CN114276359A - 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
本发明公开了一种1,2,3,4‑四氢苯并[4,5]呋喃[2,3‑C]吡啶衍生物的制备方法，其包括如下步骤：3‑烷基苯并呋喃，甲醛和伯胺类化合物或其盐在溶剂中发生三组分Mannich反应。反应完成后，经后处理得到所述的1,2,3,4‑四氢苯并[4,5]呋喃[2,3‑C]吡啶衍生物；该制备方法以苯并呋喃参与连续的两次Mannich反应，在温和的条件下实现了苯并呋喃和哌啶环的快速并联，反应高效简洁快速，收率较高，对于有机合成和药物化学具有深远意义。The invention discloses a preparation method of 1,2,3,4-tetrahydrobenzo[4,5]furan[2,3-C]pyridine derivative, which comprises the following steps: 3-alkylbenzofuran , a three-component Mannich reaction occurs between formaldehyde and primary amine compounds or their salts in a solvent. After the reaction is completed, the 1,2,3,4-tetrahydrobenzo[4,5]furan[2,3-C]pyridine derivative is obtained through post-processing; the preparation method uses benzofuran to participate in continuous The two Mannich reactions realize the rapid parallel connection of benzofuran and piperidine rings under mild conditions. The reaction is efficient, concise and fast, and the yield is high, which has far-reaching significance for organic synthesis and medicinal 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 predominant skeleton in natural products and pharmaceutical chemistry, and benzofuran-containing compounds are often important compounds with biological activity or medicinal value. The Mannich reaction is a classical multi-component reaction in organic synthesis, successfully realizes the high-efficiency synthesis of alkylamine compounds from aldimine and alpha-methylene carbonyl compounds, is an extremely important reaction in organic synthesis, and has a classical Mannich reaction formula shown as follows. The Mannich reaction has been under development for over a hundred years, and many new Mannich reactions and asymmetric Mannich reactions have also emerged. Substrates that participate in Mannich reactions typically require activated C-H bonds, such as aliphatic or aromatic aldehydes or ketones, carboxylic acid derivatives, β -dicarbonyl compounds, nitroalkanes, electron-rich aromatics, terminal alkynes, heterocyclic compounds such as furans, pyrroles, thiophenes, and the like. However, no report has been made on a method for synthesizing a 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative by using 3-methylbenzofuran as a Mannich reaction raw material and performing two Mannich reactions on alkyl groups at the 2-position and the 3-position of benzofuran. The Mannich reaction in which the alkyl group at position 3 participates in two Mannich reactions is not involved in an activated C-H bond, and has not 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 be used for efficiently and quickly synthesizing the 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative from 3-alkylbenzofuran, formaldehyde and primary amine compounds or salts thereof by a one-pot method.
A process for the preparation of 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivatives comprising the steps of: the three-component Mannich reaction of 3-alkyl benzofuran, formaldehyde and primary amine compound or salt thereof 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 the formula (II):
the structure of the formaldehyde is shown as a formula (III):
the primary amine compound (including various natural non-natural chiral amino acids) has a structure shown in a formula (IV) (including primary amine and hydrochloride, sulfate, hydrobromide and the like forms):
R3-NH2 (IV)；
the structure of the 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative is shown as the formula (I):
the reaction formula of the invention is as follows:
in the formulae (I) to (IV), R1Is H, C1～C6Alkyl radical, C1～C6Hydrocarbyloxy, C1～C6Alkylthio radical, C1～C6One or more of hydrocarbon amine, hydroxyl, halogen, ester, amide, borate and various substituted benzene rings, R2Is hydrogen, various substituted phenyl, ester group, amide, halogen or substituted or unsubstituted alkyl, and the substituent on the alkyl is selected from halogen and hydroxyl C1～C4Alkoxy, ester, disubstituted amino, amide or variously substituted phenyl;
R3is a substituted or unsubstituted alkyl group, and the substituent on the alkyl group is selected from C1～C4The alkoxy carbonyl, the phenyl, the alkynyl or the hydroxyphenyl are preferably substituted or unsubstituted methyl, ethyl, butyl or cyclopropyl, and the substituent on the methyl, ethyl, butyl or cyclopropyl is selected from methoxycarbonyl, alkynyl, alkenyl, halogen, ester group, amido, alkyl or various substituted phenyls.
In the "variously substituted phenyl group", 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, a vinyl group, F, Cl, Br, a carbomethoxy group, a carboxamide group, or the like.
The reaction condition is mild, and the yield is excellent. The 3-alkyl benzofuran and Mannich reaction are well combined, and the 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative is quickly and efficiently synthesized.
The 3-alkylbenzofuran can be prepared by the existing synthetic method, and can be specifically referred to the literature (Tetrahedron Letters,2008,49, 6579-.
Preferably, the molar ratio of the 3-alkyl benzofuran to the formaldehyde to the amine compound is 1: 4-8: 2-4, and the latter two components are excessive to ensure that the reaction is relatively 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 cause product decomposition, and too low a temperature can cause reaction conversion rate to be too low.
In the present invention, the reaction time can be monitored by Thin Layer Chromatography (TLC), and the reaction is complete after 0.5-3 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 more preferably one of the following compounds:
the 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivatives synthesized by the method are all compounds with novel structures, and are not reported before. The invention provides a synthesis method for rapidly combining benzofuran and piperidine, and the synthesis method has great application potential in the fields of organic synthesis and pharmaceutical chemistry.
Drawings
Representative nuclear magnetic spectra are shown below:
FIG. 1 shows the product obtained in example 1Of an object1H NMR spectrum.
FIG. 2 shows the product obtained in example 113C NMR spectrum.
FIG. 3 shows the product obtained in example 121H NMR spectrum.
FIG. 4 shows the product obtained in example 1213C NMR spectrum.
Detailed Description
The 3-alkyl benzofuran compound used as the reactant in the invention can be prepared by adopting the following method:
example 1: synthesis of Compound (IIa)
1.66g (10mmol) of paeonol and 2.76g (20 mmol) of potassium carbonate are weighed into a 100mL single-neck flask, dissolved by adding 50mL of acetone, then 2.5g (15mmol) of ethyl bromoacetate is injected, the reaction is refluxed for 4 hours, the reaction is completely converted by TLC detection, and the solvent is dried by rotation after filtration. The crude product was dissolved in 10mL of MeOH, and water (10mL) containing 1.6g of NaOH was added to react at room temperature for 2 hours. MeOH was spin dried under reduced pressure, acidified with 6M hydrochloric acid to pH about 2, and filtered to give a white solid. The crude product and 5.8g of sodium acetate were added to a single-necked flask, 10mL of acetic anhydride was added, and the reaction was allowed to proceed overnight at 120 ℃. TLC detection reaction conversion is completed, then cooling to room temperature, adding water and stirring for 1 hour, then extracting with ethyl acetate for three times, combining organic phases, washing with saturated salt water once, and drying the organic phases with anhydrous sodium sulfate. Adding silica gel, mixing, column chromatography separation (eluent is petroleum ether: ethyl acetate: 20: 1) to obtain 712 mg, yield 44%.
Example 2: synthesis of Compound (Ia) with acetic acid as solvent
IIa (0.2mmol) and glycine methyl ester hydrochloride (0.4 mmol) were weighed into a dry reaction tube, 1mL of acetic acid was added, an aqueous formaldehyde solution (0.8mmol) was added, the reaction was allowed to react at 60 ℃ for 3 hours, and the reaction conversion was checked by TLC to be complete. Adding saturated aqueous solution of sodium bicarbonate to neutralize, extracting with ethyl acetate for three times, combining organic phases, washing with saturated saline once, and drying the organic phases with anhydrous sodium sulfate. Adding silica gel, mixing, column chromatography separation (eluent is petroleum ether: ethyl acetate: 4: 1) to obtain 41mg of product with yield of 74%. The reaction formula is as follows:
the physical properties and spectral data of the product are as follows: a pale yellow solid, melting point 69.2-70.4 ℃;1H NMR(500MHz,CDCl3)δ7.28(d,J＝8.5Hz,1H),6.97(d,J＝2.5Hz, 1H),6.83(dd,J1＝8.5Hz,J2＝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).13C NMR(100MHz, CDCl3)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) with acetonitrile as solvent
IIa (0.2mmol) and glycine methyl ester hydrochloride (0.4 mmol) were weighed into a dry reaction tube, 1mL acetonitrile was added, aqueous formaldehyde (0.8mmol) was added, the reaction was allowed to proceed overnight at 60 ℃ and the reaction conversion was complete by TLC. Adding saturated aqueous solution of sodium bicarbonate to neutralize, extracting with ethyl acetate for three times, combining organic phases, washing with saturated saline once, and drying the organic phases with anhydrous sodium sulfate. Adding silica gel, mixing, column chromatography separation (eluent is petroleum ether: ethyl acetate 4: 1) to obtain 39 mg of product with 70% yield. The reaction formula is as follows:
example 4: synthesis of Compound (Ib)
IIa (0.2mmol) and methyl aspartate hydrochloride (0.4 mmol) were weighed into a dry reaction tube, 1mL of acetic acid was added, an aqueous formaldehyde solution (0.8mmol) was added, the reaction was allowed to react at 60 ℃ for 3 hours, and the reaction conversion was checked by TLC to be complete. Adding saturated aqueous solution of sodium bicarbonate to neutralize, extracting with ethyl acetate for three times, combining organic phases, washing with saturated saline once, and drying the organic phases with anhydrous sodium sulfate. Adding silica gel, mixing, column chromatography separation (eluent is petroleum ether: ethyl acetate 4: 1) to obtain 37mg of product with 53% yield. The reaction formula is as follows:
the physical properties and spectral data of the product are as follows: light yellow solid, melting point 88.3-92.6 deg.C;1H NMR(600MHz,CDCl3)δ7.26(d,J＝8.4Hz,1H),6.97(d,J＝2.4Hz, 1H),6.82(dd,J1＝8.4Hz,J2＝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).13C NMR(150 MHz,CDCl3)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: synthesis of Compound (ic)
IIa (0.2mmol) and tyrosine methyl ester hydrochloride (0.4 mmol) were weighed into a dry reaction tube, 1mL of acetic acid was added, an aqueous formaldehyde solution (0.8mmol) was added, the reaction was allowed to react at 60 ℃ for 3 hours, and the reaction conversion was checked by TLC to be complete. Adding saturated aqueous solution of sodium bicarbonate to neutralize, extracting with ethyl acetate for three times, combining organic phases, washing with saturated saline once, and drying the organic phases with anhydrous sodium sulfate. Adding silica gel, mixing, column chromatography separation (eluent is petroleum ether: ethyl acetate: 2: 1) to obtain 34mg of product with 45% yield. The reaction formula is as follows:
the physical properties and spectral data of the product are as follows: a light yellow solid, melting point 121.2-123.9 ℃;1H NMR(600MHz,CDCl3)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,J1＝8.4Hz,J2＝ 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).13C NMR(150MHz,CDCl3)δ 172.2,157.3,155.7,154.5,149.9,130.3,129.5,121.6,118.6,115.4,111.2, 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: synthesis of Compound (Id)
IIa (0.2mmol) and n-butylamine hydrochloride (0.8mmol) were weighed into a dry reaction tube, 1mL of acetic acid and paraformaldehyde (1.6mmol) were added, the reaction was allowed to react at 90 ℃ for 30 minutes, and the reaction conversion was detected by TLC to be complete. Adding saturated aqueous solution of sodium bicarbonate to neutralize, extracting with ethyl acetate for three times, combining organic phases, washing with saturated saline once, and drying the organic phases with anhydrous sodium sulfate. Adding silica gel, mixing, column chromatography separation (eluent is petroleum ether: ethyl acetate: 10: 1) to obtain 37mg of product with yield of 72%. The reaction formula is as follows:
the physical properties and spectral data of the product are as follows: orange jelly;1H NMR(600MHz, CDCl3)δ7.27(d,J＝8.4Hz,1H),6.97(d,J＝2.0Hz,1H),6.83(dd,J1＝8.4 Hz,J2＝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).13C NMR(125MHz,CDCl3)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: synthesis of Compound (ie)
IIa (0.2mmol) and propargylamine hydrochloride (0.8mmol) were weighed into a dry reaction tube, 1mL of acetic acid was added, paraformaldehyde (1.6mmol) was added, the reaction was allowed to react at 90 ℃ for 30 minutes and the reaction conversion was complete as detected by TLC. Adding saturated aqueous solution of sodium bicarbonate to neutralize, extracting with ethyl acetate for three times, combining organic phases, washing with saturated saline once, and drying the organic phases with anhydrous sodium sulfate. Silica gel is added to mix the mixture, and the mixture is separated by column chromatography (eluent is petroleum ether: ethyl acetate: 10: 1) to obtain 35mg of product with 73 percent of yield. The reaction formula is as follows:
the physical properties and spectral data of the product are as follows: white solid, melting point 90.4-93.1 deg.C;1H NMR(400MHz,CDCl3)δ7.32(d,J＝8.4Hz,1H),7.02(d,J＝2.4Hz,1H), 6.88(dd,J1＝8.4Hz,J2＝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).13C NMR(100MHz,CDCl3)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: synthesis of Compound (if)
IIa (0.2mmol) and cyclopropylamine hydrochloride (0.8mmol) were weighed into a dry reaction tube, 1mL of acetic acid was added, paraformaldehyde (1.6mmol) was added, the reaction was allowed to react for 30 minutes at 90 ℃ and the reaction conversion was checked by TLC to completion. Adding saturated aqueous solution of sodium bicarbonate to neutralize, extracting with ethyl acetate for three times, combining organic phases, washing with saturated saline once, and drying the organic phases with anhydrous sodium sulfate. Adding silica gel, mixing, column chromatography separation (eluent is petroleum ether: ethyl acetate: 10: 1) to obtain 36 mg of product with yield of 74%. The reaction formula is as follows:
the physical properties and spectral data of the product are as follows: orange jelly;1H NMR(600MHz, CDCl3)δ7.27(d,J＝8.4Hz,1H),6.98(d,J＝1.8Hz,1H),6.83(dd,J1＝8.4 Hz,J2＝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).13C NMR(150MHz,CDCl3)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: synthesis of Compound (Ig)
IIb (0.2mmol) and glycine methyl ester hydrochloride (0.4 mmol) were weighed into a dry reaction tube, 1mL of acetic acid was added, an aqueous formaldehyde solution (0.8mmol) was added, the reaction was allowed to react at 60 ℃ for 3 hours, and the reaction conversion was checked by TLC. Adding saturated aqueous solution of sodium bicarbonate to neutralize, extracting with ethyl acetate for three times, combining organic phases, washing with saturated saline once, and drying the organic phases with anhydrous sodium sulfate. Adding silica gel, mixing, column chromatography separation (eluent is petroleum ether: ethyl acetate 4: 1) to obtain 69mg of product with 81% yield. The reaction formula is as follows:
the physical properties and spectral data of the product are as follows: orange jelly;1H NMR(500MHz, CDCl3)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).13C NMR(125MHz, CDCl3)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: synthesis of Compound (ih)
IIc (0.2mmol) and glycine methyl ester hydrochloride (0.4 mmol) were weighed into a dry reaction tube, 1mL of acetic acid was added, an aqueous formaldehyde solution (0.8mmol) was added, the reaction was allowed to react at 60 ℃ for 3 hours, and the reaction conversion was checked by TLC. Adding saturated aqueous solution of sodium bicarbonate to neutralize, extracting with ethyl acetate for three times, combining organic phases, washing with saturated saline once, and drying the organic phases with anhydrous sodium sulfate. Adding silica gel, mixing, column chromatography separation (eluent is petroleum ether: ethyl acetate: 2: 1) to obtain 26mg of product with 50% yield. The reaction formula is as follows:
the physical properties and spectral data of the product are as follows: orange solid, melting point 155.4-157.6 ℃;1H NMR(600MHz,CDCl3)δ7.16(d,J＝8.4Hz,1H),6.86(d,J＝1.8Hz, 1H),6.71(dd,J1＝8.4Hz,J2＝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).13C NMR(150MHz,CDCl3) 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: synthesis of Compound (II)
IId (0.2mmol) and glycine methyl ester hydrochloride (0.4 mmol) were weighed into a dry reaction tube, 1mL of acetic acid was added, an aqueous formaldehyde solution (0.8mmol) was added, the reaction was allowed to react at 60 ℃ for 3 hours, and the reaction conversion was checked by TLC. Adding saturated aqueous solution of sodium bicarbonate to neutralize, extracting with ethyl acetate for three times, combining organic phases, washing with saturated saline once, and drying the organic phases with anhydrous sodium sulfate. Adding silica gel, mixing, column chromatography separation (eluent is petroleum ether: ethyl acetate: 5: 1) to obtain 38mg of product with 65% yield. The reaction formula is as follows:
the physical properties and spectral data of the product are as follows: orange jelly;1H NMR(400MHz, CDCl3)δ7.36(d,J＝1.2Hz,1H),7.33(d,J＝8.4Hz,1H),7.17(dd,J1＝8.4 Hz,J2＝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).13C NMR(100MHz, CDCl3)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: synthesis of Compound (Ij)
IIe (0.2mmol) and glycine methyl ester hydrochloride (0.4 mmol) were weighed into a dry reaction tube, 1mL of acetic acid was added, an aqueous formaldehyde solution (0.8mmol) was added, the reaction was allowed to react at 60 ℃ for 3 hours, and the reaction conversion was checked by TLC. Adding saturated aqueous solution of sodium bicarbonate to neutralize, extracting with ethyl acetate for three times, combining organic phases, washing with saturated saline once, and drying the organic phases with anhydrous sodium sulfate. Adding silica gel, mixing, column chromatography separation (eluent is petroleum ether: ethyl acetate 4: 1) to obtain 54mg of product with 93% yield. The reaction formula is as follows:
the physical properties and spectral data of the product are as follows: light yellow colloid;1H NMR(600MHz, CDCl3)δ7.36(d,J＝8.4Hz,1H),6.96(d,J＝1.8Hz,1H),6.82(dd,J1＝8.4 Hz,J2＝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).13C NMR(150MHz,CDCl3)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 producing a 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative, comprising the steps of: carrying out three-component Mannich reaction on a 3-alkyl benzofuran compound, formaldehyde and a primary amine compound or a salt thereof in a solvent, and carrying out post-treatment after the reaction is finished to obtain the 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative;
the structure of the 3-alkyl benzofuran compound is shown as a formula (II):
the structure of the formaldehyde is shown as a formula (III):
the primary amine compound has a structure shown in a formula (IV):
R3-NH2 (IV)；
the structure of the 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative is shown as the formula (I):
in the formulae (I) to (IV), R1Is H, C1～C6Alkyl radical, C1～C6Hydrocarbyloxy, C1～C6Alkylthio radical, C1～C6One or more of hydrocarbon amine, hydroxyl, halogen, ester, amide, borate and various substituted benzene rings, R2Is hydrogen, various substituted phenyl, ester group, amide, halogen or substituted or unsubstituted alkyl, and the substituent on the alkyl is selected from halogen and hydroxyl C1～C4Alkoxy, ester, disubstituted amino, amide or variously substituted phenyl;
R3is a substituted or unsubstituted alkyl group, and the substituent on the alkyl group is selected from C1～C4Alkoxycarbonyl, alkynyl, alkenyl, halogen, ester, amide, alkyl or variously substituted phenyl.
2. The 1,2,3, 4-tetrahydrobenzo [4,5] of claim 1]Furan [2,3-C ]]A process for producing a pyridine derivative, wherein R is1Is one or more of methoxy, hydroxy, methylthio, benzyloxy, halogen, various substituted alkyl, various substituted phenyl; r2Is hydrogen, various substituted benzene rings, ester groups, amides, halogen or substituted or unsubstituted alkyl, R3Is substituted or unsubstituted methyl, ethyl, butyl or cyclopropyl, and the substituent on the methyl, ethyl, butyl or cyclopropyl is selected from C1～C4Alkoxycarbonyl, alkynyl, alkenyl, halogen, ester, amide, alkyl or variously substituted phenyl.
3. The process for producing 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative according to claim 1, wherein the primary amine compound has a chiral center and the chiral configuration is changed during the reaction.
4. The method for preparing a 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative according to claim 1, wherein the molar ratio of the 3-alkylbenzofuran, the formaldehyde and the primary amine compound is 1: 4-8: 2-4.
5. The method 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 mixture of acetonitrile, acetic acid, ethanol, methanol, acetone, dioxane, tetrahydrofuran, water, N-dimethylformamide and N, N-dimethylacetamide.
6. The method 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 method for producing a 1,2,3, 4-tetrahydrobenzo [4,5] furan [2,3-C ] pyridine derivative according to claim 1, wherein the salt of the primary amine compound is a hydrochloride, sulfate, or hydrobromide.
8. The method for preparing 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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