A kind of preparation method for treating ovarian cancer Rucaparib intermediate
Technical field
The present invention relates to a kind of preparation methods for treating ovarian cancer Rucaparib intermediate, and in particular, to
The preparation method of the fluoro- 1,3,4,5- tetrahydro-azepine Zhuo of Rucaparib intermediate 8- simultaneously [5,4,3-cd] indoles -6- ketone.
Background technique
In recent years, statistics discovery, ovarian tumors rate increase year by year, have become the big killer for threatening women's health.
Regrettably, clinically still lack active drug at present.Rucaparib (trade name Rubraca) is a kind of poly- gland
Glycosides diphosphonic acid ribose polymerase inhibitor is researched and developed by Clovis tumour company.Its chemical name are as follows: the fluoro- 2- of 8- { 4- [(first ammonia
Base) methyl] phenyl } simultaneously [5,4,3-cd] indoles -6- ketone phosphate, molecular formula are -1,3,4,5- tetrahydro -6H- azatropylidenes
C19H18FN3O·H3PO4, CAS:459868-92-9, structural formula is as follows.
Rucaparib is as the first PARP inhibitor for human cancer therapy, and preclinical study shows to show
Good bioactivity, and the drug and various PI3K/mTOR signal pathway inhibitor (such as pictilisib, AZD-
2014 and and dactolisib) combination when show good curative effect, and there is association with dactolisib and Tarceva combination
Same-action;Rucaparib and the combination of long-acting 1 inhibitor etirinotecan monoclonal antibody of topoisomerase provide antitumor synergistic effect
Without increasing toxicity.In view of the importance of Rucaparib, Pharmaceutical Chemist has prepared more report to it.Research
It was found that at present with by fluoro- 1,3,4,5- tetrahydro-azepine Zhuo of intermediate 8-, simultaneously prepared by [5,4,3-cd] indoles -6- ketone
Rucaparib method is in the majority.But 1,3,4,5- tetrahydro-azepine Zhuo fluoro- for the 8- of intermediate simultaneously [5,4,3- in the prior art
Cd] there is also more problems for the preparation of indoles -6- ketone.
(Org.Process Res.Dev.2012,16, p1897-1904) is open for example, periodical literature reports a kind of 8-
The preparation method of fluoro- 1,3,4,5- tetrahydro-azepine Zhuos simultaneously [5,4,3-cd] indoles -6- ketone, this method is with 5- fluoro-2-methylbenzene first
Acid is raw material, is nitrified, is esterified to obtain the fluoro- 2- methyl-3-nitro methyl benzoate of 5-, catalytic hydrogenation obtains after reacting with DMFDMA
To the fluoro- 1H- indoles -4- methyl formate of 6-, obtained after then being reacted with 1- dimethylamino -2- nitroethylene through reduction, catalytic hydrogenation
To fluoro- 1,3,4,5- tetrahydro-azepine Zhuo of 8-, simultaneously [5,4,3-cd] indoles -6- ketone, specific reaction route are as follows:
Although this method can smoothly prepare intermediate, this method uses a large amount of nitric acid, sulfuric acid, is unfavorable for ring
It protects, the reaction step temperature of DMFDMA is higher, very exothermic when reaction, while the reaction yield of catalytic hydrogenation is low, and in fact
Expensive raw material price, production cost is high, which is unfavorable for industrialized production.
Summary of the invention
For the fluoro- 1,3,4,5- tetrahydro-azepine Zhuo of Rucaparib intermediate 8- in the prior art simultaneously [5,4,3-cd] Yin
There is also condition harshness, complex process, the defect that the reaction time is too long and yield is relatively low, spies to mention for the preparation method of diindyl -6- ketone
It is of the invention out.
To achieve the goals above, the present invention provides a kind of preparation side for treating ovarian cancer Rucaparib intermediate
Method, the preparation method the following steps are included:
1) in the presence of protective gas and inorganic base, by the fluoro- 5- trifyl methyl benzoate of 3- and (1- diazonium
Base -2- oxo -3- cyanopropyl) dimethyl phosphonate is stirred to react in organic solvent, it is stirred to react end, reaction solution concentration,
Wash to obtain mixture M;
2) it is stirred to react the resulting mixture M of step 1) to obtain 3- cyanoethyl-in acid condition in tetrahydrofuran
The fluoro- 1H- indoles -4- methyl formate of 6-;
3) palladium carbon is catalyzed the fluoro- 1H- indoles -4- methyl formate of 3- cyanoethyl -6- for obtaining step 2) in acid condition
Hydrogen is added to obtain the fluoro- 1,3,4,5- tetrahydro-azepine Zhuo of Rucaparib intermediate 8- simultaneously [5,4,3-cd] indoles -6- ketone.
In the case of in the present invention, it is preferred to, the preparation method can be realized by step in detail below:
1) in protective gas, first by the fluoro- 5- trifyl methyl benzoate of 3- and inorganic base in organic solvent into
Then row 5~10min of mixing is added (1- diazo -2- oxo -3- cyanopropyl) dimethyl phosphonate and is stirred to react at room temperature,
It is stirred to react end, reaction solution is concentrated under reduced pressure, and washes to obtain mixture M;
2) the resulting mixture M of step 1) is mixed in tetrahydrofuran with hydrochloric acid, is warming up to 40~60 DEG C and is stirred to react,
Reaction terminates, and sodium bicarbonate adjusts pH to 7~8, and ethyl acetate extraction is concentrated under reduced pressure to give the fluoro- 1H- indoles-of 3- cyanoethyl -6-
4- methyl formate;
3) the fluoro- 1H- indoles -4- methyl formate of 3- cyanoethyl -6-, palladium carbon and acetic acid that step 2) obtains are added to methanol
In, 30~40 DEG C of hydrogenation reactions are then heated to, after reaction, reaction solution is concentrated under reduced pressure, saturated sodium bicarbonate washing, water
It washes, filters, be dried to obtain fluoro- 1,3,4,5- tetrahydro-azepine Zhuo of Rucaparib intermediate 8- simultaneously [5,4,3-cd] indoles -6- ketone.
In the present invention, inventors have found that the fluoro- 5- trifyl methyl benzoate of 3- and (1- diazonium -2- oxo -
3- cyanopropyl) dimethyl phosphonate can be reacted rapidly under alkaline condition, and condensation life occurs in hydrochloric acid for products therefrom
At the fluoro- 1H- indoles -4- methyl formate of 3- cyanoethyl -6-, can be completed within two-step reaction 2~4 hours.It is more amazing to be,
Inventor has found that the fluoro- 1H- indoles -4- methyl formate of 3- cyanoethyl -6- adds hydrogen can be completed in next step in palladium carbon and acetic acid condition
The reduction of cyano and the intramolecular ammonolysis of methyl esters are to obtain the fluoro- 1,3,4,5- tetrahydro-azepine Zhuo of Rucaparib intermediate 8- simultaneously
[5,4,3-cd] indoles -6- ketone, the use of equivalent acetic acid have greatly accelerated hydrogenation and intramolecular ammonolysis speed, and 2~3 hours i.e.
It can.
In the present invention, in order to enable reaction is more abundant, under preferable case, in step 1), (1- diazo -2-
Oxo -3- cyanopropyl) molar ratio of dimethyl phosphonate and the fluoro- 5- trifyl methyl benzoate of 3-, inorganic base is
1:1~1.5:3~6.Inventor has attempted organic base and has carried out being catalyzed the reaction, although reaction can also be gone on smoothly, has
Machine alkali cannot be directly used in by simply post-processing removing for the next step, can generate salt, coating reaction in acid condition
Object hinders the progress of reaction, therefore preferred inorganic base, the inorganic base are more preferably sodium carbonate, potassium carbonate or cesium carbonate;
The organic solvent is methylene chloride, acetonitrile, glycol monoethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, 1,4- dioxy six
Ring, tetrahydrofuran, N,N-dimethylformamide or DMAC N,N' dimethyl acetamide.It is highly preferred that the inorganic base is cesium carbonate;Institute
State organic solvent be, 1,4- dioxane or tetrahydrofuran.
It is further preferred that (1- diazonium -2- oxo -3- cyanopropyl) dimethyl phosphonate and the fluoro- 5- trifluoro methylsulfonyl of 3-
Yl benzoic acid methyl esters, inorganic base molar ratio be 1:1.1~1.3:4~6.
In step 2) of the invention, the mole dosage of the hydrochloric acid will be more than that the equivalent of mixture M can just be gone on smoothly,
Preferably, the mole dosage of hydrochloric acid is 2~5 times of equivalents of mixture M;Preferably, the mole dosage of hydrochloric acid is the 3 of mixture M
Times equivalent.The concentration of the hydrochloric acid is not particularly limited, such as 1~6mol/L.
In method provided by the invention, it is special that inventor has found that the dosage of adjustment acetic acid has the generation of target product
Big influence, it is preferable that in step 3), the dosage molar ratio of the fluoro- 1H- indoles -4- methyl formate of 3- cyanoethyl -6- and acetic acid is
1:1~2, when the usage amount of acetic acid is catalytic amount or does not use acetic acid, product yield is reduced rapidly, and is greater than 1 equivalent
When, show comparatively ideal result;The palladium carbon dosage be the fluoro- 1H- indoles -4- methyl formate weight of 3- cyanoethyl -6- 5~
15%;Described plus hydrogen hydrogenation pressure is 0.2~1.2MPa.
In the present invention, the protective gas is nitrogen, argon gas or helium.
The fluoro- 1,3,4,5- tetrahydro-azepine Zhuo of Rucaparib intermediate 8- provided by the invention simultaneously [5,4,3-cd] indoles-
The preparation method of 6- ketone can be indicated by following route:
The present invention also provides a kind of preparation method of (1- diazo -2- oxo -3- cyanopropyl) dimethyl phosphonate, the party
Method reacts to obtain (2- oxygen with dimethyl methyl phosphonate as starting material using 2- malonic methyl ester nitrile at low temperature under alkaline condition
Generation -3- cyanopropyl) dimethyl phosphonate, then reacts to obtain (1- diazo -2- oxygen with azido compound under alkaline condition
Generation -3- cyanopropyl) dimethyl phosphonate.In a specific embodiment, (1- diazo -2- oxo -3- cyano of the invention
Propyl) dimethyl phosphonate preparation method include by 2- malonic methyl ester nitrile in the presence of LiHMDS with dimethyl methyl phosphonate
Reacted in -10~10 DEG C of THF and obtain (2- oxo -3- cyanopropyl) dimethyl phosphonate, washing concentration after with TsN3In nothing
Room temperature reaction obtains (1- diazo -2- oxo -3- cyanopropyl) dimethyl phosphonate under machine alkali.This method prepares (1- diazo-
2- oxo -3- cyanopropyl) dimethyl phosphonate high income, the reaction time is short, is Rucaparib intermediate 8- fluoro- 1,3,4,5-
Simultaneously [5,4,3-cd] indoles -6- ketone provides strong raw material guarantee to tetrahydro-azepine Zhuo.
Compared with prior art, the invention has the following advantages that
(1) preparation method of Rucaparib intermediate provided by the invention, target compound high income, purity is high;
(2) preparation method of Rucaparib intermediate provided by the invention, mild condition, step is less, the reaction time
It is short, it is more suitable industrialized production;
(3) the preparation method condition temperature of (1- diazo -2- oxo -3- cyanopropyl) dimethyl phosphonate provided by the invention
It is high with high income, reaction efficiency, it is fluoro- 1,3,4,5- tetrahydro-azepine Zhuo of Rucaparib intermediate 8- simultaneously [5,4,3-cd] Yin
Diindyl -6- ketone provides strong raw material guarantee.
Specific embodiment
The present invention is further described below by way of specific embodiment, the present invention is not limited only to following embodiment.In this hair
In bright range or the contents of the present invention are not being departed from, in spirit and scope, the change that carries out to the present invention is combined or replaced
It changes, will be apparent to the person skilled in the art, and be included within the scope of the present invention.
Preparation example 1
The preparation of (1- diazo -2- oxo -3- cyanopropyl) dimethyl phosphonate
Under ice bath, 220ml LiHMDS (1mol/L in THF) is instilled into dimethyl methyl phosphonate 13.6g (110mmol)
In mixed, then by 2- malonic methyl ester nitrile 9.9g (100mmol) be added said mixture in, keep ice bath stirring reaction
2 hours, monitor end of reaction.100ml saturated ammonium chloride quenching reaction is added, ethyl acetate extraction is added three times (80mlx3),
Merge organic phase, saturated common salt water washing, anhydrous magnesium sulfate is dry, is concentrated to get (2- oxo -3- cyanopropyl) phosphonic acids diformazan
Ester crude product is directly used in next step without being further purified.
(2- oxo -3- cyanopropyl) the dimethyl phosphonate crude product, p-toluene sulfonyt azide 23.7g (TsN that will be obtained3
It 120mmol) is dissolved in acetonitrile, potassium carbonate 20.7g (150mmol) then is added, reaction 8 hours, filtering is stirred at room temperature, filtrate subtracts
Pressure concentration, petroleum ether are recrystallized to give light yellow solid (1- diazo -2- oxo -3- cyanopropyl) dimethyl phosphonate 17.7g,
Yield 92.7%.HRMS (ESI+): Calcd.For C6H9N3O4P+218.0252 Found 218.0252.
1H NMR (400MHz, CDCl3) δ: 3.51 (s, 2H) 3.90 (s, 3H) 3.93 (s, 3H).
Preparation example 2
The preparation of (1- diazo -2- oxo -3- cyanopropyl) dimethyl phosphonate
Under ice bath, 200ml LiHMDS (1mol/L in THF) is instilled in dimethyl methyl phosphonate 14.8 (120mmol)
It is mixed, then 2- malonic methyl ester nitrile 9.9g (100mmol) is added in said mixture, keep ice bath stirring reaction 2
Hour, monitor end of reaction.100ml saturated ammonium chloride quenching reaction is added, ethyl acetate extraction is added three times (80mlx3), closes
And organic phase, saturated common salt water washing, anhydrous magnesium sulfate is dry, is concentrated to get (2- oxo -3- cyanopropyl) dimethyl phosphonate
Crude product is directly used in next step without being further purified.
(2- oxo -3- cyanopropyl) the dimethyl phosphonate crude product, p-toluene sulfonyt azide 21.7g (TsN that will be obtained3
It 110mmol) is dissolved in acetonitrile, potassium carbonate 22.1g (160mmol) then is added, reaction 7 hours, filtering is stirred at room temperature, filtrate subtracts
Pressure concentration, petroleum ether are recrystallized to give light yellow solid (1- diazo -2- oxo -3- cyanopropyl) dimethyl phosphonate 17.5g,
Yield 91.7%.
Embodiment 1
The preparation of the fluoro- 1H- indoles -4- methyl formate of 3- cyanoethyl -6-
1) under nitrogen protection, first by the fluoro- 5- trifyl methyl benzoate 33.2g (110mmol) of 3- and carbonic acid
Caesium 130.3g (400mmol) carries out 5~10min of mixing in 180ml tetrahydrofuran, and (1- diazo -2- oxo-is then added
3- cyanopropyl) dimethyl phosphonate 21.7g (100mmol) is stirred to react 1.5 hours at room temperature, it is stirred to react end, reaction solution
It is concentrated under reduced pressure, washes to obtain mixture M;
2) the resulting mixture M of step 1) and 50ml hydrochloric acid (6mol/L) are mixed in 150ml tetrahydrofuran, is heated up
It is stirred to react to 55 DEG C, reaction terminates 2 hours, and sodium bicarbonate adjusts pH to 7~8, and ethyl acetate extraction is concentrated under reduced pressure to give 3-
The fluoro- 1H- indoles -4- methyl formate 20.8g of cyanoethyl -6-, yield 89.6%.HRMS (ESI+): calcd.For C12H10FN2O2 +233.0648 found 233.0645.
1H NMR (400MHz, CDCl3) δ: 3.34 (s, 2H) 3.64 (s, 3H) 7.14~7.21 (m, 2H) 7.57 (m, 1H)
11.18(s,1H)。
Embodiment 2
The preparation of the fluoro- 1H- indoles -4- methyl formate of 3- cyanoethyl -6-
1) under nitrogen protection, first by the fluoro- 5- trifyl methyl benzoate 39.3g (130mmol) of 3- and carbonic acid
Caesium 162.9g (500mmol) carries out 5~10min of mixing in 180ml Isosorbide-5-Nitrae-dioxane, and (1- diazo -2- is then added
Oxo -3- cyanopropyl) dimethyl phosphonate 21.7g (100mmol) is stirred to react 2 hours at room temperature, is stirred to react end, it reacts
Liquid is concentrated under reduced pressure, and washes to obtain mixture M;
2) the resulting mixture M of step 1) and 67ml hydrochloric acid (6mol/L) are mixed in 150ml tetrahydrofuran, is heated up
It is stirred to react 1 hour to 60 DEG C, reaction terminates, and sodium bicarbonate adjusts pH to 7~8, and ethyl acetate extraction is concentrated under reduced pressure to give 3-
The fluoro- 1H- indoles -4- methyl formate 21.2g of cyanoethyl -6-, yield 91.2%.
Embodiment 3
The preparation of the fluoro- 1H- indoles -4- methyl formate of 3- cyanoethyl -6-
1) under nitrogen protection, first by the fluoro- 5- trifyl methyl benzoate 36.3g (120mmol) of 3- and carbonic acid
Potassium 82.8g (600mmol) carries out 5~10min of mixing in 150ml tetrahydrofuran, and (1- diazo -2- oxo -3- is then added
Cyanopropyl) dimethyl phosphonate 21.7g (100mmol) is stirred to react 2 hours at room temperature, it is stirred to react end, reaction solution decompression
Concentration, washes to obtain mixture M;
2) the resulting mixture M of step 1) and 85ml hydrochloric acid (6mol/L) are mixed in 150ml tetrahydrofuran, is heated up
It is stirred to react 2 hours to 45 DEG C, reaction terminates, and sodium bicarbonate adjusts pH to 7~8, and ethyl acetate extraction is concentrated under reduced pressure to give 3-
The fluoro- 1H- indoles -4- methyl formate 20.6g of cyanoethyl -6-, yield 88.7%.
Embodiment 4
The preparation of the fluoro- 1H- indoles -4- methyl formate of 3- cyanoethyl -6-
1) under nitrogen protection, first by the fluoro- 5- trifyl methyl benzoate 45.3g (150mmol) of 3- and carbonic acid
Potassium 41.4g (300mmol) carries out 5~10min of mixing in 120ml Isosorbide-5-Nitrae-dioxane, and (1- diazo -2- oxygen is then added
Generation -3- cyanopropyl) dimethyl phosphonate 21.7g (100mmol) is stirred to react 2 hours at room temperature, it is stirred to react end, reaction solution
It is concentrated under reduced pressure, washes to obtain mixture M;
2) the resulting mixture M of step 1) and 35ml hydrochloric acid (6mol/L) are mixed in 120ml tetrahydrofuran, is heated up
It is stirred to react 3 hours to 40 DEG C, reaction terminates, and sodium bicarbonate adjusts pH to 7~8, and ethyl acetate extraction is concentrated under reduced pressure to give 3-
The fluoro- 1H- indoles -4- methyl formate 20g of cyanoethyl -6-, yield 86.2%.
Embodiment 5
The preparation of the fluoro- 1H- indoles -4- methyl formate of 3- cyanoethyl -6-
1) under nitrogen protection, first by the fluoro- 5- trifyl methyl benzoate 33.2g (110mmol) of 3- and carbonic acid
Caesium 130.3g (400mmol) carries out 5~10min of mixing in 180ml tetrahydrofuran, and (1- diazo -2- oxo-is then added
3- cyanopropyl) dimethyl phosphonate 21.7g (100mmol) is stirred to react 2 hours at room temperature, it is stirred to react end, reaction solution subtracts
Pressure concentration, washes to obtain mixture M;
2) the resulting mixture M of step 1) and 50ml hydrochloric acid (6mol/L) are mixed in 150ml tetrahydrofuran, is heated up
It is stirred to react 4 hours to 75 DEG C, reaction terminates, and sodium bicarbonate adjusts pH to 7~8, and ethyl acetate extraction is concentrated under reduced pressure to give 3-
The fluoro- 1H- indoles -4- methyl formate 17.5g of cyanoethyl -6-, yield 75.3%.
Comparative example 1
The preparation of the fluoro- 1H- indoles -4- methyl formate of 3- cyanoethyl -6-
1) under nitrogen protection, first by the fluoro- 5- trifyl methyl benzoate 33.2g (110mmol) of 3- and three second
Amine 40.4g (400mmol) carries out 5~10min of mixing in 180ml tetrahydrofuran, and (1- diazo -2- oxo -3- is then added
Cyanopropyl) dimethyl phosphonate 21.7g (100mmol) is stirred to react 6 hours at room temperature, it is stirred to react end, reaction solution decompression
Concentration, washes to obtain mixture M;
2) the resulting mixture M of step 1) and 50ml hydrochloric acid (6mol/L) are mixed in 150ml tetrahydrofuran, is heated up
It is stirred to react 8 hours to 55 DEG C, sodium bicarbonate adjusts pH to 7~8, and ethyl acetate extraction is concentrated under reduced pressure to give 3- cyanoethyl -6-
Fluoro- 1H- indoles -4- methyl formate 15.9g, yield 68.8%.
Embodiment 5
By the fluoro- 1H- indoles -4- methyl formate 23.2g (100mmol) of 3- cyanoethyl -6-, palladium carbon 2.32g (10%) and second
Sour 6g (100mmol) is added in methanol, then heats to 35 DEG C of hydrogenation reactions (hydrogenation pressure 0.2MPa), and reaction terminates
Afterwards, reaction solution filters, filtrate decompression concentration, and saturated sodium bicarbonate washing is washed, filtering, and petroleum ether recrystallization is dried to obtain
Fluoro- 1,3,4,5- tetrahydro-azepine Zhuo of rucaparib intermediate 8- simultaneously [5,4,3-cd] indoles -6- ketone 20.2g, yield 94.4%,
Purity 99.58%.HRMS (ESI+): calcd.For C11H10FN2O+205.0699 found 205.0698.
1H NMR (400MHz, CDCl3) δ: 2.77~2.82 (m, 2H), 3.40~3.45 (m, 2H), 7.31~7.39
(m,2H),7.54(m,1H),8.22(s,1H),11.25(s,1H)。
Embodiment 6
By the fluoro- 1H- indoles -4- methyl formate 23.2g (100mmol) of 3- cyanoethyl -6-, palladium carbon 1.16g (5%) and acetic acid
12g (200mmol) is added in methanol, then heats to 40 DEG C of hydrogenation reactions (hydrogenation pressure 0.6MPa), after reaction,
Reaction solution filtering, filtrate decompression concentration, saturated sodium bicarbonate washing are washed, filtering, and petroleum ether recrystallization is dried to obtain
Fluoro- 1,3,4,5- tetrahydro-azepine Zhuo of rucaparib intermediate 8- simultaneously [5,4,3-cd] indoles -6- ketone 20.5g, yield 95.7%,
Purity 99.40%.
Embodiment 7
By the fluoro- 1H- indoles -4- methyl formate 23.2g (100mmol) of 3- cyanoethyl -6-, palladium carbon 3.48g (15%) and second
Sour 9g (150mmol) is added in methanol, then heats to 30 DEG C of hydrogenation reactions (hydrogenation pressure 1.2MPa), and reaction terminates
Afterwards, reaction solution filters, filtrate decompression concentration, and saturated sodium bicarbonate washing is washed, filtering, and petroleum ether recrystallization is dried to obtain
Fluoro- 1,3,4,5- tetrahydro-azepine Zhuo of rucaparib intermediate 8- simultaneously [5,4,3-cd] indoles -6- ketone 20.2g, yield 94.2%,
Purity 99.29%.
Embodiment 8
By the fluoro- 1H- indoles -4- methyl formate 23.2g (100mmol) of 3- cyanoethyl -6-, palladium carbon 2.32g (10%) and second
Sour 0.6g (10mmol) is added in methanol, then heats to 35 DEG C of hydrogenation reactions (hydrogenation pressure 0.2MPa), and reaction terminates
Afterwards, reaction solution filters, filtrate decompression concentration, and saturated sodium bicarbonate washing is washed, filtering, and petroleum ether recrystallization is dried to obtain
Fluoro- 1,3,4,5- tetrahydro-azepine Zhuo of rucaparib intermediate 8- simultaneously [5,4,3-cd] indoles -6- ketone 17.7g, yield 82.6%,
Purity 97.49%.
Comparative example 2
The fluoro- 1H- indoles -4- methyl formate 23.2g (100mmol) of 3- cyanoethyl -6- and palladium carbon 2.32g (10%) are added
Into methanol, 35 DEG C of hydrogenation reactions (hydrogenation pressure 0.2MPa) are then heated to, after reaction, reaction solution filtering, filtrate
It is concentrated under reduced pressure, saturated sodium bicarbonate washing is washed, filtering, and it is fluoro- to be dried to obtain rucaparib intermediate 8- for petroleum ether recrystallization
1,3,4,5- tetrahydro-azepine Zhuo simultaneously [5,4,3-cd] indoles -6- ketone 9.6g, yield 44.7%, purity 95.66%.