Process for the preparation of 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compounds

Abstract

The application discloses a preparation method of 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzoazepine compounds, which couples a nitro compound with an allyl precursor compound through Rh(III) catalysis, realizes C-H allylation, and then realizes 1,3-dipolar cycloaddition in a molecule to realize synthesis of a target compound in one step. The method has the advantages of simple synthesis route, wide substrate range, efficient preparation process, high yield and good application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis, and relates to a preparation method of 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compounds. BACKGROUND

[0002] Compounds containing a tetrahydro-1-benzazepine skeleton are common compounds in pharmaceutical chemistry research. Compounds containing this fused heterocyclic unit have a wide range of biological activities, including promoting growth hormone secretion, anti-proliferative activity, antagonists targeting arginine vasopressin receptors V1A and V2, anti-HIV-1 infection, cyclin-dependent kinase and glycogen synthase kinase 3 (GSK-3) inhibitors, and anti-leishmania and anti-Chagas disease, etc.

[0003] 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compounds have anti-parasitic activity, but the synthesis route is complex. The most common method is to use a multi-step reaction developed by Ayala et al., which directly reduces and aminates the corresponding benzaldehyde using sodium cyanoborohydride to obtain an o-propenylaniline, and then starts from the o-propenylaniline to obtain 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compounds through successive amino-claisen rearrangement, oxidation / intramolecular 1,3-dipolar cycloaddition (see Prior Art 1-3 below). This method is a multi-step reaction, which requires multiple post-treatments, and the overall yield of the entire process is low (<40%). In addition, this method also requires the use of explosive reactants, which has a high safety risk. Therefore, it is necessary to develop a more efficient method to obtain various 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine drugs, which has important application value.

[0004] Prior Art Document 1: Acosta, L. M.; Palma, A. and Bahsas, A., Rational use of substituted N-allyl and N,N-diallylanilines in the stereoselective synthesis of novel 2-alkenyltetrahydro-1-benzazepines. Tetrahedron 2010, 66, 8392-8401.

[0005] Prior art document 2: Gomez Ayala, S. L.; Stashenko, E.; Palma, A.; Bahsas, A. and Amaro-Luis, J. M., Sequential Amino-Claisen Rearrangement / Intramolecular 1,3-Dipolar-Cycloaddition / Reductive Cleavage Approach to the Stereoselective Synthesis of cis-4-Hydroxy-2-aryl-2,3,4,5-tetrahydro-1(1H)-benzazepines. Synlett 2006, 2006, 2275-2277.

[0006] Prior art document 3: Gomez-Ayala, S.; Castrillon, J. A.; Palma, A.; Leal, S. M.; Escobar, P. and Bahsas, A., Synthesis, structural elucidation and in vitro antiparasitic activity against Trypanosoma cruzi and Leishmania chagasi parasites of novel tetrahydro-1-benzazepine derivatives. Biorg. Med. Chem. 2010, 18, 4721-4739. SUMMARY

[0007] The object of the present application is to provide a preparation method of 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compounds, so as to solve at least one of the above technical problems.

[0008] According to one aspect of the present application, there is provided a preparation method of 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compounds, comprising the following steps: adding a rhodium catalyst, an additive, a nitrone compound and an allyl precursor compound into an organic solvent, and heating to make the nitrone compound and the allyl precursor compound react under the protection of an inert gas, to obtain a 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound with a structure as shown in Formula I; wherein the structure of the nitrone compound is as shown in Formula II, and the structure of the allyl precursor compound is as shown in Formula III.

[0009] The reaction of the nitrone compound and the allyl precursor compound into the 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound is shown in the following reaction formula:

[0010]

[0011] In formula I and formula II, A1 and A2 can be independently selected from aryl or heteroaryl; wherein one or more hydrogen atoms at different positions of the aromatic ring of aryl or the aromatic heterocycle of heteroaryl can be independently substituted by one of the following substituents: H, halogen, alkyl or optionally substituted alkyl, alkoxy or optionally substituted alkoxy, alkylthio or optionally substituted alkylthio, aryl or optionally substituted aryl, substituted or unsubstituted unsaturated bond, cyano. The substituted or unsubstituted unsaturated bond can be substituted by a hydrogen atom on aryl or heteroaryl, and can be specifically a substituted or unsubstituted double bond, a substituted or unsubstituted triple bond.

[0012] In formula III, R can be selected from one of formyl methyl ester, formyl ethyl ester, acetyl, phosphono diethyl ester, i.e., the allyl precursor compound can be selected from one of propylene methyl carbonate, propylene ethyl carbonate, propylene acetate, propylene diethyl phosphonate.

[0013] The present application couples the nitrone compound and the allyl precursor compound by Rh(III) catalysis, realizes C-H allylation, and then performs 1,3-dipolar cycloaddition in the molecule, so as to realize the synthesis of the target compound in one step. The method provided by the present application has simple synthesis route, wide substrate range, good functional group tolerance, high yield, efficient preparation process, and good application prospect.

[0014] In some embodiments, the molar ratio of the additive, the allyl precursor compound and the nitrone compound is (1-20):(0.5-1.5):(1-2); and the amount of the rhodium catalyst is 1%-5% of the nitrone compound in terms of molar percentage.

[0015] In some embodiments, the rhodium catalyst can be selected from one or more of [Cp*Rh(CH3CN)3](SbF6)2, [Cp*RhCl2]2, Cp*RhCl2(PPh2CH2OH), Rh(OAc)3.

[0016] In some embodiments, the rhodium catalyst can be [Cp*Rh(CH3CN)3](SbF6)2.

[0017] In some embodiments, the additive can be selected from one or more of silver acetate, sodium acetate, cesium acetate, silver oxide, silver carbonate, and pivalic acid.

[0018] In some embodiments, the additive can be silver acetate.

[0019] In some embodiments, the organic solvent can be selected from one or more of 1,2-dichloroethane, toluene, trifluorotoluene, chlorobenzene, acetonitrile, 1,4-dioxane, 2,2,2-trifluoroethanol, dimethyl sulfoxide, N,N-dimethylformamide.

[0020] In some embodiments, the organic solvent can be chlorobenzene.

[0021] In some embodiments, the temperature of the heating reaction can be 80-160°C.

[0022] In some embodiments, the temperature of the heating reaction can be 120°C.

[0023] In some embodiments, the nitrone compound can be selected from one of the following compounds:

[0024]

[0025] In some embodiments, the allyl precursor compound can be propylene carbonate. DETAILED DESCRIPTION

[0026] The present application will be further described in conjunction with the following embodiments. The examples are intended to explain but not limit the present application in any manner. Unless otherwise specified, the raw materials and reagents used in the examples are conventional products that can be commercially available; the experimental methods not specifically described in the examples are generally carried out according to the conventional conditions in the art or according to the conditions recommended by the manufacturer.

[0027] Example 1

[0028]

[0029] The method for preparing 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compounds having the structure shown in Formula I-1 includes the following steps:

[0030] (1) Preparation of a nitrone compound having the structure shown in Formula II-1

[0031] At room temperature, 4-nitrotoluene (10.0 mmol, 1.0 equiv.), benzaldehyde (11.0 mmol, 1.1 equiv.) and ammonium chloride (12.0 mmol, 1.2 equiv.) were dissolved in a mixture of 40 mL of ethanol / water (v / v = 1 / 1). Then cooled to 0°C, after adding zinc powder (20.0 mmol, 2.0 equiv.), the reaction system was slowly raised to room temperature, and the stirring reaction was continued for 8 h. After the reaction was completed, filtration was performed, the filtrate was extracted with dichloromethane, the organic phase was dried with sodium sulfate and concentrated, and then purified by silica gel column chromatography to obtain compound II-1.

[0032] (2) Preparation of compound I-1

[0033] [Cp * Rh(CH3CN)3](SbF6)2(8 mg, 0.01 mmol, 5 mol%), AgOAc (50 mg, 0.3 mmol, 1.5 equiv.), compound II-1 (59 mg, 0.3 mmol, 1.5 equiv.), propylene carbonate (26 mg, 0.2 mmol, 1.0 equiv.) and chlorobenzene (2 mL) were added to a test tube. The reaction mixture was stirred at 120 °C for 10 h. After cooling to room temperature, the reaction mixture was filtered by washing with dichloromethane, the solvent was removed under reduced pressure, and the reaction mixture was purified by silica gel column chromatography with PE / EA (20:1) as eluent to obtain compound I-1 in a yield of 65%.

[0034] The spectral data of compound I-1 are as follows:

[0035] 1 H NMR (600 MHz, CDC13) δ 7.53-7.41 (m, 2H), 7.41-7.32 (m, 2H), 7.27-7.24 (m, 1H), 6.97 (d, J = 1.2 Hz, 2H), 6.94 (q, J = 1.1 Hz, 1H), 4.98-4.90 (m, 1H), 4.63-4.53 (m, 1H), 3.38 (dd, J = 16.5, 5.4 Hz, 1H), 2.68-2.57 (m, 2H), 2.51 (d, J = 16.5 Hz, 1H), 2.31 (s, 3H);

[0036] 13 C NMR (151 MHz, CDC13) δ 148.2, 143.9, 135.5, 130.3, 128.5, 127.2, 126.9, 126.4, 124.9, 121.8, 75.5, 75.1, 42.5, 34.7, 21.0;

[0037] HRMS (ESI): m / z [M+H] + calcd for C 17 H 18 NO: 252.1383, found: 252.1391.

[0038] Example 2

[0039]

[0040] The preparation method of 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compounds of structure as shown in formula I-2 is similar to that of Example 1, except that compound I-2 is prepared from nitrone compound of structure as shown in formula II-2 as substrate, with a yield of 57%.

[0041] The spectral data of compound I-2 are as follows:

[0042] 1 H NMR (600 MHz, CDC13) δ 7.47 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.27 (t, J = 7.4 Hz, 1H), 7.21-7.11 (m, 3H), 7.11-7.06 (m, 1H), 4.97 (ddd, J = 8.0, 4.7, 2.6 Hz, 1H), 4.63 (dd, J = 7.7, 3.6 Hz, 1H), 3.43 (dd, J = 16.5, 5.3 Hz, 1H), 2.66-2.58 (m, 2H), 2.56 (d, J = 16.5 Hz, 1H);

[0043] 13 C NMR (151 MHz, CDC13) δ 150.6, 143.7, 129.8, 128.5, 126.9, 126.6, 126.4, 125.9, 125.2, 122.0, 75.4, 75.1, 42.5, 34.7;

[0044] HRMS (ESI): m / z [M + H] + calcd for C 16 H 16 NO: 238.1226, found: 238.1253.

[0045] Example 3

[0046]

[0047] The preparation method of 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compounds of structure as shown in formula I-3 is similar to that of Example 1, except that compound I-3 is prepared from nitrone compound of structure as shown in formula II-3 as substrate, with a yield of 66%.

[0048] The spectral data of compound I-3 are as follows:

[0049] 1H NMR (600 MHz, CDC13) δ 7.48 - 7.41 (m, 2 H), 7.36 (dd, J = 8.5, 7.0 Hz, 2 H), 7.29 - 7.26 (m, 1 H), 7.17 - 7.11 (m, 2 H), 7.02 (d, J = 8.1 Hz, 1 H), 4.95 (ddd, J = 7.5, 5.3, 2.0 Hz, 1 H), 4.58 (dd, J = 8.5, 2.9 Hz, 1 H), 3.39 (ddd, J = 16.8, 5.5, 1.2 Hz, 1 H), 2.67 - 2.55 (m, 2 H), 2.53 (d, J = 16.7 Hz, 1 H);

[0050] 13 C NMR (151 MHz, CDC13) δ 148.10, 142.34, 130.12, 128.62, 127.50, 126.22, 126.07, 125.76, 125.33, 122.33, 74.35, 73.60, 41.48, 33.56;

[0051] HRMS (ESI): m / z [M + H] calcd for C + calcd for C 16 H 15 ClNO: 272.0837, found: 272.0867.

[0052] Example 4

[0053]

[0054] The preparation method of 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compounds of structure as shown in formula I-4 is similar to Example 1, except that compound I-4 is prepared from nitrone compound of structure as shown in formula II-4 as substrate, with a yield of 61%.

[0055] The spectral data of compound I-4 are as follows:

[0056] 1 H NMR (600 MHz, CDC13) δ 7.48 - 7.41 (m, 2 H), 7.36 (dd, J = 8.5, 7.0 Hz, 2 H), 7.29 - 7.26 (m, 1 H), 7.17 - 7.11 (m, 2 H), 7.02 (d, J = 8.1 Hz, 1 H), 4.95 (ddd, J = 7.5, 5.3, 2.0 Hz, 1 H), 4.58 (dd, J = 8.5, 2.9 Hz, 1 H), 3.39 (ddd, J = 16.8, 5.5, 1.2 Hz, 1 H), 2.67 - 2.55 (m, 2 H), 2.53 (d, J = 16.7 Hz, 1 H);

[0057] 13C NMR (151 MHz, CDCI3) δ 149.6, 143.3, 132.6, 129.7, 128.5, 127.7, 127.1, 126.3, 123.7, 118.9, 75.3, 74.6, 42.5, 34.5;

[0058] HRMS (ESI): m / z [M+H] + calcd for C 16 H 15 Br NO: 316.0332, found: 316.0361.

[0059] Example 5

[0060]

[0061] The preparation method of 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compounds of structure as shown in formula I-5 is similar to Example 1, except that compound I-5 is prepared from nitrone compound of structure as shown in formula II-5 as substrate, with a yield of 41 %.

[0062] The spectral data of compound I-5 is as follows:

[0063] 1 H NMR (600 MHz, CDCI3) δ 7.33 (dq, J = 1.9, 1.0 Hz, 1 H), 7.25-7.21 (m, 2H), 7.19-7.15 (m, 1 H), 7.15-7.12 (m, 2H), 7.08 (dd, J = 7.2, 1.3 Hz, 2H), 4.97 (ddd, J = 7.6, 5.4, 2.4 Hz, 1 H), 4.59 (dd, J = 8.1, 3.3 Hz, 1 H), 3.43 (dd, J = 16.5, 5.4 Hz, 1 H), 2.67-2.57 (m, 2H), 2.55 (d, J = 16.5 Hz, 1 H), 2.38 (s, 3H);

[0064] 13 C NMR (151 MHz, CDCI3) δ 149.6, 143.3, 132.6, 129.7, 128.5, 127.7, 127.1, 126.3, 123.7, 118.9, 75.3, 74.6, 42.5, 34.5;

[0065] HRMS (ESI): m / z [M+H] + calcd for C 17 H 18NO: 252.1383, found: 252.1326.

[0066] Examples 6-9

[0067] The preparation method is similar to Example 1, except that the allyl precursor compound is selected differently, and the yield of the compound prepared is shown in Table 1.

[0068] Table 1 Product yield in Examples 6-9

[0069] Example Allyl precursor compound Yield (%) Example 1 Propylene ethyl carbonate 65 Example 6 Propylene methyl carbonate 50 Example 7 Propylene acetate 30 Example 8 Allyl diethyl phosphate 40 Example 9 3-Bromopropene 10

[0070] Examples 10-12

[0071] The preparation method is similar to Example 1, except that the reaction system temperature is selected differently, and the yield of the compound prepared is shown in Table 2.

[0072] Table 2 Product yield in Examples 10-12

[0073] Example Reaction temperature (°C) Yield (%) Example 1 120 65 Example 10 80 43 Example 11 140 22 Example 12 160 10

[0074] Examples 13-19

[0075] The preparation method is similar to Example 1, except that the additive is selected differently, and the yield of the compound prepared is shown in Table 3.

[0076] Table 3 Product yield in Examples 13-19

[0077]

[0078]

[0079] Examples 20-27

[0080] The preparation method is similar to Example 1, except that the solvent is selected differently, and the yield of the compound prepared is shown in Table 4.

[0081] Table 4 Product yield in Examples 20-27

[0082] Example Additive Yield (%) Example 1 Chlorobenzene 65 Example 20 1,2-Dichloroethane 60 Example 21 Toluene 41 Example 22 Trifluorotoluene 47 Example 23 1,4-Dioxane 46 Example 24 2,2,2-Trifluoroethanol 19 Example 25 Acetonitrile 10 Example 26 N,N-Dimethylformamide 10 Example 27 Dimethyl sulfoxide 10

[0083] The above only describes some embodiments of the present application. For those skilled in the art, without departing from the concept of the present application, several modifications and improvements can be made, which are within the scope of protection of the present application.

Claims

1. Process for the preparation of 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compounds, characterized in that, The method comprises the following steps: adding a rhodium catalyst, an additive, a nitrone compound and an allyl precursor compound into an organic solvent, and heating to make the nitrone compound and the allyl precursor compound react under inert gas protection, so as to obtain a 2-aryl-2,3,4,5-tetrahydro-1,4-epoxybenzazepine compound shown in formula I; wherein, the nitrone compound is shown in formula II, and the allyl precursor compound is shown in formula III. A1 is aryl; A2 is selected from aryl or heteroaryl; one or more hydrogen atoms at different positions of the aryl ring or the aromatic heterocycle of the heteroaryl are independently substituted by one of the following substituents: H, halogen, alkyl, alkoxy, alkylthio, aryl and cyano; R is selected from one of formyl methyl ester, formyl ethyl ester, acetyl and phosphono diethyl ester; The rhodium catalyst is selected from one or more of [Cp*Rh(CH3CN)3](SbF6)2, [Cp*RhCl2]2, Cp*RhCl2(PPh2CH2OH) and Rh(OAc)3. The additive is selected from one or more of silver acetate, sodium acetate, cesium acetate, silver oxide, silver carbonate and pivalic acid.

2. The production method according to claim 1, characterized by, The organic solvent is selected from one or more of 1,2-dichloroethane, toluene, trifluorotoluene, chlorobenzene, acetonitrile, 1,4-dioxane, 2,2,2-trifluoroethanol, dimethyl sulfoxide and N,N-dimethylformamide.

3. The production method according to claim 1 or 2, characterized by, The molar ratio of the additive, the allyl precursor compound and the nitrone compound is (1-20):(0.5-1.5):(1-2); the amount of the rhodium catalyst is 1%-5% of the nitrone compound in terms of molar percentage.

4. The production method according to claim 3, characterized by, The temperature of the heating reaction is 80-160 DEG C.

5. The preparation method according to claim 4, characterized in that, The nitrone compound is selected from one of the following compounds: , , , , .

6. The preparation method according to claim 4, characterized in that, The allyl precursor compound is propylene carbonate.

7. The preparation method according to claim 6, characterized in that, The rhodium catalyst is [Cp * Rh(CH3CN)3](SbF6)2.

8. The preparation method according to claim 7, characterized in that, The additive is silver acetate.

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