CN103965091B - The preparation of 2-(2,3,6,7-tetramethoxy-9-phenanthrene methyl) pyrroles - Google Patents

The preparation of 2-(2,3,6,7-tetramethoxy-9-phenanthrene methyl) pyrroles Download PDF

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CN103965091B
CN103965091B CN201310027118.9A CN201310027118A CN103965091B CN 103965091 B CN103965091 B CN 103965091B CN 201310027118 A CN201310027118 A CN 201310027118A CN 103965091 B CN103965091 B CN 103965091B
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pyrroles
tetramethoxy
phenanthrene
formoxyl
methyl
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CN103965091A (en
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梁华中
徐西之
邓玉智
钱永志
巩绪干
汪清民
孙新
吴瑞磊
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JIANGSU LANFENG BIOCHEMICAL CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the preparation of 2 (the luxuriant and rich with fragrance methyl of 2,3,6,7 tetramethoxies 9) pyrroles.First (the luxuriant and rich with fragrance formoxyl of 2,3,6,7 tetramethoxies 9) pyrroles and Bis(tert-butoxycarbonyl)oxide be (i.e. (Boc) with 22O) reaction generates N tertbutyloxycarbonyl 2 (the luxuriant and rich with fragrance formoxyl of 2,3,6,7 tetramethoxies 9) pyrroles, then with NaBH4Reaction obtains 2 (the luxuriant and rich with fragrance methyl of 2,3,6,7 tetramethoxies 9) pyrroles.

Description

The preparation of 2-(2,3,6,7-tetramethoxy-9-phenanthrene methyl) pyrroles
Technical field
The present invention relates to the preparation of 2-(2,3,6,7-tetramethoxy-9-phenanthrene methyl) pyrroles.
Background technology
The viroses of plant are the most serious plant diseases, prevent and treat extremely difficult, have the title of " plant cancer ".Phytopathy The eruption and prevalence of virus disease is quite varied, and disaster is the most serious.Nearly all vegetable, cereal crops, fruit tree etc. all infect virus Disease, makes agricultural production by huge loss, reduces product quality, seriously promote the generation of other physiological disturbance of plant. The practical kind of plant virus inhibitor is little the most effectively and satisfactorily, and the especially therapeutic medicament of specially good effect is less, its The preventive effect of middle Ningnanmycin is best.Conventional has three below commercial varieties: Ningnanmycin, field using dosage is 100gai/hm2, it being 50%～60% to tobacco mosaic disease prevention effect, have good preventive effect, therapeutic effect is the best；Sick Poison azoles, field using dosage is 600gai/hm2, to plant virus, (tobacco mosaic virus (TMV), cucumber mosaic virus, Rhizoma Solani tuber osi X are sick Poison, marmor upsilon etc.) preventive effect be 30～60%；Virus A, field using dosage is 600gai/hm2, to tobacco mosaic disease Prevention effect is 50%.Guizhou University professor Song Baoan has formulated viral star, and field using dosage is 300gai/hm2.Therefore, The most urgent to the needs of efficient, safe Control of Plant Virus Disease medicament.
It is unconcerned that organic element chemistry National Key Laboratory of Nankai University finds to be distributed widely in NORTHWEST CHINA drought sandy wasteland first The leaching thing of the Cynanchun komarovii in area has high activity to very harmful tobacco mosaic virus (TMV) (TMV), gives birth to further Thing activity is followed the tracks of and chemically separated result of study shows: in this grass, the active substance of anti-TMV is that phenanthroindolizididerivative pyridine is biological Alkali, main active ingredient is antofine.The suppression ratio of tobacco mosaic virus (TMV) is up under 1.0 μ g/mL concentration by this active substance 60%, this exceeds 1-2 the order of magnitude than any activity having seen plant virus inhibitor that document reports.But Cynanchun komarovii is raw In desert and barren hillside, for herbaceos perennial, for the plant of preventing and fixing sand；Moreover, anti-TMV active ingredient antofine is cattle Content in heart Piao Zi grass is the lowest, and antofine content in Cynanchun komarovii crude extract is only about 0.2%.So, from cattle Heart Piao Zi grass extracts antofine be restricted for plant protection.Antofine illumination is unstable；Antofine water solublity is very poor, this Have a strong impact on its application in plant protection.In order to solve the problems referred to above, Nankai University is with active ingredient antofine alkaloid For guide, carry out chemosynthesis, carry out structure of modification and modification, formulate out good light stability, to have water-soluble, activity higher Control of Plant Virus Disease medicament NK-007, the results of field plot on 2 years seven ground shows: NK-007 preventing and treating Nicotiana tabacum L., peppery Green pepper, the effect of tomato virus disease are significantly larger than two comparison medicament Ningnanmycins and virus A, the preventive effect of 10 grams/ha of NK-007 With 100 grams/ha of Ningnanmycins, 600
Gram/ha viral A is suitable, to crop without poisoning phenomenon, on other non-target organism without impact.
The CA number of logging in of NK-007 (Universal Chinese character name: phenanthridines poison is clear): 1203657-55-9, chemical name: tylophorine Malate, molecular formula: C28H33NO9, structural formula is as follows:
Nankai University has applied for NK-007 and derivant thereof, has synthesized and the Chinese invention patent of application, such as, ZL200610129555.1 and ZL 201110050446.1 discloses phenanthroindolizididerivative pyridine and the western piperidine derivatives of phenanthroquinolizidalkaloid alkaloid derivatives And the application that salt is on pesticide, CN101875657A discloses tylophorine Alkaloid acylate derivant on pesticide Application, ZL 200710058173.9 discloses the preparation of phenanthroindolizididerivative derivative.Nankai University is by NK-007 Compound and derivant thereof, synthesize the exclusive transfering use right of above-mentioned patent related to application to Jiangsu Lan Feng biochemical industry Limited company, is exclusively developed by Jiangsu Lam Fung Biological Chemical Co., Ltd, produces without competition, exclusive dealing.
ZL 200710058173.9 discloses the preparation of phenanthroindolizididerivative derivative, for 2, and 3,6,7-tetra-methoxies The synthesis of base phenanthroindolizididerivative pyridine, comprises the steps: first with 3,4-dimethoxyphenylacetic acid and 3,4-dimethoxy benzene The condensation reaction of formaldehyde obtains 2, and then 3-bis--(3,4-Dimethoxyphenyl) acrylic acid obtain with ferric chloride oxidative coupling 2,3,6,7-tetramethoxy phenanthrenecarboxylic acids, this acid reacts with thionyl chloride and obtains 2,3,6,7-tetramethoxy phenanthrene formyl chlorides, SnCl4In the presence of this acyl chlorides and pyrroles react generation 2-(2,3,6,7-tetramethoxy-9-phenanthrene formoxyl) pyrroles, use NaBH4Reduction Carbonyl obtains 2-(2,3,6,7-tetramethoxy-9-phenanthrene methyl) pyrroles, then with Pd-C catalytic hydrogen reduction pyrroles obtain 2-(2,3, 6,7-tetramethoxy-9-phenanthrene methyl) nafoxidine, finally obtain 2 with formaldehyde cyclization, 3,6,7-tetramethoxy phenanthroindolizididerivatives Pyridine.
Jiangsu Lam Fung Biological Chemical Co., Ltd is carrying out the conjunction of 2,3,6,7-tetramethoxy phenanthroindolizididerivative pyridines When becoming technical study, find that 2-(2,3,6, the 7-tetramethoxy-9-phenanthrene formoxyl) pyrroles of ZL200710058173.9 protection uses NaBH4Reducing carbonyl generates the method for 2-(2,3,6,7-tetramethoxy-9-phenanthrene methyl) pyrroles, and there are the following problems: 2-(2,3, 6,7-tetramethoxy-9-phenanthrene formoxyls) pyrroles's dissolubility in isopropanol is the lowest, so it is next to need to add substantial amounts of isopropanol Dissolving 2-(2,3,6,7-tetramethoxy-9-phenanthrene formoxyl) pyrroles, therefore, the quantity of solvent that the method needs is very big, reactor Utilization rate is the lowest；When amplification quantity, even if finding to add substantial amounts of isopropanol, reaction is always incomplete, 2-(2,3,6,7-tetramethyls Epoxide-9-phenanthrene formoxyl) conversion ratio of pyrroles is low, and yield significantly declines；2-(2,3,6,7-tetramethoxy-9-phenanthrene formoxyl) The less stable of pyrroles, as bad in nitrogen protection during being heated to reflux, reactant liquor color is very deep, during amplification quantity particularly Substantially；Product 2-(2,3,6,7-tetramethoxy-9-phenanthrene methyl) pyrroles needed column chromatography.
In order to solve the problems referred to above, Jiangsu Lam Fung Biological Chemical Co., Ltd has carried out by 2-(2,3,6,7-tetramethyls Epoxide-9-phenanthrene formoxyl) pyrroles makees raw material, the Study of New Method of synthesis 2-(2,3,6,7-tetramethoxy-9-phenanthrene methyl) pyrroles, Finally invent this new method.
Summary of the invention
It is an object of the invention to provide the novel preparation method of 2-(2,3,6,7-tetramethoxy-9-phenanthrene methyl) pyrroles.
The synthetic route of 2-(2,3,6, the 7-tetramethoxy-9-phenanthrene methyl) pyrroles of the present invention is following (equation 1).Preparation Method comprises the steps: first with 2-(2,3,6,7-tetramethoxy-9-phenanthrene formoxyl) pyrroles and Bis(tert-butoxycarbonyl)oxide (i.e. (Boc)2O) reaction generates N-tertbutyloxycarbonyl-2-(2,3,6,7-tetramethoxy-9-phenanthrene formoxyl) pyrroles, then with NaBH4Instead 2-(2,3,6,7-tetramethoxy-9-phenanthrene methyl) pyrroles should be obtained.
Equation 1
Wherein, the synthesis of 2-(2,3,6,7-tetramethoxy-9-phenanthrene formoxyl) pyrroles uses ZL's 200710058173.9 Patented method.
The advantage of new method: 2-(2,3,6,7-tetramethoxy-9-phenanthrene formoxyl) pyrroles is the highest receipts after BOC protects Rate ground generation N-tertbutyloxycarbonyl-2-(2,3,6,7-tetramethoxy-9-phenanthrene formoxyl) pyrroles, N-tertbutyloxycarbonyl-2-(2,3, 6,7-tetramethoxy-9-phenanthrene formoxyls) pyrroles is that a noval chemical compound, dissolubility and stability are fine, carries out boron hydrogen the most again Changing sodium reduction, response speed is accelerated, and the response time reduces, and conversion ratio improves, and quantity of solvent reduces, and product content improves, it is not necessary to Carrying out column chromatography again, the total recovery of two steps is higher than the method for patent ZL 200710058173.9.
Detailed description of the invention
In order to make the purpose of the present invention, technical scheme and advantage definitely, below in conjunction with embodiment the present invention done into One step describes in detail, is described herein as being only limitted to preferably explain the present invention, is not intended to limit the present invention.
The synthesis of embodiment 1:N-tertbutyloxycarbonyl-2-(2,3,6,7-tetramethoxy-9-phenanthrene formoxyl) pyrroles:
41 grams of 2-(2,3,6,7-tetramethoxy-9-phenanthrene formoxyl) pyrroles it is sequentially added in tetra-mouthfuls of reaction bulbs of 1000 mL, 600 mL acetonitriles, 4.0 grams of DMAP, nitrogen is replaced, is added 40 grams of Bis(tert-butoxycarbonyl)oxides (i.e. (Boc)2O), stirring is anti-at 20 DEG C Answer 24 hours.Slough acetonitrile, add saturated sodium bicarbonate solution, regulate pH=9, sucking filtration, dry, obtain 50.0 grams of N-tertiary butyloxycarbonyls Base-2-(2,3,6,7-tetramethoxy-9-phenanthrene formoxyl) pyrroles, yield: 99.86%, fusing point: 145-146 DEG C.1H NMR(400 MHz, CDCl3): δ 8.28 (s, 1H), 7.94 (s, 1H), 7.82 (s, 1H), 7.78 (s, 1H), 7.50 (s, 1H), 7.21 (s, 1H), 6.68 (d, J=1.8 Hz, 1H), 6.26 (t, J=3.2 Hz, 1H), 4.15 (s, 3H), 4.14 (s, 3H), 4.01 (s, 6H), 1.39 (s, 9H)；13C NMR (100 MHz, CDCl3) δ 187.4,151.2,149.3,149.0,148.9,135.2, 131.5,130.4,127.3,126.8,125.2,124.4,124.0,122.8,110.3,109.3,106.9,102.6,85.0, 56.1,56.0,55.9,27.5；IR (KBr, cm-1): 3115,3067,2980,2941,2836,1748,1626,1512,1470, 1435,1313,1256,1203,1159,1134,1049,844,778,746；MS (ESI): [2M+Na] 1005.1；HRMS (ESI)calcd for C28H30NO7(M+H)+: 492.2017, found:492.2018.
The synthesis of embodiment 2:2-(2,3,6,7-tetramethoxy-9-phenanthrene methyl) pyrroles:
(2,3,6,7-tetramethoxy-9-are luxuriant and rich with fragrance to add 10.0 grams of N-tertbutyloxycarbonyl-2-in tetra-mouthfuls of reaction bulbs of 1000 mL Formoxyl) pyrroles, 11 grams of sodium borohydrides, 2 grams of tetrabutyl ammonium bromide, 500 mL newly steam isopropanol, stirring, are heated to back flow reaction 4 hours.Slough isopropanol, add 500 mL dichloromethane and 130 mL water, dilute hydrochloric acid regulation pH=6, separatory, precipitation, dry, Obtain solid 8.0 grams, content 98.56%, yield 86.22%.Fusing point: 220-222 DEG C.1H NMR (300 MHz, CDCl3)δ 8.02 (br, 1 H), 7.70 (s, 1H), 7.66 (s, 1 H), 7.35 (s, 1H), 7.34 (s, 1H), 7.09 (s, 1H), 6.62-6.63 (m, 1H), 6.16-6.18 (m, 2H), 4.36 (s, 2H), 4.05 (s, 6H), 3.96 (s, 3H), 3.88 (s, 3H)；13C NMR(75 MHz, CDCl3) δ 149.0,148.9,148.6,130.9,130.1,126.2,125.5,125.0,124.8,124.0, 116.9,108.4,108.1,106.3,105.1,103.2,102.8,56.0,55.9,55.8,55.7,32.7；IR (KBr, cm-1) 3376,3267,3006,2904,2831,1612,1510,1460,1431,1249,1191,1140,1031,981,828, 763,712,647,581,509；MS(EI)m/z 377(M+, 100), 346 (6), 311 (8), 189 (10), 80 (7)；HRMS (ESI)m/z calcd for C23H24NO4[M+H]+378.1700found378.1702.
The synthesis of embodiment 3:2-(2,3,6,7-tetramethoxy-9-phenanthrene methyl) pyrroles (uses patent The method of ZL200710058173.9)
30 grams of 2-(2,3,6,7-tetramethoxy-9-phenanthrene formoxyl) pyrroles, 30 grams of boron hydrogen are added in 5000 mL reaction bulbs Change sodium and 3500 mL isopropanols, N2The lower mixture of protection is heated to reflux 24 hours.1500mL dichloromethane is added in reactant liquor With 400 mL water, separatory, organic facies saturated brine washs, and anhydrous magnesium sulfate is dried.Precipitation, column chromatography (eluant: CH2Cl2∶ Ethyl acetate: petroleum ether (60-90 DEG C)=15: 1: 1 volume ratio) obtain white solid 16 grams, yield is 55%, fusing point: 220-222 ℃。

Claims (1)

1. the preparation method of 2-(2,3,6, a 7-tetramethoxy-9-phenanthrene methyl) pyrroles, it is characterised in that include equation below Following step shown in formula 1: first under nitrogen permutizer condition, with 2-(2,3,6,7-tetramethoxy-9-phenanthrene formoxyl) pyrroles Being reactant with Bis(tert-butoxycarbonyl)oxide, and add acetonitrile and DMAP, reaction generates N-tertbutyloxycarbonyl-2-(2,3,6,7- Tetramethoxy-9-phenanthrene formoxyl) pyrroles, then to described N-tertbutyloxycarbonyl-2-(2,3,6,7-tetramethoxy-9-phenanthrene formyls Base) pyrroles adds tetrabutyl ammonium bromide, isopropanol and NaBH4, and be heated to reflux, make described N-tertbutyloxycarbonyl-2-(2, 3,6,7-tetramethoxy-9-phenanthrene formoxyls) pyrroles and NaBH4Reaction obtains 2-(2,3,6,7-tetramethoxy-9-phenanthrene methyl) pyrrole Cough up, equation 1:
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Publication number Priority date Publication date Assignee Title
CN101189968A (en) * 2006-11-23 2008-06-04 南开大学 Phenanthroindolizidine and phenanthroquinolizidine derivatives and applications of salts in pesticides
CN101348483A (en) * 2007-07-17 2009-01-21 南开大学 Preparation of phenanthroindolizidine derivative

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JP5658575B2 (en) * 2011-01-27 2015-01-28 花王株式会社 Hair growth inhibitor

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Publication number Priority date Publication date Assignee Title
CN101189968A (en) * 2006-11-23 2008-06-04 南开大学 Phenanthroindolizidine and phenanthroquinolizidine derivatives and applications of salts in pesticides
CN101348483A (en) * 2007-07-17 2009-01-21 南开大学 Preparation of phenanthroindolizidine derivative

Non-Patent Citations (3)

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Iron(III) chloride-based mild synthesis of phenanthrene and its application to total synthesis of phenanthroindolizidine alkaloids;Kai-Liang Wang等;《Tetrahedron》;20080606;第64卷;第7508页第4.11节 *
Synthesis of Alkylpyrroles by the Sodium Borohydride Reduction of Acylpyrroles1;Robert Greenhouse等;《the Journal of Organic Chemistry》;19851231;第50卷;第2961页右栏反应式，第2962页表I *
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