CN114276359B - Preparation method of 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative - Google Patents
Preparation method of 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative Download PDFInfo
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Abstract
The invention discloses a preparation method of a 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative, which comprises the following steps: the 3-alkylbenzofuran, formaldehyde and primary amine compound or salt thereof undergo a three-component Mannich reaction in a solvent. After the reaction is finished, the 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative is obtained through post-treatment; the preparation method takes the benzofuran to participate in two continuous Mannich reactions, realizes the rapid parallel connection of the benzofuran and piperidine rings under mild conditions, has high efficiency, simplicity and rapidness, and higher yield, and has profound significance for organic synthesis and pharmaceutical chemistry.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative.
Background
Benzofuran is a dominant backbone in natural products and pharmaceutical chemistry, and benzofuran-containing compounds are often important compounds with biological or pharmaceutical value. The Mannich reaction is a classical multicomponent reaction in organic synthesis, the reaction successfully realizes the efficient synthesis of alkylamine compounds by aldimine and alpha-methylene carbonyl compounds, and is an extremely important reaction in organic synthesis, and the classical Mannich reaction formula is shown as follows. Mannich reactions have evolved for over a hundred years, as have many new Mannich and asymmetric Mannich reactions. The substrates typically required to participate in Mannich reactions have activated C-H bonds such as aliphatic or aromatic aldehydes or ketones, carboxylic acid derivatives, β -dicarbonyl compounds, nitroalkanes, electron-rich aromatic compounds, terminal alkynes, furans, pyrroles, thiophenes and other heterocyclic compounds. The method for synthesizing the 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative by twice Mannich reaction on the alkyl of the 2 nd and 3 rd positions of benzofuran by taking 3-methylbenzofuran as a Mannich reaction raw material has not been reported. The Mannich reaction involving the alkyl group in position 3 of the two Mannich reactions is not involved in activating the C-H bond, and has never been reported before.
Disclosure of Invention
The invention provides a preparation method of a 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative, which can efficiently and rapidly synthesize the 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative by a one-pot method through 3-alkyl benzofuran, formaldehyde and primary amine compounds or salts thereof.
A process for the preparation of 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivatives comprising the steps of: the 3-alkylbenzofuran, formaldehyde and primary amine compound or salt thereof undergo a three-component Mannich reaction in a solvent. After the reaction is finished, the 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative is obtained through post-treatment.
The structure of the 3-alkyl benzofuran compound is shown as a formula (II):
the formaldehyde structure is shown as a formula (III):
the primary amine compound (comprising various natural unnatural chiral amino acids) has a structure shown in a formula (IV) (comprising primary amine and hydrochloride, sulfate, hydrobromide and other forms thereof):
R 3 -NH 2 (IV)；
the structure of the 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative is shown as a formula (I):
the reaction formula of the invention is as follows:
in the formulae (I) to (IV), R 1 H, C of a shape of H, C 1 ～C 6 Alkyl, C 1 ～C 6 Hydrocarbyloxy, C 1 ～C 6 Alkylthio, C 1 ～C 6 Hydrocarbon amine groups, hydroxyl groups, halogen groups, ester groups, amide groups, borate groups, and various substituted benzenesOne or more of the rings, R 2 Is hydrogen, various substituted phenyl, ester, amide, halogen or substituted or unsubstituted alkyl, the substituents on the alkyl being selected from halogen, hydroxy C 1 ～C 4 Alkoxy, ester, disubstituted amino, amide or various substituted phenyl groups;
R 3 is a substituted or unsubstituted alkyl group, the substituents on the alkyl group being selected from C 1 ～C 4 Alkoxycarbonyl, phenyl, alkynyl or hydroxyphenyl groups, preferably substituted or unsubstituted methyl, ethyl, butyl or cyclopropyl groups, the substituents on said methyl, ethyl, butyl or cyclopropyl groups being selected from methoxycarbonyl, alkynyl, alkenyl, halogen, ester, amide, alkyl or various substituted phenyl groups.
Among the above "various substituted phenyl groups", the substituent on the phenyl group may be an alkyl group, an alkoxy group, an alkoxycarbonyl group, an alkynyl group, an alkenyl group, a halogen group or an amide group, and more preferably a methyl group, an ethyl group, a methoxy group, a methoxycarbonyl group, an ethynyl group, an vinyl group, an F, cl, br, a methyl ester group or a carboxamide group.
The reaction condition is mild and the yield is excellent. The 3-alkyl benzofuran and Mannich react well, and the 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative is quickly and efficiently synthesized.
The 3-alkylbenzofurans can be prepared by existing synthetic methods, see in particular document (Tetrahedron Letters,2008,49,6579-6584).
Preferably, the molar ratio of the 3-alkyl benzofuran to the formaldehyde to the amine compound is 1:4-8:2-4, and the excessive amounts of the two latter components ensure that the reaction is more thorough.
Preferably, the solvent is one or a mixed solvent of acetonitrile, acetic acid, ethanol, methanol, acetone, dioxane, tetrahydrofuran, water, N-dimethylformamide and N, N-dimethylacetamide.
Preferably, the reaction temperature is 60-90 ℃, and too high a temperature can lead to product decomposition, and too low a temperature can lead to too low a reaction conversion rate.
In the present invention, the reaction time can be monitored by Thin Layer Chromatography (TLC), and the reaction is complete after 0.5 to 3 hours.
In the invention, the salt of the primary amine compound is hydrochloride, sulfate or hydrobromide.
In the present invention, the 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative is further preferably one of the following compounds:
the 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivatives synthesized by the invention are all compounds with novel structures, which have not been reported before. The invention provides a synthesis method for rapidly combining benzofuran and piperidine, and has great application potential in the fields of organic synthesis and pharmaceutical chemistry.
Drawings
Representative nuclear magnetic patterns are shown below:
FIG. 1 shows the product obtained in example 1 1 H NMR spectrum.
FIG. 2 shows the product obtained in example 1 13 C NMR spectrum.
FIG. 3 shows the product obtained in example 12 1 H NMR spectrum.
FIG. 4 shows the product obtained in example 12 13 C NMR spectrum.
Detailed Description
The reactant 3-alkylbenzofuran compounds used in the invention can be prepared by the following method:
example 1: synthetic compound (IIa)
Into a 100mL single-port flask, 1.66g (10 mmol) of paeonol and 2.76g (20 mmol) of potassium carbonate were weighed, 50mL of acetone was added for dissolution, then 2.5g (15 mmol) of ethyl bromoacetate was injected, the reaction was refluxed for 4 hours, TLC detection of complete reaction conversion was performed, and the solvent was dried by spinning after filtration. The crude product was dissolved in 10mL MeOH, water (10 mL) containing 1.6g NaOH was added and reacted at room temperature for 2 hours. The MeOH was dried under reduced pressure, acidified to pH 2 with 6M hydrochloric acid and filtered to give a white solid. The crude product and 5.8g of sodium acetate were added to a single vial, 10mL of acetic anhydride was added and reacted overnight at 120 ℃. After completion of the reaction, TLC was cooled to room temperature, stirred with water for 1 hour, extracted three times with ethyl acetate, and the organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. Column chromatography separation (petroleum ether as eluent: ethyl acetate=20:1) after adding silica gel and stirring gave 712mg of the product in 44% yield.
Example 2: synthesis of Compound (Ia) Using acetic acid as solvent
In a dry reaction tube, IIa (0.2 mmol) and glycine methyl ester hydrochloride (0.4 mmol) were weighed, 1mL of acetic acid was added, aqueous formaldehyde solution (0.8 mmol) was added, and the reaction was completed by TLC at 60℃for 3 hours. Adding saturated aqueous solution of sodium bicarbonate for neutralization, extracting with ethyl acetate for three times, combining organic phases, washing with saturated common salt for one time, and drying the organic phases with anhydrous sodium sulfate. Column chromatography separation (petroleum ether as eluent: ethyl acetate=4:1) after adding silica gel and stirring gave 41mg of the product in 74% yield. The reaction formula is as follows:
the physical properties and profile data of the product are as follows: pale yellow solid with melting point of 69.2-70.4 ℃; 1 H NMR(500MHz,CDCl 3 )δ7.28(d,J＝8.5Hz,1H),6.97(d,J＝2.5Hz,1H),6.83(dd,J 1 ＝8.5Hz,J 2 ＝2.5Hz,1H),3.84(m,5H),3.75(s,3H),3.51(s,2H),2.98(t,J＝6.0Hz,2H),2.73(t,J＝6.0Hz,2H). 13 C NMR(100MHz,CDCl 3 )δ170.9,157.4,155.6,149.5,121.5,118.6,110.9,110.8,96.4,57.8,55.7,51.8,50.0,49.6,20.6.ESI-MS:m/z＝276.1239(M+H) + 。
example 3: synthesis of Compound (Ia) Using acetonitrile as solvent
In a dry reaction tube, IIa (0.2 mmol) and glycine methyl ester hydrochloride (0.4 mmol) were weighed, 1mL of acetonitrile was added, aqueous formaldehyde (0.8 mmol) was added, and the reaction was allowed to proceed overnight at 60℃and TLC was used to detect complete reaction conversion. Adding saturated aqueous solution of sodium bicarbonate for neutralization, extracting with ethyl acetate for three times, combining organic phases, washing with saturated common salt for one time, and drying the organic phases with anhydrous sodium sulfate. Column chromatography separation (petroleum ether as eluent: ethyl acetate=4:1) after adding silica gel and stirring gave 39mg of the product with a yield of 70%. The reaction formula is as follows:
example 4: synthetic compound (Ib)
In a dry reaction tube, IIa (0.2 mmol) and aspartic acid methyl ester hydrochloride (0.4 mmol) were weighed, 1mL of acetic acid was added, aqueous formaldehyde solution (0.8 mmol) was added, and the reaction was allowed to react at 60℃for 3 hours, and TLC detected completion of the reaction. Adding saturated aqueous solution of sodium bicarbonate for neutralization, extracting with ethyl acetate for three times, combining organic phases, washing with saturated common salt for one time, and drying the organic phases with anhydrous sodium sulfate. Column chromatography separation (petroleum ether as eluent: ethyl acetate=4:1) after adding silica gel and stirring gave 37mg of the product in 53% yield. The reaction formula is as follows:
the physical properties and profile data of the product are as follows: pale yellow solid with a melting point of 88.3-92.6 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.26(d,J＝8.4Hz,1H),6.97(d,J＝2.4Hz,1H),6.82(dd,J 1 ＝8.4Hz,J 2 ＝2.4Hz,1H),4.07–4.01(m,1H),3.99–3.93(m,1H),3.83(s,3H),3.78–3.70(m,4H),3.68(s,3H),3.07–2.94(m,2H),2.86–2.79(m,1H),2.79–2.71(m,1H),2.70–2.60(m,2H). 13 C NMR(150MHz,CDCl 3 )δ171.6,171.3,157.3,155.6,149.9,121.5,118.6,111.1,110.8,96.4,63.1,55.7,51.9,51.7,47.2,47.0,34.7,21.7.ESI-MS:m/z＝348.1448(M+H) + 。
example 5: synthetic compound (ic)
In a dry reaction tube, IIa (0.2 mmol) and tyrosine methyl ester hydrochloride (0.4 mmol) were weighed, 1mL of acetic acid was added, aqueous formaldehyde solution (0.8 mmol) was added, and the reaction was allowed to proceed at 60℃for 3 hours, and TLC was used to detect completion of the reaction. Adding saturated aqueous solution of sodium bicarbonate for neutralization, extracting with ethyl acetate for three times, combining organic phases, washing with saturated common salt for one time, and drying the organic phases with anhydrous sodium sulfate. Column chromatography separation (petroleum ether as eluent: ethyl acetate=2:1) after adding silica gel and stirring gave 34mg of the product in 45% yield. The reaction formula is as follows:
the physical properties and profile data of the product are as follows: pale yellow solid with a melting point of 121.2-123.9 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.27(d,J＝8.4Hz,1H),7.05(d,J＝7.8Hz,2H),7.00–6.94(d,J＝1.8Hz 1H),6.87–6.81(dd,J 1 ＝8.4Hz,J 2 ＝1.8 1H),6.70(d,J＝7.8Hz,2H),5.67(s,1H),3.96–3.86(m,2H),3.84(s,3H),3.71–3.65(m,1H),3.62(s,3H),3.16–3.04(m,2H),3.03–2.96(m,1H),2.95–2.87(m,1H),2.75–2.61(m,2H). 13 C NMR(150MHz,CDCl 3 )δ172.2,157.3,155.7,154.5,149.9,130.3,129.5,121.6,118.6,115.4,111.2,110.9,96.4,69.2,55.8,51.4,47.5,46.8,35.2,21.5.ESI-MS:m/z＝382.1657(M+H) + 。
example 6: synthetic compound (Id)
In a dry reaction tube IIa (0.2 mmol) and n-butylamine hydrochloride (0.8 mmol) were weighed, 1mL of acetic acid was added, paraformaldehyde (1.6 mmol) was added, and reaction was carried out at 90℃for 30 minutes, and TLC detected complete conversion of the reaction. Adding saturated aqueous solution of sodium bicarbonate for neutralization, extracting with ethyl acetate for three times, combining organic phases, washing with saturated common salt for one time, and drying the organic phases with anhydrous sodium sulfate. Column chromatography separation (petroleum ether as eluent: ethyl acetate=10:1) after adding silica gel and stirring gave 37mg of the product in 72% yield. The reaction formula is as follows:
the physical properties and profile data of the product are as follows: orange gum; 1 HNMR(600MHz,CDCl 3 )δ7.27(d,J＝8.4Hz,1H),6.97(d,J＝2.0Hz,1H),6.83(dd,J 1 ＝8.4Hz,J 2 ＝2.4Hz,1H),3.83(s,3H),3.63(t,J＝2.4Hz,2H),2.82(t,J＝6.0Hz,2H),2.75–2.65(m,2H),2.65–2.52(m,2H),1.68–1.44(m,2H),1.49–1.33(m,2H),0.95(t,J＝7.2Hz,3H). 13 C NMR(125MHz,CDCl 3 )δ157.2,155.6,150.4,121.7,118.6,111.1,110.7,96.4,57.5,55.8,50.6,50.3,29.6,20.9,20.7,14.1.ESI-MS:m/z＝260.1656(M+H) + 。
example 7: synthetic compound (ie)
In a dry reaction tube IIa (0.2 mmol) and propargylamine hydrochloride (0.8 mmol) were weighed into, 1mL of acetic acid was added, paraformaldehyde (1.6 mmol) was added and reacted at 90℃for 30 minutes, and TLC detected the completion of the reaction. Adding saturated aqueous solution of sodium bicarbonate for neutralization, extracting with ethyl acetate for three times, combining organic phases, washing with saturated common salt for one time, and drying the organic phases with anhydrous sodium sulfate. Column chromatography separation (petroleum ether as eluent: ethyl acetate=10:1) after adding silica gel and stirring gave 35mg of the product with a yield of 73%. The reaction formula is as follows:
the physical properties and profile data of the product are as follows: white solid with melting point of 90.4-93.1 ℃; 1 HNMR(400MHz,CDCl 3 )δ7.32(d,J＝8.4Hz,1H),7.02(d,J＝2.4Hz,1H),6.88(dd,J 1 ＝8.4Hz,J 2 ＝2.4Hz,1H),3.88(s,3H),3.82(t,J＝2.0Hz,2H),3.62(d,J＝2.4Hz,2H),2.96(t,J＝5.6Hz,2H),2.84–2.73(m,2H),2.35(t,J＝2.4Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ157.3,155.7,149.9,121.5,118.6,110.8,110.8,96.4,78.5,73.7,55.8,49.4,48.7,46.3,21.0.ESI-MS:m/z＝242.1184(M+H) + 。
example 8: synthetic compound (if)
In a dry reaction tube IIa (0.2 mmol) and cyclopropylamine hydrochloride (0.8 mmol) were weighed into a dry reaction tube, 1mL of acetic acid was added, paraformaldehyde (1.6 mmol) was added, and reaction was carried out at 90℃for 30 minutes, and TLC detected complete conversion of the reaction. Adding saturated aqueous solution of sodium bicarbonate for neutralization, extracting with ethyl acetate for three times, combining organic phases, washing with saturated common salt for one time, and drying the organic phases with anhydrous sodium sulfate. Column chromatography separation (petroleum ether as eluent: ethyl acetate=10:1) after adding silica gel and stirring gave 36mg of the product in 74% yield. The reaction formula is as follows:
the physical properties and profile data of the product are as follows: orange gum; 1 H NMR(600MHz,CDCl 3 )δ7.27(d,J＝8.4Hz,1H),6.98(d,J＝1.8Hz,1H),6.83(dd,J 1 ＝8.4Hz,J 2 ＝2.0Hz,1H),3.83(s,3H),3.81(t,J＝1.8Hz,2H),3.01(t,J＝6.0Hz,2H),2.76–2.66(m,2H),2.01–1.95(m,1H),0.56(d,J＝5.4Hz,4H). 13 CNMR(150MHz,CDCl 3 )δ157.3,155.6,150.2,121.7,118.6,111.1,110.7,96.4,55.8,50.4,37.4,20.7,6.5.ESI-MS:m/z＝244.1240(M+H) + 。
example 9: synthetic compound (Ig)
IIb (0.2 mmol) and glycine methyl ester hydrochloride (0.4 mmol) were weighed into a dry reaction tube, 1mL of acetic acid was added, aqueous formaldehyde solution (0.8 mmol) was added, and the reaction was allowed to proceed at 60℃for 3 hours, and TLC was used to detect that the reaction was complete. Adding saturated aqueous solution of sodium bicarbonate for neutralization, extracting with ethyl acetate for three times, combining organic phases, washing with saturated common salt for one time, and drying the organic phases with anhydrous sodium sulfate. Column chromatography separation (petroleum ether as eluent: ethyl acetate=4:1) after adding silica gel and stirring gave 69mg of the product in 81% yield. The reaction formula is as follows:
the physical properties and profile data of the product are as follows: orange gum; 1 H NMR(500MHz,CDCl 3 )δ7.59(s,1H),7.52–7.46(m,2H),7.42–7.35(m,2H),7.34–7.29(m,1H),7.03(s,1H),5.15(s,2H),3.82(t,J＝2.0Hz,2H),3.75(s,3H),3.50(s,2H),2.97(t,J＝5.5Hz,2H),2.77–2.65(m,2H). 13 C NMR(125MHz,CDCl 3 )δ170.8,154.4,151.9,150.7,136.5,128.6,127.9,127.1,122.9,122.3,110.6,107.5,98.1,71.4,57.8,51.9,49.9,49.5,20.6.ESI-MS:m/z＝430.0653(M+H) + 。
example 10: synthetic compound (ih)
IIc (0.2 mmol) and glycine methyl ester hydrochloride (0.4 mmol) were weighed into a dry reaction tube, 1mL of acetic acid was added, aqueous formaldehyde solution (0.8 mmol) was added, and the reaction was allowed to proceed at 60℃for 3 hours, and TLC was used to detect that the reaction was complete. Adding saturated aqueous solution of sodium bicarbonate for neutralization, extracting with ethyl acetate for three times, combining organic phases, washing with saturated common salt for one time, and drying the organic phases with anhydrous sodium sulfate. Column chromatography separation (petroleum ether as eluent: ethyl acetate=2:1) after adding silica gel and stirring gave 26mg of the product with a yield of 50%. The reaction formula is as follows:
the physical properties and profile data of the product are as follows: orange solid, melting point 155.4-157.6 ℃; 1 H NMR(600MHz,CDCl 3 )δ7.16(d,J＝8.4Hz,1H),6.86(d,J＝1.8Hz,1H),6.71(dd,J 1 ＝8.4Hz,J 2 ＝2.4Hz,1H),3.82(s,2H),3.77(s,3H),3.52(s,2H),2.98(t,J＝6.0Hz,2H),2.79–2.62(m,2H). 13 C NMR(150MHz,CDCl 3 )δ170.9,155.4,153.1,149.2,121.5,118.6,111.4,110.9,98.7,57.9,51.9,50.2,49.7,20.6.ESI-MS:m/z＝262.1081(M+H) + 。
example 11: synthetic compound (ii)
IId (0.2 mmol) and glycine methyl ester hydrochloride (0.4 mmol) were weighed into a dry reaction tube, 1mL of acetic acid was added, aqueous formaldehyde solution (0.8 mmol) was added, and the reaction was allowed to proceed at 60℃for 3 hours, and TLC was used to detect that the reaction was complete. Adding saturated aqueous solution of sodium bicarbonate for neutralization, extracting with ethyl acetate for three times, combining organic phases, washing with saturated common salt for one time, and drying the organic phases with anhydrous sodium sulfate. Column chromatography separation (petroleum ether as eluent: ethyl acetate=5:1) after adding silica gel and stirring gave 38mg of the product in 65% yield. The reaction formula is as follows:
the physical properties and profile data of the product are as follows: orange gum; 1 HNMR(400MHz,CDCl 3 )δ7.36(d,J＝1.2Hz,1H),7.33(d,J＝8.4Hz,1H),7.17(dd,J 1 ＝8.4Hz,J 2 ＝1.2Hz,1H),3.86(t,J＝1.6Hz,2H),3.76(s,3H),3.53(s,2H),3.00(t,J＝5.6Hz,2H),2.80–2.71(m,2H),2.52(s,3H). 13 C NMR(100MHz,CDCl 3 )δ170.9,155.2,150.5,133.3,126.0,122.8,118.7,111.1,110.3,57.9,51.9,49.9,49.6,20.6,17.3.ESI-MS:m/z＝292.1012(M+H) + 。
example 12: synthetic compound (ij)
IIe (0.2 mmol) and glycine methyl ester hydrochloride (0.4 mmol) were weighed into a dry reaction tube, 1mL of acetic acid was added, aqueous formaldehyde (0.8 mmol) was added, and the reaction was allowed to proceed at 60℃for 3 hours, and TLC was used to detect complete reaction conversion. Adding saturated aqueous solution of sodium bicarbonate for neutralization, extracting with ethyl acetate for three times, combining organic phases, washing with saturated common salt for one time, and drying the organic phases with anhydrous sodium sulfate. Column chromatography separation (petroleum ether as eluent: ethyl acetate=4:1) after adding silica gel and stirring gives 54mg of the product with 93% yield. The reaction formula is as follows:
the physical properties and profile data of the product are as follows: pale yellow gum; 1 HNMR(600MHz,CDCl 3 )δ7.36(d,J＝8.4Hz,1H),6.96(d,J＝1.8Hz,1H),6.82(dd,J 1 ＝8.4Hz,J 2 ＝2.4Hz,1H),3.85–3.76(m,5H),3.74(s,3H),3.49(s,2H),3.17–3.06(m,1H),3.08–2.96(m,1H),2.58–2.46(m,1H),1.32(d,J＝6.6Hz,3H). 13 C NMR(150MHz,CDCl 3 )δ170.9,157.2,155.8,149.2,121.0,119.5,115.6,110.8,96.5,58.3,57.9,55.7,51.7,49.7,27.7,17.8.ESI-MS:m/z＝290.1398(M+H) + 。
Claims (8)
1. a process for the preparation of a 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative, characterized by the steps of: 3-alkyl benzofuran compound, formaldehyde and primary amine compound or salt thereof are subjected to three-component Mannich reaction in a solvent, and after the reaction is finished, the 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative is obtained through post-treatment;
the structure of the 3-alkyl benzofuran compound is shown as a formula (II):
the formaldehyde structure is shown as a formula (III):
the structure of the primary amine compound is shown as a formula (IV):
R 3 -NH 2 (IV)；
the structure of the 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative is shown as a formula (I):
in the formulae (I) to (IV), R 1 Is H, methoxy, benzyloxy, C 1 ～C 6 One or more of alkylthio, hydroxy, halogen; r is R 2 Is hydrogen or methyl;
R 3 is that
2. The 1,2,3, 4-tetrahydrobenzo [4,5] according to claim 1]Furan [2,3-C]A process for producing a pyridine derivative, characterized in that R is 1 Is one or more of hydrogen, methoxy, hydroxy, methylthio, benzyloxy and halogen.
3. The process for producing 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative according to claim 1, wherein said primary amine compound has a chiral center and is chirally altered during the reaction.
4. The process for the preparation of 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivatives according to claim 1, characterized in that the molar ratio of 3-alkylbenzofuran, formaldehyde and primary amine compound is 1:4-8:2-4.
5. The process for preparing 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative according to claim 1, wherein the solvent is one or a mixed solvent of acetonitrile, acetic acid, ethanol, methanol, acetone, dioxane, tetrahydrofuran, water, N-dimethylformamide and N, N-dimethylacetamide.
6. The process for producing a 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative according to claim 1, wherein the reaction temperature is 60 to 90 ℃.
7. The process for the preparation of 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivatives according to claim 1, wherein the salt of a primary amine compound is a hydrochloride, a sulfate or a hydrobromide.
8. The method for producing 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative according to claim 1, wherein the 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative is one of the following compounds:
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| US4841039A (en) * | 1986-05-01 | 1989-06-20 | Emory University | 2',3'-dideoxy-5-substituted uridines and related compounds as antiviral agents |
| US4916122A (en) * | 1987-01-28 | 1990-04-10 | University Of Georgia Research Foundation, Inc. | 3'-Azido-2',3'-dideoxyuridine anti-retroviral composition |
| US5084445A (en) * | 1986-05-01 | 1992-01-28 | University Of Georgia Research Foundation, Inc. | 3'-azido-2',3'-dideoxy-5-methylcytidine |
| US4681933A (en) * | 1986-05-01 | 1987-07-21 | University Of Georgia Research Foundation, Inc. | 2',3'-dideoxy-5-substituted uridines and related compounds as antiviral agents |
| UA69420C2 (en) * | 1998-10-06 | 2004-09-15 | Янссен Фармацевтика Н.В. | TRICYCLIC D3-PIPERIDINES AS a<sub>2-ANTAGONISTS |
| WO2009003003A2 (en) * | 2007-06-25 | 2008-12-31 | Neurogen Corporation | Piperazinyl oxoalkyl tetrahydro-beta-carbolines and related analogues |
| CA2785058A1 (en) * | 2009-12-22 | 2011-07-21 | Cephalon, Inc. | Tricyclic derivatives and their pharmaceutical use and compositions |
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