CN1785977A - 17-sulfonyl diversine and its preparation method - Google Patents
17-sulfonyl diversine and its preparation method Download PDFInfo
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- CN1785977A CN1785977A CN200510123090.4A CN200510123090A CN1785977A CN 1785977 A CN1785977 A CN 1785977A CN 200510123090 A CN200510123090 A CN 200510123090A CN 1785977 A CN1785977 A CN 1785977A
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- China
- Prior art keywords
- tuduranine
- benzyloxy benzyl
- preparation
- sulfonyl
- diversine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- KUECBJOPWMRHEX-CQSZACIVSA-N (-)-Tuduranine Natural products C1C2=CC=C(O)C=C2C2=C(OC)C(OC)=CC3=C2[C@@H]1NCC3 KUECBJOPWMRHEX-CQSZACIVSA-N 0.000 claims description 69
- KUECBJOPWMRHEX-UHFFFAOYSA-N Tuduranine Natural products C1C2=CC=C(O)C=C2C2=C(OC)C(OC)=CC3=C2C1NCC3 KUECBJOPWMRHEX-UHFFFAOYSA-N 0.000 claims description 54
- -1 substituted-phenyl Chemical group 0.000 claims description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 238000006386 neutralization reaction Methods 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- OEBIVOHKFYSBPE-UHFFFAOYSA-N 4-Benzyloxybenzyl alcohol Chemical compound C1=CC(CO)=CC=C1OCC1=CC=CC=C1 OEBIVOHKFYSBPE-UHFFFAOYSA-N 0.000 claims description 2
- 244000025254 Cannabis sativa Species 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 235000010755 mineral Nutrition 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- INYYVPJSBIVGPH-UHFFFAOYSA-N 14-episinomenine Natural products C1CN(C)C2CC3=CC=C(OC)C(O)=C3C31C2C=C(OC)C(=O)C3 INYYVPJSBIVGPH-UHFFFAOYSA-N 0.000 abstract description 2
- RARWEROUOQPTCJ-RBUKOAKNSA-N cepharamine Natural products C1CC2=CC=C(OC)C(O)=C2[C@@]2(CCN3C)[C@]13C=C(OC)C(=O)C2 RARWEROUOQPTCJ-RBUKOAKNSA-N 0.000 abstract description 2
- 229930002966 sinomenine Natural products 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 201000003068 rheumatic fever Diseases 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- 206010002660 Anoxia Diseases 0.000 description 1
- 241000976983 Anoxia Species 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 238000012347 Morris Water Maze Methods 0.000 description 1
- 240000001307 Myosotis scorpioides Species 0.000 description 1
- INYYVPJSBIVGPH-QHRIQVFBSA-N Sinomenine Chemical compound C([C@@H]1N(CC2)C)C3=CC=C(OC)C(O)=C3[C@@]32[C@@H]1C=C(OC)C(=O)C3 INYYVPJSBIVGPH-QHRIQVFBSA-N 0.000 description 1
- 241001643409 Sinomenium acutum Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000007953 anoxia Effects 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000001147 anti-toxic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- VGRFVJMYCCLWPQ-UHFFFAOYSA-N germanium Chemical compound [Ge].[Ge] VGRFVJMYCCLWPQ-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Natural products O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- KKHBCIDRVKMURK-UHFFFAOYSA-N phenyl(phenylmethoxy)methanol Chemical compound C=1C=CC=CC=1C(O)OCC1=CC=CC=C1 KKHBCIDRVKMURK-UHFFFAOYSA-N 0.000 description 1
- WQALBSLRHFHMIH-UHFFFAOYSA-N propane;sulfuryl dichloride Chemical compound CCC.ClS(Cl)(=O)=O WQALBSLRHFHMIH-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Abstract
The present invention discloses a kind of 17-sulfonyl sinomenine. It has potential medicinal application prospect. Said invention also provides its structure formula, and its preparation method and concrete steps.
Description
One, technical field
The present invention relates to a class organic compound and a method for making thereof, specifically relate to class 17-sulfonyl diversine and preparation method thereof.
Two, background technology
Tuduranine (sinomenine) is morphine (morphine) Alkaloid that extracts from windproof own section plant Stem of Orientoine and hair sinomenium acutum rhizome.According to the record of relevant document (CN98120549,1142946,1149456, US9903753), have pharmacologically actives such as anti-inflammatory, analgesia, step-down, anti-arrhythmia, the clinical symptoms such as treatment rheumatoid arthritis, cerebral ischemia, maladjusted nervous system that are mainly used in.
Nearest research (WO2004048340) finds that tuduranine and derivative thereof (adopt mouse Morris watermaze test, Social recognition test, NaNO
2Induced anoxia test) also has the effect of intelligence development, antitoxin, neuroprotective.
In patent CN.1153171, the tuduranine title complex of having reported blue or green network germanium-germanium metal is as broad-spectrum anti-cancer drug, have toxic side effect little, do not reduce immune function of human body, effectively press down the advantage of knurl.CN.02137445.7 has reported that coculine-phosphatide composite is used for the treatment of rheumatic arthritis, irregular pulse.This patent points out that mixture has the lipotropy stronger than parent drug, and its anti-inflammatory activity significantly improves.
The N-demethyl tuduranine that studies show that to N-demethyl tuduranine is compared with tuduranine and is had higher physiologically active and point out that it active has certain relation with wetting ability, and its salt, phenol ester derivative have effects such as treatment functional disorder, rheumatic arthritis.(US9903753、US6372756)。
(Acta Pharmaceutica Sinica such as Ye Xianrong, 2004,39 (3), 180-183) carried out modifying and obtained series compound containing the carbonyl ring, compare with tuduranine, adopt Oleum Tiglii to cause the mouse ear method that expands and find to keep, and the analgesic activities of this compound in the test of mouse acetic acid twisting method is better than tuduranine with the two keys of carbonyl conjugated activity of (7-methoxyl group-dihydro tuduranine) when saturated.
Three, summary of the invention
The object of the present invention is to provide a class 17-sulfonyl diversine; And adopt benzyloxy benzyl protection phenolic hydroxyl group method, and carry out with rare trifluoroacetic acid/dichloromethane liquid chamber temperature during deprotection, mild condition, speed of response is fast, and the method for preparing the 17-sulfonyl diversine is provided.
The objective of the invention is to realize by following technical scheme:
One class 17-sulfonyl diversine, its structural formula is as follows:
R=R wherein
1S (O0)-, R
1Alkyl and substituted hydrocarbon radicals such as=methyl, ethyl, propyl group, trifluoromethyl; Or R
1=phenyl and substituted-phenyl.
The preparation method's of a class 17-sulfonyl diversine that the present invention relates to reaction process is as follows:
The preparation method of one class 17-sulfonyl diversine, its preparation process is as follows:
(1), the preparation of 4-benzyloxy benzyl tuduranine (IV): get tuduranine (III), triphenylphosphine, 4-benzyloxy benzylalcohol dissolution with solvents with q.s, 0-20 ℃ drips diethyl azodiformate down, 0.5-2hr in add, continue to be stirred to reaction and finish to obtain 4-benzyloxy benzyl tuduranine, yield 80.0-99.0%; Wherein the consumption of triphenylphosphine, benzylalcohol, diethyl azodiformate is all 1.5-5.0 times (mol) that green grass or young crops rises alkali (III) consumption, and described solvent is tetrahydrofuran (THF), toluene or both mixtures;
(2), the preparation of 17-demethyl-4-benzyloxy benzyl tuduranine (V): with 4-benzyloxy benzyl tuduranine with molten
The agent dissolving is reacted with chloroformate-1-chloro-ethyl ester in the presence of acid binding agent then, obtains N-(1-chloroethene oxygen formyl radical)-4-benzyloxy benzyl tuduranine; Wherein solvent for use is 1, aprotic solvent such as 2-ethylene dichloride, chloroform, methylene dichloride, acetone, toluene; Described acid binding agent is an alkaline carbonate, and as sodium bicarbonate, yellow soda ash, salt of wormwood etc., its consumption is 1.0-6.0 times (quality) of 4-benzyloxy benzyl tuduranine; The chloroformate-1-chloro-ethyl ester consumption is benzyloxy benzyl tuduranine 0.1-3.0 doubly (quality);
The residuum of last step reaction directly joins in the methyl alcohol of q.s, reflux obtains 17-demethyl-4-benzyloxy benzyl tuduranine (V) and hydrochloride mixture thereof under the nitrogen protection, this mixture disperses with chloroform, and the sodium hydrogen carbonate solution neutralization obtains 17-demethyl-4-benzyloxy benzyl tuduranine;
(3), the preparation of 17-alkylsulfonyl-4-benzyloxy benzyl tuduranine (VI): get above-mentioned 17-demethyl-4-benzyloxy benzyl tuduranine (V), after melting with solvent, in the presence of acid binding agent,, obtain 17-alkylsulfonyl-4-benzyloxy benzyl tuduranine (VI) with the SULPHURYL CHLORIDE reaction; Acid binding agent is organic bases, as triethylamine, pyridine etc., or mineral alkali, as yellow soda ash, sodium bicarbonate etc.;
(4), the preparation of 17-sulfonyl diversine (I): get 17-alkylsulfonyl-4-benzyloxy benzyl tuduranine and at room temperature obtain the 17-sulfonyl diversine with 2-20% trifluoroacetic acid/dichloromethane solution-treated.
Beneficial effect:
We in the building-up process of tuduranine 17 bit derivants, reference literature (Bruce C.Hamper, Tetrahedron Letters, 37 (21), 3671-3674.M.Mergler, Tetrahedron Letters, 29 (32), 4005-8.) reported method adopts benzyloxy benzyl protection phenolic hydroxyl group; Removing protecting group is a step of comparison key; we adopt rare trifluoroacetic acid/dichloromethane solution room temperature to remove protection; find mild condition; speed of response fast (2-10min); side reaction is few; yield height (yield is all more than 90%) removes protection under this condition, does not produce two key hydrogenation phenomenons.
The part of compounds title numbering and the physicochemical constant thereof of one class 17-sulfonyl diversine such as structural formula see the following form:
Four, embodiment
The preparation of embodiment 1 17-third sulfonyl diversine (compound 3), its preparation process is as follows:
(1), the preparation of 4-benzyloxy benzyl tuduranine (IV): with reference to (Yukiohitotsuyanagi, J.Org.Chem., 1995,60,4549-58.);
In the 100ml there-necked flask, add the 1.65g tuduranine successively, 4.08g PPh
3, 2.97g benzyloxy benzylalcohol and 40.0ml absolute thf, start stirring, ice bath is cooled to 0 ℃ and drips 2.65gDEAD down, add in the 30min, remove ice bath, continue to stir, with TLC detection reaction progress, about 10hr afterreaction finishes, removal of solvent under reduced pressure is with silica gel chromatographic column dress post, successively with the chloroform/methanol drip washing of ethyl acetate and 6: 1, obtain pale yellow product, the ether recrystallization obtains 2.6g white solid 4-benzyloxy benzyl tuduranine (IV); 72 ℃ of mp; [α]
25 D-69.0 ° of (c=0.28 CH
2Cl
2);
1HNMR (300MHz, DCCl
3) δ 7.56 (d, 2H, J=8.6Hz.), 7.48-7.34 (m, 4H), 7.02 (d, 2H, J=8.6Hz.), 6.77 (dd, 2H, J=8.4Hz.), 5.52 (d, 1H, J=1.5Hz.), 5.23 (d, 1H ,=10.5Hz.), 5.11 (s, 2H), 5.01 (d, 1H, J=10.5Hz), 4.20 (d, 1H, J=16.1Hz.), 3.83 (s, 3H), 3.53 (s, 3H), 3.18-3.16 (m, 1H), and 3.05-2.97 (m, 2H), 2.82-2.73 (m, 1H), and 2.49-2.37 (m, 2H), 2.43 (s, 3H), 1.97 (ddd, 1H, J=4.3,11.4,11.4Hz.), and 1.87-1.80 (m, 2H);
(2), the preparation of 17-demethyl-4-benzyloxy benzyl tuduranine (V): with reference to (R.A.Olofson, J.Org.Chem.49 (11), 2081-2082);
1.0g 4-benzyloxy benzyl tuduranine dissolves with the 10.0ml ethylene dichloride, add sodium bicarbonate 1.0g, be cooled to 0 ℃ under stirring, drip the 0.3g chloroformate-1-chloro-ethyl ester, insulation 1-2hr removes ice-water bath, is warming up to little backflow 0.5-1hr, cool to room temperature, filter, revolve and desolvate, the gained intermediate product is without refining, directly join in the methyl alcohol of 20ml, reflux 15min under the nitrogen protection, removal of solvent under reduced pressure, products obtained therefrom is 17-demethyl-4-benzyloxy benzyl tuduranine and hydrochloride mixture thereof, disperse with chloroform, the sodium bicarbonate neutralization obtains 17-third alkylsulfonyl-4-benzyloxy benzyl tuduranine;
(3), the preparation of 17-third alkylsulfonyl-4-benzyloxy benzyl tuduranine (VI, R=third alkylsulfonyl);
100mg 17-demethyl-4-benzyloxy benzyl tuduranine, methylene dichloride 10ml, 0.1ml triethylamine, Dropwise 5 0mg propane SULPHURYL CHLORIDE under the ice-water bath, TLC follows the tracks of reaction to fully, washes, removal of solvent under reduced pressure is refining with silica gel chromatographic column, gets 105mg 17-third alkylsulfonyl-4-benzyloxy benzyl tuduranine; [α]
25 D+ 210.5 ° of (c=0.06CH
2Cl
2)
1HNMR (300MHz, DCCl
3) 7.56 (d, 1H, J=8.7Hz), 7.48-7.34 (m, 4H), 7.03 (d, 1H, J=8.7Hz), 6.81 (d, 1H, J=8.7Hz), 6.78 (d, 1H, J=8.7Hz), 5.47 (s, 1H), 5.27 (d, 1H, J=10.5Hz), 5.11 (s, 1H), 5.01 (d, 1H, J=10.5Hz), 4.37 (s, 1H), 4.21 (d, 1H, J=15.9Hz), 3.85 (s, 3H), 3.53 (s, 3H), 3.52-3.44 (m, 1H), 3.28-3.20 (m, 1H), 2.97-2.85 (m, 4H), 2.74-2.55 (m, 1H), 2.47 (d, 1H, J=15.9Hz) 1.94-1.83 (m, 3H), 1.80-1.65 (m, 1H), 1.07 (t, 3H, J=7.2Hz);
(4), the preparation of 17-third sulfonyl diversine (compound 3): with reference to (Bruce C.Hamper, Tetrahedron Letters, 37 (21), 3671-3674.M.Mergler, Tetrahedron Letters, 29 (32), preparation 4005-8.);
50mg 17-third alkylsulfonyl-4-benzyloxy benzyl tuduranine is with 5ml 5% trifluoroacetic acid/dichloromethane solution-treated 5min, add 10% sodium hydrogen carbonate solution 20ml neutralization, tell organic layer, anhydrous sodium sulfate drying, it is refining with silica gel chromatographic column that solvent is sloughed in decompression, gets compound 3; Mp 110.0-113.0 ℃; [α]
25 D+ 48.2 ° of (c=0.35 CH
2Cl
2);
1HNMR (300MHz, DCCl
3) δ
H6.69 (d, 1H, J=8.4Hz.), 6.57 (d, 1H, J=8.4Hz.), 6.04 (s, 1H), 5.44 (d, 1H, J=1.8Hz.), 4.40-4.35 (m, 2H.), 3.84 (s, 3H), 3.56-3.54 (m, 1H), 3.51 (s, 3H), 3.18-3.16 (m, 1H), 3.02-2.95 (m, 3H), 2.91-2.85 (m, 1H), 2.83-2.76 (m, 1H), 2.48 (d, 1H, J=16.0Hz.), 2.07-2.01 (m, 1H), 1.90-1.82 (m, 3H), 1.08 (t, 3H, J=7.4Hz.).
The preparation of embodiment 2:17-p-toluenesulfonyl tuduranine (compound 4), its preparation process is as follows:
(1), the preparation of 17-(to the Methyl benzenesulfonyl base)-4-benzyloxy benzyl tuduranine
100mg 17-demethyl-4-benzyloxy benzyl tuduranine, methylene dichloride 10ml, 0.1ml triethylamine, Dropwise 5 0mg p-methyl benzene sulfonic chloride under the ice-water bath, TLC are followed the tracks of reaction to fully, wash dry pressure reducing and steaming solvent, the not purified the next step that is directly used in of product;
(2), the preparation of 17-p-toluenesulfonyl tuduranine
The crude product of 100mg17-(to the Methyl benzenesulfonyl base)-4-benzyloxy benzyl tuduranine is with 5ml 5% trifluoroacetic acid/dichloromethane solution room temperature treatment 5min, washing, drying, and pressure reducing and steaming solvent, product separate with silica gel column chromatography and obtain compound 4; Mp 141.0-143.0 ℃; [α]
25 D+ 92.4 ° of (c=0.49 CH
2Cl
2);
1HNMR (300MHz, DCCl
3) δ
H7.74 (d, 2H, J=7.6Hz.), 7.33 (d, 2H, J=7.6Hz.), 6.62 (d, 1H, J=8.3Hz.), 6.38 (d, 1H, J=8.3Hz.), 6.00 (s, 1H), 5.40 (s, 1H), 4.49 (s, 1H), 4.32 (d, 1H, J=15.70Hz.), 3.80 (s, 3H), and 3.71-3.67 (m, 1H), 3.49 (s, 3H), and 3.05-2.99 (m, 1H), 2.84 (s, 1H), and 2.74-2.59 (m, 2H), 2.46 (s, 3H), 2.37 (d, 1H, J=15.7Hz.), 1.97-1.93 (m, 1H), 1.75-1.70 (m, 1H).
Claims (5)
1, a class 17-sulfonyl diversine, its structural formula is as follows:
R=R wherein
1S (O0)-, R
1The alkyl of=methyl, ethyl, propyl group, trifluoromethyl and substituted hydrocarbon radical; R
1=phenyl and substituted-phenyl.
2, a kind of method for preparing the 17-sulfonyl diversine of claim 1, its preparation process is as follows:
(1), the preparation of 4-benzyloxy benzyl tuduranine (IV): get tuduranine (III), triphenylphosphine, 4-benzyloxy benzylalcohol dissolution with solvents, 0-20 ℃ drips diethyl azodiformate down, 0.5-2hr in add, continue to be stirred to reaction and finish to obtain 4-benzyloxy benzyl tuduranine, yield 80.0-99.0%;
(2), the preparation of 17-demethyl-4-benzyloxy benzyl tuduranine (V): with 4-benzyloxy benzyl tuduranine dissolution with solvents, in the presence of acid binding agent, react then, obtain N-(1-chloroethene oxygen formyl radical)-4-benzyloxy benzyl tuduranine with chloroformate-1-chloro-ethyl ester; The residuum of last step reaction directly joins in the methyl alcohol, reflux must generate to 17-demethyl-4-benzyloxy benzyl tuduranine (V) and hydrochloride thereof under the nitrogen protection, this mixture disperses with chloroform, and the sodium hydrogen carbonate solution neutralization obtains 17-demethyl-4-benzyloxy benzyl tuduranine;
(3), the preparation of 17-alkylsulfonyl-4-benzyloxy benzyl tuduranine (VI): get above-mentioned 17-demethyl-4-benzyloxy benzyl tuduranine (V), after dissolution with solvents, in the presence of acid binding agent,, obtain 17-alkylsulfonyl-4-benzyloxy benzyl tuduranine (VI) with the SULPHURYL CHLORIDE reaction;
(4), the preparation of 17-sulfonyl diversine (I): get 17-alkylsulfonyl-4-benzyloxy benzyl tuduranine and at room temperature obtain the 17-sulfonyl diversine with 2-20% trifluoroacetic acid/dichloromethane solution-treated.
3, the preparation method of 17-sulfonyl diversine according to claim 2; the consumption that it is characterized in that triphenylphosphine, benzylalcohol, diethyl azodiformate in step (1) is all 1.5-5.0 times (mol) that green grass or young crops rises alkali (III) consumption, and described solvent is tetrahydrofuran (THF), toluene or both mixtures.
4, the preparation method of 17-sulfonyl diversine according to claim 2 is characterized in that at the solvent described in the step (2) be 1, and 2-ethylene dichloride, chloroform, methylene dichloride, acetone, toluene are aprotic solvent; Described acid binding agent is an alkaline carbonate, and as sodium bicarbonate, yellow soda ash, salt of wormwood etc., its consumption is 1.0-6.0 times (quality) of 4-benzyloxy benzyl tuduranine; The chloroformate-1-chloro-ethyl ester consumption is 0.1-3.0 times (quality) of benzyloxy benzyl tuduranine.
5, the preparation method of 17-sulfonyl diversine according to claim 2 is characterized in that at the acid binding agent described in the step (3) organic bases or mineral alkalis such as yellow soda ash, sodium bicarbonate such as triethylamine, pyridine being arranged.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
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| CN200510123090.4A CN1785977A (en) | 2005-12-15 | 2005-12-15 | 17-sulfonyl diversine and its preparation method |
| US12/096,543 US7932264B2 (en) | 2005-12-15 | 2006-12-15 | Sinomenine derivatives and preparation and uses thereof |
| PCT/US2006/048086 WO2007070703A2 (en) | 2005-12-15 | 2006-12-15 | Sinomenine derivatives and preparation and uses thereof |
| EP06847694A EP1959956A2 (en) | 2005-12-15 | 2006-12-15 | Sinomenine derivatives and preparation and uses thereof |
| JP2008545875A JP2009519960A (en) | 2005-12-15 | 2006-12-15 | Preparation and use of sinomenine derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101148437B (en) * | 2007-11-05 | 2010-06-02 | 南京大学 | Biinomenine derivative connected with C-C bond, preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101148437B (en) * | 2007-11-05 | 2010-06-02 | 南京大学 | Biinomenine derivative connected with C-C bond, preparation method and application thereof |
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