CN112047869B - Synthetic method of aza 5, 6-heterocyclic compound - Google Patents
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Abstract
The invention belongs to the technical field of organic synthesis, and discloses a synthesis method of a 5, 6-heterocyclic compound. The synthesis method comprises the following steps: under a protective atmosphere, taking an organic solvent as a reaction medium, reacting the compound 1 under the action of methyl triphenyl phosphonium bromide and alkali, and performing subsequent treatment to obtain an aza 5, 6-heterocyclic compound which is marked as a compound 2; further, taking an organic solvent as a reaction medium, reacting the compound 2 under an acidic condition, and carrying out subsequent treatment to obtain a reaction product; the product obtained is reacted with p-toluenesulfonyl chloride to give the aza 5, 6-membered ring compound denoted as compound 3. The structural formulas of the compound 1, the compound 2 and the compound 3 are respectively as follows. The method of the invention has safe and simple operation, nontoxic raw materials and high yield.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a 5, 6-heterocyclic-fused compound.
Background
The aza 5, 6-polycyclic is used as an extremely special compound structure and widely exists in various natural products and pharmaceutically active molecules. How to efficiently construct an aza 5, 6-fused ring is always a key step of synthesis, and most of the synthesis methods adopt a nucleophilic substitution method. In 2012, there was a report of intracellular SN in the Weak light (Li, H., Wang, X., Lei, X. Total syntheses of lycopodium alkaloids (+) -Fawcettimine, (+) -Fawcettidine, and (-) -8-Deoxysperratine. Angew. chem. int. Ed.2012,51, 491-1Constructing an aza 5, 6-polycyclic ring structure in huperzine alkaloid seratine through reaction; in 2013, the Shore Association reports (Li, Z., Zhang, S., Wu, S., Shen, X., Zou, L.; Wang, F., Li, X., Peng, F., Zhang, H., Shao, Z.Enoptionally paladium-catalyzed synthesis of carbozolones: Total synthesis of (-) -Aspidospmidine and (+) -Kopsihainanine A.Angew.chem., int.Ed.2013,52,4117-4121) that SN in the molecule2Constructing a skeleton structure of quebracho alkaloid kopsihainanine A through reaction; in 2017, the Town military reports (Du, K., Yang, H., Guo, P., Feng, L., Xu, G., Zhou, Q., Chung, L.W., Tang, W.Effective synthesis of (-) -crinine and (-) -aspidospmidine, and the formal synthesis of (-) -minor by antibiotic selective intracellular cellular catalytic cyclization, chem.Sci.,2017,8,6247-2The skeleton structure of crinine alkaloid crinine is constructed through reaction. These methods require extensive modifications of functional groups and have relatively large substrate limitations and are of little reference to other types of systems.
Disclosure of Invention
In view of the shortcomings and disadvantages of the prior art, the present invention is directed to a method for synthesizing aza 5, 6-fused ring compounds.
The purpose of the invention is realized by the following technical scheme:
a method of synthesizing an aza 5, 6-fused ring compound comprising the steps of:
under a protective atmosphere, taking an organic solvent as a reaction medium, reacting the compound 1 under the action of methyl triphenyl phosphonium bromide and alkali, and performing subsequent treatment to obtain an aza 5, 6-heterocyclic compound which is marked as a compound 2;
further, taking an organic solvent as a reaction medium, reacting the compound 2 under an acidic condition, and carrying out subsequent treatment to obtain a reaction product; the product obtained is reacted with p-toluenesulfonyl chloride to give the aza 5, 6-membered ring compound denoted as compound 3.
The structural formulas of the compound 1, the compound 2 and the compound 3 are respectively as follows:
in the structural formula, "Boc" is tert-butyloxycarbonyl.
The base is an organic base, preferably potassium tert-amylate.
The molar ratio of the alkali to the compound 1 is (2.5-4.5): 1.
The molar ratio of the methyl triphenylphosphine to the compound 1 is (3.5-5): 1.
In the preparation of compound 2, the organic solvent is preferably toluene.
In the preparation process of the compound 2, the reaction temperature is 75-85 ℃; the reaction time is 1-10 h.
In the preparation process of the compound 2, the subsequent treatment refers to quenching reaction by using a saturated ammonium chloride solution, and separation and purification; the separation and purification refers to adding ethyl acetate for extraction, combining organic phases, backwashing by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, concentrating, and separating a crude product by using a flash preparative silica gel chromatographic column (petroleum ether: ethyl acetate ═ 3: 1).
The acid used in the acidic condition is trifluoroacetic acid.
In the preparation of the reaction product, the organic solvent is preferably dichloromethane.
In the preparation process of the reaction product, the volume ratio of the acid to the organic solvent adopted in the acidic condition is 1: (5-10).
In the preparation process of the reaction product, the concentration of the compound 2 in the organic solvent is 0.05-0.15 mmol/mL.
In the preparation process of the reaction product, the reaction temperature is room temperature, and the reaction time is 1-3 h;
in the preparation process of the reaction product, the subsequent treatment refers to quenching reaction by using a saturated sodium bicarbonate solution, and separating and purifying; the separation and purification refers to ethyl acetate extraction, organic phases are combined, a saturated sodium chloride solution is backwashed, anhydrous sodium sulfate is dried, and the filtration and the concentration are carried out.
In the preparation process of the compound 3, the reaction is carried out in a system of an organic solvent and an alkaline compound, wherein the alkaline compound is triethylamine; the organic solvent is preferably chloroform.
In the preparation process of the compound 3, the molar ratio of the p-toluenesulfonyl chloride (TsCl) to the compound 2 is (1-1.5): 1.
the molar ratio of the basic compound to the compound 2 is (1-3): 1.
in the preparation process of the compound 3, the reaction temperature is 0-4 ℃; the reaction time is 1-3 h.
In the preparation process of the compound 3, after the reaction is finished, a saturated sodium bicarbonate solution is used for quenching the reaction, and separation and purification are carried out; the separation and purification refers to ethyl acetate extraction, backwashing of saturated sodium chloride solution, drying of an organic phase by anhydrous sodium sulfate, filtration, concentration and column chromatography.
The synthesis method of the invention has the reaction equation:
the synthesis method of the invention has the following advantages and beneficial effects: the synthesis method of the invention has the advantages of safe and simple operation, non-toxic raw materials, cheap reagents, high yield, wide applicability and the like.
Drawings
FIG. 1 is a hydrogen spectrum of Compound 1;
FIG. 2 is a carbon spectrum of Compound 1;
FIG. 3 is a hydrogen spectrum of Compound 2 prepared in example 5;
FIG. 4 is a hydrogen spectrum of Compound 3 prepared in example 5;
fig. 5 is a carbon spectrum of compound 3 prepared in example 5.
Detailed Description
The present invention will be further described with reference to the following specific examples and drawings, but the embodiments of the present invention are not limited thereto.
Example 1
The reaction equation is
A method of synthesizing an aza 5, 6-fused ring compound comprising the steps of:
1) mixing compound 1(13.8mg,0.027mmol) with dry methyl triphenyl phosphonium bromide (48mg,0.135mmol,5 equiv.), displacing nitrogen three times, adding anhydrous toluene (0.5ml), heating to 80 ℃, rapidly adding potassium tert-amyl alcohol (69 μ l,0.12mmol,4.5 equiv.), stirring the reaction at 80 ℃ for 10 hours, returning to room temperature, quenching the reaction with saturated ammonium chloride solution, adding ethyl acetate for extraction three times, combining the organic phases, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, separating the crude product with flash preparative silica gel chromatography (petroleum ether: ethyl acetate ═ 3:1) to give compound 2 as a white solid (10.4mg, 75%);
2) dissolving compound 2(25.5mg,0.05mmol) in dichloromethane (0.5ml), adding trifluoroacetic acid (50 μ l), stirring at room temperature for 1h, quenching the reaction with saturated sodium bicarbonate solution, extracting three times with ethyl acetate, combining the organic phases, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, re-dissolving the crude product in dichloromethane (0.5ml), placing in an ice-water bath at 0 ℃, adding triethylamine (14 μ l,0.1 mmol,2.0 equivalents), p-toluenesulfonyl chloride (11.4mg,0.06mmol,1.2 equivalents), reacting for 1h while maintaining 0 ℃, quenching the reaction with saturated sodium bicarbonate solution, extracting three times with ethyl acetate, combining the organic phases, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, separating the crude product using a flash preparative silica gel chromatography column (petroleum ether: ethyl acetate: 7:1 to 5:1), compound 3 was obtained as a white solid (25.8mg, 91% (two-step yield, i.e., yield via reaction under trifluoroacetic acid and reaction with p-toluenesulfonyl chloride)).
Example 2
The reaction equation is
A method of synthesizing an aza 5, 6-fused ring compound comprising the steps of:
1) mixing compound 1(43mg,0.084mmol) with dried methyltriphenylphosphorus bromide (105mg,0.294mmol,3.5 equiv.), displacing nitrogen three times, adding anhydrous toluene (1.6ml), heating to 80 ℃, rapidly adding potassium tert-amylate (0.12ml,0.21mmol,2.5 equiv.), stirring the reaction at 80 ℃ for 1 hour, returning to room temperature, quenching the reaction with saturated ammonium chloride solution, adding ethyl acetate for extraction three times, combining the organic phases, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, separating the crude product with flash preparative silica gel chromatography column (petroleum ether: ethyl acetate 3:1) to give compound 2 as a white solid (36.3mg, 85%);
2) dissolving compound 2(400mg,0.78mmol) in dichloromethane (7.8ml), adding trifluoroacetic acid (0.78ml), stirring at room temperature for 1h, quenching the reaction with saturated sodium bicarbonate solution, extracting three times with ethyl acetate, combining the organic phases, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, re-dissolving the crude product in dichloromethane (7.8ml), placing in a 0 ℃ ice water bath, adding triethylamine (0.22ml, 1.56mmol,2.0 equiv), p-toluenesulfonyl chloride (179mg,0.94mmol,1.2 equiv), reacting for 1h while maintaining 0 ℃, quenching the reaction with saturated sodium bicarbonate solution, extracting three times with ethyl acetate, combining the organic phases, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, separating the crude product with flash preparative silica gel chromatography column (petroleum ether: ethyl acetate ═ 7:1 to 5:1), compound 3(432mg, 98% (two-step yield)) was obtained as a white solid.
Example 3
The reaction equation is
A method of synthesizing an aza 5, 6-fused ring compound comprising the steps of:
1) compound 1(394mg, 0.77mmol) was mixed with dried methyltriphenylphosphorus bromide (962mg, 2.70mmol, 3.5 eq), nitrogen was replaced three times, anhydrous toluene (15ml) was added, after warming to 80 ℃, potassium tert-amylate (1.1ml, 1.93mmol, 2.5 eq) was added rapidly, the reaction was stirred at 80 ℃ for 1.5 hours, returned to room temperature, quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, combined organic phases were back-washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was isolated using flash preparative silica gel chromatography (petroleum ether: ethyl acetate ═ 3:1) to give compound 2 as a white solid (347mg, 88%).
2) Dissolving compound 2(400mg,0.78mmol) in dichloromethane (7.8ml), adding trifluoroacetic acid (0.78ml), stirring at room temperature for 1h, quenching the reaction with saturated sodium bicarbonate solution, adding ethyl acetate to extract three times, combining the organic phases, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, re-dissolving the crude product in dichloromethane (7.8ml), placing in a 0 ℃ ice water bath, adding triethylamine (0.22ml, 1.56mmol,2.0 equiv), p-toluenesulfonyl chloride (179mg,0.94mmol,1.2 equiv), reacting for 1h while maintaining at 0 ℃ and quenching with saturated sodium bicarbonate solution, adding ethyl acetate to extract three times, combining the organic phases, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, and concentrating. The crude product was isolated using flash preparative silica gel chromatography (petroleum ether: ethyl acetate 7:1 to 5:1) to give compound 3(432mg, 98% (two-step yield)) as a white solid.
Example 4
The reaction equation is
A method of synthesizing an aza 5, 6-fused ring compound comprising the steps of:
1) compound 1(381mg,0.74mmol) was mixed with dry methyltriphenylphosphorus bromide (1.06g, 2.96mmol, 4.0 equiv.), nitrogen was replaced three times, anhydrous toluene (15ml) was added, after warming to 80 ℃, potassium tert-amylate (1.09ml, 1.83mmol, 2.5 equiv) was added rapidly, the reaction was stirred at 80 ℃ for 1.0 hour, returned to room temperature, quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, the organic phases were combined and back-washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was isolated using flash preparative silica gel chromatography (petroleum ether: ethyl acetate 3:1) to give compound 2 as a white solid (278mg, 74%).
2) Dissolving compound 2(400mg,0.78mmol) in dichloromethane (7.8ml), adding trifluoroacetic acid (0.78ml), stirring at room temperature for 1h, quenching the reaction with saturated sodium bicarbonate solution, extracting three times with ethyl acetate, combining the organic phases, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, re-dissolving the crude product in dichloromethane (7.8ml), placing in a 0 ℃ ice-water bath, adding triethylamine (0.22ml, 1.56mmol,2.0 equiv), p-toluenesulfonyl chloride (179mg,0.94mmol,1.2 equiv), reacting for 1h while maintaining at 0 ℃, quenching the reaction with saturated sodium bicarbonate solution, extracting three times with ethyl acetate, combining the organic phases, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, separating the crude product using flash preparative silica gel chromatography column (petroleum ether: ethyl acetate: 7:1 to 5:1), compound 3(432mg, 98% (two-step yield)) was obtained as a white solid.
Example 5
The reaction equation is
A method of synthesizing an aza 5, 6-fused ring compound comprising the steps of:
1) mixing compound 1(1.64g, 3.20mmol) with dried methyl triphenyl phosphonium bromide (5.20g,12.8mmol,4.0 equiv.), displacing nitrogen three times, adding anhydrous toluene (64ml), heating to 80 ℃, rapidly adding potassium tert-amyl alcohol (4.60ml, 8.0mmol, 2.5 equiv.), stirring the reaction at 80 ℃ for 3.0 hours, returning to room temperature, quenching the reaction with saturated ammonium chloride solution, adding ethyl acetate, extracting three times, combining the organic phases, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, separating the crude product with flash preparative silica gel chromatography column (petroleum ether: ethyl acetate 3:1) to obtain white solid compound 2(1.30g, 82%);
2) dissolving compound 2(400mg,0.78mmol) in dichloromethane (7.8ml), adding trifluoroacetic acid (0.78ml), stirring at room temperature for 1h, quenching the reaction with saturated sodium bicarbonate solution, extracting three times with ethyl acetate, combining the organic phases, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, re-dissolving the crude product in dichloromethane (7.8ml), placing in a 0 ℃ ice-water bath, adding triethylamine (0.22ml, 1.56mmol,2.0 equiv), p-toluenesulfonyl chloride (179mg,0.94mmol,1.2 equiv), reacting for 1h while maintaining 0 ℃, quenching the reaction with saturated sodium bicarbonate solution, extracting three times with ethyl acetate, combining the organic phases, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, separating the crude product with flash preparative silica gel chromatography column (petroleum ether: ethyl acetate ═ 7:1 to 5:1) to obtain white solid compound 3(432mg, 98% (two-step yield)).
All structures in the invention are confirmed by nuclear magnetic resonance spectrogram, and the data is as follows: compound 1:
1H NMR(500MHz,C6D6)δ＝7.97(d,J＝8.0Hz,1H),7.61(d,J＝8.2Hz,2H),7.08(t,J＝7.7Hz,1H),6.82(t,J＝7.4Hz,1H),6.62(d,J＝8.0Hz,2H),6.57(d,J＝7.3Hz,1H),3.81(d,J＝8.8Hz,1H),3.19–3.12(m,1H),2.88–2.78(m,1H),2.16(ddd,J＝16.7,12.5,4.5Hz,1H),2.07–2.01(m,1H),2.01–1.88(m,2H),1.95(s,3H),1.75(dd,J＝13.9,5.7Hz,1H),1.54(d,J＝6.7Hz,3H),1.39(s,9H),0.99(td,J＝12.8,4.8Hz,1H),0.78(d,J＝7.0Hz,3H),0.20(td,J＝12.9,4.2Hz,1H).
13C NMR(125MHz,C6D6)δ＝207.0,155.3,143.7,140.7,138.6,137.6,129.6,128.7,127.5,124.6,123.7,118.7,78.7,76.4,50.9,48.5,44.2,37.1,35.6,31.6,28.4,21.1,16.3,12.9.
compound 2 (rotamers possible, ratio about 2.5: 1):
1H NMR(400MHz,CDCl3,rotamers)δ＝7.78(d,J＝7.8Hz,1H,rotamer),7.68(d,J＝7.7Hz,3H),7.43(d,J＝8.0Hz,0H,rotamer),7.31–7.24(m,3H),7.15(dt,J＝18.9,8.9Hz,3H),7.03(q,J＝7.3,6.3Hz,1H),6.59(s,1H),5.12(s,1H),5.06(s,0H,rotamer),5.02(s,1H),4.98(s,0H,rotamer),3.97(d,J＝10.5Hz,1H),3.59(q,J＝10.1Hz,1H),3.51–3.36(m,1H,rotamer),3.31(q,J＝12.2,10.8Hz,1H),2.40(s,6H),2.35–2.13(m,5H),1.93(dd,J＝20.8,10.1Hz,3H),1.20(s,9H),1.19(s,3H),1.17(s,1H,rotamer),0.54(d,J＝5.6Hz,1H,rotamer),0.39(d,J＝4.7Hz,3H).
compound 3:
1H NMR(400MHz,CDCl3)δ＝7.85(d,J＝8.2Hz,2H),7.55(d,J＝8.1Hz,1H),7.33(d,J＝8.1Hz,2H),6.98(t,J＝7.4Hz,1H),6.76(d,J＝8.0Hz,2H),6.70–6.62(m,3H),6.47(d,J＝7.7Hz,1H),6.36(t,J＝7.5Hz,1H),5.13(s,1H),5.08(s,1H),3.94(d,J＝10.2Hz,1H),3.51(t,J＝9.3Hz,1H),2.98(q,J＝9.9Hz,1H),2.47–2.36(m,1H),2.34(s,3H),2.32–2.25(m,3H),2.23(s,3H),2.02–1.91(m,2H),1.44(d,J＝6.6Hz,3H),0.43(d,J＝5.4Hz,3H).
13C NMR(101MHz,CDCl3)δ＝148.6,144.4,141.8,136.4,134.6,133.7,129.9,129.7,128.9,127.6,127.4,126.6,126.5,123.3,119.7,109.8,73.3,52.4,43.4,42.8,40.2,38.7,27.8,21.4,21.2,17.4,16.0.
FIG. 1 is a hydrogen spectrum of Compound 1; FIG. 2 is a carbon spectrum of Compound 1;
FIG. 3 is a hydrogen spectrum of Compound 2 prepared in example 5;
FIG. 4 is a hydrogen spectrum of Compound 3 prepared in example 5; fig. 5 is a carbon spectrum of compound 3 prepared in example 5.
Claims (10)
1. A method for synthesizing an aza 5, 6-heterocyclic compound, comprising: the method comprises the following steps:
under a protective atmosphere, taking an organic solvent as a reaction medium, reacting the compound 1 under the action of methyl triphenyl phosphonium bromide and alkali, and performing subsequent treatment to obtain an aza 5, 6-heterocyclic compound which is marked as a compound 2; compound 1 has the structure
Compound 2 has the structure
2. A method of synthesizing the aza 5, 6-cyclic compound of claim 1, wherein: the base is an organic base;
the molar ratio of the alkali to the compound 1 is (2.5-4.5) to 1;
the molar ratio of the methyl triphenyl phosphonium bromide to the compound 1 is (3.5-5): 1.
3. The method of synthesizing the aza 5, 6-cyclic compound of claim 2, wherein: the alkali is potassium tert-amyl alcohol.
4. A method of synthesizing the aza 5, 6-cyclic compound of claim 1, wherein: in the preparation process of the compound 2, the organic solvent is toluene;
in the preparation process of the compound 2, the reaction temperature is 75-85 ℃; the reaction time is 1-10 h;
in the preparation process of the compound 2, the subsequent treatment refers to quenching reaction by using a saturated ammonium chloride solution, and separation and purification.
5. A process for the synthesis of an aza 5, 6-cyclic compound as defined in any of claims 1 to 4, wherein: when the aza 5, 6-ring-fused compound is compound 3, the following steps are also included:
taking an organic solvent as a reaction medium, reacting the compound 2 under an acidic condition, and carrying out subsequent treatment to obtain a reaction product; reacting the obtained product with p-toluenesulfonyl chloride to obtain an aza 5, 6-heterocyclic compound which is marked as a compound 3;
compound 3 has the structure
Compound 2 has the structure
6. The method of synthesizing the aza 5, 6-fused ring compound of claim 5, wherein:
the acid adopted in the acidic condition is trifluoroacetic acid;
in the preparation process of the compound 3, the molar ratio of the p-toluenesulfonyl chloride to the compound 2 is (1-1.5): 1.
7. the method of synthesizing the aza 5, 6-fused ring compound of claim 5, wherein:
in the preparation process of the reaction product, the volume ratio of the acid to the organic solvent adopted in the acidic condition is 1: (5-10);
in the preparation process of the reaction product, the reaction temperature is room temperature, and the reaction time is 1-3 h;
in the preparation of the compound 3, the reaction is carried out in a system of an organic solvent and a basic compound,
the molar ratio of the basic compound to the compound 2 is (1-3): 1;
in the preparation process of the compound 3, the reaction temperature is 0-4 ℃; the reaction time is 1-3 h.
8. The method of synthesizing the aza 5, 6-cyclic compound of claim 7, wherein: in the preparation process of the compound 3, the basic compound is triethylamine; the organic solvent is trichloromethane.
9. The method of synthesizing the aza 5, 6-fused ring compound of claim 5, wherein: in the preparation process of the reaction product, the organic solvent is dichloromethane; in the preparation process of the reaction product, the concentration of the compound 2 in an organic solvent is 0.05-0.15 mmol/mL;
in the preparation process of the reaction product, the subsequent treatment refers to quenching the reaction by using a saturated sodium bicarbonate solution, and separating and purifying.
10. The method of synthesizing the aza 5, 6-fused ring compound of claim 5, wherein: in the preparation process of the compound 3, after the reaction is finished, a saturated sodium bicarbonate solution is used for quenching the reaction, and separation and purification are carried out; the separation and purification refers to ethyl acetate extraction, backwashing of saturated sodium chloride solution, drying of an organic phase by anhydrous sodium sulfate, filtration, concentration and column chromatography.
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| CN107353189A (en) * | 2017-07-06 | 2017-11-17 | 荆门医药工业技术研究院 | Prepare 3,5 dichloro a（Trifluoromethyl）The method of styrene |
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