CN103864655B - A kind of synthetic method of dehydrogenation abietyl thiourea derivative - Google Patents
A kind of synthetic method of dehydrogenation abietyl thiourea derivative Download PDFInfo
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- 238000006356 dehydrogenation reaction Methods 0.000 title claims abstract description 51
- 150000003585 thioureas Chemical class 0.000 title claims abstract description 13
- 238000010189 synthetic method Methods 0.000 title abstract description 6
- -1 abietic acid acyl chlorides Chemical class 0.000 claims abstract description 66
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 claims abstract description 42
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 claims abstract description 42
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 37
- BQACOLQNOUYJCE-FYZZASKESA-N Abietic acid Natural products CC(C)C1=CC2=CC[C@]3(C)[C@](C)(CCC[C@@]3(C)C(=O)O)[C@H]2CC1 BQACOLQNOUYJCE-FYZZASKESA-N 0.000 claims abstract description 35
- 238000002360 preparation method Methods 0.000 claims abstract description 31
- BTXXTMOWISPQSJ-UHFFFAOYSA-N 4,4,4-trifluorobutan-2-one Chemical compound CC(=O)CC(F)(F)F BTXXTMOWISPQSJ-UHFFFAOYSA-N 0.000 claims abstract description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 200
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 80
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 60
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 60
- 150000001875 compounds Chemical group 0.000 claims description 56
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 42
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 40
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- 238000010992 reflux Methods 0.000 claims description 32
- 238000000605 extraction Methods 0.000 claims description 20
- 239000012044 organic layer Substances 0.000 claims description 20
- 230000000630 rising effect Effects 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- 238000005406 washing Methods 0.000 claims description 20
- 230000006837 decompression Effects 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 11
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 5
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 5
- 125000003944 tolyl group Chemical group 0.000 claims description 5
- FULZLIGZKMKICU-UHFFFAOYSA-N N-phenylthiourea Chemical compound NC(=S)NC1=CC=CC=C1 FULZLIGZKMKICU-UHFFFAOYSA-N 0.000 claims description 4
- KRXMYBAZKJBJAB-UHFFFAOYSA-N 2-(4-methylphenyl)-1,2-benzothiazol-3-one Chemical compound C1=CC(C)=CC=C1N1C(=O)C2=CC=CC=C2S1 KRXMYBAZKJBJAB-UHFFFAOYSA-N 0.000 claims description 3
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 claims description 3
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea group Chemical group NC(=S)N UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 abstract description 12
- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 abstract description 7
- 230000000855 fungicidal effect Effects 0.000 abstract description 7
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 abstract description 7
- 230000004071 biological effect Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 125000003118 aryl group Chemical group 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 abstract 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 abstract 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 abstract 1
- 230000000975 bioactive effect Effects 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 229930014626 natural product Natural products 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QUUCYKKMFLJLFS-UHFFFAOYSA-N Dehydroabietan Natural products CC1(C)CCCC2(C)C3=CC=C(C(C)C)C=C3CCC21 QUUCYKKMFLJLFS-UHFFFAOYSA-N 0.000 description 2
- NFWKVWVWBFBAOV-UHFFFAOYSA-N Dehydroabietic acid Natural products OC(=O)C1(C)CCCC2(C)C3=CC=C(C(C)C)C=C3CCC21 NFWKVWVWBFBAOV-UHFFFAOYSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 244000052616 bacterial pathogen Species 0.000 description 2
- 125000004799 bromophenyl group Chemical group 0.000 description 2
- ZRIHAIZYIMGOAB-UHFFFAOYSA-N butabarbital Chemical compound CCC(C)C1(CC)C(=O)NC(=O)NC1=O ZRIHAIZYIMGOAB-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- NFWKVWVWBFBAOV-MISYRCLQSA-N dehydroabietic acid Chemical compound OC(=O)[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3CC[C@H]21 NFWKVWVWBFBAOV-MISYRCLQSA-N 0.000 description 2
- 229940118781 dehydroabietic acid Drugs 0.000 description 2
- 125000001207 fluorophenyl group Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 235000010603 pastilles Nutrition 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000009333 weeding Methods 0.000 description 2
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- 239000002028 Biomass Substances 0.000 description 1
- 241000555706 Botryosphaeria dothidea Species 0.000 description 1
- 241001157813 Cercospora Species 0.000 description 1
- 240000008067 Cucumis sativus Species 0.000 description 1
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 description 1
- 241000223218 Fusarium Species 0.000 description 1
- 241000223195 Fusarium graminearum Species 0.000 description 1
- 235000007688 Lycopersicon esculentum Nutrition 0.000 description 1
- 240000003768 Solanum lycopersicum Species 0.000 description 1
- 238000002814 agar dilution Methods 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000003208 anti-thyroid effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940043671 antithyroid preparations Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940072185 drug for treatment of tuberculosis Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical group ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 230000008635 plant growth Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A synthetic method for dehydrogenation abietyl thiourea derivative, comprises the steps: with dehydrogenation abietic acid for raw material, prepares dehydrogenation abietic acid acyl chlorides through thionyl chloride reaction.N-substituted-phenyl thioureido quadrol prepared by aromatic yl different sulfur cyanic acid ester and reacting ethylenediamine, under DMAP catalysis, dehydrogenation abietic acid acyl chlorides and N-substituted-phenyl thioureido reacting ethylenediamine, synthesis obtains dehydrogenation abietyl thiourea derivative.The present invention achieves first and is incorporated into having multiple bioactive thiourea group in dehydrogenation abietic acid structure.Dehydrogenation abietyl thiourea derivative has multiple biological activity, particularly fungicidal activity, expands the range of application of dehydrogenation abietic acid.Dehydrogenation abietic acid used is the modified product of product of natural product rosin, and preparation method is simple, and cost is low.
Description
Technical field
The present invention relates to technical field of organic synthesis, particularly a kind of synthetic method of the novel functional deriv-dehydrogenation abietyl thiourea derivative based on dehydrogenation abietic acid and thiocarbamide.
Background technology
Thiourea shows biological activity widely, as sterilization, weeding, desinsection, coordinate plant growth, antitumor etc., has been applied to the fields such as agricultural chemicals, medicine, chiral synthesize at present.Medically, be used for synthesizing antithyroid superfunction medicine, anti-tuberculosis drugs, intravenous injection anaesthetic, thiocarbamide is a kind of important active heterocycles group, owing to having the advantages such as and anti-microbial activity low to human toxicity be good, worth people study further, thus develop more how more effective medicine.
Rosin is that one is extensively present in natural natural reproducible biomass resource.China is the country that rosin output is maximum in the world, but the deep processing rate of China's rosin is lower, needs novel method and the new technology of constantly developing rosin deep processing, thus accelerates the development of Gum Rosin Industry.Dehydrogenation abietic acid, also known as dehydroabietic acid, dehydroabietic acid, is the main component of nilox resin.Dehydrogenation abietic acid inherently has certain fungicidal activity, by the aromatic ring of dehydrogenation abietic acid and carboxy-modified and derivative that is synthesis also has multiple biological activity, as weeding, antiviral, antibacterial, antitumor etc., is worth research further.
Dehydrogenation abietyl thiourea derivative of the present invention is a kind of novel functional derivatives, and this material and synthetic method thereof are up to the present there are no domestic and international report.
Summary of the invention
The object of this invention is to provide a kind of synthetic method of dehydrogenation abietyl thiourea derivative, products therefrom cost is low, and preparation method is simple.
The present invention achieves the above object by the following technical solutions:
A kind of dehydrogenation abietyl thiourea derivative, the general structure of its compound is:
Wherein R be phenyl, o-tolyl, a tolyl, p-methylphenyl, guaiacyl, m-methoxyphenyl, p-methoxyphenyl, to fluorophenyl, rubigan, to any one in bromophenyl.
Prepare a method for described dehydrogenation abietyl thiourea derivative, react by following formula:
Wherein R be phenyl, o-tolyl, a tolyl, p-methylphenyl, guaiacyl, m-methoxyphenyl, p-methoxyphenyl, to fluorophenyl, rubigan, to any one in bromophenyl.
Described chloride reagent is phosphorus trichloride, phosphorus pentachloride, thionyl chloride, triphosgene, any one in oxalyl chloride; Chloride temperature is the reflux temperature of chloride reagent; Be in mass ratio, dehydrogenation abietic acid acyl chlorides: N-aryl thiourea base quadrol=1:1.2 reaction.
Described substituted-phenyl lsothiocyanates be PITC, o-tolyl lsothiocyanates, a tolyl lsothiocyanates, p-methylphenyl lsothiocyanates, guaiacyl lsothiocyanates, m-methoxyphenyl lsothiocyanates, p-methoxyphenyl lsothiocyanates, to any one in fluorophenylisothiocyanate, rubigan lsothiocyanates, PBIT.
Described catalyzer is DMAP DMAP.
Beneficial effect of the present invention:
With the main component of China's dominant resource nilox resin-dehydrogenation abietic acid for raw material, by a series of reaction, thiocarbamide active group is incorporated in the skeleton of dehydrogenation abietic acid and goes, prepare dehydrogenation abietyl thiourea derivative.Extend the purposes of rosin, improve the added value of rosin, the deep processing for dehydrogenation abietic acid provides new approach.
Embodiment
Below by way of specific embodiment, technical scheme of the present invention is described further.
Embodiment 1
The preparation of compound a:
Reflux condensing tube is being housed, in the there-necked flask of the 50ml of drying tube and thermometer, is adding 10.0g dehydrogenation abietic acid, under normal temperature, slowly dripping 25ml sulfur oxychloride, dripping complete heated and stirred backflow 5h.Reaction terminates rear decompression and steams excessive thionyl chloride, obtained dehydrogenation abietic acid acyl chlorides.
In 100ml there-necked flask, add quadrol 0.1mol and 10ml methylene dichloride respectively, under condition of ice bath, slowly dropping is containing the 30ml dichloromethane solution of 0.01mol PITC in flask, and TLC follows the tracks of reaction process.After having reacted, in 250ml separating funnel, wash 3 times by saturated NaCl solution, then adjust pH to 5-6 with the rare HCl of 2mol/L, get upper water solution, with the NaOH solution tune pH to 9-10 of 10%, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain N-phenylthiourea base quadrol.
In 100ml round-bottomed flask, add N-phenylthiourea base quadrol 0.0096mol, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stir and intermediate is dissolved.Be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slowly drip, 0.5h dropwises again, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal.By reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain compound a.m.p.192～194;IR(KBr,ν/cm
-1):3314(ν
NH)3072(ν
=CH),2930(ν
C-H),1626(ν
C=O),1534,1484(ν
Ar-C=C),1259(ν
C=S),1074(ν
C-N),701(δ
Ar-H);
1HNMR(DMSO-d
6,600MHz)δ/ppm:9.62(s,1H,NH),7.73(s,1H,NH),7.64(s,1H,NH),7.36(d,J=7.5Hz,2H,H-24,H-25),7.30(dd,J=10.7,5.1Hz,2H,H-28,H-29),7.15(d,J=8.2Hz,1H,H-11),7.10(t,J=7.3Hz,1H,H-28),6.96(dd,J=8.1,1.6Hz,1H,H-12),6.80(s,1H,H-14),3.58(s,2H,H-7),3.33–3.22(m,2H,H-21),2.81–2.68(m,3H,H-22,H-15),2.27(d,J=12.9Hz,1H,He-1),2.01(dd,J=12.4,1.9Hz,1H,H-5),1.71–1.58(m,4H,H-3,He-2,He-6),1.45–1.30(m,3H,Ha-1,Ha-2,Ha-6),1.16(s,3H,H-18),1.15(s,3H,H-20),1.14(s,3H,H-16),1.13(s,3H,H-17);
13CNMR(DMSO-d
6,150MHz)δ/ppm:180.50(C-23),178.20(C-19),147.10(C-25),145.05(C-13),134.39(C-9),128.71(C-8),126.42(C-24,C-26),124.34(C-14),124.01(C-27,C-29),123.63(C-11,C-12),123.30(C-28),46.43(C-4),44.76(C-21),43.92(C-22),38.72(C-5),37.62(C-1),36.66(C-10),36.42(C-3),32.92(C-15),29.54(C-7),24.94(C-20),23.96(C-16,C-17),20.55(C-6),18.45(C-2),16.38(C-18);ESI-MSm/z:476.2([M-H]
+);
+55.0(EtOH).
Embodiment 2
The preparation of compound b:
Reflux condensing tube is being housed, in the there-necked flask of the 50ml of drying tube and thermometer, is adding 10.0g dehydrogenation abietic acid, under normal temperature, slowly dripping 25ml sulfur oxychloride, dripping complete heated and stirred backflow 5h.Reaction terminates rear decompression and steams excessive thionyl chloride, obtained dehydrogenation abietic acid acyl chlorides.
In 100ml there-necked flask, add quadrol 0.1mol and 10ml methylene dichloride respectively, under condition of ice bath, slowly dropping is containing the 30ml dichloromethane solution of 0.01mol o-tolyl lsothiocyanates in flask, and TLC follows the tracks of reaction process.After having reacted, in 250ml separating funnel, wash 3 times by saturated NaCl solution, then adjust pH to 5-6 with the rare HCl of 2mol/L, get upper water solution, with the NaOH solution tune pH to 9-10 of 10%, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain N-o-tolyl thioureido quadrol.
In 100ml round-bottomed flask, add N-o-tolyl thioureido quadrol 0.0096mol, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stir and intermediate is dissolved.Be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slowly drip, 0.5h dropwises again, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal.By reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain compound b.m.p.102～104;IR(KBr,ν/cm
-1):3299(ν
NH),2928(ν
C-H),1635(ν
C=O),1530,1460(ν
Ar-C=C),1253(ν
C=S),1059(ν
C-N),738(δ
Ar-H);
1HNMR(DMSO-d
6,600MHz)δ/ppm:7.62(s,1H,NH),7.27(t,1H,NH),7.24–7.19(m,2H,H-29,H-26),7.18–7.12(m,2H,H-27,H-28),6.98(dd,J=8.1,1.8Hz,1H,H-12),6.85(d,J=1.4Hz,1H,H-11),6.64(t,J=5.1Hz,1H,NH),6.40(s,1H,H-14),3.86–3.74(m,2H,H-7),3.48–3.34(m,2H,H-21),2.84–2.78(m,3H,H-22,H-15),2.27(d,J=13.1Hz,1H,He-1),2.25(s,3H,H-30),2.04(dd,J=12.6,2.2Hz,1H,H-5),1.75–1.67(m,4H,H-3,He-2,He-6),1.49–1.43(m,2H,Ha-1,Ha-2,),1.37–1.32(m,1H,Ha-6),1.23(s,3H,H-18),1.22(s,3H,H-20),1.21(s,3H,H-16),1.19(s,3H,H-17);
13CNMR(DMSO-d
6,150MHz)δ/ppm:181.89(C-23),180.03(C-19),147.09(C-25),145.80(C-13),135.79(C-9),134.69(C-8),131.80(C-26),128.77(C-24),127.81(C-27),127.68(C-28),126.94(C-14),124.09(C-11，C-12),123.97(C-29),47.26(C-4),45.25(C-21),40.39(C-22),38.01(C-5),37.18(C-1),37.09(C-10,C-3),33.57(C-15),29.98(C-7),25.23(C-20),24.10(C-16,C-17),21.27(C-30),18.79(C-6),17.89(C-2),16.81(C-18);ESI-MSm/z:492.2([M+H]
+);
+60.0(EtOH).
Embodiment 3
The preparation of compound c:
Reflux condensing tube is being housed, in the there-necked flask of the 50ml of drying tube and thermometer, is adding 10.0g dehydrogenation abietic acid, under normal temperature, slowly dripping 25ml sulfur oxychloride, dripping complete heated and stirred backflow 5h.Reaction terminates rear decompression and steams excessive thionyl chloride, obtained dehydrogenation abietic acid acyl chlorides.
In 100ml there-necked flask, add quadrol 0.1mol and 10ml methylene dichloride respectively, under condition of ice bath, slowly dropping is containing the 30ml dichloromethane solution of tolyl lsothiocyanates between 0.01mol in flask, and TLC follows the tracks of reaction process.After having reacted, in 250ml separating funnel, wash 3 times by saturated NaCl solution, then adjust pH to 5-6 with the rare HCl of 2mol/L, get upper water solution, with the NaOH solution tune pH to 9-10 of 10%, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain tolylthiourea base quadrol between N-.
In 100ml round-bottomed flask, add tolylthiourea base quadrol 0.0096mol between N-, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stir and intermediate is dissolved.Be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slowly drip, 0.5h dropwises again, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal.By reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain compound c.m.p.165～166;IR(KBr,cm
-1)ν:3301,3190(ν
NH),2948(ν
C-H),1645(ν
C=O),1530,1450(ν
Ar-C=C),1249(ν
C=S),1059(ν
C-N),874,673(δ
Ar-H);
1HNMR(CDCl
3,600MHz)δ/ppm:7.74(s,1H,NH),7.27–7.24(m,1H,NH),7.15(d,J=8.2Hz,1H,NH),7.07(d,J=7.6Hz,1H,H-26),6.99(d,J=6.0Hz,3H,H-24,H-27,H-28),6.85(s,1H,H-11),6.76(s,1H,H-12),6.53(s,1H,H-14),3.83(dd,J=11.3,6.0Hz,2H,H-7),3.47(dd,J=9.8,5.8Hz,2H,H-21),2.87–2.74(m,3H,H-22,H-15),2.33(s,3H,H-30),2.29(d,J=12.7Hz,1H,He-1),2.06(dd,J=12.6,2.2Hz,1H,H-5),1.77–1.69(m,4H,H-3,He-2,He-6),1.48(m,2H,,Ha-1,Ha-2),1.38–1.35(m,1H,Ha-6),1.26(d,J=4.1Hz,3H,H-18),1.23(s,3H,H-20),1.22(s,3H,H-16),1.20(s,3H,H-17);
13CNMR(CDCl
3,150MHz)δ/ppm:181.52(C-23),180.07(C-19),147.10(C-29),145.82(C-13),140.49(C-9),134.71(C-8),130.01(C-25),128.39(C-27),126.97(C-24),126.05(C-26),124.12(C-28),123.99(C-14),122.43(C-11，C-12),47.34(C-30),45.74(C-4),45.31(C-21),39.96(C-22),38.05(C-5),37.14(C-1),37.11(C-10),33.59(C-3),30.00(C-15),25.26(C-7),24.12(C-16，C-17),21.46(C-20),21.26(C-6),18.81(C-2),16.79(C-18);ESI-MSm/z:492.1([M+H]
+);
+33.3(EtOH).
Embodiment 4
The preparation of compound d:
Reflux condensing tube is being housed, in the there-necked flask of the 50ml of drying tube and thermometer, is adding 10.0g dehydrogenation abietic acid, under normal temperature, slowly dripping 25ml sulfur oxychloride, dripping complete heated and stirred backflow 5h.Reaction terminates rear decompression and steams excessive thionyl chloride, obtained dehydrogenation abietic acid acyl chlorides.
In 100ml there-necked flask, add quadrol 0.1mol and 10ml methylene dichloride respectively, under condition of ice bath, slowly dropping is containing the 30ml dichloromethane solution of 0.01mol p-methylphenyl lsothiocyanates in flask, and TLC follows the tracks of reaction process.After having reacted, in 250ml separating funnel, wash 3 times by saturated NaCl solution, then adjust pH to 5-6 with the rare HCl of 2mol/L, get upper water solution, with the NaOH solution tune pH to 9-10 of 10%, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain N-p-methylphenyl thioureido quadrol.
In 100ml round-bottomed flask, add N-p-methylphenyl thioureido quadrol 0.0096mol, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stir and intermediate is dissolved.Be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slowly drip, 0.5h dropwises again, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal.By reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain compound d.
m.p.167～169;IR(KBr,ν/cm
-1):3294(ν
NH),2928,2961(ν
C-H),1623(ν
C=O),1520,1460(ν
Ar-C=C),1241(ν
C=S),1084(ν
C-N),813(δ
Ar-H);
1HNMR(DMSO-d
6,600MHz)δ/ppm:9.51(s,1H,NH),7.70(s,1H,NH),7.50(s,1H,NH),7.19(d,J=7.7Hz,2H,H-24,H-26),7.15(d,J=8.2Hz,1H,H-11),7.10(d,J=8.2Hz,2H,H-27,H-29),6.96(d,J=8.1Hz,1H,H-12),6.80(s,1H,H-14),3.56(s,2H,H-7),3.31–3.20(m,2H,H-21),2.79–2.66(m,3H,H-22,H-15),2.27(d,J=13.1Hz,1H,He-1),2.24(s,3H,H-30),1.98(dd,J=12.4,1.5Hz,H-5),1.75–1.57(m,4H,H-3,He-2,He-6),1.42(m,1H,Ha-6),1.38–1.28(m,2H,Ha-1,Ha-2),1.15(s,3H,H-18),1.15(s,3H,H-20),1.14(s,3H,H-16),1.12(s,3H,H-17);
13CNMR(DMSO-d
6,150MHz)δ/ppm:180.49(C-23),178.21(C-19),147.11(C-25),145.06(C-13),134.40(C-9),133.77(C-8),129.26(C-28),126.44(C-24,C-26),124.01(C-27,C-29),123.77(C-14),123.64(C-11,C-12),46.40(C-4),44.72(C-21),44.01(C-22),38.80(C-5),37.62(C-1),36.66(C-10),36.43(C-3),32.93(C-15),29.53(C-7),24.95(C-20),23.96(C-16,C-17),20.56(C-30),20.49(C-6),18.45(C-2),16.38(C-18);ESI-MSm/z:492.4([M+H]
+);
+25.0(EtOH).
Embodiment 5
The preparation of Verbindung:
Reflux condensing tube is being housed, in the there-necked flask of the 50ml of drying tube and thermometer, is adding 10.0g dehydrogenation abietic acid, under normal temperature, slowly dripping 25ml sulfur oxychloride, dripping complete heated and stirred backflow 5h.Reaction terminates rear decompression and steams excessive thionyl chloride, obtained dehydrogenation abietic acid acyl chlorides.
In 100ml there-necked flask, add quadrol 0.1mol and 10ml methylene dichloride respectively, under condition of ice bath, slowly dropping is containing the 30ml dichloromethane solution of 0.01mol guaiacyl lsothiocyanates in flask, and TLC follows the tracks of reaction process.After having reacted, in 250ml separating funnel, wash 3 times by saturated NaCl solution, then adjust pH to 5-6 with the rare HCl of 2mol/L, get upper water solution, with the NaOH solution tune pH to 9-10 of 10%, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain N-guaiacyl thioureido quadrol.
In 100ml round-bottomed flask, add N-guaiacyl thioureido quadrol 0.0096mol, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stir and intermediate is dissolved.Be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slowly drip, 0.5h dropwises again, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal.By reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain Verbindung.m.p.90～91;IR(KBr,ν/cm
-1):3310(ν
NH),2926(ν
C-H),1633(ν
C=O),1537,1458(ν
Ar-C=C),1250(ν
C=S),1024(ν
-C-N),744(δ
Ar-H);
1HNMR(DMSO-d
6,600MHz)δ/ppm:8.94(s,1H,NH),7.74(s,1H,H-26),7.69(s,2H,NH),7.14(dd,J=13.9,8.1Hz,2H,H-27,H-29),7.04(d,J=8.2Hz,1H,H-11),6.96(dd,J=8.1,1.5Hz,1H,H-12),6.88(t,J=7.6Hz,1H,H-28),6.81(s,1H,H-14),3.79(s,3H,H-30),3.55(s,2H,H-7),3.31–3.18(m,2H,H-21),2.79–2.69(m,3H,H-22,H-15),2.26(d,J=13.0Hz,1H,He-1),2.00(d,J=13.8Hz,1H,H-5),1.73–1.58(m,4H,,H-3,He-2,He-6),1.44–1.30(m,3H,Ha-1,Ha-2,Ha-6),1.15(s,3H,H-18),1.14(s,6H,H-20,H-17),1.12(s,3H,H-17);
13CNMR(DMSO-d
6,150MHz)δ/ppm:180.77(C-23),178.09(C-19),147.12(C-24),145.06(C-13),134.41(C-9),126.43(C-8),125.91(C-26),124.02(C-25，C-28),123.63(C-14),119.98(C-27，C-29),111.67(C-11，C-12),55.56(C-30),46.41(C-4),44.71(C-21),43.65(C-22),38.90(C-5),37.60(C-1),36.66(C-10),36.41(C-3),32.92(C-15),29.54(C-7),24.94(C-20),23.97(C-16，C-17),20.55(C-6),18.44(C-2),16.38(C-18);ESI-MSm/z:508.0([M]
+);
+40.0(EtOH).
Embodiment 6
The preparation of compound f:
Reflux condensing tube is being housed, in the there-necked flask of the 50ml of drying tube and thermometer, is adding 10.0g dehydrogenation abietic acid, under normal temperature, slowly dripping 25ml sulfur oxychloride, dripping complete heated and stirred backflow 5h.Reaction terminates rear decompression and steams excessive thionyl chloride, obtained dehydrogenation abietic acid acyl chlorides.
In 100ml there-necked flask, add quadrol 0.1mol and 10ml methylene dichloride respectively, under condition of ice bath, slowly dropping is containing the 30ml dichloromethane solution of 0.01mol m-methoxyphenyl lsothiocyanates in flask, and TLC follows the tracks of reaction process.After having reacted, in 250ml separating funnel, wash 3 times by saturated NaCl solution, then adjust pH to 5-6 with the rare HCl of 2mol/L, get upper water solution, with the NaOH solution tune pH to 9-10 of 10%, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain N-m-methoxyphenyl thioureido quadrol.
In 100ml round-bottomed flask, add N-m-methoxyphenyl thioureido quadrol 0.0096mol, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stir and intermediate is dissolved.Be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slowly drip, 0.5h dropwises again, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal.By reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain compound f.m.p.101～103;IR(KBr,ν/cm-1):3304(ν
NH),2928(ν
C-H),1610(ν
C=O),1530,1455(ν
Ar-C=C),1259(ν
C=S),1049(C-N),884,685(δ
Ar-H);
1HNMR(DMSO-d
6,600MHz)δ/ppm:9.61(s,1H,NH),7.71(s,1H,NH),7.64(s,1H,NH),7.20(t,J=8.1Hz,1H,H-27),7.15(d,J=8.2Hz,1H,H-11),7.05(s,1H,H-24),6.95(dd,J=8.2,1.4Hz,1H,H-12),6.90(s,1H,H-28),6.79(s,1H,H-14),6.69(dd,J=8.2,2.3Hz,1H,H-26),3.72(s,3H),3.57(s,2H),3.32–3.22(m,2H),2.79–2.67(m,3H),2.26(d,J=13.1Hz,1H),2.00(d,J=12.4Hz,1H),1.76–1.57(m,4H),1.45–1.29(m,3H),1.15(s,6H),1.14(s,3H),1.12(s,3H);
13CNMR(DMSO-d
6,150MHz,)δ/ppm:180.30(C-23),178.21(C-19),159.53(C-29),147.10(C-13),145.05(C-9),139.96(C-8),134.40(C-25),129.52(C-27),126.41(C-28),124.01(C-28),123.63(C-24),115.21(C-14),109.83(C-11),108.89(C-12),55.05(C-30),46.42(C-4),44.74(C-21),44.00(C-22),38.68(C-5),37.61(C-1),36.66(C-10),36.41(C-3),32.91(C-15),29.54(C-7),24.94(C-20),23.95(C-16,C-17),20.55(C-6),18.43(C-2),16.36(C-18);ESI-MSm/z:508.3([M]
+);
+55.0(EtOH).
Embodiment 7
The preparation of compound g:
Reflux condensing tube is being housed, in the there-necked flask of the 50ml of drying tube and thermometer, is adding 10.0g dehydrogenation abietic acid, under normal temperature, slowly dripping 25ml sulfur oxychloride, dripping complete heated and stirred backflow 5h.Reaction terminates rear decompression and steams excessive thionyl chloride, obtained dehydrogenation abietic acid acyl chlorides.
In 100ml there-necked flask, add quadrol 0.1mol and 10ml methylene dichloride respectively, under condition of ice bath, slowly dropping is containing the 30ml dichloromethane solution of 0.01mol p-methoxyphenyl lsothiocyanates in flask, and TLC follows the tracks of reaction process.After having reacted, in 250ml separating funnel, wash 3 times by saturated NaCl solution, then adjust pH to 5-6 with the rare HCl of 2mol/L, get upper water solution, with the NaOH solution tune pH to 9-10 of 10%, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain N-p-methoxyphenyl thioureido quadrol.
In 100ml round-bottomed flask, add N-p-methoxyphenyl thioureido quadrol 0.0096mol, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stir and intermediate is dissolved.Be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slowly drip, 0.5h dropwises again, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal.By reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain compound g.m.p.169～170;IR(KBr,cm
-1):3302(ν
NH),3013(ν
Ar-H),2926(ν
C-H),1630(ν
C=O),1518,1462(ν
Ar-C=C),1250(ν
C=S),1037(ν
C-N),824(δ
Ar-H);
1HNMR(DMSO-d
6,600MHz)δ/ppm:9.41(s,1H,NH),7.70(s,1H,NH),7.39(s,1H,NH),7.19(d,J=8.2Hz,2H,H-24,H-26),7.15(d,J=8.2Hz,1H,H-11),6.96(dd,J=8.2,1.8Hz,1H,H-12),6.89–6.84(m,2H,H-27,H-29),6.81(s,1H,H-14),3.71(s,3H,H-30),3.55(s,2H,H-7),3.31–3.20(m,2H,H-21),2.79–2.73(m,2H,H-22),2.73–2.67(m,1H,H-15),2.27(d,J=13.0Hz,1H,He-1),1.99(dd,J=12.2,2.1Hz,1H,H-5),1.75–1.58(m,4H,H-3,He-2,He-6),1.44–1.31(m,3H,Ha-1,Ha-2,Ha-6),1.15(s,3H,H-18),1.15(s,3H,H-20),1.14(s,3H,H-16),1.12(s,3H,H-17);
13CNMR(DMSO-d
6,150MHz)δ/ppm:180.77(s,C-23),178.21(s,C-19),156.71(s,C-28),147.10(s,C-13),145.06(s,C-9),134.39(s,C-8),126.44(s,C-24,C-26),126.08(s,C-25),124.00(s,C-29,C-27),123.62(s,C-11,C-12),114.04(s,C-14),55.20(s,C-30),46.40(s,C-4),44.72(s,C-21),44.02(s,C-22),38.86(s,C-5),37.62(s,C-1),36.66(s,C-10),36.43(s,C-3),32.92(s,C-15),29.53(s,C-7),24.93(s,C-20),23.95(C-16,C-17),20.56(s,C-6),18.44(s,C-12),16.36(s,C-18);ESI-MSm/z:508.2([M]
+);
+21.7(EtOH).
Embodiment 8
The preparation of compound h:
Reflux condensing tube is being housed, in the there-necked flask of the 50ml of drying tube and thermometer, is adding 10.0g dehydrogenation abietic acid, under normal temperature, slowly dripping 25ml sulfur oxychloride, dripping complete heated and stirred backflow 5h.Reaction terminates rear decompression and steams excessive thionyl chloride, obtained dehydrogenation abietic acid acyl chlorides.
In 100ml there-necked flask, add quadrol 0.1mol and 10ml methylene dichloride respectively, under condition of ice bath, slowly drip and contain 0.01mol to the 30ml dichloromethane solution of fluorophenylisothiocyanate in flask, TLC follows the tracks of reaction process.After having reacted, in 250ml separating funnel, wash 3 times by saturated NaCl solution, then adjust pH to 5-6 with the rare HCl of 2mol/L, get upper water solution, with the NaOH solution tune pH to 9-10 of 10%, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain N-semicarbazide base quadrol.
In 100ml round-bottomed flask, add N-semicarbazide base quadrol 0.0096mol, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stir and intermediate is dissolved.Be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slowly drip, 0.5h dropwises again, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal.By reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain compound h.m.p.193 ~ 194, IR (KBr, cm
-1): 3302 (ν
nH), 3065 (ν
ar-H), 2932 (ν
c-H), 1624 (ν
c=O), 1518,1437 (ν
ar-C=C), 1224 (ν
c=S), 1088 (ν
c-N), 840 (δ
ar-H),
1hNMR (DMSO-d
6, 600MHz) δ/ppm:9.57 (s, 1H, NH), 7.73 (s, 1H, NH), 7.60 (s, 1H, NH), 7.35 (s, 2H, H-24, H-26), 7.15 (d, J=8.2Hz, 1H, H-11), 7.12 (t, J=8.8Hz, 2H, H-27, H-29), 6.96 (d, J=8.1Hz, 1H, H-12), 6.80 (s, 1H, H-14), 3.55 (s, 2H, H-7), 3.33 – 3.22 (m, 2H, H-21), 2.79 – 2.72 (m, 2H, H-22), 2.73 – 2.66 (m, 1H, H-15), 2.27 (d, J=13.0Hz, 1H, He-1), 1.99 (dd, J=12.4, 1.6Hz, 1H, H-5), 1.76 – 1.56 (m, 4H, H-3, He-2, He-6), 1.44 – 1.29 (m, 3H, Ha-1, Ha-2, Ha-6), 1.15 (s, 6H, H-18, H-20), 1.14 (s, 3H, H-16), 1.12 (s, 3H, H-17),
13cNMR (DMSO-d
6, 150MHz) δ/ppm:180.89 (C-23), 178.26 (C-19), 159.94 (C-28), 158.34 (C-25), 147.10 (C-13), 145.07 (C-9), 134.38 (C-8), 126.43 (C-27, C-29), 125.85 (C-24, C-26), 124.01 (C-14), 123.64 (C-11, C-12), 46.43 (C-4), 44.79 (C-21), 44.04 (C-22), 38.69 (C-5), 37.61 (C-1), 36.66 (C-10), 36.40 (C-3), 32.91 (C-15), 29.53 (C-7), 24.93 (C-20), 23.95 (C-16, C-17), 20.53 (C-6), 18.43 (C-2), 16.37 (C-18), ESI-MSm/z:494.1 ([M-H]
+),
+ 51.7 (EtOH).
Embodiment 9
The preparation of compound i:
Reflux condensing tube is being housed, in the there-necked flask of the 50ml of drying tube and thermometer, is adding 10.0g dehydrogenation abietic acid, under normal temperature, slowly dripping 25ml sulfur oxychloride, dripping complete heated and stirred backflow 5h.Reaction terminates rear decompression and steams excessive thionyl chloride, obtained dehydrogenation abietic acid acyl chlorides.
In 100ml there-necked flask, add quadrol 0.1mol and 10ml methylene dichloride respectively, under condition of ice bath, slowly dropping is containing the 30ml dichloromethane solution of 0.01mol rubigan lsothiocyanates in flask, and TLC follows the tracks of reaction process.After having reacted, in 250ml separating funnel, wash 3 times by saturated NaCl solution, then adjust pH to 5-6 with the rare HCl of 2mol/L, get upper water solution, with the NaOH solution tune pH to 9-10 of 10%, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain N-rubigan thioureido quadrol.
In 100ml round-bottomed flask, add N-rubigan thioureido quadrol 0.0096mol, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stir and intermediate is dissolved.Be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slowly drip, 0.5h dropwises again, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal.By reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain compound i.
m.p.171～172;IR(KBr,cm
-1):3299(ν
NH),3069(ν
Ar-H),2933(ν
C-H),1625(ν
C=O),1530,1490(ν
Ar-C=C),1259(ν
C=S),1089(ν
C-N),818(δ
Ar-H);
1HNMR(CDCl
3,600MHz)δ/ppm:8.31(s,1H,NH),7.30(s,1H,NH),7.22–7.15(m,4H,H-24,H-26,H-27,H-29),7.13(d,J=8.2Hz,1H,H-11),7.00(d,J=7.8Hz,1H,H-12),6.84(s,1H,NH),6.62(s,1H,H-14),3.80(d,J=32.5Hz,2H,H-7),3.52–3.38(m,2H,H-21),2.87–2.78(m,2H,H-22),2.78–2.70(m,1H,H-15),2.26(d,J=12.8Hz,1H,He-1),2.00(d,J=12.1Hz,1H,H-5),1.76–1.64(m,4H,H-3,He-2,He-6),1.43–1.30(m,3H,Ha-1,Ha-2,Ha-6),1.24(s,3H,H-18),1.23(s,3H,20),1.22(s,3H,H-16),1.18(s,3H,H-17);
13CNMR(CDCl
3,150MHz)δ/ppm:δ181.81(C-23),180.73(C-19),146.92(C-28),145.94(C-25),134.40(C-13),132.21(C-9),129.74(C-8),126.94(C-14),126.47(C-27,C-29,C-24,C-26),124.12(C-11，C-12),47.39(C-4),45.42(C-21),40.02(C-22),37.96(C-5),37.12(C-1),37.03(C-10),33.57(C-3),29.94(C-15),29.81(C-7),25.16(C-20),24.11(C-16,C-17),21.24(C-6),18.69(C-2),16.69(C-18);ESI-MSm/z:510.1([M-H]
+);
+26.7(EtOH).
Embodiment 10
The preparation of compound j:
Reflux condensing tube is being housed, in the there-necked flask of the 50ml of drying tube and thermometer, is adding 10.0g dehydrogenation abietic acid, under normal temperature, slowly dripping 25ml sulfur oxychloride, dripping complete heated and stirred backflow 5h.Reaction terminates rear decompression and steams excessive thionyl chloride, obtained dehydrogenation abietic acid acyl chlorides.
In 100ml there-necked flask, add quadrol 0.1mol and 10ml methylene dichloride respectively, under condition of ice bath, slowly dropping is containing the 30ml dichloromethane solution of 0.01mol PBIT in flask, and TLC follows the tracks of reaction process.After having reacted, in 250ml separating funnel, wash 3 times by saturated NaCl solution, then adjust pH to 5-6 with the rare HCl of 2mol/L, get upper water solution, with the NaOH solution tune pH to 9-10 of 10%, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain N-to bromophenyl thioureido quadrol.
In 100ml round-bottomed flask, add N-to bromophenyl thioureido quadrol 0.0096mol, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stir and intermediate is dissolved.Be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slowly drip, 0.5h dropwises again, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal.By reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain compound j.m.p.112 ~ 114, IR (KBr, cm
-1): 3310 (ν
nH), 2940 (ν
c-H), 1626 (ν
c=O), 1537,1483 (ν
ar-C=C), 1246 (ν
c=S), 1074 (ν
c-N), 815 (δ
ar-H),
1hNMR (DMSO-d
6, 600MHz) δ/ppm:9.69 (s, 1H, NH), 7.73 (s, 2H, NH), 7.48 – 7.44 (m, 2H, H-24, H-26), 7.37 (d, J=7.9Hz, 2H, H-27, H-29), 7.15 (d, J=8.2Hz, 1H, H-11), 6.96 (dd, J=8.2, 1.8Hz, 1H, H-12), 6.78 (s, 1H, H-14), 3.55 (s, 2H, H-7), 3.31 – 3.22 (m, 2H, H-21), 2.79 – 2.66 (m, 3H, H-21, H-15), 2.27 (d, J=13.0Hz, 1H, He-1), 1.99 (d, J=12.5Hz, 1H, H-5), 1.74 – 1.57 (m, 4H, , H-3, He-2, He-6), 1.45 – 1.30 (m, 3H, Ha-1, Ha-2, Ha-6), 1.15 (d, J=1.5Hz, 6H, H-18, H-20), 1.13 (d, J=1.3Hz, 3H, H-16), 1.12 (s, 3H, H-17),
13cNMR (DMSO-d
6, 150MHz) δ/ppm:180.54 (C-23), 178.25 (C-19), 147.09 (C-28), 145.06 (C-25), 134.37 (C-13), 131.40 (C-9), 126.41 (C-8), 125.05 (C-14), 124.00 (C-27, C-29), 123.64 (C-24, C-26), 116.54 (C-12), 116.13 (C-11), 46.43 (C-4), 44.79 (C-21), 44.05 (C-22), 38.54 (C-5), 37.61 (C-1), 36.66 (C-10), 36.39 (C-3), 32.90 (C-15), 29.52 (C-7), 24.93 (C-20), 23.95 (C-16, C-17), 20.52 (C-6), 18.43 (C-2), 16.36 (C-18), ESI-MSm/z:556.1 ([M]
+),
+ 53.3 (EtOH).
By prepared by embodiment 1-10 dehydrogenation abietyl thiourea derivative carry out fungicidal activity test, testing method and result as follows:
(1) fungicidal activity testing method:
Adopt vitro method, namely agar dilution measures the inhibit activities of all compounds to five kinds of pathogenic bacterias respectively.
1.. test compound is dissolved in acetone, is then diluted to the test liquid of 500ppm with the Sorporl-144 emulsifying agent of 200ppm; 2.. get test liquid 1ml, be injected in culture dish, then add 9mlPSA substratum, finally make the pastille flat board that concentration is 50ppm; 3.. supply examination bacterium taking-up diameter to be 5mm bacterium cake with punch tool by cultured, be placed in pastille flat board, every ware places three pieces respectively, and puts in equilateral triangle; 4.. culture dish is placed in 24 ± 1 DEG C of incubators and cultivates 48h, measure the expansion diameter of each process mycelia, and contrast with blank (not adding medicine).Activity index: relatively suppress inhibiting rate α %.
Activity index classification: A level: α >=90%; B level: 70%≤α < 90%; C level: 50%≤α < 70%; D level: α < 50%.
(2) fungicidal activity test result:
The fungicidal activity of dehydrogenation abietyl thiourea compound
Fungicidal activity Index grading: A level: α >=90%; B level: 70%≤α < 90%; C level: 50%≤α < 70%; D level: α < 50%.
As seen from the table, under the concentration of 50 μ g/ml, synthesized dehydrogenation abietyl thiourea compound shows certain inhibit activities to Botryosphaeria berengeriana f. sp, wherein the inhibit activities of compound b (R=2-Me) is best, inhibiting rate is 64.2%, the inhibiting rate of compound c (R=3-Me) is 55.8%, and the inhibiting rate of Verbindung (R=2-OMe), f (R=3-OMe) and i (R=4-Cl) is 51.7%.All compounds all only have weak inhibit activities to other four kinds of germs, compound c (R=3-Me), d (R=4-Me) and h (R=4-F) inhibiting rate to cucumber fusarium axysporum are 48.1%, compound b (R=2-Me), g (R=4-OMe) and i (R=4-Cl) inhibiting rate to peanut Cercospora bacteria are 32.2%, compound b (R=2-Me) is 46.4% to the inhibiting rate of tomato early blight bacterium, and compound f (R=3-OMe) is 40.8% to the inhibiting rate of fusarium graminearum.
Claims (1)
1. a dehydrogenation abietyl thiourea derivative, is characterized in that, particular compound structure is as follows:
The preparation method of described compound a comprises the steps:
(1) reflux condensing tube is being housed, in the there-necked flask of the 50ml of drying tube and thermometer, is adding 10.0g dehydrogenation abietic acid, under normal temperature, slowly dripping 25ml sulfur oxychloride, drip complete heated and stirred backflow 5h, reaction terminates rear decompression and steams excessive thionyl chloride, obtained dehydrogenation abietic acid acyl chlorides
(2) in 100ml there-necked flask, add quadrol 0.1mol and 10ml methylene dichloride respectively, under condition of ice bath, slowly dropping contains the 30ml dichloromethane solution of 0.01mol PITC in flask, TLC follows the tracks of reaction process, after having reacted, in 250ml separating funnel, wash 3 times by saturated NaCl solution, pH to 5-6 is adjusted again with rare HCl of 2mol/L, get upper water solution, the NaOH solution with 10% adjusts pH to 9-10, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain N-phenylthiourea base quadrol,
(3) in 100ml round-bottomed flask, add N-phenylthiourea base quadrol 0.0096mol, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stirs and intermediate is dissolved, then be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slow dropping, 0.5h dropwises, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal, by reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain compound a;
The preparation method of described compound b comprises the steps:
(1) step is identical with the step (1) of the preparation method of compound a,
(2) in 100ml there-necked flask, quadrol 0.1mol and 10ml methylene dichloride is added respectively, under condition of ice bath, slow dropping contains the 30ml dichloromethane solution of 0.01mol o-tolyl lsothiocyanates in flask, TLC follows the tracks of reaction process, after having reacted, in 250ml separating funnel, 3 times are washed by saturated NaCl solution, pH to 5-6 is adjusted again with rare HCl of 2mol/L, get upper water solution, the NaOH solution with 10% adjusts pH to 9-10, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain N-o-tolyl thioureido quadrol,
(3) in 100ml round-bottomed flask, add N-o-tolyl thioureido quadrol 0.0096mol, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stirs and intermediate is dissolved, then be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slow dropping, 0.5h dropwises, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal, by reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain compound b;
The preparation method of described compound c comprises the steps:
(1) step is identical with the step (1) of the preparation method of compound a,
(2) in 100ml there-necked flask, quadrol 0.1mol and 10ml methylene dichloride is added respectively, under condition of ice bath, slow dropping contains the 30ml dichloromethane solution of tolyl lsothiocyanates between 0.01mol in flask, TLC follows the tracks of reaction process, after having reacted, in 250ml separating funnel, 3 times are washed by saturated NaCl solution, pH to 5-6 is adjusted again with rare HCl of 2mol/L, get upper water solution, the NaOH solution with 10% adjusts pH to 9-10, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain tolylthiourea base quadrol between N-,
(3) in 100ml round-bottomed flask, add tolylthiourea base quadrol 0.0096mol between N-, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stirs and intermediate is dissolved, then be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slow dropping, 0.5h dropwises, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal, by reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain compound c;
The preparation method of described compound d comprises the steps:
(1) step is identical with the step (1) of the preparation method of compound a,
(2) in 100ml there-necked flask, quadrol 0.1mol and 10ml methylene dichloride is added respectively, under condition of ice bath, slow dropping contains the 30ml dichloromethane solution of 0.01mol p-methylphenyl lsothiocyanates in flask, TLC follows the tracks of reaction process, after having reacted, in 250ml separating funnel, 3 times are washed by saturated NaCl solution, pH to 5-6 is adjusted again with rare HCl of 2mol/L, get upper water solution, the NaOH solution with 10% adjusts pH to 9-10, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain N-p-methylphenyl thioureido quadrol,
(3) in 100ml round-bottomed flask, add N-p-methylphenyl thioureido quadrol 0.0096mol, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stirs and intermediate is dissolved, then be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slow dropping, 0.5h dropwises, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal, by reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain compound d;
The preparation method of described Verbindung comprises the steps:
(1) step is identical with the step (1) of the preparation method of compound a,
(2) in 100ml there-necked flask, quadrol 0.1mol and 10ml methylene dichloride is added respectively, under condition of ice bath, slow dropping contains the 30ml dichloromethane solution of 0.01mol guaiacyl lsothiocyanates in flask, TLC follows the tracks of reaction process, after having reacted, in 250ml separating funnel, 3 times are washed by saturated NaCl solution, pH to 5-6 is adjusted again with rare HCl of 2mol/L, get upper water solution, the NaOH solution with 10% adjusts pH to 9-10, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain N-guaiacyl thioureido quadrol,
(3) in 100ml round-bottomed flask, add N-guaiacyl thioureido quadrol 0.0096mol, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stirs and intermediate is dissolved, then be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slow dropping, 0.5h dropwises, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal, by reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain Verbindung;
The preparation method of described compound f comprises the steps:
(1) step is identical with the step (1) of the preparation method of compound a,
(2) in 100ml there-necked flask, quadrol 0.1mol and 10ml methylene dichloride is added respectively, under condition of ice bath, slow dropping contains the 30ml dichloromethane solution of 0.01mol m-methoxyphenyl lsothiocyanates in flask, TLC follows the tracks of reaction process, after having reacted, in 250ml separating funnel, 3 times are washed by saturated NaCl solution, pH to 5-6 is adjusted again with rare HCl of 2mol/L, get upper water solution, the NaOH solution with 10% adjusts pH to 9-10, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain N-m-methoxyphenyl thioureido quadrol,
(3) in 100ml round-bottomed flask, add N-m-methoxyphenyl thioureido quadrol 0.0096mol, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stirs and intermediate is dissolved, then be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slow dropping, 0.5h dropwises, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal, by reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain compound f;
The preparation method of described compound g comprises the steps:
(1) step is identical with the step (1) of the preparation method of compound a,
(2) in 100ml there-necked flask, quadrol 0.1mol and 10ml methylene dichloride is added respectively, under condition of ice bath, slow dropping contains the 30ml dichloromethane solution of 0.01mol p-methoxyphenyl lsothiocyanates in flask, TLC follows the tracks of reaction process, after having reacted, in 250ml separating funnel, 3 times are washed by saturated NaCl solution, pH to 5-6 is adjusted again with rare HCl of 2mol/L, get upper water solution, the NaOH solution with 10% adjusts pH to 9-10, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain N-p-methoxyphenyl thioureido quadrol,
(3) in 100ml round-bottomed flask, add N-p-methoxyphenyl thioureido quadrol 0.0096mol, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stirs and intermediate is dissolved, then be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slow dropping, 0.5h dropwises, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal, by reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain compound g;
The preparation method of described compound h comprises the steps:
(1) step is identical with the step (1) of the preparation method of compound a,
(2) in 100ml there-necked flask, quadrol 0.1mol and 10ml methylene dichloride is added respectively, under condition of ice bath, slow dropping contains 0.01mol to the 30ml dichloromethane solution of fluorophenylisothiocyanate in flask, TLC follows the tracks of reaction process, after having reacted, in 250ml separating funnel, 3 times are washed by saturated NaCl solution, pH to 5-6 is adjusted again with rare HCl of 2mol/L, get upper water solution, the NaOH solution with 10% adjusts pH to 9-10, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain N-semicarbazide base quadrol,
(3) in 100ml round-bottomed flask, add N-semicarbazide base quadrol 0.0096mol, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stirs and intermediate is dissolved, then be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slow dropping, 0.5h dropwises, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal, by reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain compound h;
The preparation method of described compound i comprises the steps:
(1) step is identical with the step (1) of the preparation method of compound a,
(2) in 100ml there-necked flask, quadrol 0.1mol and 10ml methylene dichloride is added respectively, under condition of ice bath, slow dropping contains the 30ml dichloromethane solution of 0.01mol rubigan lsothiocyanates in flask, TLC follows the tracks of reaction process, after having reacted, in 250ml separating funnel, 3 times are washed by saturated NaCl solution, pH to 5-6 is adjusted again with rare HCl of 2mol/L, get upper water solution, the NaOH solution with 10% adjusts pH to 9-10, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain N-rubigan thioureido quadrol,
(3) in 100ml round-bottomed flask, add N-rubigan thioureido quadrol 0.0096mol, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stirs and intermediate is dissolved, then be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slow dropping, 0.5h dropwises, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal, by reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain compound i;
The preparation method of described compound j comprises the steps:
(1) step is identical with the step (1) of the preparation method of compound a,
(2) in 100ml there-necked flask, quadrol 0.1mol and 10ml methylene dichloride is added respectively, under condition of ice bath, slow dropping contains the 30ml dichloromethane solution of 0.01mol PBIT in flask, TLC follows the tracks of reaction process, after having reacted, in 250ml separating funnel, 3 times are washed by saturated NaCl solution, pH to 5-6 is adjusted again with rare HCl of 2mol/L, get upper water solution, the NaOH solution with 10% adjusts pH to 9-10, with dichloromethane extraction 3-4 time, get organic layer, anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for solvent, obtain N-to bromophenyl thioureido quadrol,
(3) in 100ml round-bottomed flask, N-is added to bromophenyl thioureido quadrol 0.0096mol, Dimethylamino pyridine (DMAP) 0.001mol, triethylamine 0.01mol and tetrahydrofuran (THF) 30ml, stirs and intermediate is dissolved, then be dissolved in 20ml methylene dichloride by dextrocamphoric acid acyl chlorides 0.008mol, slow dropping, 0.5h dropwises, and temperature rising reflux reacts, and TLC follows the tracks of progress to terminal, by reaction solution saturated common salt water washing three times, organic over anhydrous Na
2sO
4after dry 2h, filter, be spin-dried for, purify, obtain compound j.
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