CN114133396A - Synthesis method of 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one - Google Patents
Synthesis method of 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one Download PDFInfo
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Abstract
The invention discloses a synthetic method of 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one, which comprises the following steps: reacting the compound shown in the formula II with a formalization reagent under the action of a catalyst to obtain a compound III; reacting the compound of the formula III with a reducing agent to obtain an intermediate compound of the formula IV, and continuously adding alkali and a cyanogen source into a reaction system without separation and purification to obtain a compound of the formula V; and (2) carrying out catalytic hydrogenation on the compound of the formula V under the action of a metal catalyst and an inorganic acid to obtain the compound of the formula I, namely the 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one. The synthetic method has reasonable route design, avoids nitration reaction, has mild and easily-controlled reaction conditions in the whole process, ensures safe production and is beneficial to environmental protection; the adopted raw materials are easy to obtain, the cost is low, the total yield of the route is high, and the product purity is good; the process route is simple, the synthesis period of the product is shortened, the production cost is reduced, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of synthesis of pharmaceutical and chemical intermediates, and particularly relates to a synthesis method of a drug Rucaparib key intermediate 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one.
Technical Field
Rucaparib (rucapaib) is a poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor, developed by cloviss tumor corporation, entitled "breakthrough therapy" in the united states in 2015, the first PARP inhibitor for human cancer therapy as a monotherapy for advanced ovarian cancer in BRCA (breast cancer susceptibility gene mutation), and multiple studies have shown that PARP is a good target for tumor treatment.
Chemical name of Rucaparib: 8-fluoro-2- { (4- [ (methylamino) methyl group)]Yl }1,3,4, 5-tetrahydro-6H-azepino [5,4,3-cd]Indol-6-one phosphate of formula C19H18FN3O·H3PO4CAS: 459868-92-9, having the formula:
rucaparib can be synthesized from a key intermediate 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-ketone (a compound shown in formula I) through bromination, Suzuki coupling, reductive amination and salification with phosphoric acid (Org. Process Res. Dev.,2012,16, 1897-:
the current literature is about a synthesis method of a Rucaparib key intermediate 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one (a compound shown in a formula I), and the synthesis method mainly comprises the following steps:
1. the synthetic route in the literature (org. process res. dev.,2012,16, 1897-:
the synthesis method has some disadvantages: 1) more waste acid is generated by nitration reaction which is explosive and dangerous, and safety and environmental protection are not facilitated; 2) the reaction temperature of DMFDMA is high, and the reaction heat release phenomenon is obvious; 3) NaBH4The yield of the reduction reaction is low, column chromatography purification is required, and the method is not suitable for industrial production.
2. The synthetic route in the literature (org. process res. dev.,2012,16, 1897-:
the synthesis method has low atom economy and low yield.
3. The synthetic route in the literature (intermediates of the fine chemical industry, 2012,42(5),48-52) is shown below:
the synthetic method has more reaction steps, needs nitration reaction, generates more waste acid, and is not beneficial to safety and environmental protection.
Although the methods can successfully synthesize 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one, the methods have great improvement space, so that a new synthesis process route of 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one with mild process conditions, safety and environmental protection is developed, and the method has important significance for the synthesis of Rucaparib.
Disclosure of Invention
The invention provides a synthesis method of a Rucaparib key intermediate 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one, which has the characteristics of mild reaction conditions, high yield, short steps, good atom economy, safety, environmental protection and the like.
The synthesis method of the 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one comprises the following steps:
(1) mixing a compound shown in a formula II with a formalization reagent, a catalyst and an organic solvent A to perform a formalization reaction to obtain a compound III:
(2) mixing the compound shown in the formula III with an organic solvent B, adding a reducing agent, carrying out reduction reaction, continuously adding alkali and a cyanogen source into a reaction system without separation and purification to obtain a compound shown in the formula IV, and carrying out cyanidation reaction to obtain a compound shown in the formula V:
(3) mixing the compound shown in the formula V with inorganic acid and an organic solvent C, and carrying out catalytic hydrogenation under the action of a metal catalyst to obtain a compound shown in the formula I, namely the 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one:
further, the formalizing agent in the step (1) is one of N, N-dimethylformamide, N-diethylformamide or N, N-diisopropylformamide, and N, N-dimethylformamide is preferred.
Further, the catalyst in the step (1) is one of phosphorus oxychloride, trifluoromethanesulfonic anhydride or oxalyl chloride, and is preferably phosphorus oxychloride.
Further, the organic solvent A in the step (1) is one of dichloromethane, tetrahydrofuran or acetonitrile, preferably tetrahydrofuran.
Further, the reaction temperature in the step (1) is-20 ℃ to 80 ℃, and preferably 0 ℃ to 50 ℃; the reaction time is 1-10 h, preferably 2-4 h.
Further, the molar ratio of the compound of formula II, the formalizing agent and the catalyst in step (1) is 1: (1-20): (1 to 5), preferably 1: (5-10): (2-4).
Further, the reducing agent in step (2) is one of sodium borohydride, potassium borohydride or lithium aluminum hydride, preferably sodium borohydride.
Further, the base in step (2) is one of triethylamine, pyridine, potassium carbonate, sodium bicarbonate, sodium hydroxide or potassium dihydrogen phosphate, preferably sodium bicarbonate.
Further, the cyanogen source in the step (2) is one of sodium cyanide, potassium cyanide or trimethylsilyl cyanide, preferably sodium cyanide.
Further, the organic solvent B in the step (2) is one of methanol, ethanol or isopropanol, preferably methanol.
Further, the reduction reaction temperature in the step (2) is-40 ℃ to 60 ℃, and preferably 0 ℃ to 20 ℃; the reduction reaction time is 0.5-6 h, preferably 0.5-2 h.
Further, the temperature of the cyanidation reaction in the step (2) is 0-80 ℃, preferably 30-60 ℃; the cyaniding reaction time is 1-16 h, preferably 3-8 h.
Further, the molar ratio of the compound of formula III, the reducing agent, the base and the cyanide source in step (2) is 1: (0.5-3): (1-5): (1 to 5), preferably 1: (0.5-1.5): (2-4): (1-3).
Further, the inorganic acid in the step (3) is one of formic acid, acetic acid or concentrated hydrochloric acid, preferably formic acid.
Further, the metal catalyst in the step (3) is one of Pd/C, Pt/C or Ru/C, preferably Pd/C.
Further, the organic solvent C in the step (3) is one of methanol, ethanol or isopropanol, preferably methanol.
Further, the reaction temperature in the step (3) is 30-80 ℃, preferably 30-50 ℃; the reaction time is 1-16 h, preferably 2-10 h.
Further, the molar ratio of the compound of formula V, the metal catalyst and the inorganic acid in step (3) is 1: (0.05-0.2): (0.5 to 3), preferably 1: (0.05-0.1): (1-2).
The invention has the following beneficial effects:
(1) the synthetic method has reasonable route design, avoids nitration reaction, has mild and easily-controlled reaction conditions in the whole process, ensures safe production and is beneficial to environmental protection;
(2) the synthesis method has the advantages of easily available raw materials, low cost, high total yield of the route and good product purity;
(3) the invention has simple process route, shortens the synthesis period of the product, reduces the production cost and is suitable for industrial production.
Drawings
FIG. 1 is a drawing showing a reaction scheme of the formula III in example 11H NMR spectrum;
FIG. 2 is a drawing showing the formula V in example 11H NMR spectrum;
FIG. 3 is a drawing of formula I in example 11H NMR spectrum.
The specific implementation mode is as follows:
the invention will be further illustrated with reference to the following specific examples. It should be noted that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention, and it should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention. Although efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), some errors and deviations should be accounted for. Unless otherwise specified, temperature is in units of ° c or at ambient temperature, and pressure is at or near atmospheric pressure.
Example 1
a) Synthesis of methyl 6-fluoro-3-formyl-1H-indole-4-carboxylate (Compound of formula III)
Adding 19.3g (0.1mol) of a compound shown as a formula II, 36.6g (0.5mol) of N, N-dimethylformamide and 300mL of tetrahydrofuran into a reactor, stirring to dissolve, slowly adding 30.2g (0.2mol) of phosphorus oxychloride at 0 ℃, then raising the temperature of a reaction solution to 30 ℃, continuing to react for 3 hours, adding ammonia water to adjust the pH to 8-10, evaporating to remove most of organic solvents, separating out solids, performing suction filtration, pulping a filter cake by using 50mL of saturated sodium bicarbonate solution, performing suction filtration and drying to obtain 20.8g of a light yellow solid (a compound shown as a formula III), wherein the yield is 98.4%, the HPLC purity is 97.8%, and the melting point is: 141 ℃ and 143 ℃.
Of compounds of formula III1The H NMR spectrum is shown in figure 1.
Nuclear magnetic data:1H NMR(400MHz,DMSO)δ10.06(s,1H),8.35(s,1H),7.56(dd,J＝9.2,2.4Hz,1H),7.37(dd,J＝9.6,2.4Hz,1H),3.86(s,3H)。
b) synthesis of methyl 3- (cyanomethyl) -6-fluoro-1H-indole-4-carboxylate (Compound of formula V)
In a reactor, 19.9g (0.09mol) of the compound of formula III and 250mL of methanol are added, stirred to dissolve, after-10 ℃ 3.4g (0.09mol) of sodium borohydride are added in portions, reaction is continued at-10 ℃ for 3 hours, then 22.6g (0.27mol) of sodium bicarbonate and 8.6g (0.18mol) of sodium cyanide are added, reaction is continued at 50 ℃ for 4 hours, after evaporation of most of the solvent, 100mL of water are added to precipitate the solid, suction filtration is carried out, the filter cake is slurried with 50mL of a saturated sodium bicarbonate solution, suction filtration and drying are carried out to obtain 17.5g of a white solid (compound of formula V), yield 83.7%, HPLC purity 96.1%, melting point: 154 ℃ and 152 ℃.
Of compounds of formula V1The H NMR spectrum is shown in figure 2.
Nuclear magnetic data:1H NMR(400MHz,CDCl3)δ8.54(s,1H),7.57(dd,J＝10.0,2.4Hz,1H),7.41–7.34(m,1H),7.27(dd,J＝8.0,2.8Hz,1H),4.13(s,2H),3.97(s,3H)。
c) synthesis of 8-fluoro-2, 3,4, 6-tetrahydro-1H-azacyclo [5,4,3-cd ] indol-1-one (compound of formula I)
In a reactor, 16.2g (0.07mol) of the compound of formula V, 1.6g (10%) Pd/C, 8.4g (0.14mol) formic acid and 200mL methanol were added, hydrogenation (hydrogen pressure 0.5MPa) was carried out at 30 ℃ for 8 hours, suction filtration was carried out, the filtrate was concentrated under reduced pressure, water was added to precipitate the product, filtration was carried out, the obtained solid was purified by beating with 50mL saturated sodium bicarbonate solution, suction filtration and drying were carried out to obtain 13.5g of a white solid (compound of formula I), yield 94.5%, HPLC purity 97.7%, melting point: 181 ℃ and 182 ℃.
Of compounds of formula V1The H NMR spectrum is shown in figure 3.
Nuclear magnetic data:1H NMR(400MHz,DMSO)δ11.20(s,1H),8.18(s,1H),7.38(m,2H),7.27(s,1H),3.41(d,J＝4.0Hz,2H),2.91(t,J＝4.0Hz,2H)。
example 2
a) Synthesis of methyl 6-fluoro-3-formyl-1H-indole-4-carboxylate (Compound of formula III)
19.3g (0.1mol) of the compound of the formula II, 30.3g (0.3mol) of N, N-diethylformamide and 300mL of acetonitrile are added into a reactor, after stirring and clearing, 45.3g (0.3mol) of phosphorus oxychloride is slowly added at 30 ℃, then the reaction liquid is raised to 70 ℃ and continuously reacted for 1 hour, ammonia water is added to adjust the pH value to 8-10, most of organic solvent is evaporated, solid is separated out by suction filtration, a filter cake is beaten by 50mL of saturated sodium bicarbonate solution, and the mixture is subjected to suction filtration and drying to obtain 20.1g of light yellow solid (the compound of the formula III), the yield is 95.1%, and the HPLC purity is 98.2%.
b) Synthesis of methyl 3- (cyanomethyl) -6-fluoro-1H-indole-4-carboxylate (Compound of formula V)
19.9g (0.09mol) of the compound of the formula III and 250mL of methanol are added to a reactor, stirred to dissolve, 2.7g (0.05mol) of potassium borohydride are added in portions at 0 ℃ after being stirred to dissolve, the reaction is continued for 1 hour at 50 ℃, then 36.4g (0.36mol) of triethylamine and 17.6g (0.27mol) of potassium cyanide are added, the reaction is continued for 3 hours at 40 ℃, most of the solvent is evaporated, 100mL of water is added to precipitate a solid, the filtration is carried out, a filter cake is pulped with 50mL of saturated sodium bicarbonate solution, the filtration and drying are carried out, 17.2g of a white solid (the compound of the formula V) is obtained, the yield is 82.2%, and the HPLC purity is 96.1%.
c) Synthesis of 8-fluoro-2, 3,4, 6-tetrahydro-1H-azacyclo [5,4,3-cd ] indol-1-one (compound of formula I)
16.2g (0.07mol) of the compound of formula V, 1.6g (10%) of Pt/C, 7.3g (0.07mol) of concentrated hydrochloric acid and 200mL of isopropanol are added into a reactor, hydrogenation (hydrogen pressure 0.5MPa) is carried out at 40 ℃ for 5 hours, suction filtration is carried out, the filtrate is decompressed and concentrated, water is added to precipitate a product, filtration is carried out, the obtained solid is pulped and purified by 50mL of saturated sodium bicarbonate solution, suction filtration and drying are carried out, 13.4g of white solid (the compound of formula I) is obtained, the yield is 93.8%, and the HPLC purity is 98.8%.
Example 3
a) Synthesis of methyl 6-fluoro-3-formyl-1H-indole-4-carboxylate (Compound of formula III)
19.3g (0.1mol) of the compound of the formula II, 109.7g (1.5mol) of N, N-diisopropylformamide and 300mL of acetonitrile are added into a reactor, after stirring and clearing, 141.1g (0.5mol) of trifluoromethanesulfonic anhydride is slowly added at-10 ℃, then the reaction liquid is raised to 20 ℃ and continuously reacted for 6 hours, ammonia water is added to adjust the pH to 8-10, most of the organic solvent is evaporated, a solid is separated out, suction filtration is carried out, a filter cake is beaten by 50mL of saturated sodium bicarbonate solution, suction filtration and drying are carried out, 19.8g of light yellow solid (the compound of the formula III) is obtained, the yield is 93.9%, and the HPLC purity is 96.5%.
b) Synthesis of methyl 3- (cyanomethyl) -6-fluoro-1H-indole-4-carboxylate (Compound of formula V)
19.9g (0.09mol) of the compound of the formula III and 250mL of ethanol are introduced into a reactor, stirred to dissolve, 10.3g (0.27mol) of lithium aluminium hydride are added in portions at-30 ℃ and the reaction is continued for 2 hours at 20 ℃ and subsequently 29.3g (0.09mol) of cesium carbonate and 8.9g (0.09mol) of trimethylsilyl cyanide are added and the reaction is continued for 7 hours at 10 ℃ and after evaporation of the major part of the solvent, 100mL of water are added to precipitate the solid, suction filtration is carried out, the filter cake is slurried with 50mL of saturated sodium bicarbonate solution, suction filtration and drying are carried out to give 16.3g of a white solid (compound of the formula V), yield 78.1% and HPLC purity 94.7%.
c) Synthesis of 8-fluoro-2, 3,4, 6-tetrahydro-1H-azacyclo [5,4,3-cd ] indol-1-one (compound of formula I)
16.2g (0.07mol) of the compound of formula V, 0.8g (5%) of Ru/C, 2.4g (0.04mol) of acetic acid and 200mL of ethanol are added into a reactor, hydrogenation (hydrogen pressure 0.5MPa) is carried out at 80 ℃ for 12 hours, suction filtration is carried out, the filtrate is decompressed and concentrated, water is added to separate out the product, filtration is carried out, the obtained solid is pulped and purified by 50mL of saturated sodium bicarbonate solution, suction filtration and drying are carried out, 12.6g of white solid (the compound of formula I) is obtained, the yield is 88.4%, and the HPLC purity is 97.5%.
Example 4
a) Synthesis of methyl 6-fluoro-3-formyl-1H-indole-4-carboxylate (Compound of formula III)
19.3g (0.1mol) of the compound of the formula II, 129.1g (1.0mol) of N, N-diisopropylformamide and 300mL of dichloromethane are added into a reactor, after stirring and clearing, 45.3g (0.3mol) of phosphorus oxychloride is slowly added at 10 ℃, then the reaction liquid is heated to 40 ℃ and continuously reacted for 2 hours, ammonia water is added to adjust the pH value to 8-10, most of organic solvent is evaporated, solid is separated out, suction filtration is carried out, a filter cake is beaten by 50mL of saturated sodium bicarbonate solution, suction filtration and drying are carried out, 20.6g of light yellow solid (the compound of the formula III) is obtained, the yield is 97.3%, and the HPLC purity is 98.0%.
b) Synthesis of methyl 3- (cyanomethyl) -6-fluoro-1H-indole-4-carboxylate (Compound of formula V)
19.9g (0.09mol) of the compound of the formula III and 250mL of isopropanol are introduced into a reactor, stirred to dissolve, 6.8g (0.18mol) of sodium borohydride are added in portions at 0 ℃ after dissolution, the reaction is continued for 5 hours at 0 ℃, then 14.0g (0.18mol) of pyridine and 6.9g (0.14mol) of sodium cyanide are added further, the reaction is continued for 2 hours at 60 ℃, after evaporation of most of the solvent, 100mL of water is added to precipitate the solid, the filtration is carried out, the filter cake is slurried with 50mL of a saturated sodium bicarbonate solution, the filtration and drying are carried out to obtain 17.0g of a white solid (the compound of the formula V), the yield is 81.3%, and the HPLC purity is 96.4%.
c) Synthesis of 8-fluoro-2, 3,4, 6-tetrahydro-1H-azacyclo [5,4,3-cd ] indol-1-one (compound of formula I)
16.2g (0.07mol) of the compound of formula V, 3.2g (20%) of Pt/C, 6.3g (0.06mol) of concentrated hydrochloric acid and 200mL of methanol are added into a reactor, hydrogenation (hydrogen pressure 0.5MPa) is carried out at 50 ℃ for 2 hours, suction filtration is carried out, the filtrate is decompressed and concentrated, water is added to precipitate a product, filtration is carried out, the obtained solid is pulped and purified by 50mL of saturated sodium bicarbonate solution, suction filtration and drying are carried out, 13.1g of white solid (the compound of formula I) is obtained, the yield is 91.5%, and the HPLC purity is 97.2%.
Example 5
a) Synthesis of methyl 6-fluoro-3-formyl-1H-indole-4-carboxylate (Compound of formula III)
19.3g (0.1mol) of the compound of the formula II, 14.6g (0.2mol) of N, N-dimethylformamide and 300mL of tetrahydrofuran are added into a reactor, stirred and dissolved clearly, 12.7g (0.1mol) of oxalyl chloride is slowly added at 0 ℃, then the reaction liquid is raised to 50 ℃ and continuously reacted for 2 hours, ammonia water is added to adjust the pH value to 8-10, most of organic solvent is evaporated, solid is separated out by suction filtration, a filter cake is beaten by 50mL of saturated sodium bicarbonate solution, and the mixture is subjected to suction filtration and drying to obtain 20.4g of light yellow solid (the compound of the formula III), the yield is 96.5%, and the HPLC purity is 98.8%.
b) Synthesis of methyl 3- (cyanomethyl) -6-fluoro-1H-indole-4-carboxylate (Compound of formula V)
19.9g (0.09mol) of the compound of the formula III and 250mL of methanol are added to a reactor, stirred to dissolve, 5.3g (0.14mol) of sodium borohydride are added in portions at 20 ℃ after dissolution, the reaction is continued for 3 hours at 20 ℃, then 24.5g (0.18mol) of potassium dihydrogen phosphate and 11.7g (0.18mol) of potassium cyanide are added further, the reaction is continued for 1 hour at 80 ℃, after most of the solvent is evaporated, 100mL of water is added to precipitate a solid, the filtration is carried out, the filter cake is slurried with 50mL of a saturated sodium bicarbonate solution, the filtration and the drying are carried out to obtain 16.8g of a white solid (the compound of the formula V), the yield is 80.5%, and the HPLC purity is 94.9%.
c) Synthesis of 8-fluoro-2, 3,4, 6-tetrahydro-1H-azacyclo [5,4,3-cd ] indol-1-one (compound of formula I)
16.2g (0.07mol) of the compound of formula V, 0.8g (5%) Pd/C, 12.6g (0.21mol) formic acid and 200mL of isopropanol are added into a reactor, hydrogenation (hydrogen pressure 0.5MPa) is carried out at 30 ℃ for 6 hours, suction filtration is carried out, the filtrate is decompressed and concentrated, water is added to precipitate the product, filtration is carried out, the obtained solid is pulped and purified by 50mL of saturated sodium bicarbonate solution, suction filtration and drying are carried out, 13.2g of white solid (the compound of formula I) is obtained, the yield is 92.4%, and the HPLC purity is 97.8%.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and enhancements can be made without departing from the spirit of the present invention, and these modifications and enhancements should also be considered within the scope of the present invention.
Claims (10)
1. A method for synthesizing 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one, which is characterized by comprising the following steps:
(1) reacting a compound shown in the formula II with a formalization reagent under the action of a catalyst to obtain a compound III:
(2) reacting the compound shown in the formula III with a reducing agent to obtain an intermediate compound shown in the formula IV, and continuously adding alkali and a cyanogen source into a reaction system without separation and purification to obtain a compound shown in the formula V:
(3) the compound shown in the formula V is subjected to catalytic hydrogenation under the action of a metal catalyst and an inorganic acid to obtain a compound shown in the formula I, namely the 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-ketone:
2. the method of synthesizing 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one according to claim 1, wherein the step (1) further comprises the following detailed steps: and (3) mixing the compound shown in the formula II with a formalization reagent, a catalyst and an organic solvent A to perform a formalization reaction to obtain a compound III.
3. The method of synthesizing 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one according to claim 2, wherein the formalizing reagent in step (1) is one of N, N-dimethylformamide, N-diethylformamide or N, N-diisopropylformamide; the catalyst is one of phosphorus oxychloride, trifluoromethanesulfonic anhydride or oxalyl chloride; the organic solvent A is one of dichloromethane, tetrahydrofuran or acetonitrile.
4. The method for synthesizing 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one according to claim 2, wherein the reaction temperature in the step (1) is-20 ℃ to 80 ℃ and the reaction time is 1 to 10 hours; the molar ratio of the compound of formula II, the formalizing agent and the catalyst is 1: (1-20): (1-5).
5. The method of claim 1, wherein step (2) further comprises the detailed steps of: and (3) mixing the compound of the formula III with an organic solvent B, adding a reducing agent, carrying out reduction reaction, continuously adding alkali and a cyanogen source into a reaction system without separation and purification of the obtained intermediate compound of the formula IV, and carrying out cyanidation reaction to obtain the compound of the formula V.
6. The method of synthesizing 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one of claim 5, wherein the reducing agent in step (2) is one of sodium borohydride, potassium borohydride or lithium aluminum hydride; the organic solvent B is one of methanol, ethanol or isopropanol; the reduction reaction temperature is-40 ℃ to 60 ℃, and the reduction reaction time is 0.5 to 6 hours.
7. The method of synthesizing 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one of claim 5, wherein the base in step (2) is one of triethylamine, pyridine, potassium carbonate, sodium bicarbonate, sodium hydroxide or potassium dihydrogen phosphate; the cyanogen source is one of sodium cyanide, potassium cyanide or trimethylsilyl cyanide.
8. The method for synthesizing 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one according to claim 5, wherein the cyanidation reaction temperature in the step (2) is 0-80 ℃ and the cyanidation reaction time is 1-16 h; the molar ratio of the compound of formula III, reducing agent, base and cyanide source is 1: (0.5-3): (1-5): (1-5).
9. The method of synthesizing 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one according to claim 1, wherein the synthesizing step (3) further comprises the following detailed steps: mixing a compound shown in the formula V, an inorganic acid and an organic solvent C, and carrying out catalytic hydrogenation under the action of a metal catalyst to obtain a compound shown in the formula I, namely the 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one.
10. The method for synthesizing 8-fluoro-1, 3,4, 5-tetrahydro-azepino [5,4,3-cd ] indol-6-one according to claim 9, wherein in step (3), the metal catalyst is one of Pd/C, Pt/C or Ru/C; the inorganic acid is one of formic acid, acetic acid or concentrated hydrochloric acid; the reaction temperature is 30-80 ℃, and the reaction time is 1-16 h; the molar ratio of the compound of formula V, metal catalyst and inorganic acid is 1: (0.05-0.2): (0.5 to 3).
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