CN114736212A - A kind of furo[3,2-b]indole derivative and its synthesis method and application - Google Patents

Abstract

The invention discloses a furo [3,2-b ] indole derivative and a synthesis method and application thereof, wherein the synthesis method comprises the following specific steps: taking a 2- (2-furyl) arylamine compound protected by tosyl as a raw material, adding an organic solvent, a catalyst, an oxidant and alkali in a protective atmosphere, and catalytically synthesizing to obtain the furo [3,2-b ] indole derivative shown in the formula (I). The preparation method realizes the coupling cyclization of NH and furan ring 3-position hydrogen under the catalysis of transition metal to obtain a target product. The raw materials are simple and easy to obtain, and the reaction conditions are mild. The invention also discloses application of the furo [3,2-b ] indole derivative shown in the formula (I) in preparing medicines for resisting allergy, tumors, pain and inflammation.

Description

A kind of furo[3,2-b]indole derivative and its synthetic method and application

technical field

The invention belongs to the field of organic compound synthesis, in particular to a furano[3,2-b]indole derivative, a synthesis method and application thereof

Background technique

Furano[3,2-b]indole skeletons are abundantly present in natural products or drug molecules with physiological activity, showing different drug activities, such as antiallergic, antitumor activity, analgesic and anti-inflammatory effects. Therefore, the development of synthetic methods for these compounds has an important role in promoting the synthesis of furo[3,2-b]indole skeleton-containing drug molecules. In addition, furo[3,2-b]indole derivatives can also be used as important organic synthesis units, which can undergo a series of chemical transformation reactions under the catalysis of transition metals to construct indolin-3-one spiro rings, Indolo-heterocycle, indol-3-one-2-ene and other backbone molecules.

Currently known methods for synthesizing such skeletons are relatively few, mainly including: (1) synthesizing o-furan aryl azide compounds by multi-step synthesis, and obtaining the target product by intramolecular cyclization under high temperature conditions; (2) using The o-furanyl nitrobenzene is used as the raw material, and the intramolecular cyclization is carried out under the catalysis of alkoxy phosphorous to obtain the furanoindole skeleton; (3) the o-(3-bromo-2-furyl) arylamine is constructed by a multi-step synthesis method as The starting material is cyclized by intramolecular C-NUllmann coupling to obtain the target product. But the raw materials involved in the above-mentioned reported synthetic methods need multi-step synthesis and the yield is not high, some raw materials such as aromatic azides have certain dangers in the actual operation process, and many reaction conditions are relatively harsh. The reaction temperature is up to 160 ° C, the target The product yield is not high, and the reaction cost is relatively high. Therefore, it is extremely important to develop more cost-effective and easy-to-operate synthetic methods for furo[3,2-b]indole derivatives.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a furano[3,2-b]indole derivative, a synthesis method and application thereof, and a synthesis method with simple and easily available raw materials and mild reaction conditions.

The present invention provides a furo[3,2-b]indole derivative, the structure of which is shown in formula (I):

In formula (I),

R is hydrogen, C1-C20 alkyl or halogen.

The present invention also provides a method for synthesizing furo[3,2-b]indole derivatives. The specific steps are as follows: using a p-toluenesulfonyl-protected 2-(2-furanyl)arylamine compound as a raw material; Under the atmosphere, adding an organic solvent, a catalyst, an oxidizing agent and a base, the furo[3,2-b]indole derivative represented by the formula (I) is obtained by catalytic synthesis;

Its reaction process is shown in formula (II):

In formula (II), R is hydrogen, C1-C20 alkyl or halogen; the catalyst is a palladium catalyst.

Preferably, the molar ratio of the p-toluenesulfonyl-protected 2-(2-furyl) arylamine compound: catalyst: oxidant: base is 1: (0.1-0.5): (1-2): (0.5-2 ).

Preferably, the molar ratio of the p-toluenesulfonyl-protected 2-(2-furyl) arylamine compound: catalyst: oxidant: base is 1:0.1:2:0.5.

Preferably, the palladium catalyst is selected from the group consisting of PdCl ₂ , Pd(TFA) ₂ , Pd(OAc) ₂ , PdCl ₂ (PPh ₃ ) ₂ , Pd(PPh ₃ ) ₄ , Pd(dba) ₂ and Pd ₂ (dba) one or more of ₃ .

Preferably, the palladium catalyst is PdCl ₂ .

Preferably, the oxidant is selected from one or more of Cu(OAc) ₂ , CuSO ₄ , Cu(acac) ₂ , tetraethyl cyanide hexafluorophosphate, Cu(OTf) ₂ , AgOAc and Ag ₂ CO ₃ .

Preferably, the oxidant is Cu(OAc) ₂ .

Preferably, the base is selected from one or more of Cs ₂ CO ₃ , KO ^t Bu, K ₂ CO ₃ , KOH, NEt ₃ , DBU and K ₃ PO ₄ .

Preferably, the base is Cs ₂ CO ₃ .

Preferably, the organic solvent is selected from 1,2-dichloroethane, acetonitrile, toluene, 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N,N- One of dimethylacetamide and tetrahydrofuran.

Preferably, the temperature of the reaction is 50-120°C.

Preferably, the reaction time is 10-50h.

The invention also provides the application of a furo[3,2-b]indole derivative in the preparation of anti-allergic, anti-tumor, analgesic and anti-inflammatory drugs.

In a specific embodiment, in the preparation method of the present invention, under nitrogen, a p-toluenesulfonyl-protected 2-(2-furyl) arylamine compound is used as a raw material, and under a protective atmosphere, N,N-dimethyl acetamide as the organic solvent, PdCl ₂ as the catalyst, Cu(OAc) ₂ as the oxidant, and Cs ₂ CO ₃ as the base, at 80 °C, the furo[3,2- b] an indole derivative, as shown in the following reaction formula (III):

Wherein, R is hydrogen, C1-C20 alkyl or halogen.

Wherein, the molar ratio of the p-toluenesulfonyl-protected 2-(2-furyl) arylamine compound: PdCl ₂ : Cu(OAc) ₂ : Cs ₂ CO ₃ is 1:0.1:2:0.5.

Wherein, the time of the reaction is 24-40h.

The beneficial effects of the present invention are as follows: the method for synthesizing a furano[3,2-b]indole derivative of the present invention realizes the coupling cyclization of NH and the hydrogen at the 3-position of the furan ring under the action of a palladium catalyst to obtain target product. The reaction conditions are mild, the raw materials are simple and easy to obtain, and it has the advantages of good universality, high atom economy, simple post-processing, good yield (60%-80%), and environmental friendliness. The furo[3,2-b]indole skeleton in the furo[3,2-b]indole derivatives synthesized by the preparation method of the present invention is an important structural unit in many natural products and drug molecules, and most of them have It has strong biological activity and can further undergo subsequent chemical transformation reactions, and has great research value in drug synthesis.

Detailed ways

In order to make the technical problems, technical solutions and beneficial effects solved by the present invention clearer, the present invention will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention, but not to limit the present invention. Variations and advantages that can occur to those skilled in the art without departing from the spirit and scope of the inventive concept are included in the present invention, and the appended claims are the scope of protection. The process, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common knowledge in the field, and the present invention has no special limited contents.

Example 1: Synthesis of 4-Ts furo[3,2-b]indole compound (IA)

Under a nitrogen atmosphere, 0.3 mmol of Ts (p-toluenesulfonyl) protected o-furan arylamine compound, 6 mL of N,N-dimethylacetamide, 0.03 mmol of palladium dichloride, and anhydrous copper acetate were added to the reaction tube. 0.6 mmol, 0.15 mmol of cesium carbonate. The reaction was carried out at 80° C. for 24 hours, and after TLC detection was completed, the reaction was cooled to room temperature to obtain the target product of formula (IA), a yellow solid, and the isolated yield was 75%. MP 128-131°C.

Product NMR data: ¹ H NMR (CDCl ₃ , 500MHz): δ 2.27(s, 3H), 7.01(s, 1H), 7.12(d, J=5.0Hz, 2H), 7.26-7.28(m, 2H) , 7.53-7.56 (m, 2H), 7.67 (d, J=5.0Hz, 2H), 8.12-8.14 (m, 1H). ¹³ C NMR (CDCl ₃ , 125MHz): δ 21.46, 102.50, 115.34, 116.68, 118.83, 124.02, 126.67, 129.65, 130.23, 134.35, 139.15, 144.44, 144.93, 146.42.

High resolution mass spectral data: HRMS (ESI, m/z) calcd. for _C17H14NO3S [ _M +H] ⁺ calc.: _312.0694 ; found: 312.0698.

Example 2: Synthesis of 6-chloro-4-Ts furo[3,2-b]indole compound (IB)

Under a nitrogen atmosphere, 0.3 mmol of Ts-protected 2-furan-5-chloroarylamine compound, 6 mL of N,N-dimethylacetamide, 0.03 mmol of palladium dichloride, and 0.6 mL of anhydrous copper acetate were added to the reaction tube. mmol, cesium carbonate 0.15mmol. The reaction was carried out at 80° C. for 24 hours, and after TLC detection was completed, the reaction was cooled to room temperature to obtain the target product of formula (IB) as a brown solid with an isolation yield of 70%. MP 114-116°C.

Product NMR data: ¹ H NMR (CDCl ₃ , 500MHz): δ 2.31 (s, 3H), 7.00 (d, J=2.0 Hz, 1H), 7.17 (d, J=8.5 Hz, 2H), 7.25 (dd ,J=8.5,2.0Hz,1H),7.47(d,J=8.5Hz,1H),7.54(d,J=2.0Hz,1H),7.69-7.71(m,2H),8.15(d,J= 2.0Hz, 1H). ¹³ C NMR (CDCl ₃ , 125MHz): δ 21.54, 102.47, 115.54, 117.23, 117.29, 124.56, 126.71, 129.83, 129.87, 130.76, 134.20, 139.31, 143.64, 145.31, 146.81.

High resolution mass spectral data: HRMS (ESI, m/z) calcd. for _C17H13ClNO3S [ _M +H]+calc.: _346.0305 ; found: 346.0310.

Example 3: Synthesis of 6-methyl-4-Ts furo[3,2-b]indole compound (IC)

Under nitrogen atmosphere, into the reaction tube, add 0.3 mmol of Ts-protected 5-methyl-2-furanarylamine compound, 6 mL of N,N-dimethylacetamide, 0.03 mmol of palladium dichloride, and anhydrous copper acetate 0.6 mmol, 0.15 mmol of cesium carbonate. The reaction was carried out at 80° C. for 24 hours, and after TLC detection was completed, the reaction was cooled to room temperature to obtain the target product of formula (IC) as a yellow solid, and the isolated yield was 72%. MP 135-136°C.

Product NMR data: ¹ H NMR (CDCl ₃ , 500MHz): δ 2.27(s, 3H), 2.48(s, 3H), 6.98(d, J=2.5Hz, 1H), 7.08(d, J=7.5Hz) ,1H),7.13(d,J＝8.0Hz,2H),7.43(d,J＝8.0Hz,1H),7.49(d,J＝2.0Hz,1H),7.68(d,J＝8.5Hz,2H ), 7.94(s, 1H). ¹³ C NMR (CDCl ₃ , 125MHz): δ 21.47, 21.94, 102.57, 115.60, 116.27, 116.72, 125.32, 126.64, 129.63, 129.65, 134.26, 134.46, 139.65, 144.59, 144.83, 145.

High resolution mass spectral data: HRMS (ESI, m/z) calcd. for _C18H16NO3S [ _M +H]+calc.: _326.0851 ; found: 326.0855.

Example 4: Synthesis of 7-bromo-4-Ts furo[3,2-b]indole compound (ID)

Under a nitrogen atmosphere, 0.3 mmol of Ts-protected 2-furan-4-bromoarylamine compound, 6 mL of N,N-dimethylacetamide, 0.03 mmol of palladium dichloride, and 0.6 mL of anhydrous copper acetate were added to the reaction tube. mmol, cesium carbonate 0.15mmol. The reaction was carried out at 80° C. for 24 hours. After the reaction was detected by TLC, the reaction was cooled to room temperature to obtain the target product of formula (ID) as a yellow liquid with a separation yield of 60%.

Product NMR data: ¹ H NMR (CDCl ₃ , 500MHz): δ2.31(s, 3H), 7.00-7.01(m, 1H), 7.16(d, J=8.0Hz, 2H), 7.37-7.39(m, 1H), 7.55-7.56 (m, 1H), 7.66-7.70 (m, 3H), 7.99 (d, J=8.5Hz, 1H). ¹³ C NMR (CDCl ₃ , 125MHz): δ 21.54, 102.47, 116.68, 117.61, 119.56, 120.14, 126.67, 126.75, 129.81, 131.45, 134.11, 137.77, 143.03, 145.29, 147.26.

High resolution mass spectral data: HRMS (ESI, m/z) calcd. for _C17H13BrNO3S [ _M +H]+calc.: _389.9800 ; found: 389.9805.

Example 5: Synthesis of 7-fluoro-4-Ts furo[3,2-b]indole compound (IE)

Under a nitrogen atmosphere, 0.3 mmol of Ts-protected 2-furan-4-fluoroarylamine compound, 6 mL of N,N-dimethylacetamide, 0.03 mmol of palladium dichloride, and 0.6 mL of anhydrous copper acetate were added to the reaction tube. mmol, cesium carbonate 0.15mmol. The reaction was carried out at 80° C. for 24 hours. After TLC detection was completed, the reaction was cooled to room temperature to obtain the target product of formula (IE) as a brown solid with an isolated yield of 67%. MP 114-116°C.

Product NMR data: ¹ H NMR (CDCl ₃ , 500MHz): δ 2.29 (s, 3H), 6.97-7.02 (m, 2H), 7.14 (d, J=8.0 Hz, 2H), 7.21 (dd, J= 8.25, 3.0Hz, 1H), 7.55 (d, J=2.0Hz, 1H), 7.66 (d, J=8.5Hz, 2H), 8.07 (dd, J=9.3, 4.5Hz, 1H). ¹³ C NMR (CDCl ₃ , 125MHz): δ 21.51, 102.60, 103.07 (d, J=25.9 Hz), 111.47 (d, J=24.9 Hz), 116.48 (d, J=9.6 Hz), 119.60 (d, J= 10.9Hz), 126.67, 129.73, 131.94, 134.08, 135.37, 143.85 (d, J=2.5Hz), 145.16, 147.12, 159.95 (d, J=240.3Hz).

High resolution mass spectral data: HRMS (ESI, m/z) calcd. for _C17H13FNO3S [ _M +H]+calc.: _330.0600 ; found: 330.0609.

Example 6: 7-Methyl-4-Ts furo[3,2-b]indole compound (IF) synthesis

Under nitrogen atmosphere, into the reaction tube, add 0.3 mmol of Ts-protected 4-methyl-2-furanarylamine compound, 6 mL of N,N-dimethylacetamide, 0.03 mmol of palladium dichloride, and anhydrous copper acetate 0.6 mmol, 0.15 mmol of cesium carbonate. The reaction was carried out at 80° C. for 24 hours. After TLC detection was completed, the reaction was cooled to room temperature to obtain the target product of formula (IF) as a brown solid and a brown liquid, and the isolated yield was 69%.

Product NMR data: ¹ H NMR (CDCl ₃ , 500MHz): δ2.26(s, 3H), 2.40(s, 3H), 6.98(d, J=2.0Hz, 1H), 7.08-7.12(m, 3H) , 7.34 (bs, 1H), 7.51 (d, J=2.0Hz, 1H), 7.65-7.67 (m, 2H), 7.99 (d, J=8.5Hz, 1H). ¹³ C NMR (CDCl ₃ , 125MHz): δ 21.30, 21.46, 102.55, 115.09, 116.78, 119.06, 125.26, 126.66, 129.60, 130.36, 133.88, 134.31, 137.48, 144.25, 144.79, 146.

High resolution mass spectral data: HRMS (ESI, m/z) calcd. for _C18H16NO3S [ _M +H] ⁺ calc.: _326.0851 ; found: 326.0855.

Example 7: Synthesis of 6-Ts phenylpropylfuro[3,2-b]indole compound (IG)

Under nitrogen atmosphere, into the reaction tube, add 0.3 mmol of Ts-protected 2-benzofuran arylamine compound, 6 mL of N,N-dimethylacetamide, 0.03 mmol of palladium dichloride, 0.6 mmol of anhydrous copper acetate, Cesium carbonate 0.15mmol. The reaction was carried out at 80° C. for 24 hours. After the reaction was detected by TLC, the reaction was cooled to room temperature to obtain the target product of formula (IG) as a brown solid with an isolation yield of 75%. MP 174-176°C.

Product NMR data: ¹ H NMR (CDCl ₃ , 400MHz): δ2.23(s, 3H), 7.05(d, J=8.0Hz, 2H), 7.33-7.44(m, 4H), 7.59-7.61(m, 1H), 7.64-7.69 (m, 3H), 8.28 (d, J=8.0Hz, 1H), 8.39-8.41 (m, 1H). ¹³ C NMR(CDCl ₃ ,100MHz):δ21.46,112.57,115.77,117.53,118.52,119.24,120.58,123.91,124.39,124.57,124.93,125.39,126.77,129.73,134.20,139.49,144.94,146.67,159.26。

High resolution mass spectral data: HRMS (ESI, m/z) calcd. for _C21H16NO3S [ _M +H] ⁺ calc.: _362.0851 ; found: 362.0859.

The above descriptions are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements and improvements made within the spirit and principles of the present invention shall be included in the protection of the present invention. within the range.

Claims (10)

1. A furo [3,2-b ] indole derivative is characterized by having a structure shown in formula (I):

in the formula (I), the compound is shown in the specification,

r is hydrogen, C1-C20 alkyl or halogen.

2. A synthetic method of furo [3,2-b ] indole derivatives shown in formula (I) is characterized by comprising the following specific steps:

taking a 2- (2-furyl) arylamine compound protected by tosyl as a raw material, adding an organic solvent, a catalyst, an oxidant and alkali in a protective atmosphere, and catalytically synthesizing to obtain a furo [3,2-b ] indole derivative shown in a formula (I);

the reaction process is shown as the formula (II):

in the formula (II), R is hydrogen, C1-C20 alkyl or halogen; the catalyst is a palladium catalyst.

3. The method for synthesizing a furo [3,2-b ] indole derivative according to claim 2, wherein the p-toluenesulfonyl protected 2- (2-furyl) arylamine compound: catalyst: oxidizing agent: the molar ratio of the alkali is 1: (0.1-0.5): (1-2): (0.5-2).

4. A furo [3,2-b ] according to claim 2]The synthesis method of the indole derivative is characterized in that the palladium catalyst is selected from PdCl₂、Pd(TFA)₂、Pd(OAc)₂、PdCl₂(PPh₃)₂、Pd(PPh₃)₄、Pd(dba)₂And Pd₂(dba)₃One or more of (a).

5. A furo [3,2-b ] according to claim 2]The synthesis method of indole derivatives is characterized in that the oxidant is selected from Cu (OAc)₂、CuSO₄、Cu(acac)₂Copper hexachloro-tetra-cyanide, Cu (OTf)₂AgOAc and Ag₂CO₃One or more of (a).

6. A furo [3,2-b ] according to claim 2]A process for the synthesis of indole derivatives, characterized in that the base is selected from Cs₂CO₃、KO^tBu、K₂CO₃、KOH、NEt₃DBU and K₃PO₄One or more of (a).

7. The method for synthesizing furo [3,2-b ] indole derivative according to claim 2, wherein the organic solvent is one selected from 1, 2-dichloroethane, acetonitrile, toluene, 1, 4-dioxane, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide and tetrahydrofuran.

8. The method for synthesizing furo [3,2-b ] indole derivative according to claim 2, wherein the reaction temperature is 50-120 ℃.

9. The method for synthesizing furo [3,2-b ] indole derivative according to claim 2, wherein the reaction time is 10-50 h.

10. Use of the furo [3,2-b ] indole derivative according to claim 1 for preparing anti-allergic, anti-tumor, analgesic and anti-inflammatory drugs.