CN108299445B

CN108299445B - Synthesis method of 1, 5-azaspiro [2,4] heptane

Info

Publication number: CN108299445B
Application number: CN201810262528.4A
Authority: CN
Inventors: 徐华栋; 刘太上; 沈美华; 周皓
Original assignee: Changzhou University
Current assignee: Changzhou University
Priority date: 2018-03-28
Filing date: 2018-03-28
Publication date: 2020-03-20
Anticipated expiration: 2038-03-28
Also published as: CN108299445A

Abstract

The invention relates to a synthesis method of 1, 5-azaspiro [2,4] heptane, which comprises the steps of taking a vinyl azide compound as a raw material, heating the vinyl azide compound in an organic solvent for reaction, and carrying out an Alder alkene reaction on an azapropene intermediate to obtain the required 1, 5-azaspiro [2,4] heptane compound. The preparation method has the advantages of convenient preparation of reaction raw materials, no need of any catalyst and acid-base additive in the reaction, simple operation, quick and easily obtained product and only single cis-configuration.

Description

Synthesis method of 1, 5-azaspiro [2,4] heptane

Technical Field

The invention belongs to the technical field of chemical pharmacy and fine chemical preparation, and particularly relates to a synthesis method of 1, 5-azaspiro [2,4] heptane.

Background

The azaspiro compounds are important organic compounds, and a plurality of natural products and artificial products with azaspiro structures show good biological activity. The anticancer activity of origamin derivatives is reported in US patent (US20160096844a1), which includes compounds of 1-azaspiro [2,4] heptane structure. European patent WO2016182938A1 reports a class of anti-hepatitis C virus compounds, which also include compounds of the 1-azaspiro [2,4] heptane structure. Thus, the 1-azaspiro [2,4] heptane structure has potential biological activity. However, the construction methods of 1-azaspiro [2,4] heptane structures have been so far limited, and the synthetic methods reported in the literature can be summarized as the following two methods:

(1) taking (1-aminocyclopentyl) methanol as a starting material, protonating, dehydrating and cyclizing under an acidic condition to synthesize the 1-azaspiro [2,4] heptane, wherein the synthetic route is shown as an equation A. The method has the disadvantages of severe pollution and difficult industrialization due to the use of strong acid and strong alkali.

Equation a:

(2) sulfenimide indolone is used as a starting material, trimethyl sulfoxide iodide is used as a sulfonium oxide salt, NaH is used as an alkali, and sulfur ylide is generated on site to be added with imine to obtain 1, 5-azaspiro [2,4] heptane, wherein the synthetic route is shown as an equation B. The disadvantage is that the reaction also requires the addition of strong bases and the substrates are not easy to prepare.

Equation B:

disclosure of Invention

The technical problem to be solved by the invention is as follows: based on the problems, the invention provides a method for synthesizing 1, 5-azaspiro [2,4] heptane.

The technical scheme adopted by the invention for solving the technical problems is as follows: a method for synthesizing 1, 5-azaspiro [2,4] heptane comprises the following steps: under the protection of nitrogen, dissolving vinyl azide compound 1 in an organic solvent, heating for reaction, controlling the reaction temperature and the reaction time, removing the organic solvent by reduced pressure distillation after the reaction is stopped, and separating and purifying the residue by silica gel column chromatography by using ethyl acetate and petroleum ether as eluent to obtain 1, 5-azaspiro [2,4] heptane compound 2.

The synthetic route of the invention is shown in equation (1):

further, the general structural formula of the vinyl azide 1 is as follows:

wherein R is₁Is any one of phenyl, benzyl and p-toluenesulfonyl; when R is₂When it is methyl, R₃Is any one of hydrogen, methyl, phenyl and chlorine, when R is₃When it is methyl, R₂Is any one of methyl and phenyl; r₂And R₃The structure may be a cyclic structure connected end to end, specifically, any of the following structures.

Further, 1, 5-azaspiro [2,4]]The structural general formula of the heptane compound 2 is:

wherein R is₁Is any one of phenyl, benzyl and p-toluenesulfonyl; r₄Is any one of the structures shown below.

Further, the organic solvent is an aprotic solvent, toluene.

Further, the reaction temperature is 60-120 ℃, and the reaction time is 6-15 hours.

The preparation method of the raw material vinyl azide adopted by the invention is shown as an equation (2):

firstly, primary amine s1 and propargyl bromide s2 are utilized to carry out nucleophilic substitution reaction to obtain a series of propargyl amine compounds s 3; then, nucleophilic substitution reaction is carried out on propargylamine compound s3 and allyl bromide s4 containing different substituent groups again to obtain enepropargylamine compound s 5; finally, under the catalysis of silver carbonate, DMSO is used as a solvent, 2 equivalent of water and TMSN are added into s5 at 80 DEG C₃And reacting to generate the required raw material vinyl azide 1.

Preparation of 1, 5-azaspiro [2,4] from vinyl azide]Heptane, the reaction mechanism of which is vinyl azide compound 1a, as shown in equation (3), alkenyl azide generates ternary azapropenidine intermediate M under reaction conditions, and the intermediate stereoselectively obtains the final 1, 5-azaspiro [2,4] through intramolecular Alder alkene reaction]Heptane compound 2 a. The cis-structure of the product 2a can be deduced from the characteristics of the ene reaction, while passing through 2a¹H-¹H COSY two-dimensional spectrum is obtained and proved.

The invention has the beneficial effects that: the 1, 5-azaspiro [2,4] heptane compound is prepared by taking a vinyl azide compound as a raw material, heating the vinyl azide compound in an organic solvent for reaction and carrying out an Alder alkene reaction on an azapropene intermediate. The preparation of reaction raw materials is convenient, the reaction does not need any catalyst or acid-base additive, the operation is simple, the product is fast and easy to obtain, and only has single cis-configuration.

Detailed Description

The invention will now be further illustrated by reference to specific examples, which are intended to be illustrative of the invention and are not intended to be a further limitation of the invention.

The reagent used in the invention is prepared by reference to relevant documents, and the solvent is purified and refined.

Example 1

10mL of the tube was sealed, and 1a 100mg was weighed, 2mL of toluene was added, and the reaction was carried out for 15 hours at 60 ℃ under vacuum with nitrogen exchange. The reaction was stopped, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using petroleum ether and ethyl acetate as an eluent to give yellow liquid 2a in a yield of 72%.¹H NMR(400MHz,CDCl₃)δ7.34–7.25(m,4H),7.25–7.21(m,1H),4.80–4.79(m,1H),4.62(d,J＝2.1Hz,1H),3.65–3.56(m,2H),3.00–2.90(m,2H),2.72(d,J＝9.6Hz,1H),2.64–2.58(m,2H),1.76(s,3H),1.74(s,1H),1.64(s,1H).¹³C NMR(100MHz,CDCl₃) δ 143.0,138.7,128.8,128.3,127.1,114.6,61.5,60.7,58.5,50.0,41.6,31.3,20.5 HRMS (ESI) m/z theoretical value C₁₅H₂₁N₂ ⁺[M+H]⁺229.1699, found 229.1703.

Example 2

10mL of the tube was sealed, and 1b 100mg was weighed, 2mL of toluene was added, and the reaction was carried out for 6 hours at 120 ℃ under vacuum with nitrogen exchange. The reaction was stopped, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using petroleum ether and ethyl acetate as an eluent to give yellow liquid 2b in 73% yield.¹H NMR(400MHz,CDCl₃)δ7.33–7.23(m,5H),5.68–5.59(m,1H),5.07(dd,J＝10.2,1.8Hz,1H),4.96(dd,J＝17.1,1.7Hz,1H),3.62(s,2H),3.06(dd,J＝9.1,7.2Hz,1H),2.90(q,J＝8.2Hz,1H),2.83(d,J＝9.8Hz,1H),2.54(d,J＝9.7Hz,1H),2.45(t,J＝8.6Hz,1H),1.76(s,1H),1.65(s,1H).¹³C NMR(75MHz,CDCl₃) δ 137.4,134.6,127.9,127.3,126.1,117.2,60.0,59.6,59.3,46.0,41.1,28.7 HRMS (ESI) m/z theoretical value C₁₄H₁₉N₂ ⁺[M+H]⁺215.1543, found 215.1545.

Example 3

10mL of the tube was sealed, and 1c 100mg was weighed, 2mL of toluene was added, and the reaction was carried out for 8 hours at 100 ℃ under vacuum with nitrogen exchange. The reaction was stopped, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using petroleum ether and ethyl acetate as an eluent to give 2c as a yellow liquid in a yield of 79%.¹H NMR(400MHz,CDCl₃)δ7.42–7.26(m,10H),5.47(s,1H),5.20(s,1H),3.69–3.64(m,3H),3.16(dd,J＝9.2,7.4Hz,1H),2.95(d,J＝9.7Hz,1H),2.74(d,J＝9.8Hz,1H),2.69(t,J＝9.0Hz,1H),1.77(s,1H),1.66(s,1H).¹³C NMR(75MHz,CDCl₃) δ 146.2,141.0,138.6,128.8,128.4,128.3,127.8,127.1,126.7,116.7,61.7,60.7,60.4,47.2,42.8,31.2 HRMS (ESI) m/z theoretical value C₂₀H₂₃N₂ ⁺[M+H]⁺291.1856, found 291.1856.

Example 4

10mL of the tube was sealed, 1d of 100mg was weighed, 2mL of toluene was added, vacuum was applied and nitrogen was exchanged, and the reaction was carried out at 100 ℃ for 8 hours. The reaction was stopped, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using petroleum ether and ethyl acetate as an eluent to give 2d as a yellow liquid in a yield of 78%.¹H NMR(400MHz,CDCl₃)δ7.42–7.32(m,5H),7.28–7.25(m,2H),6.74(t,J＝7.3Hz,1H),6.59(d,J＝8.2Hz,2H),5.58(s,1H),5.30(s,1H),3.83(t,J＝8.2Hz,1H),3.73(s,1H),3.58(dt,J＝9.3,3.2Hz,2H),3.45(d,J＝9.7Hz,1H),1.78(s,1H),1.71(s,1H),0.63(s,1H).¹³C NMR(100MHz,CDCl₃) δ 147.7,145.2,141.3,129.3,128.7,128.0,126.5,116.4,116.1,111.8,55.1,53.2,46.3,42.8,29.1 HRMS (ESI) m/z theoretical value C₁₉H₂₁N₂ ⁺[M+H]⁺277.1699, found 277.1701.

Example 5

10mL of the tube was sealed, and 1e 100mg was weighed, 2mL of toluene was added, vacuum was applied and nitrogen was exchanged, and the reaction was carried out at 100 ℃ for 8 hours. The reaction was stopped, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and purification using petroleum ether and ethyl acetate as an eluent to give 2e as a yellow liquid in 83% yield.¹H NMR(400MHz,CDCl₃)δ7.33–7.22(m,5H),5.36(s,1H),3.59(s,2H),2.90–2.88(m,2H),2.72(d,J＝9.6Hz,1H),2.57–2.52(m,2H),1.98–1.95(m,4H),1.70–1.68(m,2H),1.66–1.57(m,2H),1.56–1.45(m,2H).¹³C NMR(75MHz,CDCl₃) δ 138.7,134.8,128.9,128.3,127.0,126.5,61.6,60.8,58.0,50.4,41.7,31.4,26.6,25.3,22.8,22.4 HRMS (ESI) m/z theoretical value C₁₈H₂₅N₂ ⁺[M+H]⁺269.2012, found 269.2016.

In light of the foregoing description of the preferred embodiment of the present invention, many modifications and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.

Claims

1. A method for synthesizing 1, 5-azaspiro [2,4] heptane is characterized in that: the synthesis method comprises the following steps: under the protection of nitrogen, dissolving a vinyl azide compound in an organic solvent, heating for reaction, controlling the reaction temperature and the reaction time, removing the organic solvent by reduced pressure distillation after the reaction is stopped, and separating and purifying residues by silica gel column chromatography by using ethyl acetate and petroleum ether as eluent to obtain a1, 5-azaspiro [2,4] heptane compound;

the general structural formula of the vinyl azide is as follows:

，

wherein R is₁Is any one of phenyl, benzyl and p-toluenesulfonyl; when R is₂When it is methyl, R₃Is any one of hydrogen, methyl, phenyl and chlorine, when R is₃When it is methyl, R₂Is any one of methyl and phenyl; or R₂And R₃Is a cyclic structure connected end to end;

the R is₂And R₃Is a cyclic structure connected end to end, and specifically any one of the following structures:

。

2. the 1, 5-azaspiro [2,4] of claim 1]The heptane synthesizing process features that: the prepared 1, 5-azaspiro [2, 4%]The structural general formula of the heptane compound is:

wherein R is₁Is any one of phenyl, benzyl and p-toluenesulfonyl; r₄Is any one of the structures shown below:

。

3. a process for the synthesis of 1, 5-azaspiro [2,4] heptane as claimed in claim 1 wherein: the solvent is an aprotic solvent toluene.

4. A process for the synthesis of 1, 5-azaspiro [2,4] heptane as claimed in claim 1 wherein: the reaction temperature is 60-120 ℃, and the reaction time is 6-15 h.