CN112010797A - Benzazepine polycyclic compound and synthetic method thereof - Google Patents

Abstract

The invention discloses a benzazepine polycyclic compound and a synthesis method thereof, wherein the compound takes beta-keto ester as an initial raw material, is subjected to substitution with (2- (bromomethyl) benzyl) triphenyl phosphonium bromide and Wittig reaction under an alkaline condition through a one-pot method to obtain a benzazepine polycyclic containing double bonds, and is prepared by catalytic hydrogenation reduction. The invention realizes the synthesis of various benzoazepine polycycles by a one-pot method, has simple and convenient operation, can realize the rapid preparation in a laboratory, and can be used as an important intermediate in the pharmaceutical and pesticide industries.

Description

A kind of benzazepine heteropolycyclic compound and synthetic method thereof

technical field

The invention relates to a benzazepine heteropolycyclic compound and a synthesis method thereof, in particular to a β-ketoester as a starting material, through substitution and Wittig one-pot reaction, catalytic hydrogenation reduction reaction to prepare various Benzazepine method.

Background technique

Various benzazepine polycycles and related derivatives have wide application value in medicinal chemistry and organic synthesis. At present, there are few reports on the synthesis of benzazepine heteropolycycles, and the reaction routes similar to those in the literature are relatively long and the operating conditions are relatively harsh.

Reimann (Scientia Pharmaceutica, 1996, vol.64, #3-4, p.637-646) et al. reported that 4-benzylpiperidine-3-ethyl carboxylate was used as raw material, under polyphosphoric acid system, 140 ℃ reaction, cyclization reaction to obtain carbonyl-containing benzazepine polycycle. Then in the system of perchloric acid/hydrogen/palladium carbon/acetic acid, the carbonyl group is reduced to prepare the method of benzazepine polycycle. The raw materials used in this method are not only difficult to purchase directly, but also the synthetic method is rarely reported, and polyphosphoric acid is used in the operation process, which is inconvenient to operate, and the reaction temperature is high, which is difficult to realize rapid laboratory preparation, and more difficult to apply to industrial production. .

SUMMARY OF THE INVENTION

The present invention relates to a benzazepine heteropolycyclic compound and a synthesis method thereof. The raw materials are readily available, the operation is convenient, the reaction is easy to control, and the overall yield is suitable.

To achieve this purpose, the method used in the present invention is: a benzazepine polycyclic compound, characterized in that the compound structure is formula I:

wherein R is COOEt or COOMe or pyridine; G is Boc or Bn; m=1 or 2; n=1 or 2.

Preferred R=COOMe, G=Boc, m=1, n=1;

Preferred R=COOEt, G=Boc, m=2, n=1;

Preferred R=COOEt, G=Boc, m=2, n=2;

Preferred R=COOEt, G=Bn, m=1, n=1;

Preferred R=COOEt, G=Bn, m=2, n=1;

Preferred R=COOEt, G=Bn, m=2, n=2;

Preferred R=2-pyridyl, G=Boc, m=2, n=1.

A method for synthesizing a benzazepine heteropolycyclic compound, the steps of the method for synthesizing are that the raw material formula II is substituted with (2-(bromomethyl)benzyl)triphenylphosphonium bromide under basic conditions and Wittig One-pot reaction generates a compound such as formula III, followed by palladium-carbon catalytic hydrogenation to reduce the double bond to obtain formula I, and the reaction formula is as follows:

The specific process of the substitution and Wittig one-pot reaction is as follows: dissolving the β-ketoester as described in formula II in an aprotic solvent, adding a base under cooling, stirring for 30 min, and then adding (2-(bromine). Methyl)benzyl)triphenylphosphonium bromide, after overnight reaction, quenching, and purification to obtain a double bond-containing benzazepine polycycle as described in formula III, wherein β-ketoester and (2- The molar ratio of (bromomethyl)benzyl)triphenylphosphonium bromide was 1:1.1.

The specific process of the catalytic hydrogenation reduction of double bonds is as follows: dissolving the double bond-containing benzazepine polycyclic ring as described in formula III in methanol, adding palladium carbon, reacting under a hydrogen atmosphere, filtering, concentrating, Purification affords formula I.

The alkali is sodium hydrogen, potassium tert-butoxide, lithium bis-trimethylsilylamide or lithium diisopropylamide, preferably sodium hydrogen.

The aprotic solvent is tetrahydrofuran, diethyl ether, dioxane, N,N-dimethylformamide or N,N-dimethylacetamide, preferably tetrahydrofuran.

The reaction temperature is -10 to 25°C, preferably 0 to 10°C.

The beneficial effects are as follows: the present invention discloses a class of benzazepine heteropolycyclic compounds, which can be used as important chemical intermediates and are widely used in industries such as medicine and pesticides. The method for synthesizing the benzazepine polycyclic compound of the present invention adopts a "one-pot reaction" to obtain a double bond-containing benzazepine polycyclic compound through a two-step reaction of substitution and Wittig, and then undergoes catalytic hydrogenation reduction to obtain the The benzazepine polycyclic ring has the advantages of simple operation method, readily available raw materials and low production cost, and can realize rapid preparation in the laboratory.

Detailed ways

All features disclosed in this specification, or all disclosed steps in a method or process, may be combined in any way except mutually exclusive features and/or steps.

Any feature disclosed in this specification (including any accompanying claims, abstract), unless expressly stated otherwise, may be replaced by other equivalent or alternative features serving a similar purpose. That is, unless stated otherwise, each feature is only one example of a series of equivalent or similar features.

A benzazepine polycyclic compound, the compound structure is formula I:

wherein R is COOEt or COOMe or pyridine; G is Boc or Bn; m=1 or 2; n=1 or 2.

Preferred R=COOMe, G=Boc, m=1, n=1;

Preferred R=COOEt, G=Boc, m=2, n=1;

Preferred R=COOEt, G=Boc, m=2, n=2;

Preferred R=COOEt, G=Bn, m=1, n=1;

Preferred R=COOEt, G=Bn, m=2, n=1;

Preferred R=COOEt, G=Bn, m=2, n=2;

Preferred R=2-pyridyl, G=Boc, m=2, n=1.

A method for synthesizing a benzazepine heteropolycyclic compound, the steps of the method for synthesizing are that the raw material formula II is substituted with (2-(bromomethyl)benzyl)triphenylphosphonium bromide under basic conditions and Wittig One-pot reaction generates a compound such as formula III, followed by palladium-carbon catalytic hydrogenation to reduce the double bond to obtain formula I, and the reaction formula is as follows:

The specific process of the substitution and Wittig one-pot reaction is as follows: dissolving the β-ketoester as described in formula II in an aprotic solvent, adding a base under cooling, stirring for 30 min, and then adding (2-(bromine). Methyl)benzyl)triphenylphosphonium bromide, after overnight reaction, quenching, and purification to obtain a double bond-containing benzazepine polycycle as described in formula III, wherein β-ketoester and (2- The molar ratio of (bromomethyl)benzyl)triphenylphosphonium bromide was 1:1.1.

The specific process of the catalytic hydrogenation reduction of double bonds is as follows: dissolving the double bond-containing benzazepine polycyclic ring as described in formula III in methanol, adding palladium carbon, reacting under a hydrogen atmosphere, filtering, concentrating, Purification affords formula I.

The alkali is sodium hydrogen, potassium tert-butoxide, lithium bis-trimethylsilylamide or lithium diisopropylamide, preferably sodium hydrogen.

The aprotic solvent is tetrahydrofuran, diethyl ether, dioxane, N,N-dimethylformamide or N,N-dimethylacetamide, preferably tetrahydrofuran.

The reaction temperature is -10 to 25°C, preferably 0 to 10°C.

Example 1 Preparation method of dimethyl 2-tert-butyl-3-methyl-3a,4,9,9a-tetrahydro-1H-benzo[f]isoindole-2,3a-dicarboxylate, namely Its R=COOMe, G=Boc, m=1, n=1.

1.1 Preparation of 2-tert-butyl-3a,4-dihydro-1H-benzo[f]isoindole-2,3a(3H)-dicarboxylate methyl ester

Under N ₂ atmosphere, 1-tert-butyl 3-methyl ester of 4-oxopyrrolidine-1,3-dicarboxylate (125 mg, 0.51 mmol) was dissolved in 3 mL of anhydrous THF, and cooled to 0 °C with stirring. Add 60% NaH (51.4 mg, 1.29 mmol) and stir for 30 min. Then bromine (2-(bromomethyl)benzyl)triphenyl-15-phosphine (298 mg, 0.57 mmol) was added, and the reaction was carried out for 1 h. The reaction was followed by TLC, and the reaction was completed. 2 mL of water was added to the system, extracted with ethyl acetate (2 mL x 2), the organic phases were combined, washed with water, dried, concentrated, and purified by column chromatography to obtain 95 mg of white solid, namely the 2-tert-butyl-3a , 4-dihydro-1H-benzo[f]isoindole-2,3a(3H)-dicarboxylate methyl ester (yield: 56.1%). LC-MS (ESI+): m/z 352.2 (M+Na); ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.20-7.15 (m, 3H), 7.06 (d, J=6.9Hz, 1H), 6.49(s, 0.5H), 6.45(s, 0.5H), 4.40-4.36(m, 1H), 4.21-4.07(m, 2H), 3.59(s, 3H), 3.51-3.34 (m, 2H), 2.86 (d, J=15.3 Hz, 1H), 1.49 (s, 9H).

1.2 Preparation of 2-tert-butyl-3-methyl-3a,4,9,9a-tetrahydro-1H-benzo[f]isoindole-2,3a-dicarboxylic acid dimethyl ester

2-tert-Butyl-3a,4-dihydro-1H-benzo[f]isoindole-2,3a(3H)-dicarboxylate methyl ester (90 mg, 0.27 mmol) was dissolved in 2 mL of methanol, Add Pd/C (18 mg, 20% wt), stir at room temperature, and stir overnight under _H2 atmosphere. The reaction was followed by TLC and the reaction was complete. Filtration, concentration, and purification by column chromatography gave 72 mg of colorless oil, the 2-tert-butyl-3-methyl-3a,4,9,9a-tetrahydro-1H-benzo[f]isoindole - Dimethyl 2,3a-dicarboxylate (yield: 79.5%). LC-MS (ESI+): m/z 354.0 (M+Na); ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.17-7.12 (m, 4H), 3.77 (d, J=15.3Hz, 1H), 3.69(s, 3H), 3.58(d, J=6.3Hz, 1H), 3.40-3.14(m, 2H), 3.02-3.2.62(m, 5H), 1.42(s, 9H).

Example 2 Preparation method of ethyl 2-tert-butyl-3,4,5,10,10-hexahydrobenzo[g]isoquinoline-2,9-dicarboxylate, namely its R=COOEt, G= Boc, m=2, n=1.

2.1 Preparation of 2-tert-butyl-3,4,5-tetrahydrobenzo[g]isoquinoline-2,1-dicarboxylic acid ethyl ester

Under _N2 atmosphere, 1-tert-butyl 3-oxopiperidine-1,4-dicarboxylate 4-ethyl ester (100 mg, 0.37 mmol) was dissolved in 3 mL of anhydrous THF, and cooled to 0 °C with stirring. 60% NaH (37 mg, 0.93 mmol) was added and stirred for 30 min. Bromine (2-(bromomethyl)benzyl)triphenyl-15-phosphine (214 mg, 0.41 mmol) was added, and the reaction was carried out for 1 h. The reaction was followed by TLC, and the reaction was completed. 2 mL of water was added to the system, and extracted with ethyl acetate (2 mL x 2), the organic phases were combined, washed with water, concentrated, and purified by column chromatography to obtain 130 mg of colorless oil, namely the 2-tert-butyl-3 , 4,5-tetrahydrobenzo[g]isoquinoline-2,1-dicarboxylic acid ethyl ester (yield: 98.7%). LC-MS (ESI+): m/z 380.0 (M+Na); ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.15-7.03 (m, 4H), 6.45 (s, 1H), 4.59 (s, 1H) ,4.07-3.95(m,4H),3.25(d,J＝15.3 Hz,1H),3.08-3.01(m,1H),2.81(d,J＝15.3Hz,1H),2.33(d,J＝10.8 Hz, 1H), 1.73 (m, 1H), 1.48 (s, 9H), 1.09 (t, J=6.9Hz, 3H).

2.2 Preparation of 2-tert-butyl-3,4,5,10,10-hexahydrobenzo[g]isoquinoline-2,9-dicarboxylic acid ethyl ester

Ethyl 2-tert-butyl-3,4,5-tetrahydrobenzo[g]isoquinoline-2,1-dicarboxylate (120 mg, 0.34 mmol) was dissolved in 2.5 mL of methanol, and Pd/C ( 24 mg, 20% wt), stirred at room temperature, stirred overnight under H ₂ atmosphere, followed the reaction by TLC, and the reaction was completed. Filtration, concentration, and purification by column chromatography gave 112 mg of colorless oil, the 2-tert-butyl-3,4,5,10,10-hexahydrobenzo[g]isoquinoline-2,9- Ethyl diformate (yield: 92.8%). LC-MS (ESI+): m/z 382.2 (M+Na); ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.11-7.04 (m, 4H), 4.19-4.14 (m, 1H), 4.01 (q, J=7.2Hz, 2H), 3.41-3.08(m, 3H), 2.96-2.59(m, 4H), 2.19-1.88(m, 2H), 1.61(s, 1H), 1.47 (s, 9H), 1.08 (t, J=7.2 Hz, 3H).

Example 3 Preparation of ethyl 3-tert-butyl-4,5,6,11,11a-hexahydro-1H-naphtho[2,3-d]aza-3,11a(2H)-dicarboxylate method, ie its R=COOEt, G=Boc, m=2, n=2.

3.1 Preparation of 3-tert-butyl-4,5,6-tetrahydro-1H-naphtho[2,3-d]aza-3,6-dicarboxylic acid ethyl ester

Under _N2 atmosphere, 1-tert-butyl 5-oxoazepane-1,4-dicarboxylate 4-ethyl ester (100 mg, 0.35 mmol was dissolved in 3 mL of anhydrous THF, stirred and cooled to 0 °C. Add 60% NaH (35mg, 0.88 mmol), stir for 30min. Then add bromo(2-(bromomethyl)benzyl)triphenyl-15-phosphine (203mg, 0.39 mmol), react for 1h, follow the reaction by TLC, the reaction 2 mL of water was added to the system, and extracted with ethyl acetate (2 mL x 2), the organic phases were combined, washed with water, concentrated, and purified by column chromatography to obtain 130 mg of colorless oil, the 3-tert-butyl -4,5,6-Tetrahydro-1H-naphtho[2,3-d]aza-3,6-dicarboxylate (yield: 99.9%). LC-MS (ESI+): m/z 394.2 (M+Na); ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.11-7.08 (m, 3H), 6.97 (s, 1H), 6.34 (s, 0.5H), 6.30 (s, 0.5H ),4.20(q,J＝6.9Hz,2H),3.76-3.57(m,2H),3.32-3.14(m,3H),2.85-2.72(m,3H), 1.88-1.72(m,2H), 1.45-1.32 (m, 9H), 1.25 (t, J=7.2Hz, 3H).

3.2 Preparation of 3-tert-butyl-4,5,6,11,11a-hexahydro-1H-naphtho[2,3-d]aza-3,11a(2H)-ethyl dicarboxylate

3-tert-Butyl-4,5,6-tetrahydro-1H-naphtho[2,3-d]aza-3,6-dicarboxylate (120 mg, 0.32 mmol) was dissolved in 2.5 mL of methanol , added Pd/C (24 mg, 20% wt), stirred at room temperature, stirred overnight under H ₂ atmosphere, followed the reaction by TLC, and the reaction was completed. Filtration, concentration, and purification by column chromatography gave 102 mg of colorless oil, the 3-tert-butyl-4,5,6,11,11a-hexahydro-1H-naphtho[2,3-d]azepine -3,11a(2H)-ethyl dicarboxylate (yield: 84.5%). LC-MS (ESI+): m/z 396.2 (M+Na); ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.12-7.04 (m, 4H), 4.18-3.98 (m, 2H), 3.91-3.68 (m, 1H), 3.51-3.25(m, 2H), 3.21-2.61(m, 5H), 2.40-1.88(m, 2H), 1.87-1.66(m, 3H), 1.45(s, 9H), 1.25 -1.06(m, 3H).

Example 4 Preparation method of 2-benzyl-1,3,4,5,10,10-hexahydrobenzo[g]isoquinoline-1(2H)-carboxylic acid ethyl ester, that is, its R=COOEt, G =Bn, m=2, n=1.

4.1 Preparation of the trifluoroacetate salt of ethyl 3-oxopiperidine-4-carboxylate

1-(tert-butyl)4-ethyl 3-oxopiperidine-1,4-dicarboxylate (5.6 g, 20.6 mmol) was dissolved in 32 mL of DCM, 8 mL of TFA was added, and the reaction was stirred overnight. The reaction was followed by TLC. After the reaction, the reaction system was directly concentrated under reduced pressure to obtain 5.5 g of a yellow viscous product, that is, the trifluoroacetic acid salt of the ethyl 3-oxopiperidine-4-carboxylate (yield: 93% ). LC-MS (ESI+): m/z 172.2 (M+1).

4.2 Preparation of 1-benzyl-3-oxopiperidine-4-carboxylic acid ethyl ester

The trifluoroacetate salt of ethyl 3-oxopiperidine-4-carboxylate (2 g, 7.02 mmol) and benzaldehyde (0.82 g, 7.72 mmol) were dissolved in 30 mL of DCM, and the reaction was stirred at room temperature for 1 h, and then NaBH ( OAc) ₃ (2.98g, 14.0mmol), the reaction was stirred at room temperature overnight, TLC followed the reaction, after the reaction, 15mL of water was added to the system, and extracted with ethyl acetate (15mL×3), the organic phases were combined, and the organic phases were washed with saturated brine. phase, concentrated, and purified by column chromatography to obtain 1.38 g of yellow oily liquid, namely the ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (yield: 78%). LC-MS (ESI+): m/z 262.2 (M+1); ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.53-7.36 (m, 5H), 4.37 (s, 2H), 4.25 (q, J= 7.2Hz, 2H), 3.91-3.78(m, 1H), 3.62-3.35(m, 2H), 2.53-2.30(m, 2H), 1.73-1.50(m, 2H), 1.01(t, J＝7.2Hz , 3H).

4.3 Preparation of ethyl 2-benzyl-1,3,4,5-tetrahydrobenzo[g]isoquinolinecarboxylate

Under N atmosphere, ethyl ₁ -benzyl-3-oxopiperidine-4-carboxylate (230 mg, 0.88 mmol) was dissolved in 15 mL of THF, stirred and cooled to 0 °C, and 60% NaH (70 mg, 1.76 mmol) was added. ), stirred for 30 min, added bromo(2-(bromomethyl)benzyl)triphenyl-15-phosphine (510 mg, 0.97 mmol), and reacted overnight. The reaction was followed by TLC, after the reaction was completed, 20 mL of water was added to the system, and extracted with ethyl acetate (10 mL x 3), the organic phases were combined, the organic phases were washed with saturated brine, concentrated, and purified by column chromatography to obtain 180 mg of a yellow oily liquid, namely The ethyl 2-benzyl-1,3,4,5-tetrahydrobenzo[g]isoquinolinecarboxylate (yield: 59%). LC-MS (ESI+): m/z 348.2 (M+1); ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.42-7.27 (m, 5H), 7.12-6.98 (m, 4H), 6.40 (s ,1H),4.73(s,2H),4.04(q,J=6.9Hz,2H),3.71-3.53(m,2H),3.25(d,J=15.6Hz,1H),3.14(d,J= 15.6Hz, 1H), 2.96-2.80(m, 2H), 2.25-2.09(m, 1H), 1.97-1.82(m, 1H), 1.08(t, J=7.2Hz, 3H).

4.4 Preparation of 2-benzyl-1,3,4,5,10,10-hexahydrobenzo[g]isoquinoline-1(2H)-carboxylic acid ethyl ester

2-Benzyl-1,3,4,5-tetrahydrobenzo[g]isoquinolinecarboxylate ethyl ester (60mg, 0.17mmol) was dissolved in 10mL methanol, added Pd/C (6mg), stirred at room temperature , under _H2 atmosphere, stirred overnight, followed the reaction by TLC, after the reaction was over, filtered, concentrated, and purified by thin layer chromatography to obtain 48 mg of oily liquid, namely the 2-benzyl-1,3,4,5,10,10 - Hexahydrobenzo[g]isoquinoline-1(2H)-carboxylic acid ethyl ester (yield: 80%). LC-MS (ESI+): m/z 350.2 (M+1); ¹ H NMR (300 MHz, MeOD): δ 7.42-7.27 (m, 5H), 7.12-6.98 (m, 4H), 4.07 (q, J ＝6.9Hz, 2H), 3.78-3.60(s, 2H), 3.25-3.13(m, 2H), 2.98-2.88(m, 2H), 2.72-2.64(m, 2H), 2.33-2.21(m, 2H) ), 2.01-1.92(m, 1H), 1.89-1.76(m, 1H), 1.70-1.53(m, 1H), 1.02(t, J=7.2Hz, 3H).

Example 5 Preparation method of 4a-(pyridin-2-yl)-3,4,4a,5,10,10a-hexahydrobenzo[g]isoquinoline-2(1H)-carboxylic acid tert-butyl ester, namely Its R=2-pyridyl, G=Boc, m=2, n=1.

5.1 Preparation of 3-oxo-4-(pyridin-2-yl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl)4-ethyl ester

Under N atmosphere, 1-(tert-butyl) 4-ethyl ₃ -oxopiperidine-1,4-dicarboxylate (5 g, 18.4 mmol) was dissolved in 100 mL of THF, the system was cooled to -78 °C, added LHMDS (37 mL, 37 mmol, 1 M in THF) was stirred for 30 min. Then 2-fluoropyridine (3.58 g, 36.8 mmol) was added and the reaction was stirred overnight. The reaction was followed by TLC. After the reaction was completed, water was added to the system, extracted with ethyl acetate (30 mL x 3), the organic phases were combined, concentrated, and purified by column chromatography to obtain 2.5 g of a yellow viscous product, that is, the 3-oxygen Sub-4-(pyridin-2-yl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl)4-ethyl ester (yield: 39%). LC-MS (ESI+): m/z 349.2 (M+1).

5.2 Preparation of tert-butyl 3-oxo-4-(pyridin-2-yl)piperidine-1-carboxylate

Under N atmosphere, ₃ -oxo-4-(pyridin-2-yl)piperidine-1,4-dicarboxylic acid 1-(tert-butyl)4-ethyl ester (2 g, 5.7 mmol) was mixed with LiCl (1.95 g, 46 mmol) was dissolved in 70 mL of DMF, stirred and heated to 110 °C to react. The reaction was followed by TLC, after the reaction was completed, 150 mL of water was added to the system, and extracted with ethyl acetate (30 mL x 3), the organic phases were combined, the organic phases were washed with saturated brine, concentrated, and purified by column chromatography to obtain 900 mg of a yellow solid, namely the tert-butyl 3-oxo-4-(pyridin-2-yl)piperidine-1-carboxylate (yield: 56%). LC-MS (ESI+): m/z 277.2 (M+1).

5.3 Preparation of 4a-(pyridin-2-yl)-3,4,4a,5-tetrahydrobenzo[g]isoquinoline-2(1H)-carboxylic acid tert-butyl ester

Under _N2 atmosphere, tert-butyl 3-oxo-4-(pyridin-2-yl)piperidine-1-carboxylate (900 mg, 3.3 mmol) was dissolved in 20 mL of THF, stirred and cooled to 0 °C, added 60% NaH (300 mg, 7.5 mmol), stirred for 30 min, added bromo(2-(bromomethyl)benzyl)triphenyl-15-phosphine (1.89 g, 3.6 mmol) dissolved in 5 mL of THF solution, and reacted overnight. The reaction was followed by TLC. After the reaction was completed, 20 mL of water was added to the system, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, the organic phases were washed with saturated brine, concentrated, and purified by column chromatography to obtain 600 mg of solid, that is, the 4a-(Pyridin-2-yl)-3,4,4a,5-tetrahydrobenzo[g]isoquinoline-2(1H)-carboxylic acid tert-butyl ester (yield: 51%). LC-MS (ESI+): m/z 363.2 (M+1); ¹ H NMR (300 MHz, MeOD): δ 8.40 (d, J=4.2 Hz, 1H), 7.50-7.47 (m, 1H), 7.45 -7.44(m, 2H), 7.27-7.11(m, 3H), 6.96-6.93(m, 1H), 6.17-6.16(m, 1H), 4.14-4.00(m, 2H), 3.52-3.46(m, 1H), 3.31-3.30(m, 1H), 2.92-2.90(m, 1H), 2.37-2.28(m, 2H), 1.82-1.78(m, 1H), 1.12(s, 9H).

5.4 Preparation of 4a-(pyridin-2-yl)-3,4,4a,5,10,10a-hexahydrobenzo[g]isoquinoline-2(1H)-carboxylic acid tert-butyl ester

4a-(Pyridin-2-yl)-3,4,4a,5-tetrahydrobenzo[g]isoquinoline-2(1H)-carboxylic acid tert-butyl ester (600 mg, 1.7 mmol) was dissolved in 15 mL of methanol , added Pd/C (200 mg), stirred at room temperature, and stirred overnight under H ₂ atmosphere. The reaction was followed by TLC. After the reaction was completed, it was filtered, concentrated, and purified by column chromatography to obtain 480 mg of white solid, namely the 4a-(pyridin-2-yl)-3,4,4a,5,10,10a-hexahydrobenzo [g] Isoquinoline-2(1H)-carboxylate tert-butyl ester (yield: 80%). LC-MS (ESI+): m/z 363.2 (M+1); ¹ H NMR (300MHz, MeOD): δ8.42 (d, J=4.2Hz, 1H), 7.61-7.55 (m, 1H), 7.26-7.14(m, 4H), 7.10-7.05(m, 1H), 6.93(d, J=7.5Hz, 1H), 3.99-3.93(m, 2H), 3.58-3.53(m, 1H), 3.30- 3.24(m,1H), 2.48-2.39(m,2H), 2.14-2.13(m,1H), 1.94-1.89(m,2H), 1.68-1.50(m,2H), 1.10(s,9H).

In the above embodiment, DCM is dichloromethane, TFA is trifluoroacetic acid, DMF is N,N-dimethylformamide, LHMDS is lithium bistrimethylsilylamide, TLC is thin layer chromatography, LC-MS For liquid chromatography mass spectrometry.

The present invention is not limited to the foregoing specific embodiments. The present invention extends to any new features or any new combination disclosed in this specification, as well as any new method or process steps or any new combination disclosed.

Claims (9)

1. a benzazepine heteropolycyclic compound, is characterized in that, described compound structure is formula I:

2 . The benzazepine polycyclic compound according to claim 1 , wherein R is COOEt or COOMe or pyridine; G is Boc or Bn; m=1 or 2; n=1 or 2. 3 . 3. The benzazepine polycyclic compound according to claim 2, wherein Preferred R=COOMe, G=Boc, m=1, n=1; Preferred R=COOEt, G=Boc, m=2, n=1; Preferred R=COOEt, G=Boc, m=2, n=2; Preferred R=COOEt, G=Bn, m=1, n=1; Preferred R=COOEt, G=Bn, m=2, n=1; Preferred R=COOEt, G=Bn, m=2, n=2; Preferred R=2-pyridyl, G=Boc, m=2, n=1. 4. a kind of synthetic method of preparing the described benzazepine polycyclic compound of claim 1, is characterized in that, described synthetic method step is to mix raw material formula II with (2-(bromomethyl) benzyl under basic condition base) triphenylphosphonium bromide generation substitution and Wittig one-pot reaction to generate compound such as formula III, followed by palladium-carbon catalytic hydrogenation reduction double bond, to obtain formula I, the reaction formula is as follows:

5. the synthetic method of benzazepine heteropolycyclic compound according to claim 4, is characterized in that, the concrete process of described substitution and Wittig one-pot reaction is: the β-ketoester as described in formula II is dissolved In an aprotic solvent, add a base under cooling, stir for 30 min, then add (2-(bromomethyl)benzyl)triphenylphosphonium bromide, after overnight reaction, quench and purify to obtain formula III In the double bond-containing benzazepine polycyclic ring, the molar ratio of β-ketoester to (2-(bromomethyl)benzyl)triphenylphosphonium bromide is 1:1.1. 6. the synthetic method of benzazepine heteropolycyclic compound according to claim 4, is characterized in that, the concrete process of described catalytic hydrogenation reduction double bond is, will be as described in formula III containing the benzophenone containing double bond The nitrogen heteropolycycle is dissolved in methanol, added with palladium carbon, reacted under a hydrogen atmosphere, filtered, concentrated and purified to obtain formula I. 7. the synthetic method of benzazepine heteropolycyclic compound according to claim 5, is characterized in that, described alkali is sodium hydrogen, potassium tert-butoxide, bistrimethylsilyl amide lithium or diisopropyl Lithium amide, preferably sodium hydrogen. 8. the synthetic method of benzazepine heteropolycyclic compound according to claim 5 is characterized in that, aprotic solvent is tetrahydrofuran, ether, dioxane, N,N-dimethylformamide or N, N-dimethylacetamide, preferably tetrahydrofuran. 9 . The method for synthesizing benzazepine heteropolycyclic compounds according to claim 5 , wherein the reaction temperature is -10 to 25° C., preferably 0 to 10° C. 10 .