CN102329320B - Method for synthesizing natural product (+/-)-folicanthine and intermediate product thereof - Google Patents
Method for synthesizing natural product (+/-)-folicanthine and intermediate product thereof Download PDFInfo
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Abstract
The invention discloses a method for synthesizing a natural product (+/-)-folicanthine and an intermediate product thereof, belonging to the field of medicine. The method for synthesizing the intermediate product comprises the steps of: dissolving 4-methyl-N-(2-(1-methyl-1H-indole-3-)ethyl) p-toluenesulfonamide and Cs2CO3 in a solvent; adding a catalyst; and stirring to obtain the intermediate product. The method for synthesizing the natural product comprises the steps of: preparing the intermediate product; adding sodium in tetrahydrofuran to generate a sodium-naphthalene solution; adding the sodium-naphthalene solution into a tetrahydrofuran solution of the intermediate product to prepare a compound c; and adding sodium triacetoxyborohydride and formalin into an acetonitrile solution of the compound c, stirring, dropwise-adding an ammonia-saturated mixed solution of methanol and methylene dichloride, and concentrating and purifying a reactant to obtain the natural product. The method disclosed by the invention has the advantages of less reaction steps, environment friendliness in reaction, no use of metallic catalyst, high yield rate, moderate reaction conditions, no need of further treatment of the solvent and less pollution to the environment.
Description
Technical field
The synthetic method that the present invention relates to a kind of natural product 1,1',8,8'-tetramethyl-2,2',3,3',8,8a,8',8'a-octahydro-1H,1'H-3a,3'a-bipyrrolo[2,3-b and intermediate product thereof, belongs to medical technical field.
Background technology
In recent years, some reactions of indole derivatives and synthetic be the focus of organic chemistry filed research, because a lot of medicines are to be derived on the skeleton of indoles with having bioactive natural product, it has become the important forward position research direction of organic chemistry.The chemical formula of hexahydropyrrolo indoles is C
24h
30n
4, be a natural product, structure uniqueness can be derived more natural products from its skeleton.
These alkaloidal structures are so charming is in recent years because their biological activity has caused that the method that these natural products of very big interest of complete synthesis worker are generally promoted is to carry out intramolecular cyclization from the derivative of tryptamines, for example, Michael A.Schmidt works together and has reported that seven step synthesis of natural products (+)-folicanthine (folicanthine) productive rate only has 17% with him.But these processes are most of needs expensive metal catalyst and metal onidiges, and selectivity ratios is poor.In prior art, prepare intermediate product 8,8 '-dimethyl-1,1 '-ditosyl-2,2 ', 3,3 ', 8,8a, 8 ', 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-bipyrrolo[2,3-b] multi-step is synthetic often for the step of indole, and productive rate is lower.At this, the good reaction conditions of nonmetallic selectivity that iodine participates in is reaction conditions more satisfactory in modern organic synthesis.The study on the synthesis of hexahydropyrrolo indoles is more in recent years, but will use a large amount of metals, to environment; Reactions steps is many, and productive rate is low, and the more high factor of temperature of reaction, brings certain difficulty to suitability for industrialized production.
Summary of the invention
The object of the embodiment of the present invention is the defect for above-mentioned prior art; the intermediate product 8 that a kind of reactions steps is few, productive rate is high is provided; 8 '-dimethyl-1; 1 '-bis-p-toluenesulfonyl-2,2 ', 3; 3 '; 8,8a, 8 '; 8 ' a-octahydro-1H; 1 ' H-3a, the synthetic method of 3 ' a-, bis-pyrroles [2,3-b] indoles; the present invention also provides and in a kind of reaction process, only uses a small amount of metal; few to environment, reactions steps is few, productive rate is high, the synthetic method of natural product (±)-folicanthine that temperature of reaction is lower.
The technical scheme that the present invention takes is to achieve these goals:
The synthetic method of the intermediate product of a kind of natural product (±)-folicanthine ,-10-30 DEG C, be 4-methyl-N-(2-(1-Methyl-1H-indole-3-) ethyl) para toluene sulfonamide and Cs by compound a
2cO
3be dissolved in solvent, add at catalyzer-10-30 DEG C and stir 10-30 minute, prepare compound b through aftertreatment; Wherein, compound a, Cs
2cO
3with the ratio of the amount of substance of catalyzer be 2: 1: 1-1: 3: 5; Described solvent is the one in acetonitrile, methylene dichloride, tetrahydrofuran (THF), dioxane, dimethyl formamide, toluene or ethylene dichloride; Described catalyzer is iodine or N-N-iodosuccinimide.
Further, described aftertreatment is in reaction solution, adds saturated Na
2s
2o
3cancellation reaction, continues to add saturated Na
2s
2o
3constantly shake, until catalyzer eliminates, is extracted with ethyl acetate, and merges organic phase; be dried, remove desolventizing, column chromatography or recrystallization obtain i.e. 8,8 '-dimethyl-1 of compound b; 1 '-bis-p-toluenesulfonyl-2,2 ', 3; 3 ', 8,8a; 8 ', 8 ' a-octahydro-1H, 1 ' H-3a; the white solid of 3 ' a-, bis-pyrroles [2,3-b] indoles.
Preferably, described compound a, Cs
2cO
3with the ratio of the amount of substance of iodine be 1: 2: 2; Described solvent is acetonitrile; Described catalyzer is iodine.
The synthetic method of preparing natural product (±)-folicanthine taking compound b of the present invention as intermediate product, is characterized in that, comprises the steps:
Step 1 :-10-30 DEG C, be 4-methyl-N-(2-(1-Methyl-1H-indole-3-) ethyl) para toluene sulfonamide and Cs by compound a
2cO
3be dissolved in solvent, add catalyzer to stir 10-30 minute at-10-30 DEG C; Add again saturated Na
2s
2o
3cancellation reaction, continues to add saturated Na
2s
2o
3constantly shake, until catalyzer eliminates, is extracted with ethyl acetate, and merges organic phase, is dried, removes desolventizing, the compound b white solid that column chromatography or recrystallization obtain;
Step 2: under room temperature protection of inert gas, add sodium in tetrahydrofuran (THF) (THF), stir and generate bottle-green sodium naphthalene solution for 2-3 hour; At-75-(80) DEG C, freshly prepd sodium naphthalene solution is joined in the tetrahydrofuran solution of compound b, until the blueness of solution do not change, stir 30-50 minute, add saturated NH at-75-(80) DEG C
4cl cancellation reaction, reaction mixture is warming up to room temperature and is extracted with ethyl acetate, and with dry, concentrating under reduced pressure after saturated sodium-chloride drip washing, residuum adopts column chromatography, obtains compound c;
Step 3: under protection of inert gas; sodium triacetoxy borohydride, Fu Er morpholine are added in the acetonitrile solution of compound c; stir after 30-40 minute; drip with saturated methyl alcohol and the methylene dichloride mixing solutions of ammonia; after 5-15 minute, by column chromatography after reactant concentrating under reduced pressure, obtain i.e. (±)-folicanthine of compound d.
Further, compound a, Cs in described step 1
2cO
3with the ratio of the amount of substance of catalyzer be 2: 1: 1-1: 3: 5; The volume of described solvent is 10 with the amount of substance of compound a ratio: 1-1: 1.In the time that solvent unit is milliliter, the unit of the amount of substance of compound a is mmole.
Further, solvent described in described step 1 is the one in acetonitrile, methylene dichloride, tetrahydrofuran (THF) (THF), dioxane, dimethyl formamide, toluene or ethylene dichloride; Described catalyzer is iodine or N-N-iodosuccinimide.
Further, in described step 3, the amount of substance ratio of sodium triacetoxy borohydride, formalin and compound c is 5.2: 5.2: 1; The described volume ratio with methyl alcohol and methylene dichloride in the saturated methyl alcohol of ammonia and methylene dichloride mixing solutions is 5: 95.
Composition and the volume ratio of the moving phase using when column chromatography in described step 1 further, are sherwood oil: ethyl acetate=8: 1.
Composition and the volume ratio of the moving phase using when column chromatography in step 2 further, are methyl alcohol: methylene dichloride=1: 3; Composition and the volume ratio of the moving phase using when column chromatography in step 3 are methyl alcohol: methylene dichloride=1: 100.
Preferably, compound a, Cs in described step 1
2cO
3with the ratio of the amount of substance of iodine be 1: 2: 2; The volume of described solvent is 5: 1 with the amount of substance of compound a ratio.
The beneficial effect that the technical scheme that the embodiment of the present invention provides is brought is: prepare 8,8 of intermediate product '-dimethyl-1,1 '-bis-p-toluenesulfonyl-2,2 ', 3,3 ', 8,8a, 8 ', 8 ' a-octahydro-1H, 1 ' H-3a, the reactions steps of 3 ' a-, bis-pyrroles [2,3-b] indoles is few, react environmentally friendly, without metal catalyst; Productive rate is high, and productive rate can reach more than 90%; Reaction conditions gentleness, under normal temperature in air; Solvent does not need further processing; In the synthetic reaction process of natural product (±)-folicanthine, only use a small amount of metal, few to environment, reactions steps is few, productive rate is high, and temperature of reaction is lower.
Brief description of the drawings
Fig. 1: the hydrogen spectrum spectrogram of the nucleus magnetic resonance of the intermediate product compound b of the embodiment of the present invention 1;
Fig. 2: the carbon spectrum spectrogram of the nucleus magnetic resonance of the intermediate product compound b of the embodiment of the present invention 1;
Fig. 3: the hydrogen spectrum spectrogram of the nucleus magnetic resonance of the intermediate product compound c of the embodiment of the present invention 1;
Fig. 4: the carbon spectrum spectrogram of the nucleus magnetic resonance of the intermediate product compound c of the embodiment of the present invention 1;
Fig. 5: the hydrogen spectrum spectrogram of the nucleus magnetic resonance of the intermediate product compound d of the embodiment of the present invention 1;
Fig. 6: the carbon spectrum spectrogram of the nucleus magnetic resonance of the intermediate product compound d of the embodiment of the present invention 1.
Embodiment
The specification of quality such as the purity grade of each reaction raw materials, auxiliary material, catalyzer: solvent is analytical pure, and all the other are chemically pure reagent.
The English name difference of compound a-d in the present invention:
Compound a: 4-methyl-N-(2-(1-methyl-1H-indol-3-y1) ethyl) benzenesulfonamide
Compound b:8,8 '-dimethyl-1,1 '-ditosyl-2,2 ', 3,3 ', 8,8a, 8 ', 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-bipyrrolo[2,3-b] indole
Compound c:8,8 '-dimethyl-2,2 ', 3,3 ', 8,8a, 8 ', 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-bipyrrolo[2,3-b] indole
Compound d:1,1 ', 8,8 '-tetramethyl-2,2 ', 3,3 ', 8,8a, 8 ', 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-bipyrrolo[2,3-b] indole
The Chinese difference of compound a-d in the present invention:
Compound a: 4-methyl-N-(2-(1-Methyl-1H-indole-3-) ethyl) para toluene sulfonamide
Compound b:8,8 '-dimethyl-1,1 '-bis-p-toluenesulfonyl-2,2 ', 3,3 ', 8,8a, 8 ', 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-, bis-pyrroles [2,3-b] indoles
Compound c:8,8 '-dimethyl-2,2 ', 3,3 ', 8,8a, 8 ', 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-, bis-pyrroles [2,3-b] indoles
Compound d:1,1 ' 8,8 '-tetramethyl--2,2 ', 3,3 ', 8,8a, 8 ', 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-, bis-pyrroles [2,3-b] indoles
Embodiment 1
The synthetic method of the intermediate product of a kind of natural product (±)-folicanthine, described method is:
At 25 DEG C, by 10 mmole compound as and 20 mmole Cs
2cO
3be dissolved in 50 milliliters of acetonitriles, add 20 mmole iodine to stir 30min at 25 DEG C; Add again saturated Na
2s
2o
3cancellation reaction, continues to add saturated Na
2s
2o
3constantly shake, until iodine eliminates, is extracted with ethyl acetate 3 times, and each consumption is 100 milliliters.Merge organic phase, use anhydrous Na
2sO
4dry, screw out solvent, on silica gel pillar, use moving phase sherwood oil: ethyl acetate=8: 1 drip washing separates; the compound b obtaining i.e. 8,8 '-dimethyl-1,1 '-bis-p-toluenesulfonyl-2; 2 ', 3,3 '; 8,8a, 8 '; 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-, bis-pyrroles [2; 3-b] white solid of indoles, productive rate is 90%.
The characterization data of compound b: white solid Mp:149-152 DEG C, 1H NMR (400MHz, CDCl
3, TMS) δ 7.36 (d, J=8.0Hz, 4H), 7.21-7.27 (m, 6H), 6.86 (d, J=7.6Hz, 2H), 6.65 (t, J=4.8Hz, 2H), 6.50 (d, J=7.6Hz, 2H), 5.05 (s, 2H), 3.21-3.25 (m, 2H), 2.99 (s, 6H), 2.74-2.76 (m, 2H), 2.44 (s, 6H) 1.79-1.87 (m, 4H) .13C NMR (100MHz, CDCl3, TMS) δ 151.6, 142.9, 136.1, 129.9, 129.5, 127.7, 127.2, 124.6, 117.7, 106.9, 87.23, 60.4, 47.4, 32.6, 31.5, 21.5, HRMS (ESI): calc for C36H38N4O4S2[M+1]+: 655.2407 Found:655.2401 (the hydrogen spectrum spectrogram of the nucleus magnetic resonance of compound b is shown in Fig. 1, and the carbon spectrum spectrogram of the nucleus magnetic resonance of compound b is shown in Fig. 2).
The synthetic method of preparing natural product (±)-folicanthine taking compound b as intermediate product, is characterized in that, comprises the steps:
Step 1: under normal temperature, by 10mmol compound a and 20mmolCs
2cO
3be dissolved in 50ml acetonitrile, add 20mmol iodine to stir at normal temperatures 30min; Add again saturated Na
2s
2o
3cancellation reaction, continues to add saturated Na
2s
2o
3constantly shake, until iodine eliminates, is extracted with ethyl acetate 3 times, and each consumption is 100ml.Merge organic phase, use anhydrous Na
2sO
4dry, screw out solvent, on silica gel pillar, be sherwood oil by component and volume ratio: ethyl acetate=8: 1 moving phase drip washing separates; the compound b obtaining i.e. 8,8 '-dimethyl-1,1 '-bis-p-toluenesulfonyl-2; 2 ', 3,3 '; 8,8a, 8 '; 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-, bis-pyrroles [2; 3-b] white solid of indoles, productive rate is 90%.
The characterization data of compound b: white solid Mp:149-152 DEG C, 1H NMR (400MHz, CDCl
3, TMS) δ 7.36 (d, J=8.0Hz, 4H), 7.21-7.27 (m, 6H), 6.86 (d, J=7.6Hz, 2H), 6.65 (t, J=4.8Hz, 2H), 6.50 (d, J=7.6Hz, 2H), 5.05 (s, 2H), 3.21-3.25 (m, 2H), 2.99 (s, 6H), 2.74-2.76 (m, 2H), 2.44 (s, 6H) 1.79-1.87 (m, 4H) .13C NMR (100MHz, CDCl3, TMS) δ 151.6, 142.9, 136.1, 129.9, 129.5, 127.7, 127.2, 124.6, 117.7, 106.9, 87.23, 60.4, 47.4, 32.6, 31.5, 21.5, HRMS (ESI): calc for C36H38N4O4S2[M+1]+: 655.2407 Found:655.2401 (the hydrogen spectrum spectrogram of the nucleus magnetic resonance of compound b is shown in Fig. 1, and the carbon spectrum spectrogram of the nucleus magnetic resonance of compound b is shown in Fig. 2).
Step 2: under the protection of room temperature noble gas, add sodium Metal 99.5 5.0mmol (115mg) in 70mlTHF, stir and generate bottle-green sodium naphthalene solution (0.5M) for 2 hours; At-78 DEG C, freshly prepd sodium naphthalene solution is slowly joined in the THF solution of compound b (163.5mg, 0.25mmol), until the blueness of solution does not change (about 5mL); Stir 30 minutes at-78 ° of C, add saturated NH
4cl (2ml) cancellation reaction; Reaction mixture is slowly warming up to room temperature and is extracted with ethyl acetate 3 times, and the each consumption of ethyl acetate is 30ml; With saturated sodium-chloride drip washing 3 times, the each consumption 20ml of saturated sodium-chloride; After drip washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure, be methyl alcohol with forming with volume ratio: methylene dichloride=1: 3 moving phase separates on silica gel pillar, obtains compound c, productive rate 50%.
The characterization data white solid Mp:186-188 DEG C of compound c; 1H NMR (400MHz, CDCl
3, TMS) and δ 7.17 (d, J=7.2Hz, 2H), 7.08 (t, J=7.6Hz, 2H), 6.57 (t, J=7.2Hz, 2H), 6.29 (d, J=8.0,2H), 4.38 (s, 2H), 2.98-3.00 (m, 2H), 2.80 (s, 6H), 2.42-2.49 (m, 4H), 2.12-2.16 (m, 2H), 1.81 (s, 2H) .13CNMR (100MHz, CDCl3, TMS) δ 152.6,131.4,128.5,124.2,116.1,104.8,87.5,62.1,45.8,38.7,31.1; HRMS (ESI): calc for C22H26N4[M+1]+: 347.2230 Found:347.2236 (the hydrogen spectrum spectrogram of the nucleus magnetic resonance of compound c is shown in Fig. 3, and the carbon spectrum spectrogram of the nucleus magnetic resonance of compound b is shown in Fig. 4).
Step 3: under noble gas protection, sodium triacetoxy borohydride (15.6mg, 0.0734mmol), Fu Er morpholine (37%, 5.5mL, 0.0734mmol) be added to compound c (4.88mg, in acetonitrile solution 0.0141mmol), stir after 30 minutes, drip with the saturated methyl alcohol of ammonia and methylene dichloride (volume ratio of methyl alcohol and methylene dichloride is 5: 95) mixing solutions, after 5 minutes by after reactant concentrating under reduced pressure, the methyl alcohol saturated with ammonia separates on silica gel pillar with the moving phase of methylene dichloride (1: 100), obtain i.e. (±)-folicanthine of compound d, productive rate is 99%.
The characterization data of compound d: white solid Mp:164-167 DEG C; 1H NMR (400MHz, CDCl
3, TMS) and δ 6.91-6.99 (m, J=8.0Hz, 4H), 6.48-6.51 (t, J=6.8Hz, 2H), 6.26 (d, J=6.8Hz, 2H), 4.39 (s, 2H), 2.99 (s, 6H), 2.63-2.65 (m, 2H), 2.40-2.47 (m, 10H), 1.94-1.99 (m, 2H) .13C NMR (100MHz, CDCl3, TMS) δ 152.8,132.7,128.0,123.6,116.6,105.8,91.9,62.6,52.6,37.8,35.4,35.2; HRMS (ESI): calc for C24H30N4[M+1]+: 375.2543 Found:375.2547 (the hydrogen spectrum spectrogram of the nucleus magnetic resonance of compound d is shown in Fig. 5, and the carbon spectrum spectrogram of the nucleus magnetic resonance of compound d is shown in Fig. 6).
Embodiment 2
The synthetic method of the intermediate product of a kind of natural product (±)-folicanthine, described method is:
Under normal temperature, by 5 mmole compound as and 10 mmole Cs
2cO
3be dissolved in 25 milliliters of acetonitriles, add 10 mmole iodine to stir at normal temperatures 10 minutes; Add again saturated Na
2s
2o
3cancellation reaction, continues to add saturated Na
2s
2o
3constantly shake, until iodine eliminates, is extracted with ethyl acetate 3 times, and each consumption is 50 milliliters.Merge organic phase, use anhydrous Na
2sO
4dry, screw out solvent, on silica gel pillar, use moving phase sherwood oil: ethyl acetate=8: 1 drip washing separates; the compound b obtaining i.e. 8,8 '-dimethyl-1,1 '-bis-p-toluenesulfonyl-2; 2 ', 3,3 '; 8,8a, 8 '; 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-, bis-pyrroles [2; 3-b] white solid of indoles, productive rate is 91%.
The synthetic method of preparing natural product (±)-folicanthine taking compound b as intermediate product, is characterized in that, comprises the steps:
Step 1: under normal temperature, by 5mmol compound a and 10mmolCs
2cO
3be dissolved in 25ml acetonitrile, add 10mmol iodine to stir at normal temperatures 10min; Add again saturated Na
2s
2o
3cancellation reaction, continues to add saturated Na
2s
2o
3constantly shake, until iodine eliminates, is extracted with ethyl acetate 3 times, and each consumption is 50ml.Merge organic phase, use anhydrous Na
2sO
4dry, screw out solvent, on silica gel pillar, be sherwood oil by component and volume ratio: ethyl acetate=8: 1 moving phase drip washing separates; the compound b obtaining i.e. 8,8 '-dimethyl-1,1 '-bis-p-toluenesulfonyl-2; 2 ', 3,3 '; 8,8a, 8 '; 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-, bis-pyrroles [2; 3-b] white solid of indoles, productive rate is 91%.
Step 2: under the protection of room temperature noble gas, add sodium Metal 99.5 2.5mmol (57.5mg) in 35mlTHF, stir and generate bottle-green sodium naphthalene solution (0.25M) for 2.5 hours; At-75 DEG C, freshly prepd sodium naphthalene solution is slowly joined in the THF solution of compound b (81.75mg, 0.125mmol), until the blueness of solution does not change (about 2.5mL); Stir 40 minutes at-75 DEG C, add saturated NH
4cl (1ml) cancellation reaction, reaction mixture is slowly warming up to room temperature and is extracted with ethyl acetate 3 times, and the each consumption of ethyl acetate is 15ml; With saturated sodium-chloride drip washing 3 times, the each consumption 10ml of saturated sodium-chloride; After drip washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure, be methyl alcohol with forming with volume ratio: methylene dichloride=1: 3 moving phase separates on silica gel pillar, obtains compound c, productive rate 51%.
Step 3: under noble gas protection, sodium triacetoxy borohydride (7.8mg, 0.0367mmol), Fu Er morpholine (37%, 2.75mL, 0.0367mmol) be added to compound c (2.44mg, in acetonitrile solution 0.00705mmol), stir after 35 minutes, drip with the saturated methyl alcohol of ammonia and methylene dichloride (volume ratio of methyl alcohol and methylene dichloride is 5: 95) mixing solutions, after 10 minutes by after reactant concentrating under reduced pressure, the methyl alcohol saturated with ammonia separates on silica gel pillar with the moving phase of methylene dichloride (1: 100), obtain i.e. (±)-folicanthine of compound d, productive rate is 98.5%.
Embodiment 3
The synthetic method of the intermediate product of a kind of natural product (±)-folicanthine, described method is:
Under normal temperature, by 2 mmole compound as and 4 mmole Cs
2cO
3be dissolved in 10 milliliters of acetonitriles, add 4 mmole iodine to stir at normal temperatures 20 minutes; Add again saturated Na
2s
2o
3cancellation reaction, continues to add saturated Na
2s
2o
3constantly shake, until iodine eliminates, is extracted with ethyl acetate 3 times, and each consumption is 20 milliliters.Merge organic phase, use anhydrous Na
2sO
4dry, screw out solvent, on silica gel pillar, use moving phase sherwood oil: ethyl acetate=8: 1 drip washing separates; the compound b obtaining i.e. 8,8 '-dimethyl-1,1 '-bis-p-toluenesulfonyl-2; 2 ', 3,3 '; 8,8a, 8 '; 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-, bis-pyrroles [2; 3-b] white solid of indoles, productive rate is 92%.
The synthetic method of preparing natural product (±)-folicanthine taking compound b as intermediate product, is characterized in that, comprises the steps:
Step 1: under normal temperature, by 2mmol compound a and 4mmolCs
2cO
3be dissolved in 10ml acetonitrile, add 4mmol iodine to stir at normal temperatures 20min; Add again saturated Na
2s
2o
3cancellation reaction, continues to add saturated Na
2s
2o
3constantly shake, until iodine eliminates, is extracted with ethyl acetate 3 times, and each consumption is 20ml.Merge organic phase, use anhydrous Na
2sO
4dry, screw out solvent, on silica gel pillar, be sherwood oil by component and volume ratio: ethyl acetate=8: 1 moving phase drip washing separates; the compound b obtaining i.e. 8,8 '-dimethyl-1,1 '-bis-p-toluenesulfonyl-2; 2 ', 3,3 '; 8,8a, 8 '; 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-, bis-pyrroles [2; 3-b] white solid of indoles, productive rate is 92%.
Step 2: under the protection of room temperature noble gas, add sodium Metal 99.5 1.0mmol (23mg) in 14mlTHF, stir and generate bottle-green sodium naphthalene solution (0.1M) for 2 hours; At-78 DEG C, freshly prepd sodium naphthalene solution is slowly joined in the THF solution of compound b (32.7mg, 0.05mmol), until the blueness of solution does not change (about 1mL); Stir 30 minutes at-78 DEG C, add saturated NH
4cl (0.4ml) cancellation reaction, reaction mixture is slowly warming up to room temperature and is extracted with ethyl acetate 3 times, and the each consumption of ethyl acetate is 6ml; With saturated sodium-chloride drip washing 3 times, the each consumption 4ml of saturated sodium-chloride; After drip washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure, be methyl alcohol with forming with volume ratio: methylene dichloride=1: 3 moving phase separates on silica gel pillar, obtains compound c, productive rate 51%.
Step 3: under noble gas protection, sodium triacetoxy borohydride (3.12mg, 0.01468mmol), Fu Er morpholine (37%, 1.1mL, 0.01468mmol) be added to compound c (0.976mg, in acetonitrile solution 0.0028mmol), stir after 50 minutes, drip with the saturated methyl alcohol of ammonia and methylene dichloride (volume ratio of methyl alcohol and methylene dichloride is 5: 95) mixing solutions, after 15 minutes by after reactant concentrating under reduced pressure, the methyl alcohol saturated with ammonia separates on silica gel pillar with the moving phase of methylene dichloride (1: 100), obtain i.e. (±)-folicanthine of compound d, productive rate is 98%.
Embodiment 4
The synthetic method of the intermediate product of a kind of natural product (±)-folicanthine, described method is:
At-10 DEG C, by 10 mmole compound as and 5 mmole Cs
2cO
3be dissolved in 10 milliliters of methylene dichloride, add 5 mmole N-N-iodosuccinimides at-10 DEG C, to stir 30 minutes; Add again saturated Na
2s
2o
3cancellation reaction, continues to add saturated Na
2s
2o
3constantly shake, until iodine eliminates, is extracted with ethyl acetate 3 times, and each consumption is 100 milliliters.Merge organic phase, use anhydrous Na
2sO
4dry, screw out solvent, on silica gel pillar, use moving phase sherwood oil: ethyl acetate=8: 1 drip washing separates; the compound b obtaining i.e. 8,8 '-dimethyl-1,1 '-bis-p-toluenesulfonyl-2; 2 ', 3,3 '; 8,8a, 8 '; 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-, bis-pyrroles [2; 3-b] white solid of indoles, productive rate is 90%.
The synthetic method of preparing natural product (±)-folicanthine taking compound b as intermediate product, is characterized in that, comprises the steps:
At step 1:-10 DEG C, by 10mmol compound a and 5mmolCs
2cO
3be dissolved in 10ml acetonitrile, add 5mmol iodine to stir 30min at-10 DEG C; Add again saturated Na
2s
2o
3cancellation reaction, continues to add saturated Na
2s
2o
3constantly shake, until iodine eliminates, is extracted with ethyl acetate 3 times, and each consumption is 100ml.Merge organic phase, use anhydrous Na
2sO
4dry, screw out solvent, on silica gel pillar, be sherwood oil by component and volume ratio: ethyl acetate=8: 1 moving phase drip washing separates; the compound b obtaining i.e. 8,8 '-dimethyl-1,1 '-bis-p-toluenesulfonyl-2; 2 ', 3,3 '; 8,8a, 8 '; 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-, bis-pyrroles [2; 3-b] white solid of indoles, productive rate is 90%.
Step 2: under the protection of room temperature noble gas, add sodium Metal 99.5 5.0mmol (115mg) in 70mlTHF, stir and generate bottle-green sodium naphthalene solution (0.5M) for 2 hours; At-75 DEG C, freshly prepd sodium naphthalene solution is slowly joined in the THF solution of compound b (163.5mg, 0.25mmol), until the blueness of solution does not change (about 5mL); Stir 30 minutes at-78 ° of C, add saturated NH
4cl (2ml) cancellation reaction, reaction mixture is slowly warming up to room temperature and is extracted with ethyl acetate 3 times, and the each consumption of ethyl acetate is 30ml; With saturated sodium-chloride drip washing 3 times, the each consumption 20ml of saturated sodium-chloride; After drip washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure, be methyl alcohol with forming with volume ratio: methylene dichloride=1: 3 moving phase separates on silica gel pillar, obtains compound c, productive rate 50%.
Step 3: under noble gas protection, sodium triacetoxy borohydride (15.6mg, 0.0734mmol), Fu Er morpholine (37%, 5.5mL, 0.0734mmol) be added to compound c (4.88mg, in acetonitrile solution 0.0141mmol), stir after 30 minutes, drip with the saturated methyl alcohol of ammonia and methylene dichloride (volume ratio of methyl alcohol and methylene dichloride is 5: 95) mixing solutions, after 5 minutes by after reactant concentrating under reduced pressure, the methyl alcohol saturated with ammonia separates on silica gel pillar with the moving phase of methylene dichloride (1: 100), obtain i.e. (±)-folicanthine of compound d, productive rate is 99%.
Embodiment 5
The synthetic method of the intermediate product of a kind of natural product (±)-folicanthine, described method is:
At 30 DEG C, by 10 mmole compound as and 30 mmole Cs
2cO
3be dissolved in 100 milliliters of tetrahydrofuran (THF)s, add 50 mmole N-N-iodosuccinimides at 30 DEG C, to stir 30 minutes; Add again saturated Na
2s
2o
3cancellation reaction, continues to add saturated Na
2s
2o
3constantly shake, until iodine eliminates, is extracted with ethyl acetate 3 times, and each consumption is 100 milliliters.Merge organic phase, use anhydrous Na
2sO
4dry, screw out solvent, on silica gel pillar, use moving phase sherwood oil: ethyl acetate=8: 1 drip washing separates; the compound b obtaining i.e. 8,8 '-dimethyl-1,1 '-bis-p-toluenesulfonyl-2; 2 ', 3,3 '; 8,8a, 8 '; 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-, bis-pyrroles [2; 3-b] white solid of indoles, productive rate is 90.5%.
The synthetic method of preparing natural product (±)-folicanthine taking compound b as intermediate product, is characterized in that, comprises the steps:
At step 1:30 DEG C, by 10mmol compound a and 30mmolCs
2cO
3be dissolved in 100ml tetrahydrofuran (THF), add 50mmol iodine to stir 30min at 30 DEG C; Add again saturated Na
2s
2o
3cancellation reaction, continues to add saturated Na
2s
2o
3constantly shake, until iodine eliminates, is extracted with ethyl acetate 3 times, and each consumption is 100ml.Merge organic phase, use anhydrous Na
2sO
4dry, screw out solvent, on silica gel pillar, be sherwood oil by component and volume ratio: ethyl acetate=8: 1 moving phase drip washing separates; the compound b obtaining i.e. 8,8 '-dimethyl-1,1 '-bis-p-toluenesulfonyl-2; 2 ', 3,3 '; 8,8a, 8 '; 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-, bis-pyrroles [2; 3-b] white solid of indoles, productive rate is 90.5%.
Step 2: under the protection of room temperature noble gas, add sodium Metal 99.5 5.0mmol (115mg) in 70mlTHF, stir and generate bottle-green sodium naphthalene solution (0.5M) for 2 hours; At-80 DEG C, freshly prepd sodium naphthalene solution is slowly joined in the THF solution of compound b (163.5mg, 0.25mmol), until the blueness of solution does not change (about 5mL); Stir 50 minutes at-78 ° of C, add saturated NH
4cl (2ml) cancellation reaction, reaction mixture is slowly warming up to room temperature and is extracted with ethyl acetate 3 times, and the each consumption of ethyl acetate is 30ml; With saturated sodium-chloride drip washing 3 times, the each consumption 20ml of saturated sodium-chloride; After drip washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure, be methyl alcohol with forming with volume ratio: methylene dichloride=1: 3 moving phase separates on silica gel pillar, obtains compound c, productive rate 50%.
Step 3: under noble gas protection, sodium triacetoxy borohydride (15.6mg, 0.0734mmol), Fu Er morpholine (37%, 5.5mL, 0.0734mmol) be added in the acetonitrile solution of compound c, stir after 30 minutes, drip with the saturated methyl alcohol of ammonia and methylene dichloride (volume ratio of methyl alcohol and methylene dichloride is 5: 95) mixing solutions, after 5 minutes by after reactant concentrating under reduced pressure, the methyl alcohol saturated with ammonia separates on silica gel pillar with the moving phase of methylene dichloride (1: 100), obtain i.e. (±)-folicanthine of compound d, productive rate is 99%.
Embodiment 6
The difference of the present embodiment and embodiment is:
The synthetic method of the intermediate product of a kind of natural product (±)-folicanthine, described method is:
Under normal temperature, by 10 mmole compound as and 20 mmole Cs
2cO
3be dissolved in 50 milliliters of dioxanes, add 20 mmole iodine to stir at normal temperatures 30 minutes; Add again saturated Na
2s
2o
3cancellation reaction, continues to add saturated Na
2s
2o
3constantly shake, until iodine eliminates, is extracted with ethyl acetate 3 times, and each consumption is 100 milliliters.Merge organic phase, use anhydrous Na
2sO
4dry, screw out solvent, on silica gel pillar, use moving phase sherwood oil: ethyl acetate=8: 1 drip washing separates; the compound b obtaining i.e. 8,8 '-dimethyl-1,1 '-bis-p-toluenesulfonyl-2; 2 ', 3,3 '; 8,8a, 8 '; 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-, bis-pyrroles [2; 3-b] white solid of indoles, productive rate is 90%.
Embodiment 7
The difference of the present embodiment and embodiment is:
The synthetic method of the intermediate product of a kind of natural product (±)-folicanthine, described method is:
Under normal temperature, by 10 mmole compound as and 20 mmole Cs
2cO
3be dissolved in 50 milliliters of dimethyl formamides, add 20 mmole iodine to stir at normal temperatures 30 minutes; Add again saturated Na
2s
2o
3cancellation reaction, continues to add saturated Na
2s
2o
3constantly shake, until iodine eliminates, is extracted with ethyl acetate 3 times, and each consumption is 100 milliliters.Merge organic phase, use anhydrous Na
2sO
4dry, screw out solvent, on silica gel pillar, use moving phase sherwood oil: ethyl acetate=8: 1 drip washing separates; the compound b obtaining i.e. 8,8 '-dimethyl-1,1 '-bis-p-toluenesulfonyl-2; 2 ', 3,3 '; 8,8a, 8 '; 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-, bis-pyrroles [2; 3-b] white solid of indoles, productive rate is 90%.
Embodiment 8
The difference of the present embodiment and embodiment is:
The synthetic method of the intermediate product of a kind of natural product (±)-folicanthine, described method is:
Under normal temperature, by 10 mmole compound as and 20 mmole Cs
2cO
3be dissolved in 50 milliliters of ethylene dichloride, add 20 mmole N-points for succimide, stir at normal temperatures 30 minutes; Add again saturated Na
2s
2o
3cancellation reaction, continues to add saturated Na
2s
2o
3constantly shake, until iodine eliminates, is extracted with ethyl acetate 3 times, and each consumption is 100 milliliters.Merge organic phase, use anhydrous Na
2sO
4dry, screw out solvent, on silica gel pillar, use moving phase sherwood oil: ethyl acetate=8: 1 drip washing separates; the compound b obtaining i.e. 8,8 '-dimethyl-1,1 '-bis-p-toluenesulfonyl-2; 2 ', 3,3 '; 8,8a, 8 '; 8 ' a-octahydro-1H, 1 ' H-3a, 3 ' a-, bis-pyrroles [2; 3-b] white solid of indoles, productive rate is 90%.
Embodiment 9
The difference of the present embodiment and embodiment is:
The synthetic method of the intermediate product of a kind of natural product (±)-folicanthine, described method is:
Under normal temperature, by 10 mmole compound as and 20 mmole Cs
2cO
3be dissolved in 50 milliliters of toluene, add 20 mmole iodine to stir at normal temperatures 30 minutes; Add again saturated Na
2s
2o
3cancellation reaction, continues to add saturated Na
2s
2o
3constantly shake, until iodine eliminates, is extracted with ethyl acetate 3 times, and each consumption is 100 milliliters.Merge organic phase, use anhydrous Na
2sO
4dry, screw out solvent, the compound b obtaining by re-crystallizing in ethyl acetate i.e. 8,8 '-dimethyl-1,1 '-bis-p-toluenesulfonyl-2,2 '; 3,3 ', 8,8a, 8 '; 8 ' a-octahydro-1H, 1 ' H-3a, the white solid of 3 ' a-, bis-pyrroles [2,3-b] indoles, productive rate is 90%.
The foregoing is only preferred embodiment of the present invention, in order to limit the present invention, within the spirit and principles in the present invention not all, any amendment of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (10)
1. the synthetic method of the intermediate product of a natural product (±)-folicanthine, it is characterized in that :-10-30 DEG C, be 4-methyl-N-(2-(1-methyl isophthalic acid H-indoles-3-by compound a) ethyl) para toluene sulfonamide and Cs2CO3 be dissolved in solvent, add catalyzer to stir 10-30 minute at-10-30 DEG C, prepare compound b through aftertreatment; Wherein, compound a, Cs2CO3 are 2:1:1-1:3:5 with the ratio of the amount of substance of catalyzer; Described solvent is the one in acetonitrile, methylene dichloride, tetrahydrofuran (THF), dioxane, dimethyl formamide, toluene or ethylene dichloride; Described catalyzer is iodine or N-N-iodosuccinimide; The Chinese of described compound b is: 8,8'-dimethyl-1,1'-bis-p-toluenesulfonyl-2,2', 3,3', 8,8a, 8', 8'a-octahydro-1H, 1'H-3a, 3'a-bis-pyrroles [2,3-b] indoles; Its structural formula is:
。
2. according to the synthetic method described in claim 1; it is characterized in that: described aftertreatment, in reaction solution, adds saturated Na2S2O3 cancellation reaction, continues to add saturated Na2S2O3 constantly to shake until catalyzer eliminates; be extracted with ethyl acetate; merge organic phase, be dried, remove desolventizing, it is 8 that column chromatography or recrystallization obtain compound b; 8'-dimethyl-1; 1'-bis-p-toluenesulfonyl-2,2', 3; 3'; 8,8a, 8'; 8'a-octahydro-1H; 1'H-3a, the white solid of 3'a-bis-pyrroles [2,3-b] indoles.
3. according to the synthetic method described in claim 1, it is characterized in that: described compound a, Cs2CO3 are 1:2:2 with the ratio of the amount of substance of iodine; Described solvent is acetonitrile; Described catalyzer is iodine.
4. the synthetic method of preparing natural product (±)-folicanthine taking the compound b described in claim 1-3 any one as intermediate product, is characterized in that, comprises the steps:
Step 1: at-10-30 DEG C, be 4-methyl-N-(2-(1-methyl isophthalic acid H-indoles-3-by compound a) ethyl) para toluene sulfonamide and Cs2CO3 be dissolved in solvent, adds catalyzer to stir 10-30 minute at-10-30 DEG C; Add again saturated Na2S2O3 cancellation to react, continue to add saturated Na2S2O3 constantly to shake until catalyzer eliminates, be extracted with ethyl acetate, merge organic phase, be dried, remove desolventizing, the compound b white solid that column chromatography or recrystallization obtain;
Step 2: under room temperature protection of inert gas, add sodium in tetrahydrofuran (THF), stir and generate bottle-green sodium naphthalene solution for 2-3 hour;-75-(-80) DEG C, freshly prepd sodium naphthalene solution is joined in the tetrahydrofuran solution of compound b, until the blueness of solution does not change,-75-(-80) DEG C stirring 30-50 minute, add saturated NH4Cl cancellation reaction, reaction mixture is warming up to room temperature and is extracted with ethyl acetate, with dry, concentrating under reduced pressure after saturated sodium-chloride drip washing, residuum adopts column chromatography, obtains compound c;
Step 3: under protection of inert gas; sodium triacetoxy borohydride, formalin are added in the acetonitrile solution of compound c; stir after 30-40 minute; drip with saturated methyl alcohol and the methylene dichloride mixing solutions of ammonia; after 5-15 minute, by column chromatography after reactant concentrating under reduced pressure, obtain i.e. (±)-folicanthine of compound d.
5. according to the synthetic method described in claim 4, it is characterized in that: in described step 1, compound a, Cs2CO3 are 2:1:1-1:3:5 with the ratio of the amount of substance of catalyzer; The volume of described solvent is 10:1-1:1 with the amount of substance of compound a ratio.
6. according to the synthetic method described in claim 4, it is characterized in that: solvent described in described step 1 is the one in acetonitrile, methylene dichloride, tetrahydrofuran (THF), dioxane, dimethyl formamide, toluene or ethylene dichloride; Described catalyzer is iodine or N-N-iodosuccinimide.
7. according to the synthetic method described in claim 4, it is characterized in that: in described step 3, the amount of substance of sodium triacetoxy borohydride, formalin and compound c is than being 5.2:5.2:1; The described volume ratio with methyl alcohol and methylene dichloride in the saturated methyl alcohol of ammonia and methylene dichloride mixing solutions is 5:95.
8. according to the synthetic method described in claim 4, it is characterized in that: composition and the volume ratio of the moving phase using when column chromatography in described step 1 are sherwood oil: ethyl acetate=8:1.
9. according to the synthetic method described in claim 4, it is characterized in that: composition and the volume ratio of the moving phase using when column chromatography in step 2 are methyl alcohol: methylene dichloride=1:3; Composition and the volume ratio of the moving phase using when column chromatography in step 3 are methyl alcohol: methylene dichloride=1:100.
10. according to the synthetic method described in claim 5, it is characterized in that: in described step 1, compound a, Cs2CO3 are 1:2:2 with the ratio of the amount of substance of iodine; The volume of described solvent is 5:1 with the amount of substance of compound a ratio.
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| EP0216165A1 (en) * | 1985-08-29 | 1987-04-01 | Roche Diagnostics GmbH | Benzodipyrroles, processes for their preparation and pharmaceutical compositions containing these compounds |
| CN102046632A (en) * | 2008-11-24 | 2011-05-04 | 马林克罗特公司 | Azo and diaza derivatives and uses thereof in phototherapy |
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| EP0216165A1 (en) * | 1985-08-29 | 1987-04-01 | Roche Diagnostics GmbH | Benzodipyrroles, processes for their preparation and pharmaceutical compositions containing these compounds |
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