CN103232467B - A kind of Sinomenine structure-modified compound and preparation method thereof - Google Patents
A kind of Sinomenine structure-modified compound and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of Sinomenine structure-modified compound and preparation method thereof.Sinomenine structure-modified compound of the present invention is parent with tuduranine, prepared, comprising substituting group derivative new on A, C, D or C, D ring by chemical synthesis process.Sinomenine structure-modified compound of the present invention has certain activity in the effect experiments such as anti-inflammatory, immunity, analgesia, anaphylaxis.
Description
Patent application of the present invention is divisional application, and original bill application number is 200710111253.6, and the applying date is on June 19th, 2007, and denomination of invention is a kind of Sinomenine structure-modified compound and preparation method thereof.
Technical field
The present invention relates to a kind of compound and preparation method thereof, particularly a kind of Sinomenine structure-modified compound and preparation method thereof.
Background technology
Tuduranine is the alkaloids medicament of the most effectively treating rheumatism and rheumatoid arthritis disease extracted from Stem of Orientoine plant, has significant analgesia, calmness, anti-inflammatory, immunosuppression, the effect such as hypotensive.It can act on central nervous system and to unify endocrine system, and by two-ways regulation, improve immunity and anti-inflammatory mechanisms, eliminate paathogenic factor in body, repair tissue damages.If the sinomenium acutum alkali salt drug main of present widespread use is bulk drug with sinomenine hydrochloride, make various types of tablet, capsule, injection liquid etc.Only a few patient appearance untoward reaction is to a certain degree found that there is, as muscle redness, itch etc. in medication process.The present invention is intended to develop than sinomenine hydrochloride or the curative effect of blue or green Teng alkali and the Sinomenine structure-modified new compound of more excellent performance.
Summary of the invention
First object of the present invention is open a kind of compound; Second object of the present invention is the preparation method disclosing this compound; 3rd object of the present invention is the new pharmaceutical use disclosing this compound.
The present invention seeks to be achieved through the following technical solutions:
Sinomenine structure-modified compound of the present invention take tuduranine as parent, be prepared from by chemical synthesis process, comprise new substituting group derivative on each ring, such as: a class A ring connects new substituent Sinomenine derivate, a class C ring connects new substituent Sinomenine derivate or a class D ring or C, D ring connect new substituent Sinomenine derivate.
The chemical structural formula of described tuduranine parent is:
An above-mentioned class A ring connects new substituent Sinomenine derivate, and its structural formula is optional following a kind of:
An above-mentioned class C ring connects new substituent Sinomenine derivate, and its structural formula is optional following a kind of:
An above-mentioned class D ring or C, D ring connect new substituent Sinomenine derivate, and its structural formula is optional following a kind of:
The preparation method of all kinds of Sinomenine structure-modified compound of the present invention is: water or 2000-3000 milliliter/mole organic solvent in, under room temperature-reflux conditions, tuduranine and reagent react 1-48 hour with the ratio of 1:1.0-2.0, the method of product recrystallization is carried out being separated or using column chromatography method and is separated, and obtains Sinomenine structure-modified compound.
The preparation method of all kinds of Sinomenine structure-modified compound of the present invention is preferably: in the organic solvent of water or 2500 milliliters/mole, under room temperature-reflux conditions, tuduranine and reagent react 24 hours with the ratio of 1:1.5, the method of product recrystallization is carried out being separated or using column chromatography method and is separated, and obtains Sinomenine structure-modified compound.
Organic solvent of the present invention includes but not limited to methyl alcohol, ethanol, propyl alcohol, butanols, Virahol, the trimethyl carbinol, methylene dichloride, chloroform, 1,2-ethylene dichloride, tetracol phenixin, ethyl acetate, ether, tetrahydrofuran (THF), 1,4-dioxy six alkane, benzene, toluene, acetone, second cyanogen, methyl-sulphoxide or DMF.
Reagent of the present invention can select conventional reagent according to the constructional feature of compound.
Sinomenine structure-modified compound of the present invention is for the preparation of anti-inflammatory, analgesia, calmness or immunoregulatory medicine.
Sinomenine structure-modified compound of the present invention confirms through pharmacodynamics test: have the analgesia similar to sinomenine hydrochloride or blue or green Teng alkali, calmness, anti-inflammatory and immunosuppressive action, Sinomenine structure-modified compound has the toxicity lower than tuduranine and more significant drug action.Sinomenine structure-modified compound building-up reactions method of the present invention is simple, reaction conditions is gentle, easily operate, and Suitable commercial is produced.
Following experiment and embodiment are used for further illustrating but are not limited to the present invention.
Experimental example 1 pair of mouse ear Oleum Tiglii inhibition of inflammation
To mouselet subcutaneous injection Sinos50mg/kg, 0.5h rear left ear is coated with 2% crotons fluid 50ul and causes inflammation, and auricle under 4h backlash, weighs, and left and right two auricle weight difference is swelling, represents anti-inflammatory action intensity, the results are shown in Table 1 with inhibitory rate of intumesce.
Table 1Sinos is to mouse ear Oleum Tiglii inhibition of inflammation
In 40 compounds of experiment, have 12 new compounds to have stronger restraining effect to mouse ear Oleum Tiglii inflammation, wherein the strongest with Sino-14, Sino-30, Sino-23, Sino-31 take second place.
The restraining effect of experimental example 2 pairs of Rat Carrageenan colloidalities foot swelling
To big rat subcutaneous injection Sinos50mg/kg, the carrageenin 100ul of 0.5h rear left metapedes stone intradermal injection 1% causes inflammation, measures a Guo joint girth, continuous 6 hours every 1h later, so that behind left and right, Guo joint girth difference is for swelling, inhibitory rate of intumesce represents anti-inflammatory action intensity.The results are shown in Table-2
Table 2Sinos is to the restraining effect of Rat Carrageenan colloidality foot swelling
Result shows: compound S ino-14,26,29, and the foot swelling of 25 pairs of Rat Carrageenan colloidalities has stronger restraining effect, and wherein Sino-14,26 than Sino-0 Be very effective.
Experimental example 3 analgesic activity
Mouse subcutaneous injection Sinos50 or 25mg/kg, 0.5h pneumoretroperitoneum injects 7% acetic acid 10ml/kg, observe immediately and record writhing number of times in mouselet writhing time first time (writhing latent period) and 15min, representing the analgesic activities of compound with prolongation of latency rate and writhing number of times decrement.The results are shown in Table 3
Table 3Sinos is to rat analgesic activity
Result shows: 18 new compounds listed in above-mentioned table all have certain effect to rat analgesia, compound S ino-28, and the analgesic activity of 25,14,30 is comparatively strong, wherein Sino-28,25, and 14 than Sino-0 Be very effective.
Experimental example 4 pairs of rat peritoneal mast cells degranulations
Get big rat peripheral white blood cells, add Sinos, final concentration is 10-5mol/L, 37 DEG C of 2min, neutral red staining, Microscopic observation the mast cell degranulation percentage that counts, and represents retting conditions intensity with half retting conditions and full retting conditions percentage sum.The results are shown in Table 4.
Table-4Sinos, to rat peritoneal mast cells degranulation,
Result shows: 30 new compounds in upper table all have certain effect to rat peritoneal mast cells degranulation, compound S ino-31,46,3, and the mast cell degranulation of 33 is comparatively strong, and wherein Sino-33 is than Sino-0 Be very effective.
Experimental example 5 is on the impact of sensitization big rat peritoneal cavity mast cells release histamine
Big rat is with variola powder antiserum(antisera) sensitization, get peritoneal cavity mast cells, adjustment concentration is 106 cells/mL, get enchylema 0.1mL, add testing compound (final concentration 10-5mol/L) and Snakegourd Root liquid, cumulative volume 1mL, cultivate 10min for 37 DEG C, release histamine is successively with alkali-propyl carbinol and acid extraction purifying, o-phthalaldehyde(OPA) derivatize, measure fluorescence intensity (excitation wavelength 355nm, emission wavelength 440nm), histamine release level is reflected with this, calculate the percentage that testing compound fluorescence intensity accounts for full threshing pipe fluorescence intensity, judge the impact of testing compound on histamine release of mast cell, and discharge histamine degree with Sinos and compare, the results are shown in Table-5
Table-5Sinos is on the impact of sensitization big rat peritoneal cavity mast cells release histamine
Result shows: the effect of 11 new compounds in upper table to sensitization big rat peritoneal cavity mast cells release histamine all has certain effect, and the mast cell degranulation of compound S ino-28 is comparatively strong, and wherein Sino-28 is than Sino-0 Be very effective.
Experimental example 6 is on the impact of big rat splenocyte release IL-2
Get big rat splenocyte, removing red corpuscle, regulates cell concn to be 5 × 10
6/ ml, gets 1 milliliter, enchylema, and (final concentration is 10 to add ConA10ul (final concentration is 10ul/ml) and testing compound
-5mol/L) cultivate 24 hours for 37 DEG C, survey IL-2 level in supernatant.The results are shown in Table-6:
Table-6 is on the impact of big rat splenocyte release IL-2
Result shows: the impact of 4 new compounds in upper table on big rat splenocyte release IL-2 all has certain effect, compound S ino-34,26,14, and 30 effects are comparatively strong, and wherein Sino-26,30 than Sino-0 Be very effective.
Following embodiment all can realize the effect of above-mentioned experimental example
Embodiment
Embodiment 1:
Sino-14 compound, prepare by the following method:
The protection of A, phenolic hydroxyl group: take 10mmol tuduranine; join in 250 milliliter of three neck round-bottomed flask; add KOH10% ethanol (containing KOH11mmol); add 150 milliliters of ethanol again and make solvent, heating, stirs simultaneously; react 30 minutes under reflux conditions; drip 20mmol chloromethyl ether, after adding, more under reflux conditions react 2 hours; follow the tracks of with thin-layer chromatography in reaction process; within about 2 hours, react, stopped heating, cooling; in flask in material impouring 150 ml water; divide 3 extractions with 150 milliliters of chloroforms, merge the chloroformic solution of extraction, with anhydrous Na
2sO
4drying, evaporating solvent chloroform, to dry, obtains solid mixture, by column chromatography for separation, the hexanaphthene with 8:1 volume ratio: ethyl acetate is developping agent, the rare bismuth potassium iodide of developer, obtains tuduranine protection product 3.35 grams, yield 90%, fusing point 92-93 DEG C;
B, formylation reaction: measure 1 milliliter of POCl3 and join in 100 milliliter of three neck round-bottomed flask, flask is placed in ice bath and is cooled to 0 DEG C, slowly instill 10 milliliters of DMF, the bath of 10 minutes recession deicings, stir 30 minutes in dry conditions, add 40 milliliters of DMF solvents again, take 10mmol tuduranine protection product, join in flask, stir simultaneously, react more violent, heat release, then react 4 hours under 60 DEG C of conditions, follow the tracks of with thin-layer chromatography in reaction process, within about 4 hours, react, stop heating, cooling, in flask in material impouring 150 milliliters of 2N sodium acetate solns, 3 extractions are divided with 150 milliliters of chloroforms, merge the chloroformic solution of extraction, with anhydrous Na
2sO
4drying, evaporating solvent chloroform, to dry, obtains solid mixture, by column chromatography for separation, the hexanaphthene with 8:1 volume ratio: ethyl acetate is developping agent, the rare bismuth potassium iodide of developer, obtain the tuduranine hydroformylation product 3.08 grams of hydroxyl protection, yield 77%., fusing point 114-116 DEG C,
C, deprotection reaction: the tuduranine hydroformylation product taking 10mmol hydroxyl protection, join in 250 milliliter of three neck round-bottomed flask, add the methyl alcohol of 3:1 volume ratio: methylene dichloride mixed solvent 150 milliliters, add 10 milliliters of concentrated hydrochloric acids again, stirring reaction 24 hours at ambient temperature, follow the tracks of with thin-layer chromatography in reaction process, within about 24 hours, react, in flask in material impouring 150 ml water, being neutralized to pH value with 1moL/LNaOH solution is 9-10, filtering solids product, filtrate divides 3 extractions with 150 milliliters of chloroforms, merge the chloroformic solution of extraction, with anhydrous Na
2sO
4drying, evaporating solvent chloroform is to dry, and obtain solid mixture, by column chromatography for separation, the methylene dichloride of 8:1 volume ratio: methyl alcohol is developping agent, the rare bismuth potassium iodide of developer, obtains Sino-14 compound products 2.28 grams, yield 64%. fusing point 102-104 DEG C.
Embodiment 2:
The synthesis of Sino-1 compound:
Take the dry refined tuduranine of 60mmol, grinding powder, joins in 250 milliliters of three mouthfuls of round-bottomed flasks, be solvent with toluene, drip equimolar to fluorobenzoyl chloride, after dripping, under 80 degree of temperature condition, continuously stirring reacts 4 hours, cooling reactant, with the sodium hydroxide solution of 5%, regulate pH value, solid product is separated out completely, filtering solids, ethyl alcohol recrystallization, obtains Sino-1 compound products, fusing point 96-100 DEG C, yield 54%.
Embodiment 3:
The synthesis of Sino-2, Sino-3, Sino-9 compound:
Take the dry refined tuduranine of 60mmol, grinding powder, join in 250 milliliters of three mouthfuls of round-bottomed flasks, with methanol solvate, at room temperature drip bromine water, after dripping, continuously stirring reacts 2 hours, with the sodium hydroxide solution of 5%, regulate pH value, solid product is separated out completely, filtering solids, pass through column chromatography for separation, the methylene dichloride of 8:1 volume ratio: methyl alcohol is developping agent, the rare bismuth potassium iodide of developer, obtains compound products Sino-2 and Sino-3, yield be respectively 77% and 64%. fusing point be respectively 130-135 DEG C and 144-143 DEG C; By Sino-3 with after saturated sodium carbonate solution process, obtain new compound Sino-9 in another, fusing point is 129-131 DEG C, yield 27%.
Embodiment 4:
The synthesis of Sino-4, Sino-5, Sino-6 compound:
Take the dry refined tuduranine of 60mmol, grinding powder, join in 250 milliliters of three mouthfuls of round-bottomed flasks, add 50 milliliter of 40% Hydrogen bromide, neutralize pH value with the sodium hydroxide of 5% in 80 DEG C of reactions after 6 hours and equal 9, filtering solids, ethyl alcohol recrystallization, obtain compound products Sino-6, fusing point 121-122 DEG C, yield 84%; Sino-6 is joined in diacetyl oxide pyridine solvent, add the DMPA of catalytic amount simultaneously, 80 degree of stirring reactions 3 hours, regulate pH value that solid is separated out, by column chromatography for separation, the methylene dichloride of 8:1 volume ratio: methyl alcohol is developping agent, the rare bismuth potassium iodide of developer, compound products Sino-4 and Sino-5, yield be respectively 53% and 73%. fusing point be respectively 85-87 DEG C and 61-64 DEG C.
Embodiment 5:
The synthesis of Sino-7 compound:
Take the dry refined tuduranine of 60mmol, grinding powder, joins in 250 milliliters of three mouthfuls of round-bottomed flasks, is solvent, drips equimolar (C with toluene
2h
5) NSF
3, under 80 degree of temperature condition, continuously stirring reacts 4 hours, cooling reactant, with the sodium hydroxide solution of 5%, regulates pH value, solid product is separated out completely, filtering solids, ethyl alcohol recrystallization, obtain compound products Sino-7, fusing point 152-153 DEG C, yield 33%.
Embodiment 6:
The synthesis of Sino-8 compound:
Take the dry refined tuduranine of 60mmol, grinding powder, joins in 250 milliliters of three mouthfuls of round-bottomed flasks, be solvent with toluene, drip equimolar to diacetyl oxide, add the DMPA of triethylamine and catalytic amount, after dripping, under 80 degree of temperature condition, continuously stirring reacts 4 hours, cooling reactant, with the sodium hydroxide solution of 5%, regulates pH value, solid product is separated out completely, filtering solids, ethyl alcohol recrystallization, obtain compound products Sino-8, fusing point 82-84 DEG C, yield 83%.
Embodiment 7:
The synthesis of Sino-10 compound:
Take the dry refined tuduranine of 60mmol, grinding powder, joins in 250 milliliters of three mouthfuls of round-bottomed flasks, with CH
2cl
2for solvent, drip equimolar CH
3cOONO
2, control temperature is-78 DEG C, and continuously stirring reacts 1 hour, with the sodium hydroxide solution of 5%, regulates pH value, solid product is separated out completely, filtering solids, ethyl alcohol recrystallization, obtain compound products Sino-10, fusing point 136-138 DEG C, yield 30%.
Embodiment 8:
The synthesis of Sino-11, Sino-12, Sino-13, Sino-17, Sino-18 compound:
Take the dry refined tuduranine of 60mmol, grinding powder, join in 250 milliliters of three mouthfuls of round-bottomed flasks, add the paraformaldehyde of equivalent, add the 2N hydrochloric acid of 10 milliliters again, in 60 DEG C of reactions 2 hours, with the sodium hydroxide solution neutralizing acid of 10% after cooling, pH value is regulated to equal 9-10, filtering solids, pass through column chromatography for separation, the methylene dichloride of 8:1 volume ratio: methyl alcohol is developping agent, the rare bismuth potassium iodide of developer, obtain compound products Sino-12 and Sino-13, yield be respectively 58% and 44%. fusing point be respectively 247 DEG C (decomposition) and 263 DEG C (decomposition), Sino-12 is dissolved in dichloromethane solvent, adds reagent D EAD and PPh3, react 2 hours under room temperature, obtain new compound Sino-11, be separated by column chromatography purification, the methylene dichloride of 8:1 volume ratio: methyl alcohol is developping agent, fusing point is 120-123 DEG C, yield 81%, Sino-12 is dissolved in acetone solvent, adds 2N sodium hydroxide, drip the hydrogen peroxide of 30%, react 2 hours under room temperature, obtain new compound Sino-17, be separated by column chromatography purification, the methylene dichloride of 8:1 volume ratio: methyl alcohol is developping agent, fusing point is 122-124 DEG C, yield 43%, Sino-12 is dissolved in acetone solvent, by solution with to nitroso-group N, accelerine is oxidized, then add oxammonium hydrochloride, room temperature reaction 2 hours, product is separated by column chromatography purification, the methylene dichloride of 8:1 volume ratio: methyl alcohol is developping agent, obtain compound product Sino-18, fusing point is 233-236 DEG C, yield 39%.
Embodiment 9:
The synthesis of Sino-16, Sino-15 compound:
Take the dry refined tuduranine of 60mmol, grinding powder, join in 250 milliliters of flasks to the stupid aryldiazonium salt of methoxyl group now prepared, maintain the temperature at 0-5 DEG C, stirring reaction 1 hour, filtering solids, ethyl alcohol recrystallization, obtain new compound Sino-15, fusing point is 114-118 DEG C, yield 79%; Sino-15 is dissolved in acetone solvent, add the diacetyl oxide of equivalent and the DMPA of triethylamine and catalytic amount, 60 DEG C are reacted 2 hours, product is separated by column chromatography purification, the methylene dichloride of 8:1 volume ratio: methyl alcohol is developping agent, obtain compound product Sino-16, fusing point is 105-108 DEG C, yield 81%.
Embodiment 10:
The synthesis of Sino-22, Sino-21 compound:
Take the dry refined tuduranine of 60mmol, grinding powder, adds the oxammonium hydrochloride containing equivalent and sodium acetate soln, and room temperature reaction 1 hour, obtains new compound Sino-21, filtering solids, ethyl alcohol recrystallization, and new compound fusing point is 238 DEG C, yield 99%; Under similarity condition, react with 2,4-dinitraniline/acetic acid and tuduranine, obtain new compound Sino-22.
Embodiment 11:
The synthesis of Sino-23 compound:
Take the dry refined tuduranine of 60mmol, grinding powder, joins in 250 ml flasks, add methanol as solvent, Pd/C is catalyzer, passes into hydrogen, then adds p-Chlorobenzoic acid amide, continue to pass into hydrogen, thorough reaction, obtains new compound Sino-23, ethyl alcohol recrystallization, new compound fusing point is 124-127 DEG C, yield 28%.
Embodiment 12:
The synthesis of Sino-20 compound:
Take the dry refined tuduranine of 60mmol, grinding powder, joins in 250 ml flasks, adds methanol as solvent, Pd/C is catalyzer, pass into hydrogen, then add oxammonium hydrochloride and the sodium acetate soln of equivalent, under room temperature, react half an hour, obtain compound S ino-20, ethyl alcohol recrystallization, new compound fusing point is 244-246 DEG C, yield 54%.
Embodiment 13:
The synthesis of Sino-19 compound:
Take the dry refined tuduranine of 60mmol, grinding powder, joins in 250 ml flasks, adds methanol as solvent, the ethylene glycol of equivalent, passes into dry hydrogen chloride gas, reacts 4 hours, obtain new compound Sino-19, ethyl alcohol recrystallization, new compound fusing point is 87 DEG C, yield 64%.
Embodiment 14:
The synthesis of Sino-24, Sino-25, Sino-26, Sino-27, Sino-28, Sino-29, Sino-30, Sino-31 compound
The reduction of A, carbonyl: take the dry refined tuduranine of 60mmol, grinding powder, joins in 250 milliliters of three mouthfuls of round-bottomed flasks, and adding 200 ml methanol is solvent, stirs and tuduranine is all dissolved, separately take 180mmolNaBH
4crystal, is placed on crystal in a small beaker, is positioned in moisture eliminator, slowly adds NaBH with little spoon gradation
4crystal is in reaction flask, and a large amount of heat is released in reaction, and flask external application cold water cools, and temperature controls to be advisable below 10 DEG C, adds NaBH
4speed be advisable not release a large amount of gas, greatly can by NaBH within the time of 1.5-2 hour
4add, add NaBH
4after, remove water cooling, continue reaction stirred 2 hours, make it fully react completely, then slowly drip the hydrochloric acid of 1mol/L, make unreacted NaBH
4react completely, by the Rotary Evaporators vaporizes most solvent methanol of the material in flask, till being evaporated to into viscous pasty state, sticky mass is poured into while hot in the beaker of 200 ml waters, and then add 100 ml waters, vigorous stirring makes thick material thoroughly be dissolved in water, solution becomes light yellow, static several minutes, separate out the thick shape crystal of white immediately, regulate pH value to 9-11 with the hydrochloric acid of 1mol/L, stir half an hour, filter to obtain crystal, wash crystal 2-3 time with water, drain to obtain solid 17.84 grams, vacuum-drying obtains solid 13.3 grams, mother liquor places crystallize out 2.0 grams after 2 hours, mother liquor after filtration is placed in refrigerator and spends the night, crystallize out 1.2 grams, obtain dry thick product 16.5 grams altogether, productive rate 83%, crude product recrystallizing methanol, obtain crystalline substance, fusing point 216-217 DEG C,
B, chlorination: the crystalline substance prepared is got 30mmol above and be dissolved in 250 milliliters of there-necked flasks, add 50 milliliters of pyridinium dissolution, after connecting gas absorbing device, in flask, slowly drip 33mmol sulfur oxychloride, after dripping, be heated to 45 DEG C, react half an hour, frozen water cools, filtering solids, after filtrate decompression boils off solvent, the sodium bicarbonate that residue adds 10% more fully stirs in 10 points, filters, dry 7.7 grams of white solids, i.e. chloro-product, fusing point 134-136 DEG C;
C, get the chloro-product 10mmol prepared above and be dissolved in 250 milliliters of there-necked flasks, add 100 milliliters of acetonitriles to dissolve, add the para-bromoaniline of 10.1mmol again, under reflux conditions successive reaction 6 hours, adds the sodium hydrogen carbonate solution of 5%, fully by reactant after boiling off solvent, filtering solids, solids with methanol recrystallization, obtains 6.6 grams of white crystal Sino-24, fusing point 155-157 DEG C; Under the same reaction conditions, respectively with para-fluoroaniline, p-Chlorobenzoic acid amide, p-trifluoromethylaniline, aniline, P-nethoxyaniline, to trifluoro-methoxyaniline, m-chloro aniline replace para-bromoaniline react, obtain Sino-25 respectively, Sino-26, Sino-27, Sino-28, Sino-29, Sino-30, Sino-31 seven new compounds, its fusing point is respectively: 115-120 DEG C, 120-123 DEG C, 143-147 DEG C, 155-160 DEG C, 93-97 DEG C, 126-130 DEG C, 137-140 DEG C.
Embodiment 15:
The synthesis of Sino-33, Sino-34, Sino-35, Sino-36 compound:
Take the dry refined tuduranine of 60mmol, grinding powder, join in 250 milliliters of three mouthfuls of round-bottomed flasks, adding 200 ml methanol is solvent, stirs and tuduranine is all dissolved, add 60mmol cyanogen bromide, add 8.4 grams of powdered sodium carbonates in 60 DEG C of reactions after 2 hours, continue to react 4 hours at this temperature, evaporating solvent methyl alcohol, precipitation compounds Sino-33, fusing point 171-172 DEG C; Joined by Sino-33 in the hydrochloric acid of 2N, boil 1 hour, the sodium hydroxide with 5% neutralizes pH value and equals 9, filtering solids, ethyl alcohol recrystallization, obtains 8.7 g of compound product Sino-34, fusing point 121-123 DEG C; Take the dry refined Sino-34 compound of 10mmol, grinding powder, joins in 250 milliliters of three mouthfuls of round-bottomed flasks, add 15mmol sodium bicarbonate powder again, add 100 ml methanol and make solvent, add 10mmol2-methyl isophthalic acid-n-butyl bromide, under reflux conditions stir, successive reaction 3 hours, boil off methyl alcohol, residue cold water washing, ethyl alcohol recrystallization, obtain 3.1 g of compound product Sino-36, fusing point 171-172 DEG C; Separately take the dry refined Sino-34 compound of 10mmol, grinding powder, joins in 250 milliliters of three mouthfuls of round-bottomed flasks, add 15mmol powdered sodium carbonate again, add 100 ml methanol and make solvent, drip 10mmol Acetyl Chloride 98Min., then under reflux conditions stir, successive reaction 3 hours, boil off methyl alcohol, residue cold water washing, ethyl alcohol recrystallization, obtain 3.3 g of compound product Sino-35, fusing point 150-153 DEG C.
Embodiment 16:
The synthesis of Sino-32 compound:
Take the dry refined tuduranine of 60mmol, grinding powder, joins in 250 milliliters of three mouthfuls of round-bottomed flasks, add 200 milliliters of carbon tetrachloride solvents, stir and tuduranine is all dissolved, then add oxygenant mCPBA, react 48 hours under room temperature condition, obtain new compound Sino-32.
Embodiment 17:
The synthesis of Sino-37 compound:
Take the dry refined tuduranine of 60mmol, grinding powder, join in 250 milliliters of three mouthfuls of round-bottomed flasks, add 200 milliliters of carbon tetrachloride solvents, stirring makes tuduranine all dissolve, and then adds diacetyl oxide and Acetyl Chloride 98Min., reacts 8 hours under 90 DEG C of conditions, then new compound Sino-37 is obtained, fusing point 72-74 DEG C with the hydrogen peroxide oxidation of 30%.
Embodiment 18:
The synthesis of Sino-38, Sino-39, Sino-40 compound:
Take the dry refined tuduranine of 60mmol, grinding powder, join in 250 milliliters of three mouthfuls of round-bottomed flasks, add 200 milliliters of carbon tetrachloride solvents, stir and tuduranine is all dissolved, then add reagent N BS, react 12 hours under room temperature condition, obtain new compound Sino-38, fusing point 84 DEG C, yield 69.6%; Under the same terms, replace NBS to be obtained by reacting new compound Sino-39, fusing point 92 DEG C with NCS, yield 50%, is put in Sino-38 in 2N sulfuric acid and boils 1 hour, obtains new compound Sino-40, fusing point 150-153 DEG C.
Claims (4)
1. a compound, it is characterized in that with tuduranine be parent each ring on new substituent derivative, C ring connects new substituent Sinomenine derivate, and its structural formula is optional following a kind of:
2. a compound, it is characterized in that with tuduranine be parent each ring on new substituent derivative, D ring connects new substituent Sinomenine derivate, and its structural formula is optional following a kind of:
3. the preparation method of the compound as described in as arbitrary in claim 1-2, it is characterized in that the method is: take the dry refined tuduranine of 60mmol, grinding powder, joins in 250 ml flasks, add methanol as solvent, Pd/C is catalyzer, passes into hydrogen, then adds oxammonium hydrochloride and the sodium acetate soln of equivalent, half an hour is reacted under room temperature, obtain compound 20, ethyl alcohol recrystallization, melting point compound is 244-246 DEG C; Or
Take the dry refined tuduranine of 60mmol, grinding powder, joins in 250 ml flasks, adds methanol as solvent, Pd/C is catalyzer, pass into hydrogen, then add p-Chlorobenzoic acid amide, continue to pass into hydrogen, thorough reaction, obtain compound 23, ethyl alcohol recrystallization, melting point compound is 124-127 DEG C; Or
The reduction of A, carbonyl: take the dry refined tuduranine of 60mmol, grinding powder, joins in 250 milliliters of three mouthfuls of round-bottomed flasks, and adding 200 ml methanol is solvent, stirs and tuduranine is all dissolved, separately take 180mmolNaBH
4crystal, is placed on crystal in a small beaker, is positioned in moisture eliminator, slowly adds NaBH with little spoon gradation
4crystal is in reaction flask, and a large amount of heat is released in reaction, and flask external application cold water cools, and temperature controls to be advisable below 10 DEG C, adds NaBH
4speed be advisable not release a large amount of gas, greatly can by NaBH within the time of 1.5-2 hour
4add, add NaBH
4after, remove water cooling, continue reaction stirred 2 hours, make it fully react completely, then slowly drip the hydrochloric acid of 1mol/L, make unreacted NaBH
4react completely, by the Rotary Evaporators vaporizes most solvent methanol of the material in flask, till being evaporated to into viscous pasty state, sticky mass is poured into while hot in the beaker of 200 ml waters, and then add 100 ml waters, vigorous stirring makes thick material thoroughly be dissolved in water, solution becomes light yellow, static several minutes, separate out the thick shape crystal of white immediately, regulate pH value to 9-11 with the hydrochloric acid of 1mol/L, stir half an hour, filter to obtain crystal, wash crystal 2-3 time with water, drain to obtain solid 17.84 grams, vacuum-drying obtains solid 13.3 grams, mother liquor places crystallize out 2.0 grams after 2 hours, mother liquor after filtration is placed in refrigerator and spends the night, crystallize out 1.2 grams, obtain dry thick product 16.5 grams altogether, productive rate 83%, crude product recrystallizing methanol, obtain crystalline substance, fusing point 216-217 DEG C,
B, chlorination: the crystalline substance prepared is got 30mmol above and be dissolved in 250 milliliters of there-necked flasks, add 50 milliliters of pyridinium dissolution, after connecting gas absorbing device, in flask, slowly drip 33mmol sulfur oxychloride, after dripping, be heated to 45 DEG C, react half an hour, frozen water cools, filtering solids, after filtrate decompression boils off solvent, the sodium bicarbonate that residue adds 10% more fully stirs in 10 points, filters, dry 7.7 grams of white solids, i.e. chloro-product, fusing point 134-136 DEG C;
C, get the chloro-product 10mmol prepared above and be dissolved in 250 milliliters of there-necked flasks, add 100 milliliters of acetonitriles to dissolve, add the para-bromoaniline of 10.1mmol again, under reflux conditions successive reaction 6 hours, adds the sodium hydrogen carbonate solution of 5%, fully by reactant after boiling off solvent, filtering solids, solids with methanol recrystallization, obtains 6.6 grams of white crystalline Compound 24, fusing point 155-157 DEG C; Under the same reaction conditions, respectively with p-Chlorobenzoic acid amide, p-trifluoromethylaniline, P-nethoxyaniline, to trifluoro-methoxyaniline, m-chloro aniline replace para-bromoaniline react, obtain compound 26 respectively, compound 27, compound 29, compound 30, compound 31, its fusing point is respectively: 120-123 DEG C, 143-147 DEG C, 93-97 DEG C, 126-130 DEG C, 137-140 DEG C; Or
Take the dry refined tuduranine of 60mmol, grinding powder, join in 250 milliliters of three mouthfuls of round-bottomed flasks, adding 200 ml methanol is solvent, stirs and tuduranine is all dissolved, add 60mmol cyanogen bromide, add 8.4 grams of powdered sodium carbonates in 60 DEG C of reactions after 2 hours, continue to react 4 hours at this temperature, evaporating solvent methyl alcohol, precipitation compounds compound 33, fusing point 171-172 DEG C; Join in the hydrochloric acid of 2N by compound 33, boil 1 hour, the sodium hydroxide with 5% neutralizes pH value and equals 9, filtering solids, ethyl alcohol recrystallization, obtains 8.7 g of compound product compounds 34, fusing point 121-123 DEG C; Take dry refined compound 34 compound of 10mmol, grinding powder, joins in 250 milliliters of three mouthfuls of round-bottomed flasks, add 15mmol sodium bicarbonate powder again, add 100 ml methanol and make solvent, add 10mmol2-methyl isophthalic acid-n-butyl bromide, under reflux conditions stir, successive reaction 3 hours, boil off methyl alcohol, residue cold water washing, ethyl alcohol recrystallization, obtain 3.1 g of compound product compounds 36, fusing point 171-172 DEG C.
4. the compound as described in as arbitrary in claim 1-2 has the application in the medicine of anti-inflammatory, analgesia, calmness or immunoregulation effect in preparation.
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