CN106831793B - A kind of synthesis technology for treating ovarian cancer Rucaparib intermediate - Google Patents
A kind of synthesis technology for treating ovarian cancer Rucaparib intermediate Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
Abstract
The invention discloses a kind of synthesis technologies for treating ovarian cancer Rucaparib intermediate, which is characterized in that the synthesis technology includes: to react Formula II compound represented in acid condition to obtain Rucaparib intermediate shown in Formulas I；
Description
Technical field
The present invention relates to a kind of synthesis technologies of ovarian cancer intermediate, and in particular, to Rucaparib intermediate 8-
The synthesis technology of fluoro- 1,3,4,5- tetrahydro-azepine Zhuo 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 research report to it.
At present the preparation method of Rucaparib mainly pass through the fluoro- 1,3,4,5- tetrahydro-azepine Zhuo of intermediate 8- simultaneously [5,4,
3-cd] preparation of indoles -6- ketone, and intermediate 8- fluoro- 1, simultaneously prepared by [5,4,3-cd] indoles -6- ketone for 3,4,5- tetrahydro-azepine Zhuos
In mainly by small molecule synthesis of indole then again cyclization obtain intermediate.That there are reaction steps is various for these methods, yield is high,
The defects of higher cost, and there is also largely use nitric acid, sulfuric acid.Indoles or substituted indole are a kind of works of maturation
Industry compound, if it is considered that being reacted from indoles basis, production cost will necessarily be reduced and reaction step can also be reduced,
It is more favorable for industrialized production.However there is no not similar or to be suitable for the fluoro- 1,3,4,5- tetrahydro-azepine of intermediate 8- tall and erect at present
And the report of [5,4,3-cd] indoles -6- ketone preparation.
Summary of the invention
It is an object of the invention to overcome the existing fluoro- 1,3,4,5- tetrahydro-azepine Zhuo of Rucaparib intermediate 8- simultaneously
The synthesis technology existence condition of [5,4,3-cd] indoles -6- ketone is harsh, reaction step is more, the reaction time is too long and yield is relatively low
The defects of, provide a kind of reaction step it is few, high income be more suitable industrialized production Rucaparib intermediate preparation
Method.
To achieve the goals above, the present invention provides a kind of synthesis work for treating ovarian cancer Rucaparib intermediate
Skill, wherein the synthesis technology includes: to react Formula II compound represented in acid condition to obtain shown in Formulas I
Rucaparib intermediate；
In the present invention, inventor's discovery directly obtains targeted by Beckmann rearrangement by the ketoxime of specific structure
Object is closed, simple synthetic method, high income, effect is better than existing commonsense method.Under preferable case, the condition of the synthesis technology
Include: reaction temperature it is 40~50 DEG C, resets speed faster at this temperature, and change of configuration will not occur for raw material, avoid out
Existing by-product.The acid condition refers to carry out in the presence of acidic materials, and the acidic materials are sulfuric acid, polyphosphoric acids, five
One of phosphorus chloride, phosphorus trichloride, phosphorus oxychloride and benzene sulfonyl chloride are a variety of, the acidic materials be preferably phosphorus trichloride or
Phosphorus oxychloride；The solvent of reaction is acetonitrile or tetrahydrofuran.
In the present invention, since the configuration of Formula II compound represented ketoxime directly affects product, in order to enable react to
The direction of production II compound represented carries out, and is preferably prepared by following steps:
1) the fluoro- indole -5-carboxylic acid methyl esters of 7- in the presence of palladium catalyst and acid binding agent with glycol dibromide in acetonitrile
Back flow reaction obtains the fluoro- indole -5-carboxylic acid methyl esters of 3- (2- bromoethyl) -7-；
2) the fluoro- indole -5-carboxylic acid methyl esters of 3- (2- bromoethyl) -7- obtained step 1) and a small amount of iodine are in absolute ether
Middle magnesium chips is stirred to the fluoro- indole -5-carboxylic acid methyl esters of 3- (2- ethylmagnesium bromide) -7- is generated, and gained reacting liquid temperature is adjusted to
35~50 DEG C are stirred to react 3~5 hours, and reaction terminates, and are poured into saturated ammonium chloride under ice bath, and methylene chloride extraction washs, is dense
Contract dry the fluoro- cyclohexyl of 8- simultaneously [5,4,3-cd] indoles -6- ketone；
3) by the fluoro- cyclohexyl of 8-, simultaneously [5,4,3-cd] indoles -6- ketone, hydroxylamine hydrochloride and copper acetate are added in ethyl alcohol,
Then the lower ammonium hydroxide that instills of stirring adjusts pH to 8~9, back flow reaction 20~30 minutes, filters while hot, cooling, crystallization filters to obtain formula
II compound represented.
In the present invention, it is preferred in step 1), the fluoro- indole -5-carboxylic acid methyl esters of 7- and acid binding agent, 1,2- dibromo second
The mole dosage ratio of alkane can be 1:3~5:1~1.2；The palladium catalyst is tetra-triphenylphosphine palladium, and palladium catalyst dosage is
The 5~10% of the fluoro- indole -5-carboxylic acid methyl esters weight of 7-；The acid binding agent is sodium carbonate, potassium carbonate or cesium carbonate.
In the case of in the present invention, it is preferred to, in step 2), the fluoro- indole -5-carboxylic acid first of 3- (2- the bromoethyl) -7-
The mole dosage of ester and magnesium chips ratio is 1:1~1.1；Relative to the fluoro- indole -5-carboxylic acid methyl esters of every g 3- (2- bromoethyl) -7-),
The dosage of the absolute ether is 10~30ml.Step 2) is the generation step of Grignard Reagent, very crucial for the present invention, should
Step requires stringent waterless operation, and the absolute ether refers to that absolutely anhydrous ether, preparation method can be according to this field routines
Method, such as add sodium silk dry anhydrous ether, then benzophenone agent of giving instruction is steamed to blue, then steams use.
In the present invention, inventor has found that the use of a large amount of solvents can be especially intermolecular to avoid the generation of by-product
The generation of the product of reaction, it is further preferred that relative to the fluoro- indole -5-carboxylic acid methyl esters of every g 3- (2- bromoethyl) -7-), institute
The dosage for stating absolute ether is 18~25ml.
In the present invention, although the preparation of ketoxime can be carried out using conventional method, since oxime configuration is for reaction
As a result importance, such mistake are unfavorable for the purifying of subsequent product, and formula can be improved by using copper acetate in inventor's discovery
The ketoxime compounds of structure shown in II generate, it is preferable that in step 3), the fluoro- cyclohexyl of 8- simultaneously [5,4,3-cd] indoles -6- ketone
Molar ratio with hydroxylamine hydrochloride, copper acetate is 1:1.2~1.5:0.1~0.3.
Preferably, step 1) and step 2) separately carry out in the presence of protective gas, and the protective gas is nitrogen
Gas, argon gas or helium.
Compared with prior art, the invention has the following advantages that
(1) synthesis technology of Rucaparib intermediate provided by the invention, reaction step is few, and production cost is low, is more suitable for
Industrialized production；
(2) the synthesis technology reaction time of Rucaparib intermediate provided by the invention is short, high production efficiency；
(3) synthesis technology of Rucaparib intermediate provided by the invention, target compound high income, purity is high.
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.
Embodiment 1
The synthesis of the fluoro- indole -5-carboxylic acid methyl esters of 3- (2- bromoethyl) -7-
Under nitrogen protection, by the fluoro- indole -5-carboxylic acid methyl esters 19.3g (100mmol) of 7-, tetra-triphenylphosphine palladium 0.97g, carbon
Sour potassium 41.4g (300mmol) and back flow reaction 2 hours in 150ml acetonitrile 1,2- Bromofume 20.7g (110mmol), monitoring
Reaction terminates, and reaction solution is cooled to room temperature, filtering, and filtrate washing, ethyl acetate extracts three times, merges organic phase, anhydrous slufuric acid
Sodium is dry, is concentrated under reduced pressure, and petroleum ether is recrystallized to give 3- (2- bromoethyl) fluoro- indole -5-carboxylic acid methyl esters 27.5g of -7-, yield
91.7%.
1H NMR (400MHz, CDCl3) δ: 2.40 (t, 2H) 3.51 (t, 2H) 3.64 (s, 3H) 7.11~7.18 (m, 2H)
7.44(m,1H)11.22(s,1H)。
Embodiment 2
The synthesis of the fluoro- indole -5-carboxylic acid methyl esters of 3- (2- bromoethyl) -7-
Under nitrogen protection, by the fluoro- indole -5-carboxylic acid methyl esters 38.6g (200mmol) of 7-, tetra-triphenylphosphine palladium 3.8g
(10%), cesium carbonate 130.3g (400mmol) and glycol dibromide 22.6g (120mmol) back flow reaction in 200ml acetonitrile
2 hours, monitoring reaction terminated, and reaction solution is cooled to room temperature, filtering, and filtrate washing, ethyl acetate extracts three times, merged organic
Phase, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and petroleum ether is recrystallized to give the fluoro- indole -5-carboxylic acid methyl esters of 3- (2- bromoethyl) -7-
56.2g, yield 93.6%.
Comparative example 1
Under nitrogen protection, by the fluoro- indole -5-carboxylic acid methyl esters 19.3g (100mmol) of 7-, potassium carbonate 41g and 1,2- dibromo second
Back flow reaction 6 hours in 150ml acetonitrile alkane 20.7g (110mmol), monitoring reaction terminate, and reaction solution is cooled to room temperature, mistake
Filter, filtrate washing, ethyl acetate extract three times, merge organic phase, and anhydrous sodium sulfate is dry, are concentrated under reduced pressure, petroleum ether recrystallization
Obtain 3- (2- bromoethyl) fluoro- indole -5-carboxylic acid methyl esters 19.2g of -7-, yield 64.2%.
Embodiment 3
The synthesis of Formula II compound represented:
Under nitrogen protection, the fluoro- indole -5-carboxylic acid methyl esters 6g (20mmol) of 3- (2- bromoethyl) -7- that step 1) is obtained,
Iodine 0.2g and dry magnesium chips 0.5g (21mmol), which are added in 120ml absolute ether, stirs 1.5 hours to initiation generation 3- (2-
Ethylmagnesium bromide) the fluoro- indole -5-carboxylic acid methyl esters of -7-, gained reacting liquid temperature is then adjusted to 45 DEG C and is stirred to react 3 hours,
Monitoring to reaction terminates, and ice bath cooling is poured into saturated ammonium chloride, and methylene chloride extraction washs, is concentrated and dried to obtain the fluoro- hexamethylene of 8-
Base simultaneously [5,4,3-cd] indoles -6- ketone 3.44g.
By the fluoro- cyclohexyl of 8- simultaneously [5,4,3-cd] indoles -6- ketone 3.78g (20mmol), hydroxylamine hydrochloride 21.7g (24mmol)
And copper acetate 0.73g (4mmol) is added in ethyl alcohol, then stirring is lower instills ammonium hydroxide adjusting pH to 8~9, and temperature rising reflux is anti-
It answers 20~30 minutes, filters while hot, cooling, crystallization filters to obtain Formula II compound represented 3.8g, yield 93.1%.
1H NMR (400MHz, DMSO-d6) δ: 2.83~2.90 (m, 4H) 3.64 (s, 3H) 7.15~7.22 (m, 2H)
7.46(m,1H)11.18(s,1H)11.34(s,1H)。
Embodiment 4
The synthesis of Formula II compound represented:
Under nitrogen protection, the fluoro- indole -5-carboxylic acid methyl esters 6g (20mmol) of 3- (2- bromoethyl) -7- that step 1) is obtained,
Iodine 0.1g and dry magnesium chips 0.5g (21mmol), which are added in 150ml absolute ether, stirs 1.5 hours to initiation generation 3- (2-
Ethylmagnesium bromide) the fluoro- indole -5-carboxylic acid methyl esters of -7-, gained reacting liquid temperature is then adjusted to 50 DEG C and is stirred to react 3 hours,
Monitoring to reaction terminates, and ice bath cooling is poured into saturated ammonium chloride, and methylene chloride extraction washs, is concentrated and dried to obtain the fluoro- hexamethylene of 8-
Base simultaneously [5,4,3-cd] indoles -6- ketone 3.39g.
By the fluoro- cyclohexyl of 8- simultaneously [5,4,3-cd] indoles -6- ketone 3.78g (20mmol), hydroxylamine hydrochloride 21.7g (26mmol)
And copper acetate 1.1g (6mmol) is added in ethyl alcohol, then the lower ammonium hydroxide that instills of stirring adjusts pH to 8~9, temperature rising reflux reaction
It 20~30 minutes, filters while hot, cooling, crystallization filters to obtain Formula II compound represented 3.74g, yield 91.7%.
Embodiment 5
The synthesis of Formula II compound represented:
Under nitrogen protection, the fluoro- indole -5-carboxylic acid methyl esters 30g of 3- (2- bromoethyl) -7- that step 1) is obtained
(100mmol), iodine 0.6g and dry magnesium chips 2.5g, which are added in 250ml absolute ether, stirs 1.5 hours to initiation generation 3-
The fluoro- indole -5-carboxylic acid methyl esters of (2- ethylmagnesium bromide) -7-, gained reacting liquid temperature is then adjusted to 35 DEG C, and to be stirred to react 4 small
When, monitoring terminates to reaction, and ice bath cooling is poured into saturated ammonium chloride, methylene chloride extraction, wash, be concentrated and dried 8- is fluoro-
Cyclohexyl simultaneously [5,4,3-cd] indoles -6- ketone 17.33g.
By the fluoro- cyclohexyl of 8- simultaneously [5,4,3-cd] indoles -6- ketone 9.38g (50mmol), hydroxylamine hydrochloride 5.25g (75mmol)
And copper acetate 0.9g (5mmol) is added in ethyl alcohol, then the lower ammonium hydroxide that instills of stirring adjusts pH to 8~9, temperature rising reflux reaction
It 20~30 minutes, filters while hot, cooling, crystallization filters to obtain Formula II compound represented 9.43g, yield 92.4%.
Embodiment 6
The synthesis of the fluoro- cyclohexyl of 8- simultaneously [5,4,3-cd] indoles -6- ketone:
Under nitrogen protection, the fluoro- indole -5-carboxylic acid methyl esters 6g (20mmol) of 3- (2- bromoethyl) -7- that step 1) is obtained,
Iodine 0.2g and dry magnesium chips, which are added in 60ml absolute ether, stirs 1.5 hours to initiation generation 3- (2- ethylmagnesium bromide)-
Then gained reacting liquid temperature is adjusted to 35 DEG C and is stirred to react 5 hours by the fluoro- indole -5-carboxylic acid methyl esters of 7-, monitoring to reaction knot
Beam, ice bath cooling are poured into saturated ammonium chloride, methylene chloride extraction, are washed, are concentrated and dried to obtain the fluoro- cyclohexyl of 8- simultaneously [5,4,3-
Cd] indoles -6- ketone 2.46g.
Embodiment 7
The synthesis of Formula II compound represented:
By the fluoro- cyclohexyl of 8- simultaneously [5,4,3-cd] indoles -6- ketone 9.38g (50mmol), hydroxylamine hydrochloride 4.17g (60mmol)
And copper acetate 0.36g (2mmol) is added in ethyl alcohol, then stirring is lower instills ammonium hydroxide adjusting pH to 8~9, and temperature rising reflux is anti-
It answers 20~30 minutes, filters while hot, cooling, crystallization filters to obtain Formula II compound represented 7.8g, yield 77.3%.
Comparative example 2
The synthesis of Formula II compound represented:
By the fluoro- cyclohexyl of 8- simultaneously [5,4,3-cd] indoles -6- ketone 3.78g (20mmol) and hydroxylamine hydrochloride 21.7g
(24mmol) is added in ethyl alcohol, and then the lower ammonium hydroxide that instills of stirring adjusts pH to 8~9, and temperature rising reflux is reacted 20~30 minutes, taken advantage of
Heat filtering, cooling, crystallization filters to obtain Formula II compound represented 2.1g, yield 50.8%.
Embodiment 8
Formula II compound represented 10.2g (50mmol), phosphorus trichloride 1.37g (10mmol) and 80ml acetonitrile are added to
In reaction flask, 40 DEG C are warming up to, is reacted 2 hours, end of reaction is monitored, is concentrated under reduced pressure, ethyl alcohol recrystallization obtains shown in Formulas I
Rucaparib intermediate 9.46g, yield 92.7%, purity 99.81%.HRMS (ESI+): calcd.For C11H10FN2O+
205.0699 found 205.0697.
1H NMR (400MHz, CDCl3) δ: 2.78~2.82 (m, 2H), 3.41~3.45 (m, 2H), 7.33~7.40
(m,2H),7.55(m,1H),8.24(s,1H),11.25(s,1H)。
Embodiment 9
Formula II compound represented 10.2g (50mmol), phosphorus trichloride 0.69g (5mmol) and 100ml acetonitrile are added to
In reaction flask, 50 DEG C are warming up to, is reacted 2.5 hours, end of reaction is monitored, is concentrated under reduced pressure, ethyl alcohol recrystallization obtains Formulas I institute
The Rucaparib intermediate 9.38g shown, yield 91.9%, purity 99.66%.
Embodiment 10
Formula II compound represented 10.2g (50mmol), phosphorus trichloride 2.75g (20mmol) and 80ml acetonitrile are added to
In reaction flask, 45 DEG C are warming up to, is reacted 2 hours, end of reaction is monitored, is concentrated under reduced pressure, ethyl alcohol recrystallization obtains shown in Formulas I
Rucaparib intermediate 9.27g, yield 90.8%, purity 99.74%.
Comparative example 3
Formula II compound represented 10.2g (50mmol), phosphorus trichloride 1.37g (10mmol) and 80ml acetonitrile are added to
In reaction flask, back flow reaction 8 hours, end of reaction is monitored, is concentrated under reduced pressure, ethyl alcohol recrystallization obtains shown in Formulas I
Rucaparib intermediate 5.93g, yield 58.1%, purity 99.42%.
Claims (9)
1. a kind of synthesis technology for treating ovarian cancer Rucaparib intermediate, which is characterized in that the synthesis technology includes:
Formula II compound represented is reacted in acid condition and obtains Rucaparib intermediate shown in Formulas I；
2. synthesis technology as described in claim 1, which is characterized in that the condition of the synthesis technology includes: that reaction temperature is
40~50 DEG C；The acid condition refers to carry out in the presence of acidic materials, and the acidic materials are sulfuric acid, polyphosphoric acids, five
One of phosphorus chloride, phosphorus trichloride, phosphorus oxychloride and benzene sulfonyl chloride are a variety of；The solvent of reaction is acetonitrile or tetrahydrofuran.
3. synthesis technology as claimed in claim 2, which is characterized in that the acidic materials are phosphorus trichloride or phosphorus oxychloride.
4. synthesis technology as claimed in claim 1 or 2, which is characterized in that Formula II compound represented is prepared by the following steps:
1) the fluoro- indole -5-carboxylic acid methyl esters of 7-
Back flow reaction obtains 3- (2- bromoethyl) -7- in acetonitrile with glycol dibromide in the presence of palladium catalyst and acid binding agent
Fluoro- indole -5-carboxylic acid methyl esters；
2) the fluoro- indole -5-carboxylic acid methyl esters of 3- (2- bromoethyl) -7- and a small amount of iodine magnesium in absolute ether obtained step 1)
Bits stirring to generating the fluoro- indole -5-carboxylic acid methyl esters of 3- (2- ethylmagnesium bromide) -7-, by gained reacting liquid temperature is adjusted to 35~
50 DEG C are stirred to react 3~5 hours, and reaction terminates, and are poured into saturated ammonium chloride under ice bath, methylene chloride extraction, and washing, concentration are dry
It is dry to obtain formula III compound represented；
3) formula III compound represented, hydroxylamine hydrochloride and copper acetate are added in ethyl alcohol, then stirring is lower instills ammonium hydroxide tune
PH to 8~9 is saved, back flow reaction 20~30 minutes, is filtered while hot, cooling, crystallization filters to obtain Formula II compound represented；
5. synthesis technology as claimed in claim 4, which is characterized in that in step 1), the fluoro- indole -5-carboxylic acid methyl esters of 7- with
Acid binding agent, glycol dibromide mole dosage ratio be 1:3~5:1~1.2；The palladium catalyst is tetra-triphenylphosphine palladium,
Palladium catalyst dosage is the 5~10% of the fluoro- indole -5-carboxylic acid methyl esters weight of 7-；The acid binding agent is sodium carbonate, potassium carbonate or carbon
Sour caesium.
6. synthesis technology as claimed in claim 4, which is characterized in that in step 2), 3- (2- the bromoethyl) -7- is fluoro-
The mole dosage of indole -5-carboxylic acid methyl esters and magnesium chips ratio is 1:1~1.1；Relative to the fluoro- indoles-of every g 3- (2- bromoethyl) -7-
5- methyl formate, the dosage of the absolute ether are 10~30ml.
7. synthesis technology as claimed in claim 6, which is characterized in that relative to the fluoro- indoles-of every g 3- (2- bromoethyl) -7-
5- methyl formate, the dosage of the absolute ether are 18~25ml.
8. synthesis technology as claimed in claim 4, which is characterized in that in step 3), formula III compound represented and hydrochloric acid
Azanol, copper acetate molar ratio be 1:1.2~1.5:0.1~0.3.
9. synthesis technology as claimed in claim 4, which is characterized in that step 1) and step 2) are separately in protective gas
In the presence of carry out, the protective gas be nitrogen, argon gas or helium.
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| CN110229162B (en) * | 2018-03-05 | 2020-08-11 | 新发药业有限公司 | Simple preparation method of Ruipab |
| CN108752353B (en) * | 2018-04-28 | 2020-05-08 | 程春晓 | Preparation method of key intermediate 1408282-26-7 of anti-ovarian cancer drug Rucaparib |
| CN109180687A (en) * | 2018-08-31 | 2019-01-11 | 山东轩德医药科技有限公司 | A kind of preparation method of auspicious Kappa step intermediate |
| CN109575035B (en) * | 2019-01-02 | 2021-04-16 | 江苏开元药业有限公司 | Preparation method of medicine Rucaparib intermediate for treating ovarian cancer |
| CN114516877B (en) * | 2020-11-20 | 2023-10-27 | 烟台弘邦医药科技有限公司 | Preparation method of rebamipa intermediate |
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