g, 0.62mmol) be dissolved in absolute methanol with The mixed liquor (1: 1) of anhydrous DMSO, argon shield, stir 40h at 80 DEG C.React complete, column chromatography (Pe/EtOAc=7: 1) obtains yellow solid intermediate.This intermediate is dissolved in anhydrous acetonitrile, adds four triphenylphosphines Palladium (60.1mg, 0.052mmol), potassium acetate (0.20g, 2.08mmol), argon shield 80 DEG C stirring 10h. Reacting complete, column chromatography (Pe/EtOAc=5: 1) obtains yellow solid and is 2-(4 '-methoxyl group-3 '-isopropoxy benzene Base) and-3-(3 ", 4 ", 5 " and-trimethoxybenzoy)-6-methoxy-Indole (5) (130.2mg).1H NMR (500MHz, CDCl3) δ 8.61 (s, 1H), 7.93 (d, J=9.3Hz, 1H), 6.99 (s, 3H), 6.91 (dd, J= 4.7,2.4Hz, 2H), 6.75 (dd, J=5.0,3.1Hz, 2H), 4.17 (dt, J=12.2,6.1Hz, 1H), 3.86 (s, 3H), 3.79 (s, 6H), 3.67 (s, 6H), 1.20 (d, J=6.1Hz, 6H).；13C NMR (126MHz, CDCl3) δ 191.9,157.5,152.7,151.2,147.4,142.4,141.4,136.5,134.7,125.0,123.4, 122.6,121.1,117.5,112.9,111.8,107.5,94.7,71.9,60.9,56.1,55.9,29.8,22.1. ESI-MS:[M+H]+506.2[M+Na]+528.4.HRMS (ESI): m/z calcd for C29H31NO7 [M+H]+: 506.2173, found506.2158.
4th step: 2-(3 '-hydroxyl-4 '-methoxyphenyl)-3-(3 ", 4 ", 5 " and-trimethoxybenzoy)-6-methoxyl group The synthesis of indole (OXi8006)
By intermediate 2-(4 '-methoxyl group-3 '-isopropyl phenyl-3-(3 ", 4 ", 5 "-trimethoxybenzoy)-6-first Epoxide indole (5) (40mg, 0.079mmol) is dissolved in dry toluene, and argon shield, in-50 DEG C of stirrings, slowly The hydrochloric acid dichloromethane solution (0.316ml, 0.316mmol) of dropping 1mol/L, drips and complete is warming up to room Temperature continues stirring 1h, reacts complete, adds saturated aqueous common salt cancellation, and dichloromethane extracts, and anhydrous sodium sulfate is done Dry, thickness is prepared plate and is obtained yellow solid OXi8006 (26mg).1H NMR (500MHz, Acetone-d6)δ 7.89 (d, J=8.7Hz, 1H), 7.02 (d, J=2.3Hz, 1H), 6.92 (d, J=3.2Hz, 3H), 6.86 (dd, J=8.7,2.3Hz, 1H), 6.83-6.81 (m, 1H), 6.79 (d, J=8.3Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.68 (s, 6H), 3.67 (s, 3H)；13C NMR (126MHz, Acetone) δ 192.1,158.2, 153.7,148.8,147.3,143.9,142.1,137.9,136.5,126.6,124.2,122.9,122.3,117.1, 113.3,112.1,108.23 (s), 95.5,60.6,56.4,55.9 (2 × C) .ESI-MS:[M+H]+464.2 [M+Na]+486.4.HRMS (ESI): m/z calcd for C26H25NO7[M+H]+: 464.1704, found 464.1716。
Embodiment 3:
The first step: with the synthesis of embodiment 1 intermediate (1).
Second step: 3-(3-isopropoxy-4-methoxybenzene)-1-'s (3,4,5-trimethoxy-benzene)-2-alkynyl acetone (3) Synthesis
Intermediate 3-isopropoxy-4-methoxybenzene ethyl-acetylene (1) (0.40g, 2.10mmol) is dissolved in anhydrous benzene, Argon shield ,-78 DEG C of stirrings, slowly dropping 1.6mol/L Sodamide. THF solution (1.31ml, 2.10mmol), Drip after this temperature of complete holding continues stirring 1h and drip 3,4, the 5-trimethoxy-benzene first being dissolved in THF in advance again Aldehyde (2) (0.41g, 2.10mmol), is warming up to room temperature after this temperature stirring 0.5h and continues stirring 2h.React Finish, add H2O, EtOAc extract, and saturated common salt is washed, and anhydrous sodium sulfate is dried, and concentrate, chromatographic column (Pe/EtOAc=5: 1) obtains 0.71g solid chemical compound, and this solid is soluble in anhydrous THF, adds sulfur trioxide pyrrole Pyridine (1.17g, 7.35mmol), 30 DEG C of stirring 10h.Reacting complete, filter, concentrate, recrystallization obtains white Color solid is 3-(3-isopropoxy-4-methoxybenzene)-1-(3,4,5-trimethoxy-benzene)-2-alkynyl acetone (3)(0.58)。1H NMR (500MHz, CDCl3) δ 7.50 (s, 2H), 7.29 (d, J=1.8Hz, 1H), 7.27 (d, J=1.8Hz, 1H), 7.17 (d, J=1.7Hz, 1H), 6.89 (d, J=8.4Hz, 1H), 4.54 (dt, J= 12.1,6.1Hz, 1H), 3.96 (d, J=4.4Hz, 9H), 3.90 (s, 3H), 1.39 (d, J=6.1Hz, 6H)；13C NMR (126MHz, CDCl3) δ 177.0,153.3,153.2,147.4,143.6,132.5,127.5,119.7, 111.98,111.9,107.0,94.5,86.5,71.9,61.2,56.4,56.2,22.1.ESI-MS:[M+H]+385.2 [M+Na]+407.4.HRMS (ESI): m/z calcd for C22H24O6[M+H]+: 385.1676, found 385.1689。
3rd step: 2-(4 '-methoxyl group-3 '-isopropyl phenyl)-3-(3 ", 4 ", 5 " and-trimethoxybenzoy)-6-first The synthesis of epoxide indole (5)
By intermediate 3-(3-isopropoxy-4-methoxybenzene)-1-(3,4,5-trimethoxy-benzene)-2-alkynyl acetone (3) (0.20g, 0.52mmol), 2-iodo-5-aminoanisole (4) (0.16g, 0.62mmol) are dissolved in absolute methanol With the mixed liquor (5: 1) of anhydrous DMSO, argon shield, at 150 DEG C, stir 80h.React complete, column chromatography (Pe/EtOAc=7: 1) obtains yellow solid intermediate.This intermediate is dissolved in anhydrous tetrahydro furan, adds Palladous chloride. (9.23mg, 0.052mmol), Disilver carbonate (0.57g, 2.08mmol), argon shield 150 DEG C stirring 18h.Instead Should be complete, column chromatography (Pe/EtOAc=5: 1) obtains yellow solid and is 2-(4 '-methoxyl group-3 '-isopropoxy benzene Base) and-3-(3 ", 4 ", 5 " and-trimethoxybenzoy)-6-methoxy-Indole (5) (131.1mg).1H NMR(500 MHz, CDCl3) δ 8.61 (s, 1H), 7.93 (d, J=9.3Hz, 1H), 6.99 (s, 3H), 6.91 (dd, J=4.7, 2.4Hz, 2H), 6.75 (dd, J=5.0,3.1Hz, 2H), 4.17 (dt, J=12.2,6.1Hz, 1H), 3.86 (s, 3H), 3.79 (s, 6H), 3.67 (s, 6H), 1.20 (d, J=6.1Hz, 6H).；13C NMR (126MHz, CDCl3) δ 191.9,157.5,152.7,151.2,147.4,142.4,141.4,136.5,134.7,125.0,123.4,122.6, 121.1,117.5,112.9,111.8,107.5,94.7,71.9,60.9,56.1,55.9,29.8,22.1. ESI-MS:[M+H]+506.2[M+Na]+528.4.HRMS (ESI): m/z calcd for C29H31NO7 [M+H]+: 506.2173, found506.2158.
4th step: 2-(3 '-hydroxyl-4 '-methoxyphenyl)-3-(3 ", 4 ", 5 " and-trimethoxybenzoy)-6-methoxyl group The synthesis of indole (OXi8006)
By intermediate 2-(4 '-methoxyl group-3 '-isopropyl phenyl)-3-(3 ", 4 ", 5 "-trimethoxybenzoy)-6- Methoxy-Indole (5) (40mg, 0.079mmol) is dissolved in absolute ether, argon shield, in 30 DEG C of stirrings, delays The slow boron chloride dichloromethane solution (0.316ml, 0.316mmol) dripping 1mol/L, drips complete intensification Continuing stirring 5h to room temperature, react complete, add saturated aqueous common salt cancellation, dichloromethane extracts, anhydrous slufuric acid Sodium is dried, and thickness is prepared plate and obtained yellow solid OXi8006 (27.8mg).1H NMR (500MHz, Acetone-d6) δ 7.89 (d, J=8.7Hz, 1H), 7.02 (d, J=2.3Hz, 1H), 6.92 (d, J=3.2Hz, 3H), 6.86 (dd, J=8.7,2.3Hz, 1H), 6.83-6.81 (m, 1H), 6.79 (d, J=8.3Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.68 (s, 6H), 3.67 (s, 3H)；13C NMR (126MHz, Acetone) δ 192.1,158.2,153.7,148.8,147.3,143.9,142.1,137.9,136.5,126.6,124.2,122.9, 122.3,117.1,113.3,112.1,108.23 (s), 95.5,60.6,56.4,55.9 (2 × C) .ESI-MS:[M+H]+ 464.2[M+Na]+486.4.HRMS (ESI): m/z calcd for C26H25NO7[M+H]+: 464.1704, found 464.1716.
The above is only the preferred embodiment of the present invention, it is noted that common for the art Technical staff, on the premise of without departing from the inventive method, it is also possible to makes some improvement and supplements, these Improve and supplement and also should be regarded as protection scope of the present invention.

Claims (1)

1. 2-(3 '-hydroxyl-4 '-methoxyphenyl)-3-(3 ", 4 ", 5 "-trimethoxybenzoy)-6-methoxyl group The preparation method of indole, it is characterised in that described method comprises the following steps:
The first step: the synthesis of intermediate 3-isopropoxy-4-methoxybenzene ethyl-acetylene；
Second step: intermediate 3-isopropoxy-4-methoxybenzene ethyl-acetylene and intermediate 3,4,5-trimethoxy-benzene Formaldehyde prepares arylalkyne ketone intermediate 3-(3-isopropoxy-4-through nucleophilic addition and oxidation reaction successively Methoxybenzene)-1-(3,4,5-trimethoxy-benzene)-2-alkynyl acetone；
3rd step: arylalkyne ketone intermediate 3-(3-isopropoxy-4-methoxybenzene)-1-(3,4,5-trimethoxy Benzene)-2-alkynyl acetone further with 3-methoxyl group-6-iodo aniline initial ring close reaction, prepare compound 2-(4 '- Methoxyl group-3 '-isopropyl phenyl) and-3-(3 ", 4 ", 5 " and-trimethoxybenzoy)-6-methoxy-Indole；
4th step: compound 2-(4 '-methoxyl group-3 '-isopropyl phenyl)-3-(3 ", 4 ", 5 "-trimethoxybenzoyl Base)-6-methoxy-Indole selectivity sloughs protection group isopropyl and realizes target compound 2-(3 '-hydroxyl-4 '-methoxy Base phenyl) synthesis of-3-(3 ", 4 ", 5 "-trimethoxybenzoy)-6-methoxy-Indole；
Described second step nucleophilic addition refers under solvent condition, intermediate 3-isopropoxy-4-methoxyl group The reaction that phenylacetylene is occurred with compound TMB by base catalysis；
Described second step oxidation reaction refers to oxidized dose of the product of nucleophilic addition oxidation under solvent condition Reaction for intermediate 3-(3-isopropoxy-4-methoxybenzene)-1-(3,4,5-trimethoxy-benzene)-2-alkynyl acetone；
Described 3rd step ring-closure reaction refers to intermediate 3-(3-isopropoxy-4-methoxybenzene)-1-(3,4,5-front three Epoxide benzene) first there is miscellaneous Michael addition reaction again in-2-alkynyl acetone and intermediate 3-methoxyl group-6-iodo aniline Through intramolecular Heck reaction cyclization；
Described miscellaneous Michael addition reaction refers to intermediate 3-(3-isopropoxy-4-methoxybenzene)-1-(3,4,5-tri- Methoxybenzene) anti-under solvent and temperature conditions of-2-alkynyl acetone and intermediate 3-methoxyl group-6-iodo aniline Should；
Described intramolecular Heck reaction refer to miscellaneous Michael addition reaction product under solvent condition, via palladium-catalyzed Agent and alkali effect generation coupling reaction generate 2-(4 '-methoxyl group-3 '-isopropyl phenyl)-3-(3 ", 4 ", 5 "-front threes Epoxide benzoyl)-6-methoxy-Indole；
Described 4th step selectivity deprotection reaction refers under solvent condition, compound 2-(4 '-methoxyl group-3 '- Isopropyl phenyl)-3-(3 ", 4 ", 5 "-trimethoxybenzoy)-6-methoxy-Indole selects under reagent effect Property sloughs the reaction of isopropyl；
Described second step nucleophilic addition use solvent be selected from: acetonitrile, benzene, toluene, dioxane, Oxolane, N,N-dimethylformamide and/or dimethyl sulfoxide；Alkali used is selected from: sodium hydrogen, Sodamide., One in potassium tert-butoxide, n-BuLi, tert-butyl lithium or diisopropylamine lithium；
Described second step oxidation reaction use solvent be selected from: dichloromethane, acetonitrile, toluene, dioxane, One in oxolane, N,N-dimethylformamide or dimethyl sulfoxide；Oxidant used is selected from: two Manganese oxide, sulfur trioxide pyridine, chromic acid pyridine, pyridinium chlorochromate, selenium dioxide or Dess-Martin One in oxidant；
Solvent used by the described 3rd miscellaneous Michael addition reaction of step is: absolute methanol mixes with dimethyl sulfoxide Solvent；Reaction temperature is 120 DEG C；Response time is 60 hours；Described absolute methanol mixes with dimethyl sulfoxide The proportioning of bonding solvent is 1:1～5:1；
Solvent used by described 3rd step intramolecular Heck reaction is N,N-dimethylformamide；Palladium used Catalyst is: palladium；Alkali used is triethylamine；Reaction temperature is 120 DEG C；Response time is 14 little Time；
Described 3-(3-isopropoxy-4-methoxybenzene)-1-(3,4,5-trimethoxy-benzene)-2-alkynyl acetone, 3-methoxy The consumption of base-6-iodo aniline is respectively 0.52mmol and 0.62mmol；
Solvent used by described 4th step selectivity deprotection reaction is selected from: ether, acetonitrile, dioxane, One in dichloromethane, toluene, N,N-dimethylformamide or dimethyl sulfoxide；Reagent used is selected from: One in boron chloride, Boron tribromide, hydrobromic acid or hydrochloric acid；Reaction temperature is-50～30 DEG C；Reaction Time is 1～5 hour.
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