CN108033947A - Treat the preparation method that non-small cell lung cancer drug Ai Li replaces Buddhist nun - Google Patents
Treat the preparation method that non-small cell lung cancer drug Ai Li replaces Buddhist nun Download PDFInfo
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
Treat the preparation method that non-small cell lung cancer drug Ai Li replaces Buddhist nun, the treatment non-small cell lung cancer drug Ai Li is 9 ethyls 6 for Buddhist nun's chemical name, 6 dimethyl 8 (4 morpholine, 4 phenylpiperidines, 1 base) 11 oxa-s 6,11 dihydro 5H benzos [b] carbazole, 3 formonitrile HCN, its structural formula are：
Description
Technical field
The present invention relates to pharmaceutical technology field, more particularly to treatment non-small cell lung cancer drug Ai Li to replace the preparation side of Buddhist nun
Method.
Background technology
Ai Li is by the Choongwae Pharmacutical Corp of Japan of branch company of Roche Holding Ag (Roche) for Buddhist nun (Alectinib)
A kind of new anaplastic lymphoma kinase (ALK) inhibitor of (Chugai Pharmaceutical) exploitation, for treating ALK bases
Because of the Patients with Non-small-cell Lung of rearrangement, because the medicine does not have the Chinese translation of standard also, therefore the applicant is herein by its transliteration
For " Ai Li replaces Buddhist nun ", its structural formula is：
Patent No. CN201410635005 discloses the preparation method that a kind of Ai Li replaces Buddhist nun (Alectinib, I), passes through 6-
Cyano-1 H-indol -3- carboxylate methyl esters or 6- cyano-1 H-indol -3- carboxylic acid, ethyl esters (II) and 4- ethyls -3- (4- morpholines -4-
Base-piperidin-1-yl)-α, alpha-alpha-dimethyl phenmethylol (III) occur under catalyst action condensation reaction be made respectively 6- cyano group-
2- [2- [4- ethyls -3- (4- morpholines -4- bases-piperidin-1-yl) phenyl] propane -2- bases] -1H- indole -3-carboxylic acid methyl esters or 6-
Cyano group -2- [2- [4- ethyls -3- (4- morpholines -4- bases-piperidin-1-yl) phenyl] propane -2- bases] -1H- indole -3-carboxylic acid's ethyl esters
(IV), 6- cyano group -2- [2- [4- ethyls -3- (4- morpholines -4- bases-piperidin-1-yl) phenyl] third then through hydrolysis are made
Alkane -2- bases] -1H- indole -3-carboxylic acids (V)；Finally generation ring-closure reaction is made Ai Li and replaces Buddhist nun (I) under the effect of alkali accelerating agent.Its
Reaction equation is：
Although said synthesis route step is few, synthesis is simple, required 6- cyano-1 H-indol -3- carboxylate methyl esters or 6-
Cyano-1 H-indol -3- carboxylic acid, ethyl esters (II), 4- ethyls -3- (4- morpholines -4- bases-piperidin-1-yl)-α, alpha-alpha-dimethyl phenmethylol
(III) raw material are difficult to obtain, and reaction yield does not significantly improve, and are not easy to mass produce, and the raw material used still needs to again
Prepare, it is therefore desirable to it is a kind of not only easy to operate, and also high income, the Ai Li of the suitable industrialized production of relative inexpensiveness are replaced
The preparation method of Buddhist nun.
The content of the invention
Treat the preparation method that non-small cell lung cancer drug Ai Li replaces Buddhist nun；It is easy to get present invention employs raw material, is economic and environment-friendly
And the technology of preparing having good quality, seek to can adapt to the process of industrialized production, its preparation process is novel, simplifies
Reaction process, so as to improve reaction yield, has important reality to anticipate Ai Li for the raising of the economic and social benefit of Buddhist nun
Justice.
To achieve the above object, the specific route of preparation method of the invention is as follows：
Technical scheme is implemented as follows：
The preparation method that non-small cell lung cancer drug Ai Li replaces Buddhist nun is treated, is comprised the following steps that：
A. ring-closure reaction
Prepare acid solution by acid is soluble in water, add 3- itrile groups phenylhydrazine 1. with the bromo- 1- hydroxyls -1,2 of 6- nitros -4,4- bis-,
2. -3 ketone of 3,4- naphthanes is 1 by the ratio between amount of material:1~1:1.2 mixture, after stirring add promote reactant with it is organic molten
Agent 1,2- dichloroethanes, n,N-Dimethylformamide (DMF), heating water bath to 20~25 DEG C, reaction 3~5 it is small when after, to reaction
Continue that acid solution and oxidative dehydrogenation agent is added dropwise in liquid, be sufficiently stirred, be warming up to 60~65 DEG C of progress ring-closure reactions, after reaction
2~10 DEG C are cooled to by ice-water bath, removes organic solvent, recrystallization, obtains the bromo- 8- nitros -11- hydroxyls -6,11- of 6,6- bis-
Dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs are 3..
B. Zi-Fei Dixi reactions are inspired confidence in
Bromo- 8- nitros -11- hydroxyls -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs of 6,6- bis- that step A is obtained
3. being dissolved in ether, add metallic sodium and inspire confidence in Zi-Fei Dixi reagents, heating water bath is to 20 DEG C and is stirred continuously, and inspires confidence in Zi-Fei Di
Uncommon reaction, 2~3 it is small when after, TLC detections terminate, and the liquid after reaction is poured into frozen water and is filtered, 6 are obtained by filtration cakes torrefaction,
6- dimethyl -8- nitro -11- hydroxyl -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs are 4..
C. oxidation reaction
Acid solution is prepared by acid is soluble in water first, is added oxidant, is secondly added organic solvent and the volume ratio of water is
1:1.5~1:2.5 mixed liquor, stirs evenly, and heating water bath is eventually adding 6, the 6- diformazans obtained in step B to 100 DEG C
4. base -8- nitro -11- hydroxyl -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs, are stirred continuously, reaction a period of time, cold
But, filter, is dry, obtaining 6,6- dimethyl -8- nitro -11- oxa- -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs 5..
D. reduction reaction
6,6- dimethyl -8- nitros -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole -3- first that step C is generated
5. nitrile is added in the reaction vessel for filling organic solvent, add metallic catalyst and reducing agent, is passed through hydrogen, reaction a period of time
Afterwards, TLC detections are completed, and filtration washing concentration, occurs reduction reaction, generate 6,6- dimethyl -8- amino -11- oxa-s -6,11-
Dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs are 6..
E. hydrolysis
6,6- dimethyl -8- amino -11- oxa-s -6,11- dihydro -5H- benzos [b] click that will be generated first in step D
6. azoles -3- formonitrile HCNs are 1 by the ratio between amount of material with sodium nitrate:0.2~1:0.4 mixing, is added to and fills organic solvent dimethylbenzene
Reaction vessel in, be secondly slowly stirred continuously, when reaction 2~3 is small, TLC has been detected to the sulfuric acid solution that 80% is instilled in it
Into, generation 3- formonitrile HCNs base 6,6- dimethyl -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole -8- diazonium sulfate 7., most
Water is added in backward container so that the volume ratio of water and reaction solution is 1:1.5~1:2, heating water bath is simultaneously sufficiently stirred, and water occurs
Solution reaction, filters, washs, concentration, obtaining 6,6- dimethyl -8- hydroxyl -11- oxa- -6,11- dihydro -5H- benzos [b] afterwards
Carbazole -3- formonitrile HCNs are 8..
F. condensation reaction
6,6- dimethyl -8- hydroxyl -11- oxa- -6,11- dihydro -5H- benzo [b] carbazoles -3- that will be obtained in step E
8. formonitrile HCN is 1 by the ratio between amount of material with chloroethanes:1.1~1:1.3 mixing, are dissolved in tetrahydrofuran, catalyst are added, in nitrogen
Stirring is sufficiently mixed under gas shielded, after the completion of TLC detections, excessive 4- Chloperastines is added, slowly instills dilute hydrochloric acid solution, constantly
Stirring, increase pressure to 2.5~3MPa, heating water bath to 230 DEG C, generation 9- ethyl -6,6- dimethyl -8- (the chloro- piperidines of 4- -
1- yls) -11- oxa- -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs are 9..
G. condensation reaction
9- ethyl -6,6- dimethyl -8- (the chloro- piperidin-1-yls of the 4-) -11- oxa-s -6,11- bis- that will be obtained in step F
9. hydrogen -5H- benzos [b] carbazole -3- formonitrile HCNs are 1 by the ratio between amount of material with morpholine:1.1~1:1.3 mixing, are dissolved in tetrahydrofuran
In, dilute hydrochloric acid solution is slowly instilled under nitrogen protection, is stirred continuously, increases pressure, increases temperature, it is cold after the completion of TLC detections
But, tetrahydrofuran is removed, ethyl acetate extracts 3 times, water phase is collected, after water mutually adjusts Ph8~9 with potassium carbonate, then with acetic acid second
Ester extracts 3 times, merges water phase, dry, obtains 9- ethyl -6,6- dimethyl -8- (4- morpholines -4- bases-piperidin-1-yl) -11- oxygen
10. miscellaneous -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs, that is, treat non-small cell lung cancer drug Ai Li and replace Buddhist nun.
The hydrochloric acid that acid in the A is 90%, the rush reactant are boron trifluoride or trifluoromethanesulfonic acid, and the oxidation is de-
Hydrogen agent is tetrachloroquinone or Raney's nickel.
Ether in the step B is the one or more in ether, ethyl methyl ether, positive propyl ether or tetrahydrofuran, it is described inspire confidence in hereby-
Fei Dixi reagents are bromomethane.
Acid in the C is 98% concentrated sulfuric acid, and the oxidant is sodium dichromate or potassium bichromate, the organic solvent
For acetonitrile, n,N-Dimethylformamide (DMF), toluene, Isosorbide-5-Nitrae dioxane or tetrahydrofuran, the reaction time is 10~12
Hour.
Organic solvent in the D is ethanol, ether, benzene or oil, and the metallic catalyst is iron or tin, the reducing agent
For hydrochloric acid or acetic acid, the reaction time for 10~15 it is small when.
Catalyst in the F is alchlor.
Reaction pressure in the step G is 2.5~3MPa, and reaction temperature is 230 DEG C.
The explanation present invention in detail below.
The preparation method that non-small cell lung cancer drug Ai Li replaces Buddhist nun is treated, is comprised the following steps that：
A. ring-closure reaction
Prepare acid solution by acid is soluble in water, add 3- itrile groups phenylhydrazine 1. with the bromo- 1- hydroxyls -1,2 of 6- nitros -4,4- bis-,
2. -3 ketone of 3,4- naphthanes is 1 by the ratio between amount of material:1~1:1.2 mixture, after stirring add promote reactant with it is organic molten
Agent 1,2- dichloroethanes, n,N-Dimethylformamide (DMF), heating water bath to 20~25 DEG C, reaction 3~5 it is small when after, to reaction
Continue that acid solution and oxidative dehydrogenation agent is added dropwise in liquid, be sufficiently stirred, be warming up to 60~65 DEG C of progress ring-closure reactions, after reaction
2~10 DEG C are cooled to by ice-water bath, removes organic solvent, recrystallization, obtains the bromo- 8- nitros -11- hydroxyls -6,11- of 6,6- bis-
Dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs are 3..
In step A add promote reactant be in order to make 3- itrile groups phenylhydrazine 1. with the bromo- 1- hydroxyls -1,2 of 6- nitros -4,4- bis-,
2. -3 ketone of 3,4- naphthane is first condensed into corresponding imines, then by resetting cyclisation, the reaction was continued in acid condition again；Add
The purpose for entering organic solvent be in order to dissolve 3- itrile groups phenylhydrazine 1. with the bromo- 1- hydroxyls -1,2 of 6- nitros -4,4- bis-, 3,4- tetrahydrochysenes
The ketone of naphthalene -3 is 2.；The method for removing organic solvent is to be concentrated under reduced pressure to remove organic solvent；The mode of recrystallization is addition second alcohol and water
Recrystallization.
B. Zi-Fei Dixi reactions are inspired confidence in
Bromo- 8- nitros -11- hydroxyls -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs of 6,6- bis- that step A is obtained
3. being dissolved in ether, add metallic sodium and inspire confidence in Zi-Fei Dixi reagents, heating water bath is to 20 DEG C and is stirred continuously, and inspires confidence in Zi-Fei Di
Uncommon reaction, 2~3 it is small when after, TLC detections terminate, and the liquid after reaction is poured into frozen water and is filtered, 6 are obtained by filtration cakes torrefaction,
6- dimethyl -8- nitro -11- hydroxyl -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs are 4..
Reaction temperature is to reduce side reaction for 20 DEG C in step B, reduces reaction impurities, increases yield.
C. oxidation reaction
Acid solution is prepared by acid is soluble in water first, is added oxidant, is secondly added organic solvent and the volume ratio of water is
1:1.5~1:2.5 mixed liquor, stirs evenly, and heating water bath is eventually adding 6, the 6- diformazans obtained in step B to 100 DEG C
4. base -8- nitro -11- hydroxyl -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs, are stirred continuously, reaction a period of time, cold
But, filter, is dry, obtaining 6,6- dimethyl -8- nitro -11- oxa- -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs 5..
D. reduction reaction
6,6- dimethyl -8- nitros -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole -3- first that step C is generated
5. nitrile is added in the reaction vessel for filling organic solvent, add metallic catalyst and reducing agent, is passed through hydrogen, reaction a period of time
Afterwards, TLC detections are completed, and filtration washing concentration, occurs reduction reaction, generate 6,6- dimethyl -8- amino -11- oxa-s -6,11-
Dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs are 6..
The purpose that organic solvent is added in step D is to dissolve 6,6- dimethyl -8- nitro -11- oxa-s -6,11- bis-
Hydrogen -5H- benzos [b] carbazole -3- formonitrile HCNs are 5.；Add metallic catalyst and reducing agent be in order to promote the progress of reduction reaction,
Reaction yield is high, and accessory substance is few.
E. hydrolysis
6,6- dimethyl -8- amino -11- oxa-s -6,11- dihydro -5H- benzos [b] click that will be generated first in step D
6. azoles -3- formonitrile HCNs are 1 by the ratio between amount of material with sodium nitrate:0.2~1:0.4 mixing, is added to and fills organic solvent dimethylbenzene
Reaction vessel in, be secondly slowly stirred continuously, when reaction 2~3 is small, TLC has been detected to the sulfuric acid solution that 80% is instilled in it
Into, generation 3- formonitrile HCNs base 6,6- dimethyl -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole -8- diazonium sulfate 7., most
Water is added in backward container so that the volume ratio of water and reaction solution is 1:1.5~1:2, heating water bath is simultaneously sufficiently stirred, and water occurs
Solution reaction, filters, washs, concentration, obtaining 6,6- dimethyl -8- hydroxyl -11- oxa- -6,11- dihydro -5H- benzos [b] afterwards
Carbazole -3- formonitrile HCNs are 8..
Sodium nitrate and 80% sulfuric acid solution are added in step E be in order to enable 6,6- dimethyl -8- amino -11- oxa-s -
6. 6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs first carry out diazotising, generate diazol, further hydrolysis is anti-for convenient progress
Should.
F. condensation reaction
6,6- dimethyl -8- hydroxyl -11- oxa- -6,11- dihydro -5H- benzo [b] carbazoles -3- that will be obtained in step E
8. formonitrile HCN is 1 by the ratio between amount of material with chloroethanes:1.1~1:1.3 mixing, are dissolved in tetrahydrofuran, catalyst are added, in nitrogen
Stirring is sufficiently mixed under gas shielded, after the completion of TLC detections, excessive 4- Chloperastines is added, slowly instills dilute hydrochloric acid solution, constantly
Stirring, increase pressure to 2.5~3MPa, heating water bath to 230 DEG C, generation 9- ethyl -6,6- dimethyl -8- (the chloro- piperidines of 4- -
1- yls) -11- oxa- -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs are 9..
It is to ensure 6,6- dimethyl -8- hydroxyl -11- oxa-s -6,11- bis- that excessive 4- Chloperastines are added in step F
Hydrogen -5H- benzos [b] carbazole -3- formonitrile HCNs 8. on hydroxyl reacted away completely, reaction is thorough, and yield is high；Dilute hydrochloric acid is quality point
Hydrochloric acid of the number less than 40%.
G. condensation reaction
9- ethyl -6,6- dimethyl -8- (the chloro- piperidin-1-yls of the 4-) -11- oxa-s -6,11- bis- that will be obtained in step F
9. hydrogen -5H- benzos [b] carbazole -3- formonitrile HCNs are 1 by the ratio between amount of material with morpholine:1.1~1:1.3 mixing, are dissolved in tetrahydrofuran
In, dilute hydrochloric acid solution is slowly instilled under nitrogen protection, is stirred continuously, increases pressure, increases temperature, it is cold after the completion of TLC detections
But, tetrahydrofuran is removed, ethyl acetate extracts 3 times, water phase is collected, after water mutually adjusts Ph8~9 with potassium carbonate, then with acetic acid second
Ester extracts 3 times, merges water phase, dry, obtains 9- ethyl -6,6- dimethyl -8- (4- morpholines -4- bases-piperidin-1-yl) -11- oxygen
10. miscellaneous -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs, that is, treat non-small cell lung cancer drug Ai Li and replace Buddhist nun.
Compared with prior art, the present invention have the advantages that：
It is easy to get present invention employs raw material, the economic and environment-friendly and technology of preparing that has good quality, has sought to can adapt to industry
The process of metaplasia production, its preparation process is novel, simplifies reaction process, so as to improve reaction yield, Buddhist nun is replaced to Ai Li
The raising of economic and social benefit have important realistic meaning.
Embodiment
The present invention is further elaborated with reference to specific embodiment.
Embodiment 1
The preparation method that non-small cell lung cancer drug Ai Li replaces Buddhist nun is treated, is comprised the following steps that：
A. ring-closure reaction
90% hydrochloric acid (30ml) is dissolved in water (60ml) and prepares hydrochloric acid solution, add 3- itrile groups phenylhydrazines 1. (22g,
2.4mol) with the bromo- 1- hydroxyls -1,2 of 6- nitros -4,4- bis-, the mixture of -3 ketone of 3,4- naphthane 2. (25g, 2.78mol), is stirred
Added after mixing and promote reactant boron trifluoride (5.4g, 1.7mol) and organic solvent 1,2- dichloroethanes (40ml), N, N- dimethyl
Formamide (DMF) (40ml), heating water bath to 20 DEG C, reaction 3 it is small when after, continue into reaction solution be added dropwise hydrochloric acid solution (30ml)
With oxidative dehydrogenation agent tetrachloroquinone (3.9g, 1.5mol), it is sufficiently stirred, is warming up to 60 DEG C of progress ring-closure reactions, after reaction
2 DEG C are cooled to by ice-water bath, removes organic solvent, recrystallization, obtains the bromo- 8- nitros -11- hydroxyls -6,11- bis- of 6,6- bis-
Hydrogen -5H- benzos [b] carbazole -3- formonitrile HCNs are 3. (35.72g, 7.26mol).
B. Zi-Fei Dixi reactions are inspired confidence in
Bromo- 8- nitros -11- hydroxyls -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs of 6,6- bis- that step A is obtained
(3. 35.72g, 7.26mol) is dissolved in positive propyl ether (150ml), add metallic sodium and inspire confidence in Zi-Fei Dixi reagents bromomethane (15g,
1.6mol), heating water bath to 20 DEG C and is stirred continuously, and inspires confidence in Zi-Fei Dixi reactions, 2 it is small when after, TLC detections terminate, will be anti-
Should after liquid pour into frozen water and filter, by filtration cakes torrefaction obtain 6,6- dimethyl -8- nitro -11- hydroxyls -6,11- dihydro -
5H- benzos [b] carbazole -3- formonitrile HCNs are 4. (39.8g, 8.2mol).
C. oxidation reaction
98% concentrated sulfuric acid (30ml) is dissolved in water (50ml) first and prepares sulfuric acid solution, adds oxidant dichromic acid
Sodium, secondly adds organic solvent n,N-Dimethylformamide (DMF) (60ml) and the mixed liquor of water (60ml), stirs evenly, water
Bath is heated to 100 DEG C, is eventually adding 6,6- dimethyl -8- nitro -11- hydroxyl -6, the 11- dihydro -5H- benzene obtained in step B
And [b] carbazole -3- formonitrile HCNs are 4. (39.8g, 8.2mol), are stirred continuously, when reaction 10 is small, cooling, filtering, drying, obtain 6,6-
Dimethyl -8- nitro -11- oxa- -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs are 5. (31.84g, 7.8mol).
D. reduction reaction
6,6- dimethyl -8- nitros -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole -3- first that step C is generated
Nitrile 5. (31.84g, 7.8mol) add fill in the reaction vessel of organic solvent ethanol (80ml), add metallic catalyst tin with
Reducing agent acetic acid (50ml), is passed through hydrogen, when reaction 10 is small after, TLC detections are completed, and filtration washing concentration, occurs reduction reaction,
Generate 6,6- dimethyl -8- amino -11- oxa- -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs 6. (25.7g,
4.6mol)。
E. hydrolysis
6,6- dimethyl -8- amino -11- oxa-s -6,11- dihydro -5H- benzos [b] click that will be generated first in step D
6. (25.7g, 4.6mol) is mixed azoles -3- formonitrile HCNs with sodium nitrate (1.4g, 1.25mol), is added to and is filled organic solvent dimethylbenzene
In the reaction vessel of (90ml), 80% sulfuric acid solution (25ml) is secondly slowly instilled into it, is stirred continuously, when reaction 2 is small,
TLC detections are completed, generation 3- formonitrile HCNs base 6,6- dimethyl -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole -8- diazonium sulphur
7. (20.08g, 4.2mol) hydrochlorate, adds water (75ml) in most backward container, heating water bath is simultaneously sufficiently stirred, and it is anti-that hydrolysis occurs
Should, afterwards filter, wash, concentration, obtain 6,6- dimethyl -8- hydroxyls -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole -
3- formonitrile HCNs are 8. (16.56g, 3.8mol).
F. condensation reaction
6,6- dimethyl -8- hydroxyl -11- oxa- -6,11- dihydro -5H- benzo [b] carbazoles -3- that will be obtained in step E
8. (16.56g, 3.8mol) is mixed formonitrile HCN with chloroethanes (9.5g, 2.0mol), is dissolved in tetrahydrofuran (100ml), is added catalysis
Agent alchlor, is sufficiently mixed stirring under nitrogen protection, after the completion of TLC detections, add excessive 4- Chloperastines (11g,
2.5mol), dilute hydrochloric acid solution (45ml) is slowly instilled, is stirred continuously, for increase pressure to 2.5MPa, heating water bath is raw to 230 DEG C
Into 9- ethyl -6,6- dimethyl -8- (the chloro- piperidin-1-yls of 4-) -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole -3- first
Nitrile is 9. (25.2g, 5.1mol).
G. condensation reaction
9- ethyl -6,6- dimethyl -8- (the chloro- piperidin-1-yls of the 4-) -11- oxa-s -6,11- bis- that will be obtained in step F
9. (25.2g, 5.1mol) is mixed hydrogen -5H- benzos [b] carbazole -3- formonitrile HCNs with morpholine (7.06g, 1.3mol), is dissolved in tetrahydrofuran
In (80ml), dilute hydrochloric acid solution (20ml) is slowly instilled under nitrogen protection, is stirred continuously, increase pressure to 2.7MPa, increase
Temperature is to 230 DEG C, and after the completion of TLC detections, cooling, removes tetrahydrofuran, and ethyl acetate extracts 3 times, collects water phase, and water mutually uses carbon
After sour potassium adjusts Ph8~9, then it is extracted with ethyl acetate 3 times, merges water phase, it is dry, obtain 9- ethyl -6,6- dimethyl -8-
(4- morpholines -4- bases-piperidin-1-yl) -11- oxa- -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs 10. (26.9g,
7.8mol)。
Embodiment 2
The preparation method that non-small cell lung cancer drug Ai Li replaces Buddhist nun is treated, is comprised the following steps that：
A. ring-closure reaction
90% hydrochloric acid (60ml) is dissolved in water (120ml) and prepares hydrochloric acid solution, add 3- itrile groups phenylhydrazines 1. (60g,
5.8mol) with the bromo- 1- hydroxyls -1,2 of 6- nitros -4,4- bis-, the mixture of -3 ketone of 3,4- naphthane 2. (57g, 4.6mol), stirring
Add afterwards and promote reactant boron trifluoride (11.5g, 2.6mol) and organic solvent 1,2- dichloroethanes (80ml), N, N- dimethyl methyls
Acid amides (DMF) (80ml), heating water bath to 25 DEG C, reaction 4.5 it is small when after, continue into reaction solution be added dropwise hydrochloric acid solution
(100ml) and oxidative dehydrogenation agent tetrachloroquinone (5.9g, 2.7mol), is sufficiently stirred, and is warming up to 64 DEG C of progress ring-closure reactions, reaction
After by ice-water bath be cooled to 5 DEG C, remove organic solvent, recrystallization, obtains bromo- 8- nitros -11- hydroxyl -6 of 6,6- bis-,
11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs are 3. (93.6g, 18.5mol).
B. Zi-Fei Dixi reactions are inspired confidence in
Bromo- 8- nitros -11- hydroxyls -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs of 6,6- bis- that step A is obtained
(3. 93.6g, 18.5mol) is dissolved in positive propyl ether (300ml), add metallic sodium and inspire confidence in Zi-Fei Dixi reagents bromomethane (30g,
3.5mol), heating water bath to 20 DEG C and is stirred continuously, inspire confidence in Zi-Fei Dixi reaction, 2.8 it is small when after, TLC detection terminates, will
Liquid after reaction, which is poured into frozen water, to be filtered, and 6,6- dimethyl -8- nitro -11- hydroxyls -6,11- bis- are obtained by filtration cakes torrefaction
Hydrogen -5H- benzos [b] carbazole -3- formonitrile HCNs are 4. (97.8g, 15.6mol).
C. oxidation reaction
98% concentrated sulfuric acid (80ml) is dissolved in water (150ml) first and prepares sulfuric acid solution, adds oxidant dichromic acid
Sodium, secondly adds organic solvent n,N-Dimethylformamide (DMF) (80ml) and the mixed liquor of water (150ml), stirs evenly, water
Bath is heated to 100 DEG C, is eventually adding 6,6- dimethyl -8- nitro -11- hydroxyl -6, the 11- dihydro -5H- benzene obtained in step B
And [b] carbazole -3- formonitrile HCNs are 4. (97.8g, 15.6mol), are stirred continuously, when reaction 12 is small, cooling, filtering, drying, obtain 6,6-
Dimethyl -8- nitro -11- oxa- -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs are 5. (79.7g, 12.1mol).
D. reduction reaction
6,6- dimethyl -8- nitros -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole -3- first that step C is generated
Nitrile 5. (79.7g, 12.1mol) add fill in the reaction vessel of organic solvent ethanol (120ml), add metallic catalyst tin with
Reducing agent acetic acid (100ml), is passed through hydrogen, when reaction 14 is small after, TLC detections are completed, and filtration washing concentration, it is anti-to occur reduction
Should, generation 6,6- dimethyl -8- amino -11- oxa- -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs 6. (63.76g,
8.5mol)。
E. hydrolysis
6,6- dimethyl -8- amino -11- oxa-s -6,11- dihydro -5H- benzos [b] click that will be generated first in step D
6. (63.76g, 8.5mol) is mixed azoles -3- formonitrile HCNs with sodium nitrate (8.4g, 2.8mol), is added to and is filled organic solvent dimethylbenzene
In the reaction vessel of (130ml), 80% sulfuric acid solution (50ml) is secondly slowly instilled into it, is stirred continuously, reaction 2 is small
When, TLC detections are completed, generation 3- formonitrile HCNs base 6,6- dimethyl -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole -8- diazonium
7. (51.6g, 6.3mol) sulfate, adds water (300ml) in most backward container, heating water bath is simultaneously sufficiently stirred, hydrolyzes
Reaction, filters, washs, concentration, obtaining 6,6- dimethyl -8- hydroxyls -11- oxa-s -6,11- dihydro -5H- benzos [b] click afterwards
Azoles -3- formonitrile HCNs are 8. (42.1g, 6.62mol).
F. condensation reaction
6,6- dimethyl -8- hydroxyl -11- oxa- -6,11- dihydro -5H- benzo [b] carbazoles -3- that will be obtained in step E
8. (42.1g, 6.62mol) is mixed formonitrile HCN with chloroethanes (16.53g, 2.6mol), is dissolved in tetrahydrofuran (200ml), addition is urged
Agent alchlor, is sufficiently mixed stirring under nitrogen protection, after the completion of TLC detections, add excessive 4- Chloperastines (14.5g,
3.1mol), dilute hydrochloric acid solution (90ml) is slowly instilled, is stirred continuously, for increase pressure to 2.9MPa, heating water bath is raw to 230 DEG C
Into 9- ethyl -6,6- dimethyl -8- (the chloro- piperidin-1-yls of 4-) -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole -3- first
Nitrile is 9. (58.5g, 7.4mol).
G. condensation reaction
9- ethyl -6,6- dimethyl -8- (the chloro- piperidin-1-yls of the 4-) -11- oxa-s -6,11- bis- that will be obtained in step F
9. (58.5g, 7.4mol) is mixed hydrogen -5H- benzos [b] carbazole -3- formonitrile HCNs with morpholine (26.3g, 2.78mol), is dissolved in tetrahydrochysene furan
Mutter in (200ml), slowly instill dilute hydrochloric acid solution (50ml) under nitrogen protection, be stirred continuously, increase pressure to 3MPa, increase
Temperature is to 230 DEG C, and after the completion of TLC detections, cooling, removes tetrahydrofuran, and ethyl acetate extracts 3 times, collects water phase, and water mutually uses carbon
After sour potassium adjusts Ph8~9, then it is extracted with ethyl acetate 3 times, merges water phase, it is dry, obtain 9- ethyl -6,6- dimethyl -8-
(4- morpholines -4- bases-piperidin-1-yl) -11- oxa- -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs 10. (67.84g,
18.6mol)。
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of from which, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention is by appended right
It is required that rather than described above limit, it is intended that all changes in the implication and scope of the equivalency of claim will be fallen
Change is included in the present invention.Any mark in claim should not be considered as to the involved claim of limitation.
Based on the embodiments of the present invention, those of ordinary skill in the art are obtained without making creative work
The every other embodiment obtained, belongs to the scope of protection of the invention.
Claims (7)
1. treating the preparation method that non-small cell lung cancer drug Ai Li replaces Buddhist nun, the treatment non-small cell lung cancer drug Ai Li replaces Buddhist nun
Chemical name is 9- ethyl -6,6- dimethyl -8- (4- morpholines -4- bases-piperidin-1-yl) -11- oxa- -6,11- dihydro -5H- benzene
And [b] carbazole -3- formonitrile HCNs, its structural formula are：
,
It is characterized in that：The treatment non-small cell lung cancer drug Ai Li is made to walk including following technique for the preparation method of Buddhist nun
Suddenly：
A. ring-closure reaction
Prepare acid solution by acid is soluble in water, add 3- itrile groups phenylhydrazine 1. with the bromo- 1- hydroxyls -1,2 of 6- nitros -4,4- bis-, 3,4-
2. the ketone of naphthane -3 is 1 by the ratio between amount of material:1~1:1.2 mixture, adds after stirring and promotees reactant and organic solvent 1,
2- dichloroethanes, n,N-Dimethylformamide（DMF）, heating water bath to 20~25 DEG C, reaction 3~5 it is small when after, into reaction solution
Continue that acid solution and oxidative dehydrogenation agent is added dropwise, be sufficiently stirred, be warming up to 60~65 DEG C of progress ring-closure reactions, pass through after reaction
Ice-water bath is cooled to 2~10 DEG C, removes organic solvent, recrystallization, obtains the bromo- 8- nitros -11- hydroxyls -6,11- bis- of 6,6- bis-
Hydrogen -5H- benzos [b] carbazole -3- formonitrile HCNs are 3.；
B. Zi-Fei Dixi reactions are inspired confidence in
Bromo- 8- nitros -11- hydroxyls -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs of 6,6- bis- that step A is obtained are 3. molten
In ether, add metallic sodium and inspire confidence in Zi-Fei Dixi reagents, heating water bath is to 20 DEG C and is stirred continuously, and it is anti-to inspire confidence in Zi-Fei Dixi
Should, 2~3 it is small when after, TLC detection terminates, the liquid after reaction is poured into frozen water and is filtered, 6,6- bis- is obtained by filtration cakes torrefaction
Methyl -8- nitro -11- hydroxyl -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs are 4.；
C. oxidation reaction
Acid solution is prepared by acid is soluble in water first, is added oxidant, is secondly added the volume of organic solvent and water
Than for 1:1.5~1:2.5 mixed liquor, stirs evenly, and heating water bath is eventually adding 6 obtained in step B to 100 DEG C,
4. 6- dimethyl -8- nitro -11- hydroxyl -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs, are stirred continuously, when reacting one section
Between, cooling, filtering, drying, obtain 6,6- dimethyl -8- nitros -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole -3- first
Nitrile is 5.；
D. reduction reaction
6,6- dimethyl -8- nitro -11- oxa- -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs that step C is generated are 5.
Addition is filled in the reaction vessel of organic solvent, adds metallic catalyst and reducing agent, is passed through hydrogen, after reacting a period of time,
TLC detections are completed, filtration washing concentration, and reduction reaction, generation 6,6- dimethyl -8- amino -11- oxa-s -6,11- bis- occurs
Hydrogen -5H- benzos [b] carbazole -3- formonitrile HCNs are 6.；
E. hydrolysis
6,6- dimethyl -8- amino -11- oxa- -6,11- dihydro -5H- benzo [b] carbazoles -3- that will be generated first in step D
6. formonitrile HCN is 1 by the ratio between amount of material with sodium nitrate:0.2~1:0.4 mixing, is added to the reaction for filling organic solvent dimethylbenzene
In container, 80% sulfuric acid solution is secondly slowly instilled into it, is stirred continuously, when reaction 2~3 is small, TLC detections are completed, generation
3 formonitrile HCN base -6,6- dimethyl -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole -8- diazonium sulfate 7., most backward container
Interior addition water so that the volume ratio of water and reaction solution is 1:1.5~1:2, heating water bath is simultaneously sufficiently stirred, and hydrolysis occurs,
Filter, wash afterwards, concentration, obtaining 6,6- dimethyl -8- hydroxyl -11- oxa- -6,11- dihydro -5H- benzo [b] carbazoles -3-
Formonitrile HCN is 8.；
F. condensation reaction
6,6- dimethyl -8- hydroxyls -11- oxa-s -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs that will be obtained in step E
It is 1 that 8. the ratio between amount of material is pressed with chloroethanes:1.1~1:1.3 mixing, are dissolved in tetrahydrofuran, add catalyst, are protected in nitrogen
Stirring is sufficiently mixed under shield, after the completion of TLC detections, excessive 4- Chloperastines is added, slowly instills dilute hydrochloric acid solution, constantly stir
Mix, for increase pressure to 2.5~3MPa, heating water bath generates 9- ethyl -6,6- dimethyl -8- (chloro- piperidines -1- of 4- to 230 DEG C
Base) -11- oxa- -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs are 9.；
G. condensation reaction
9- ethyl -6,6- dimethyl -8- (the chloro- piperidin-1-yls of 4-) -11- oxa- -6, the 11- dihydros -5H- that will be obtained in step F
9. benzo [b] carbazole -3- formonitrile HCNs are 1 by the ratio between amount of material with morpholine:1.1~1:1.3 mixing, are dissolved in tetrahydrofuran,
Dilute hydrochloric acid solution is slowly instilled under nitrogen protection, is stirred continuously, increases pressure, increases temperature, after the completion of TLC detections, cooling, goes
Except tetrahydrofuran, ethyl acetate extracts 3 times, collects water phase, after water mutually adjusts Ph8~9 with potassium carbonate, then is extracted with ethyl acetate
3 times, merge water phase, it is dry, 9- ethyl -6,6- dimethyl -8- (4- morpholines -4- bases-piperidin-1-yl) -11- oxa- -6 are obtained,
10. 11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs, that is, treat non-small cell lung cancer drug Ai Li and replace Buddhist nun.
2. treatment non-small cell lung cancer drug Ai Li according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that：Institute
The hydrochloric acid that the acid in A is 90% is stated, the rush reactant is boron trifluoride or trifluoromethanesulfonic acid, and the oxidative dehydrogenation agent is tetrachloro
Benzoquinones or Raney's nickel.
3. treatment non-small cell lung cancer drug Ai Li according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that：Institute
It is the one or more in ether, ethyl methyl ether, positive propyl ether or tetrahydrofuran to state the ether in step B, described to inspire confidence in Zi-Fei Dixi reagents
For bromomethane.
4. treatment non-small cell lung cancer drug Ai Li according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that：Institute
The concentrated sulfuric acid that the acid in C is 98% is stated, the oxidant is sodium dichromate or potassium bichromate, and the organic solvent is acetonitrile, N, N-
Dimethylformamide（DMF）, toluene, Isosorbide-5-Nitrae dioxane or tetrahydrofuran, the reaction time for 10~12 it is small when.
5. treatment non-small cell lung cancer drug Ai Li according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that：Institute
It is ethanol, ether, benzene or oil to state the organic solvent in D, and the metallic catalyst is iron or tin, and the reducing agent is hydrochloric acid or vinegar
Acid, when the reaction time is 10~15 small.
6. treatment non-small cell lung cancer drug Ai Li according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that：Institute
It is alchlor to state the catalyst in F.
7. treatment non-small cell lung cancer drug Ai Li according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that：Institute
It is 2.5~3MPa to state the reaction pressure in step G, and reaction temperature is 230 DEG C.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11014919B2 (en) | 2018-12-07 | 2021-05-25 | Fresenius Kabi Ipsum S.R.L. | Process for the preparation of alectinib |
| US11098037B2 (en) | 2017-07-05 | 2021-08-24 | Fresenius Kabi Oncology Ltd. | Process for preparing alectinib or a pharmaceutically acceptable salt thereof |
| WO2022051983A1 (en) * | 2020-09-10 | 2022-03-17 | 苏州富德兆丰生化科技有限公司 | Synthesis method of alectinib |
-
2018
- 2018-01-19 CN CN201810051600.9A patent/CN108033947A/en not_active Withdrawn
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11098037B2 (en) | 2017-07-05 | 2021-08-24 | Fresenius Kabi Oncology Ltd. | Process for preparing alectinib or a pharmaceutically acceptable salt thereof |
| US11465999B2 (en) | 2017-07-05 | 2022-10-11 | Fresenius Kabi Oncology Ltd. | Process for preparing Alectinib or a pharmaceutically acceptable salt thereof |
| US11014919B2 (en) | 2018-12-07 | 2021-05-25 | Fresenius Kabi Ipsum S.R.L. | Process for the preparation of alectinib |
| WO2022051983A1 (en) * | 2020-09-10 | 2022-03-17 | 苏州富德兆丰生化科技有限公司 | Synthesis method of alectinib |
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