CN101348483A - Preparation of phenanthroindolizidine derivative - Google Patents
Preparation of phenanthroindolizidine derivative Download PDFInfo
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Abstract
The invention relates to a method for making phenanthrene combined indolizidine derivative. 2,3-diarylate crylic ester or 2,3-diarylate acrylonitril reacts with ferric chloride to firstly produce phenanthrene methyl formate or 9-cyanophenanthrene, which is subsequently hydrolyzed to obtain 9-phenanthrene formic acid; or 2,3-diarylate crylic acid is coupled with ferric chloride directly to obtain 9-phenanthrene formic acid. Then 9-phenanthrene formic acid is converted to 9-methoxyphenanthrene chloride or 9-phenanthrene formamide, which reacts with pyrrole to produce 2- methoxyphenanthrene pyrrole, which undergoes of carbonyl deoxidization to produce 2- methyl phenanthrene pyrrole, then the pyrrole is deoxidized to obtain 2-methyl phenanthrene tetrahydrogen pyrrole, and finally the ring is closed to obtain phenanthrene combined indolizidine derivative, which react with an inorganic salt or an organic acid to obtain the salt. The invention also provides a method for making 2,3,6,7-tetra methoxy-14- hydroxyl phenanthrene combined [9, 10, 3', 4'] indolizidine, 2,3,6,7-tetra methoxy phenanthrene combined [9, 10, 3', 4'] indolizidine and the picrate thereof, all of which have the novel structure.
Description
Technical field
The present invention relates to the preparation of phenanthroindolizididerivative derivative.
Background technology
WO03070166 disclose phenanthroindolizididerivative pyridine and phenanthro-quinoline in the preparation method of western piperidine derivatives and they in pharmaceutically application.
Summary of the invention
The preparation method who the purpose of this invention is to provide phenanthroindolizididerivative derivative.
The synthetic route of phenanthroindolizididerivative derivative of the present invention following (equation 1).The preparation method comprises the steps: at first to have obtained 2 with the condensation reaction of substituted phenylacetic acid and substituted benzaldehyde, and the 3-diaryl acrylic acid has obtained the 9-phenanthrenecarboxylic acid with the iron trichloride oxidative coupling then.Be converted into luxuriant and rich with fragrance formyl chloride of 9-or the luxuriant and rich with fragrance methane amide of 9-again; it and pyrroles's reaction obtain the luxuriant and rich with fragrance formyl radical pyrroles of 2-; reducing carbonyl obtains the luxuriant and rich with fragrance methylpyrrole of 2-; restore the pyrroles and obtain the luxuriant and rich with fragrance methyl Pyrrolidine of 2-; close ring at last and obtain phenanthroindolizididerivative derivative, it and mineral acid or organic acid reaction obtain salt.
Equation 1:
Wherein, R
1And R
2Represent hydrogen, one to four halogen atom, one to four 1-6 carbon alkoxyl group, one to four hydroxyl, one to four ester group, one to two OCH respectively
2O, one to two OCH
2CH
2O; X represents Cl, NMe
2, N (CH
2CH
2)
2O, N (CH
2)
5Deng; HB represents mineral acid and organic acid, represents HCl, HBr, HI, CF respectively
3CO
2H, HCO
2H, CH
3CO
2H, PhCO
2H, HOC (CH
2CO
2H)
2CO
2H, (CHOHCO
2H)
2, 2,4,6-(NO
2)
3-Ph-OH.
9-phenanthrenecarboxylic acid of the present invention can also prepare (equation 2) with following method.Specifically comprise the steps: 2,3-diaryl acrylic acid ester or 2,3-diaryl acrylonitrile and ferric chloride reaction at first generate phenanthrenecarboxylic acid ester or 9-cyano group phenanthrene, and hydrolysis obtains the 9-phenanthrenecarboxylic acid again.
Equation 2:
Wherein, R
1And R
2Represent hydrogen, one to four halogen atom, one to four 1-6 carbon alkoxyl group, one to four hydroxyl, one to four ester group, one to two OCH respectively
2O, one to two OCH
2CH
2O; Y represents CN, CO
2Me, CO
2Et etc.;
Of the present invention 2,3,6, the synthetic route of phenanthroindolizididerivative pyridine of 7-tetramethoxy and hydrochloride thereof following (equation 3).The preparation method comprises the steps: at first with 3,4-dimethoxyphenylacetic acid and 3, and the condensation reaction of 4-dimethoxy benzaldehyde obtains 2,3-two-(3, the 4-Dimethoxyphenyl) vinylformic acid has obtained 2 with the iron trichloride oxidative coupling then, 3,6,7-tetramethoxy phenanthrenecarboxylic acid, this acid and thionyl chloride reaction obtain 2,3,6, the luxuriant and rich with fragrance formyl chloride of 7-tetramethoxy is at SnCl
4This acyl chlorides and pyrroles react and generate the luxuriant and rich with fragrance formyl radical pyrroles of 2-(2,3,6, the 7-tetramethoxy) under existing, and use NaBH
4Reducing carbonyl obtains 2-(2,3,6, the luxuriant and rich with fragrance methyl of 7-tetramethoxy-9-) pyrroles obtains 2-(2,3 with Pd-C catalytic hydrogenation reduction pyrroles again, 6, the luxuriant and rich with fragrance methyl of 7-tetramethoxy-9-) Pyrrolidine, close ring with formaldehyde at last and obtain 2,3,6, the pyridine of 7-tetramethoxy phenanthroindolizididerivative, it and hydrogen chloride gas precursor reactant obtain 2,3,6, the hydrochloride of 7-tetramethoxy phenanthroindolizididerivative pyridine.
Equation 3:
Of the present invention 2,3,6,7-tetramethoxy phenanthrenecarboxylic acid can also be with following method preparation (equation 4).Specifically comprise the steps: 2,3-two-(3, the 4-Dimethoxyphenyl) acrylate or 2,3-two-(3, the 4-Dimethoxyphenyl) vinyl cyanide and ferric chloride reaction at first generate 2,3,6,7-tetramethoxy phenanthrenecarboxylic acid ester or 2,3,6,7-tetramethoxy-9-cyano group phenanthrene, hydrolysis obtains 2,3 again, 6,7-tetramethoxy phenanthrenecarboxylic acid.
Equation 4:
Wherein, Y represents CN, CO
2Me, CO
2Et etc.;
Of the present invention 2,3,6, the synthetic route following (equation 5) of western pyridine in 7-tetramethoxy-14-hydroxyl phenanthro-[9,10,3 ', the 4 '] indoles.The preparation method comprises the steps: that N-(3, the 4-dimethoxy) phenylacetyl morpholine and pyrroles reaction obtains 3, again with 3,4-dimethoxy benzene oxalyl chloride react product 4, generate 5 with the Pd-C catalytic hydrogenation.In the presence of sodium hydride, 5 generate 6 with iodomethane reaction.Obtain 7 with trifluoro vanadyl oxidative coupling 6, generate 8 with the Pd-C catalytic hydrogenation once more.Obtained 2,3,6 with lithium aluminum hydride and aluminum chloride reduction 8 at last, western pyridine in 7-tetramethoxy-14-hydroxyl phenanthro-[9,10,3 ', the 4 '] indoles.
Equation 5:
Of the present invention 2,3,6, the synthetic route following (equation 6) of western pyridine and picrate thereof in 7-tetramethoxy phenanthro-[9,10,3 ', the 4 '] indoles.The preparation method comprises the steps: that in the presence of trifluoroacetic acid compound 6 generates 10 with the reaction of trifluoro vanadyl, sloughs hydroxyl with triethyl silicane again and obtains 11.11 usefulness sodium borohydride reductions obtain 12, and triphenyl phosphorus and carbon tetrabromide become 12 hydroxyl into 13 bromine, slough bromine with the Pd-C catalytic hydrogenation and generate 14.Obtained 2,3,6 with lithium aluminum hydride and aluminum chloride reduction 14 at last, western pyridine in 7-tetramethoxy phenanthro-[9,10,3 ', the 4 '] indoles, it and picric acid reaction generation 2,3,6, western pyridine picrate 16 in 7-tetramethoxy phenanthro-[9,10,3 ', the 4 '] indoles.
Equation 6:
Wherein, 2,3,6, western pyridine 9 and 2 in 7-tetramethoxy-14-hydroxyl phenanthro-[9,10,3 ', the 4 '] indoles, 3,6,7-tetramethoxy phenanthro-[9,10,3 ', 4 '] western pyridine 15 and 2 in the indoles, 3,6,7-tetramethoxy phenanthro-[9,10,3 ', 4 '] western pyridine picrate 16 is the novel fully phenanthroindolizididerivative acridine compounds of skeleton structure in the indoles.
Embodiment
Among the following embodiment, fusing point is not calibrated, and yield is without optimization.
Embodiment 1:2,3-two-(3, the 4-Dimethoxyphenyl) are acrylic acid synthetic:
In the 500mL four-hole bottle, add 35.0 grams 3 successively, 4-dimethoxyphenylacetic acid, 27.0 grams 3,4-dimethoxy benzaldehyde and diacetyl oxide and triethylamine, heating reflux reaction is 24 hours under the nitrogen protection.Reaction solution is poured in the aqueous solution that fills salt of wormwood.With extracted with diethyl ether reaction solution (50mL * 3), it is 5 that the gained water is transferred pH value, separates out solid, gets white solid 38.7 grams behind the recrystallization, yield: 70%.Fusing point: 214-216 ℃.
Embodiment 2:2,3,6,7-tetramethoxy phenanthrenecarboxylic acid synthetic:
10.32 restrain 2, add the 500mL methylene dichloride in 3-two-(3, the 4-Dimethoxyphenyl) vinylformic acid, add 17.1 gram FERRIC CHLORIDE ANHYDROUS under the nitrogen protection room temperature, mixture continues stirring at room reaction 12 hours.In reaction solution, add methyl alcohol, filter, obtain yellow solid product 8.93 grams, yield: 87.04%, fusing point:＞300 ℃.
Embodiment 3:2,3,6,7-tetramethoxy phenanthrenecarboxylic acid methyl esters synthetic:
0.1792 restrain 2, add the 50ml methylene dichloride in 3-two-(3, the 4-Dimethoxyphenyl) methyl acrylate, feed nitrogen, add 0.28 gram FERRIC CHLORIDE ANHYDROUS again, stirring at room 2 hours.Add entry, separatory, the organic layer dried over sodium sulfate, precipitation, it is 99% that HPLC detects productive rate, product is the white powder solid, fusing point: 202-203 ℃.
Embodiment 4:2,3,6,7-tetramethoxy-9-cyano group phenanthrene synthetic:
Synthetic method is with embodiment 3, and it is 99% that HPLC detects productive rate, and product is the white powder solid, fusing point: 272-273 ℃.
Embodiment 5:2-2,3,6,7-tetramethoxy) luxuriant and rich with fragrance formyl radical pyrroles's is synthetic
In the 500mL four-hole bottle, add 6.84 grams 2,3,6,7-tetramethoxy phenanthrenecarboxylic acid and 40mL CHCl
3, drip 9.52 gram thionyl chlorides.Reaction solution rose to room temperature reaction 1 hour, reflux 3 hours, thionyl chloride that pressure reducing and steaming is excessive and CHCl
3In reaction flask, add CHCl
3, N
2Protection adds 5.22 gram SnCl down
4, drip 1.34 gram pyrroles again, drip and finish, mixture rose to room temperature reaction 10 hours.In reaction solution, add aqueous hydrochloric acid, separatory, organic phase is through washing (100mL * 2), saturated common salt washing (100mL * 2), anhydrous Na
2SO
4Drying, precipitation, column chromatography get yellow solid product 5.4 grams, yield: 69%, and fusing point: 258-260 ℃.
Embodiment 6:2-(2,3,6, the luxuriant and rich with fragrance methyl of 7-tetramethoxy-9-) pyrroles's is synthetic
In the 1000mL four-hole bottle, add 4.0 gram 2-(2,3,6, the 7-tetramethoxy) luxuriant and rich with fragrance formyl radical pyrroles and Virahol and NaBH
4, N
2Protection mixture heating up down refluxed 24 hours, added CH in reaction solution
2Cl
2And water, separatory, organic phase is with saturated brine washing, MgSO
4Dry.Precipitation, column chromatography get white solid product 3.51 grams, yield: 91%, and fusing point: 220-222 ℃.
Synthesizing of embodiment 7:2-(2,3,6, the luxuriant and rich with fragrance methyl of 7-tetramethoxy-9-) Pyrrolidine
In autoclave, add 2-(2,3,6, the luxuriant and rich with fragrance methyl of 7-tetramethoxy-9-) pyrroles's 5.0 grams, 1.5 gram 10%Pd-C and Glacial acetic acid, in autoclave, charge into hydrogen, reacted 30 hours, in mixture, add CH
2Cl
2And water, transfer PH＞11 with the NaOH aqueous solution, separatory gets organic phase, drying, precipitation, column chromatography get white solid product 4.8 grams, yield: 95%, fusing point: 155-157 ℃.
Embodiment 8:2,3,6, phenanthroindolizididerivative pyridine of 7-tetramethoxy and hydrochloride thereof synthetic
In 500mL four-hole reaction flask, add 3.81 gram 2-(2,3,6, the luxuriant and rich with fragrance methyl of 7-tetramethoxy-9-) Pyrrolidine, ethanol, formaldehyde solution and concentrated hydrochloric acid successively, N
2Protection mixture heating up down refluxed 24 hours, added CH
2Cl
2With the water diluting soln, stir down and transfer PH＞11 with the NaOH aqueous solution, separatory gets organic phase, drying, precipitation, column chromatography get 2,3,6,7-tetramethoxy phenanthroindolizididerivative pyridine 3.73 grams, yield: 95%, fusing point: 275-282 ℃.
1H?NMR(CDCl
3，300MHz)：δ(ppm)7.84(s，2H)，7.32(s，1H)，7.17(s，1H)，4.63(d，
2J
HH＝15Hz，1H)，4.12(s，6H)，4.06(s，6H)，3.70(d，
2J
HH＝15Hz，1H)，3.49(m，1H)，3.38(m，1H)，2.92(m，1H)，2.48(m，2H)，2.25(m，1H)，1.71-2.11(m，3H)。
With 2,3,6, the pyridine of 7-tetramethoxy phenanthroindolizididerivative is dissolved in trichloromethane, logical people's hydrogen chloride gas, and suction filtration, drying obtains 2,3,6, the hydrochloride of 7-tetramethoxy phenanthroindolizididerivative pyridine, yield: 96%, fusing point: 258-260 ℃.
1H?NMR(DMSO，300MHz)：δ(ppm)8.08(s，1H)，8.07(s，1H)，7.38(s，1H)，7.21(s，1H)，5.14-5.21(m，1H)，4.54-4.65(m，1H)，4.05(s，6H)，3.97(s，6H)，3.58-3.91(m，5H)，2.09-2.28(m，3H)，1.91-2.07(m，1H)。
Use the same method and to synthesize following phenanthroindolizididerivative derivative and salt thereof, see Table 1.
Table 1 phenanthroindolizididerivative derivative and salt thereof
Embodiment 9:2-(3, the 4-dimethoxy) phenylacetyl pyrroles's (3) is synthetic:
12.0 gram N-(3, the 4-dimethoxy) phenylacetyl morpholine joins 1, in the 2-ethylene dichloride, nitrogen protection drips the 9.1mL phosphorus oxychloride down, drips and finishes room temperature reaction 5 hours.Drip 3.18 gram pyrroles' 1, the 2-dichloroethane solution drips and finishes, and refluxes 4 hours.Drip aqueous sodium carbonate, separatory, saturated common salt water washing, drying.Precipitation, column chromatography get product 10.66 grams, yield 92%.Fusing point: 101-102 ℃.
Embodiment 10: compound 4 synthetic:
Digest adding triethylamine and CHCl in the compound 3 4.65
3, stir down and drip 3, the CHCl of 4-dimethoxy benzene oxalyl chloride
3Solution drips and finishes room temperature reaction 10 hours.Reaction solution is used H successively
2SO
4The aqueous solution, the NaOH aqueous solution, water washing, MgSO
4Drying, suction filtration, precipitation get dark red solid, and recrystallization gets product 4, yield 90%, fusing point: 200-202 ℃.
Embodiment 11: compound 5 synthetic:
Digest adding ethanol and 10%Pd-C in the compound 4 0.71, under the room temperature, blasted hydrogen reaction 4 hours.Reaction finishes, and filters Pd-C, and precipitation, recrystallization get faint yellow solid 0.71 gram, yield 99%, fusing point: 196-198 ℃.
Embodiment 12: compound 6 synthetic:
N
2Protection adds the 10mL tetrahydrofuran (THF) down in 100mL four-hole round-bottomed flask, 0.05 gram, 60% sodium hydride; the 15mL tetrahydrofuran solution of compound 5 is digested in adding 0.2 under the room temperature; reflux conditions drips the 10mL tetrahydrofuran solution of 0.08 gram methyl iodide down, drips and finishes, and continues to reflux 1 hour.Add entry and methylene dichloride, separatory is through saturated common salt water washing, dried over sodium sulfate.Precipitation, column chromatography get faint yellow solid 0.19 gram, yield 93%.Fusing point: 180-182 ℃.
Embodiment 13: compound 7 synthetic:
Add 0.61 gram 6,30mL methylene dichloride in 100mL four-hole round-bottomed flask, cryosel is bathed and N
2Protection adds 0.35 gram trifluoro vanadyl and 1.4mL trifluoroacetic acid down, continues stirring reaction 10 hours, reaction solution is poured in the NaOH aqueous solution into separatory, organic phase saturated common salt water washing, dried over sodium sulfate.Suction filtration, precipitation, column chromatography gets yellow solid, yield: 63.5%.Fusing point: 265 ℃ begin to decompose.
Embodiment 14: compound 8 synthetic:
Add ethanol and 0.13 gram 10%Pd-C in 0.2 gram 7, blasted hydrogen reaction 30 hours under stirring, filter out Pd-C, precipitation, column chromatography get the white solid product, yield: 100%.Fusing point: 216 ℃ begin to decompose.
Embodiment 15:2,3,6, western pyridine 9 is synthetic in 7-tetramethoxy-14-hydroxyl phenanthro-[9,10,3 ', the 4 '] indoles:
Add the 15mL tetrahydrofuran (THF) in the 100mL four-hole boiling flask, the nitrogen protection cryosel is bathed down, adds 0.12 gram lithium aluminum hydride, 0.13 gram aluminum chloride; stir the 20mL tetrahydrofuran solution that drips 0.14 gram 8 down, drip and finish, continue reaction 2 hours; transferring pH value with the KOH aqueous solution is 11; add ethyl acetate, separatory, organic phase saturated common salt water washing; dried over sodium sulfate; suction filtration, precipitation, column chromatography gets white solid, yield 90%.Fusing point: 167-169 ℃.
1HNMR(300Mz，DMSO)：δ1.39-1.68(m，2H)，1.74-2.00(m，2H)，2.86-3.04(m，1H)，3.08-3.24(m，2H)，3.87(s，3H，OCH3)，3.91(s，3H)，4.03(s，6H)，4.20-4.64(m，3H)，5.11(br，1H)，7.10(s，1H)，7.84(s，1H)，8.01(s，1H)，8.05(s，1H)。
Embodiment 16: compound 10 synthetic:
Add in 6 in methylene dichloride and the trifluoroacetic anhydride 1.5 restrain, cryosel is bathed and N
2Protection adds 0.94 gram trifluoro vanadyl and 10mL trifluoroacetic acid down.Stir after 10 hours, add aqueous citric acid solution, separatory, organic phase NH
4OH and washing, Na
2SO
4Dry.Precipitation, column chromatography gets faint yellow solid, yield 91%.Fusing point:＞300 ℃.
Embodiment 17: compound 11 synthetic:
In 1.31 grams 10, add CH
2Cl
2With trifluoroacetic acid and 1.74 gram triethyl silicanes, stirred 10 minutes, add entry, use dichloromethane extraction, dried over mgso is filtered, precipitation, column chromatography gets white solid, yield 92%.Fusing point: 230-240 ℃ (dec).
Embodiment 18: compound 12 synthetic:
In 0.45 gram 11, add ethanol and sodium borohydride, stirring at room 6 hours.Add entry, use dichloromethane extraction, dried over mgso is filtered, precipitation, and column chromatography gets white solid, yield 96%.Fusing point: 238-240 ℃.
Embodiment 19: compound 13 synthetic:
In 1.06 grams 12, add tetrahydrofuran (THF) and 1.31 gram triphenyl phosphorus and 1.66 gram carbon tetrabromides, stirred 3 hours at 50 ℃.Add saturated sodium bicarbonate aqueous solution, use dichloromethane extraction, dried over mgso is filtered, precipitation, and column chromatography gets faint yellow solid, yield 96%.Fusing point: 172 ℃ (dec).
Embodiment 20: compound 14 synthetic:
Obtain 14 with embodiment 14 identical methods, white solid, yield 95%.Fusing point: 221-223 ℃.
Embodiment 21:2,3,6, western pyridine 15 is synthetic in 7-tetramethoxy phenanthro-[9,10,3 ', the 4 '] indoles:
Obtain 15 with embodiment 15 identical methods, white solid, yield 89%.Fusing point: 210-219 ℃ (dec).
1H?NMR(300MHz，CDCl
3)：7.83(s，1H)，7.81(s，1H)，7.18(s，1H)，7.00(s，1H)，4.45-4.57(m，2H)，4.30-4.34(m，1H)，4.11(s，6H)，4.02(s，3H)，4.01(s，3H)，3.32-3.37(m，1H)，3.04-3.19(m，1H)，2.24-2.39(m，1H)，1.88-2.00(m，1H)，1.40-1.85(m，4H)。
Embodiment 22:2,3,6, western pyridine picrate 16 is synthetic in 7-tetramethoxy phenanthro-[9,10,3 ', the 4 '] indoles:
2,3,6, western pyridine 15 is dissolved in trichloromethane in 7-tetramethoxy phenanthro-[9,10,3 ', the 4 '] indoles, adds picric chloroform soln, filters, and drying obtains white powder.Yield 95%.Fusing point: 170-184 ℃ (dec).
1H?NMR(400MHz，DMSO)：10.79(br.，1H)，8.58(s，2H)，8.09(s，2H)，7.30(s，1H)，7.20(s，1H)，5.24-5.37(m，1H)，4.90-5.09(m，2H)，4.06(s，6H)，3.95(s，6H)，3.29-3.50(m，2H)，1.57-2.00(m，5H)，1.35-1.53(m，1H)。
Claims (6)
1. the preparation method of a phenanthroindolizididerivative derivative, it is characterized in that comprising the following step shown in the following equation 1: at first the condensation reaction with substituted phenylacetic acid and substituted benzaldehyde has obtained 2, the 3-diaryl acrylic acid has obtained the 9-phenanthrenecarboxylic acid with the iron trichloride oxidative coupling then.Be converted into luxuriant and rich with fragrance formyl chloride of 9-or the luxuriant and rich with fragrance methane amide of 9-again; it and pyrroles's reaction obtain the luxuriant and rich with fragrance formyl radical pyrroles of 2-; reducing carbonyl obtains the luxuriant and rich with fragrance methylpyrrole of 2-; restore the pyrroles and obtain the luxuriant and rich with fragrance methyl Pyrrolidine of 2-; close ring at last and obtain phenanthroindolizididerivative derivative, it and mineral acid or organic acid reaction obtain salt.
Equation 1:
Wherein, R
1And R
2Represent hydrogen, one to four halogen atom, one to four 1-6 carbon alkoxyl group, one to four hydroxyl, one to four ester group, one to two OCH respectively
2O, one to two OCH
2CH
2O; X represents Cl, NMe
2, N (CH
2CH
2)
2O, N (CH
2)
5Deng; HB represents mineral acid and organic acid, represents HCl, HBr, HI, CF respectively
3CO
2H, HCO
2H, CH
3CO
2H, PhCO
2H, HOC (CH
2CO
2H)
2CO
2H, (CHOHCO
2H)
2, 2,4,6-(NO
2)
3-Ph-OH.
2. the preparation method of the described phenanthroindolizididerivative derivative of claim 1 is characterized in that the method preparation shown in the also available equation 2 of 9-phenanthrenecarboxylic acid.Specifically comprise the steps: 2,3-diaryl acrylic acid ester or 2,3-diaryl acrylonitrile and ferric chloride reaction at first generate phenanthrenecarboxylic acid ester or 9-cyano group phenanthrene, and hydrolysis obtains the 9-phenanthrenecarboxylic acid again.
Equation 2:
Wherein, R
1And R
2Represent hydrogen, one to four halogen atom, one to four 1-6 carbon alkoxyl group, one to four hydroxyl, one to four ester group, one to two OCH respectively
2O, one to two OCH
2CH
2O; Y represents CN, CO
2Me, CO
2Et etc.
3. according to the preparation method of the described phenanthroindolizididerivative derivative of claim 1, it is characterized in that 2,3,6, phenanthroindolizididerivative pyridine of 7-tetramethoxy and hydrochloride thereof can prepare with the method shown in the equation 3.Specifically comprise the steps: at first with 3,4-dimethoxyphenylacetic acid and 3, the condensation reaction of 4-dimethoxy benzaldehyde obtains 2,3-two-(3, the 4-Dimethoxyphenyl) vinylformic acid has obtained 2 with the iron trichloride oxidative coupling then, 3,6,7-tetramethoxy phenanthrenecarboxylic acid, this acid and thionyl chloride reaction obtain 2,3,6, the luxuriant and rich with fragrance formyl chloride of 7-tetramethoxy is at SnCl
4This acyl chlorides and pyrroles react and generate the luxuriant and rich with fragrance formyl radical pyrroles of 2-(2,3,6, the 7-tetramethoxy) under existing, and use NaBH
4Reducing carbonyl obtains 2-(2,3,6, the luxuriant and rich with fragrance methyl of 7-tetramethoxy-9-) pyrroles obtains 2-(2,3 with Pd-C catalytic hydrogenation reduction pyrroles again, 6, the luxuriant and rich with fragrance methyl of 7-tetramethoxy-9-) Pyrrolidine, close ring with formaldehyde at last and obtain 2,3,6, the pyridine of 7-tetramethoxy phenanthroindolizididerivative, it and hydrogen chloride gas precursor reactant obtain 2,3,6, the hydrochloride of 7-tetramethoxy phenanthroindolizididerivative pyridine.
Equation 3:
4. according to the preparation method of the described 9-phenanthrenecarboxylic acid of claim 2, it is characterized in that 2,3,6,7-tetramethoxy phenanthrenecarboxylic acid can also prepare with the method shown in the equation 4.Specifically comprise the steps: 2,3-two-(3, the 4-Dimethoxyphenyl) acrylate or 2,3-two-(3, the 4-Dimethoxyphenyl) vinyl cyanide and ferric chloride reaction at first generate 2,3,6,7-tetramethoxy phenanthrenecarboxylic acid ester or 2,3,6,7-tetramethoxy-9-cyano group phenanthrene, hydrolysis obtains 2,3 again, 6,7-tetramethoxy phenanthrenecarboxylic acid.
Equation 4:
Wherein, Y represents CN, CO
2Me, CO
2Et etc.
5. the preparation method of a phenanthroindolizididerivative derivative, it is characterized in that comprising the following step shown in the following equation 5 prepare skeleton structure novel fully 2,3,6, western pyridine in 7-tetramethoxy-14-hydroxyl phenanthro-[9,10,3 ', the 4 '] indoles.Comprise the steps: that specifically N-(3, the 4-dimethoxy) phenylacetyl morpholine and pyrroles reaction obtains 3, again with 3,4-dimethoxy benzene oxalyl chloride react product 4, generate 5 with the Pd-C catalytic hydrogenation.In the presence of sodium hydride, 5 generate 6 with iodomethane reaction.Obtain 7 with trifluoro vanadyl oxidative coupling 6, generate 8 with the Pd-C catalytic hydrogenation once more.Obtained 2,3,6 with lithium aluminum hydride and aluminum chloride reduction 8 at last, western pyridine in 7-tetramethoxy-14-hydroxyl phenanthro-[9,10,3 ', the 4 '] indoles.
Equation 5:
6. the preparation method of a phenanthroindolizididerivative derivative, it is characterized in that comprising the following step shown in the following equation 6 prepare skeleton structure novel fully 2,3,6, western pyridine and picrate thereof in 7-tetramethoxy phenanthro-[9,10,3 ', the 4 '] indoles.Comprise the steps: specifically that in the presence of trifluoroacetic acid compound 6 generates 10 with the reaction of trifluoro vanadyl, sloughs hydroxyl with triethyl silicane again and obtains 11.11 usefulness sodium borohydride reductions obtain 12, and triphenyl phosphorus and carbon tetrabromide become 12 hydroxyl into 13 bromine, slough bromine with the Pd-C catalytic hydrogenation and generate 14.Obtained 2,3,6 with lithium aluminum hydride and aluminum chloride reduction 14 at last, western pyridine in 7-tetramethoxy phenanthro-[9,10,3 ', the 4 '] indoles, it and picric acid reaction generation 2,3,6, western pyridine picrate 16 in 7-tetramethoxy phenanthro-[9,10,3 ', the 4 '] indoles.
Equation 6:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100581739A CN101348483B (en) | 2007-07-17 | 2007-07-17 | Preparation of phenanthroindolizidine derivative |
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