CN106995433A - A kind of Ai Le replaces the preparation method of Buddhist nun - Google Patents

A kind of Ai Le replaces the preparation method of Buddhist nun Download PDF

Info

Publication number
CN106995433A
CN106995433A CN201710263682.9A CN201710263682A CN106995433A CN 106995433 A CN106995433 A CN 106995433A CN 201710263682 A CN201710263682 A CN 201710263682A CN 106995433 A CN106995433 A CN 106995433A
Authority
CN
China
Prior art keywords
morpholine
bromo
acid
piperidin
bases
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201710263682.9A
Other languages
Chinese (zh)
Inventor
陈健
黄伟
钟云健
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
HUNAN BOAODE BIOPHARMACEUTICAL TECHNOLOGY DEVELOPMENT Co Ltd
Original Assignee
HUNAN BOAODE BIOPHARMACEUTICAL TECHNOLOGY DEVELOPMENT Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by HUNAN BOAODE BIOPHARMACEUTICAL TECHNOLOGY DEVELOPMENT Co Ltd filed Critical HUNAN BOAODE BIOPHARMACEUTICAL TECHNOLOGY DEVELOPMENT Co Ltd
Priority to CN201710263682.9A priority Critical patent/CN106995433A/en
Publication of CN106995433A publication Critical patent/CN106995433A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Abstract

The invention discloses the preparation method that a kind of Ai Le replaces Buddhist nun.This method, by carrying out triflated reaction with trifluoromethyl sulfonic acid anhydride, obtains triflated compound using 2 (hydroxy phenyl of 4 bromine 3) ethyl acetate as raw material；Then substitution reaction is carried out with another raw material 4 (4 piperidyl) morpholine, obtains 2 { 4 bromine 3 [4 (base of morpholine 4) piperidinyl-1 base] phenyl } ethyl acetate；Then double methylation reactions and hydrolysis are carried out, 2 obtained { 4 bromine 3 [4 (base of morpholine 4) piperidinyl-1 base] phenyl } 2 methylpropanoic acids carry out condensation reaction with mono-tert-butyl malonate, obtain the oxopentanoate of 4 { 4 bromine 3 [4 (base of morpholine 4) piperidinyl-1 base] phenyl } 4 methyl 3；Fischer indole synthesis methods are reacted by using classics, carbonyl is cyclized under acid catalysis with phenylhydrazine and forms indoles parent nucleus, finally pass through cyclization, boration and catalyzed coupling reaction again, Ai Le is prepared for Buddhist nun, the route methods are reasonable in design, raw material is cheap and easy to get, and reaction condition is easily effectively controlled.

Description

A kind of Ai Le replaces the preparation method of Buddhist nun
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, and in particular to a kind of Ai Le replaces the preparation method of Buddhist nun.
Background technology
New anaplastic lymphoma kinase (ALK) inhibitor Ai Le replaces chemical entitled 9- ethyl -6 of Buddhist nun (Alectinib), 6- dimethyl -8- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxos -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs, Its chemical structural formula is：
Ai Le is the original new drug of the branch company Chugai Pharmaceutical inventions of company of Roche Group for Buddhist nun, Through obtaining the breakthrough medicine recognition of qulifications of U.S. FDA, accelerate examination ＆ approval as oral anti-lung cancer new drug, for treating ALK Late period (metastatic) non-small cell lung cancer (NSCLC) of gene mutation, or to (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine be resistant to patient treatment.
It is a kind of disclosed in patent US20130143877 and WO2012023597A1 to prepare the synthetic route that Ai Le replaces Buddhist nun：With 7- methoxyl group -3,4- dihydro -2- naphthalenones are initiation material, are methylated and bromination reaction by double, then with the Fischer of phenylhydrazine Indole synthesis carry out ring-closure reaction, are then passed through oxidation and introduce 11- carbonyls, then the hydroxyl obtained by methoxy hydrolysis is carried out It is triflated, it is condensed with 4- (4- piperidyls) morpholine, last 9- bromos are replaced by acetenyl, then are obtained through reduction reaction Ai Le replaces Buddhist nun, and process route is as follows：
Because whole synthetic route step is longer, cumbersome, cost is higher, is unfavorable for amplification production and industrialization is pushed away Extensively.
Ai Le disclosed in patent US20120083488 replaces the synthetic route of Buddhist nun, with iodo- 4 second of mono-tert-butyl malonate and 3- Base tert-butyl benzene is initiation material, and by condensation, cyclization, the condensation with 4- (4- piperidyls) morpholine, last cyclization obtains Ai Le For Buddhist nun, process route is as follows：
Ai Le disclosed in patent CN104402862A is as follows for the synthetic route of Buddhist nun, wherein needing to use indoles parent nucleus Compound is used as starting raw material：
The above two is combined into the initiation material of route costly, is difficult to obtain, thus needs synthetically prepared；Due to two The midbody product and final products for being combined into route are impure more with accessory substance, thus purifying needs to use a large amount of solvents, Cumbersome, yield is relatively low, is unfavorable for industrialization production popularization, it is therefore necessary to explore that technological process is short, simple to operate, cost Ai Le that is cheap and using suitable industrialized production replaces the preparation method of Buddhist nun.
The content of the invention
It is contemplated that overcoming the deficiencies in the prior art, there is provided the preparation method that a kind of Ai Le replaces Buddhist nun.
In order to achieve the above object, the technical scheme that provides of the present invention is：
The Ai Le comprises the following steps for the preparation method of Buddhist nun：
(1) 5- [(ethoxy carbonyl) methyl] -2- bromophenyl triflates are prepared：By 2- (the bromo- 3- hydroxy benzenes of 4- Base) ethyl acetate and trifluoromethyl sulfonic acid anhydride carry out triflated reaction in acid binding agent alkali systems, obtains 5- [(second Epoxide carbonyl) methyl] -2- bromophenyl triflates, reaction equation is：
(2) 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } ethyl acetate is prepared：By 5- [(ethyoxyl carbonyls Base) methyl] -2- bromophenyls triflate and 4- (4- piperidyls) morpholines enter in the system that acid binding agent alkali and solvent are constituted Row substitution reaction, obtains 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } ethyl acetate, and reaction equation is：
(3) 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester is prepared：By 2- { 4- Bromo- 3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } ethyl acetate and iodomethane be in the system that base reagent and solvent are constituted Double methylation reactions are carried out, 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester is obtained, Reaction equation is：
(4) 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid is prepared：By 2-, { 4- is bromo- 3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester is added to the body being made up of base reagent, solvent and water Reaction is hydrolyzed in system, 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid is obtained, reacts Formula is：
(5) 4- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } tertiary fourth of -4- methyl -3- oxopentanoic acids is prepared Ester：By 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acids and mono-tert-butyl malonate in chlorination Condensation reaction is carried out in the system that magnesium, acid binding agent alkali, condensing agent and solvent are constituted, 4- { the bromo- 3- of 4- [4- (morpholine -4- bases) are obtained Piperidin-1-yl] phenyl } -4- methyl -3- oxopentanoates, reaction equation is：
(6) 6- cyano group -2- { 2- [the bromo- 3- of 4- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- is prepared Indole -3-carboxylic acid：By 4- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -3- oxopentanoates Cyclization is carried out in the presence of acid catalyst with 3- cyanophenylhydrazines, reaction is then hydrolyzed, 6- cyano group -2- { 2- are obtained [the bromo- 3- of 4- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- indole -3-carboxylic acids, reaction equation is：
(7) prepare 9- bromo- 6,6- dimethyl -8- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxo -6,11- dihydros - 5H- benzos [b] carbazole -3- formonitrile HCNs：By 6- cyano group -2- { 2- [the bromo- 3- of 4- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl-s 2- yls } -1H- indole -3-carboxylic acids carry out cyclization in the system that acid catalyst and solvent are constituted, and obtain bromo- 6, the 6- bis- of 9- Methyl -8- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxos -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs, reaction Formula is：
(8) prepare Ai Le and replace Buddhist nun：By the bromo- 6,6- dimethyl -8- of 9- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxos - 6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs first react, then in the solvent reacted for boration with n-BuLi With organoboron reagent carry out boration reaction, then by obtained 6,6- dimethyl -8- [4- (morpholine -4- bases) piperidin-1-yl] - 11- oxos -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCN -9- boric acid and bromoethane are in metallic catalyst, inorganic salts, use Catalyzed coupling reaction is carried out in the system that the solvent and water of catalyzed coupling reaction are constituted, Ai Le is obtained for Buddhist nun, reaction equation is：
Preferably, the acid binding agent alkali described in step (1) is triethylamine, diethylamine, DIPEA, pyridine, piperazine Pyridine, tri-n-butylamine, trimethylamine, tri-isopropyl amine, aniline, N, N- dimethylanilines, N, N- diethylanilines, 2,6- lutidines, DMAP, TMG, 1-METHYLPYRROLIDONE, N- methylmorpholines, N-ethylmorpholine, 1,8- diazabicyclos [5.4.0] 11 carbon -7- alkene；Wherein, 2- (the bromo- 3- hydroxy phenyls of 4-) ethyl acetate, trifluoromethyl sulfonic acid anhydride, acid binding agent alkali three Mol ratio between person is 1.0: (1.2~1.5): (1.5~2.5).
Preferably, the acid binding agent alkali described in step (2) is sodium methoxide, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide or isopropanol Sodium；Described solvent is N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, toluene or 1,4- dioxane；Wherein, 5- Mol ratio between [(ethoxy carbonyl) methyl] -2- bromophenyls triflate, 4- (4- piperidyls) morpholine, acid binding agent alkali For 1.0: (1.8~2.7): (2.0~3.0), solvent for reaction medium, be not involved in reaction, be not required to limit its with reactant and The molar ratio of reagent.
Preferably, the base reagent described in step (3) is sodium methoxide, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide or isopropanol Sodium；Described solvent is methanol, ethanol, the tert-butyl alcohol or isopropanol；Wherein, 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidines -1- Base] phenyl } ethyl acetate, iodomethane, the mol ratio between base reagent be 1.0: (1.8~3.0): (1.8~3.0), solvent is The medium of reaction, reaction is not involved in, is not required to limit itself and reactant and the molar ratio of reagent.
Preferably, the base reagent described in step (4) is sodium hydroxide, potassium hydroxide, lithium hydroxide or cesium hydroxide；It is described Solvent be methanol, ethanol, isopropanol, normal propyl alcohol, the tert-butyl alcohol or n-butanol；Wherein, 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) Piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester, base reagent, solvent, the mol ratio between water be 1.0: (1.1~1.4): (10.0~25.0): (5.0~10.0).
Preferably, the acid binding agent alkali described in step (5) is triethylamine, diethylamine, DIPEA, pyridine, piperazine Pyridine, tri-n-butylamine, trimethylamine, tri-isopropyl amine, aniline, N, N- dimethylanilines, N, N- diethylanilines, 2,6- lutidines, DMAP, TMG, 1-METHYLPYRROLIDONE, N- methylmorpholines, N-ethylmorpholine, 1,8- diazabicyclos [5.4.0] 11 carbon -7- alkene；Described condensing agent be N, N '-carbonyl dimidazoles, N, N '-dicyclohexylcarbodiimide, N, N '- DIC, 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides, 1- hydroxy benzo triazoles or 1,8- phenodiazines Miscellaneous bicyclic [5.4.0]-ten one -7- alkene；Described solvent is methyl tertiary butyl ether(MTBE), N,N-dimethylformamide or N, N- dimethyl Acetamide；Wherein, 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid, the tertiary fourth of malonic acid list Mol ratio between ester, magnesium chloride, acid binding agent alkali, condensing agent is 1.0: (1.4~1.8): (1.0~1.2): and (4.0~5.6): (1.1~1.2), solvent is the medium of reaction, is not involved in reaction, is not required to limit itself and reactant and the molar ratio of reagent.
Preferably, the acid catalyst described in step (6) is trifluoroacetic acid, acetic acid, formic acid, oxalic acid, propionic acid, n-butyric acie or different Butyric acid；Wherein, 4- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -3- oxopentanoates, 3- Mol ratio between cyanophenylhydrazine and acid catalyst is 1.0: (1.1~1.4): (40.0~70.0).
Preferably, the acid catalyst described in step (7) is trifluoroacetic acid, TFAA, acetic acid, acetic anhydride, formic acid, grass Acid, oxalyl chloride, phosphorus pentoxide, POCl3, thionyl chloride, phosphorus pentachloride, phosphorus trichloride, polyphosphoric acids, to toluene sulphur Acid, paratoluensulfonyl chloride, methanesulfonic acid or mesyl chloride；Described solvent is toluene, N,N-dimethylformamide, N, N- dimethyl Acetamide or 1,4- dioxane；Wherein, 6- cyano group -2- { 2- [the bromo- 3- of 4- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] Propyl- 2- yls } -1H- indole -3-carboxylic acids, the mol ratio between acid catalyst be 1.0: (2.0~10.0), solvent for reaction matchmaker It is situated between, is not involved in reaction, is not required to limit itself and reactant and the molar ratio of reagent.
Preferably, the solvent for being used for boration reaction described in step (8) is DMF, N, N- dimethyl Acetamide, tetrahydrofuran, toluene, dichloromethane, 1,2- dichloroethanes, chloroform, methyl tertiary butyl ether(MTBE) or 1,4- dioxane；Institute The organoboron reagent stated is connection boric acid pinacol ester, trimethylborate, triethyl borate or triisopropyl borate ester；Described metal Catalyst is four (triphenyl phosphorus) palladiums, [double (diphenylphosphino) ferrocene of 1,1'-] palladium chloride or two (triphenylphosphine) dichloros Change palladium；Described inorganic salts be potassium carbonate, sodium carbonate, potassium phosphate, lithium chloride, sodium bromide, KBr, potassium acetate, KI or Potassium chloride；The described solvent for catalyzed coupling reaction is N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, tetrahydrochysene furan Mutter, toluene, dichloromethane, 1,2- dichloroethanes, chloroform, methyl tertiary butyl ether(MTBE) or 1,4- dioxane；Wherein, 9- bromo- 6,6- Dimethyl -8- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxo -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs, just Mol ratio between butyl lithium, organoboron reagent, bromoethane, metallic catalyst, inorganic salts is 1.0: (1.1~1.3): (1.25 ~1.75): (1.0~1.2): (0.045~0.075): (1.45~2.00), for boration react solvent, for being catalyzed The solvent and water of coupling reaction are the medium of reaction, are not involved in reaction, are not required to limit itself and reactant and the molar ratio of reagent.
Preferably, the temperature of the triflated reaction described in step (1) is 0~25 DEG C, and the reaction time is 1~4 Hour；The temperature of substitution reaction described in step (2) is 90~110 DEG C, and the reaction time is 6~18 hours；Described in step (3) The temperature of double methylation reactions is 60~80 DEG C, and the reaction time is 2~6 hours；The temperature of hydrolysis described in step (4) is 60~90 DEG C, the reaction time is 6~12 hours；The temperature of condensation reaction described in step (5) is 60~80 DEG C, and the reaction time is 2~4 hours；The temperature of cyclization described in step (6) is 90~120 DEG C, and the reaction time is 6~12 hours；Described water The temperature of solution reaction is 50~70 DEG C, and the reaction time is 2~4 hours；The temperature of cyclization described in step (7) be 100~ 120 DEG C, the reaction time is 12~20 hours；Described in step (8) boration reaction temperature be -78 DEG C, then 20~25 DEG C, Reaction time is 1~3 hour；The temperature of described catalyzed coupling reaction is 90~120 DEG C, and the reaction time is 12~24 hours.
The invention will be further described below：
A kind of Ai Le of the present invention replaces the preparation method of Buddhist nun, first with 2- (the bromo- 3- hydroxy phenyls of 4-) ethyl acetate For raw material, by obtaining corresponding triflated close with the triflated reaction that trifluoromethyl sulfonic acid anhydride is carried out Thing, then carries out substitution reaction with another raw material 4- (4- piperidyls) morpholine, prepares 2- { the bromo- 3- of 4- [4- (morpholine -4- Base) piperidin-1-yl] phenyl } ethyl acetate, then carry out double methylation reactions and hydrolysis, the obtained 2- { bromo- 3- [4- of 4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid and mono-tert-butyl malonate carry out condensation reaction, prepares 4- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -3- oxopentanoates, by using classical anti- Fischer indole synthesis methods are answered, carbonyl is cyclized under acid catalysis with phenylhydrazine and forms indoles parent nucleus, it is finally anti-by cyclisation again Should, boration and catalyzed coupling reaction, prepare Ai Le for Buddhist nun, the route methods are reasonable in design, and raw material is cheap and easy to get, reaction Condition is easily effectively controlled.
The technical scheme that the present invention is provided has following technique effect：First, only making after being completed due to the reaction of each step normal The post processing and purifying of rule property are without column chromatography, and impurity is less, controllable, can directly carry out next step reaction, therefore Operation is simplified, while each step can obtain higher yield；Second, the process route initiation material and used of the present invention Reagent is easy to get, and the technical scheme of synthetic reaction rationally, can largely produce to meet the use demand of bulk drug, it is adaptable to industry Metaplasia is produced；Third, due to pollutant will not be produced in preparation process, thus environmental protection effect can be embodied.
Embodiment
Embodiment 1
A 5- [(ethoxy carbonyl) methyl] -2- bromophenyl triflates) are prepared：
2- (the bromo- 3- hydroxy phenyls of 4-) ethyl acetate (13.0g, 47.6mmol) be dissolved in triethylamine (10.2g, 100.8mmol), it is slowly added dropwise trifluoromethyl sulfonic acid anhydride (19.1g, 67.7mmol), 20 DEG C of stirring reactions 2 hours, through locating later Reason and purifying, obtain 5- [(ethoxy carbonyl) methyl] -2- bromophenyl triflates, light yellow solid (16.6g), yield 89%.
B 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } ethyl acetate) is prepared：
5- [(ethoxy carbonyl) methyl] -2- bromophenyls triflate (16.5g, 42.2mmol) is dissolved in N, N- diformazans Base formamide (250mL), adds 4- (4- piperidyls) morpholine (16.2g, 95.2mmol), sodium methoxide (5.7g, 105.5mmol), 100 DEG C of reactant mixture stirring reaction 12 hours, reaction solution is down to room temperature, adds water (150mL), is cooled to 0 DEG C of crystallization 4 small When, filtering obtains 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } ethyl acetate, and white solid (14.8g) is received Rate 85%.
C 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester) is prepared：
2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } ethyl acetate (14.0g, 34.0mmol) is dissolved in first Alcohol (250mL), is slowly added to sodium methoxide (4.6g, 85.2mmol), is cooled to 0 DEG C or so, be added dropwise iodomethane (12.1g, 85.3mmol), 70 DEG C of reactant mixture stirring reaction 4 hours, reaction solution is down to room temperature, adds watery hydrochloric acid and adjusts to neutrality, rotation Steaming is concentrated to dryness, and adds ethyl acetate extraction, and magnesium sulfate is dried, and concentrated by rotary evaporation is to doing, and recrystallizing methanol obtains 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester, off-white powder (13.3g), yield 89%.
D 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid) is prepared：
2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester (13.0g, Methanol (25mL) 29.6mmol) is dissolved in, 30% sodium hydroxide solution (5mL) is added, 75 DEG C is heated to and reacts 9 hours, be down to room Temperature, by post-processing and purifying, obtains 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid, class White solid (11.7g), yield 96%.
E 4- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } tertiary fourth of -4- methyl -3- oxopentanoic acids) is prepared Ester：
2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acids (11.2g, 27.2mmol) and Mono-tert-butyl malonate (7.0g, 43.7mmol) is dissolved in methyl tertiary butyl ether(MTBE) (250mL), add magnesium chloride (2.9g, 30.5mmol), triethylamine (13.2g, 130.5mmol), N, N '-carbonyl dimidazoles (5.1g, 31.5mmol) are heated to 70 DEG C instead Answer 3 hours, be down to room temperature, washed successively with 1N hydrochloric acid, water, saturated sodium bicarbonate solution, anhydrous magnesium sulfate is dried, and vacuum rotary steam is extremely Dry, recrystallisation from isopropanol obtains 4- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -3- oxopentanoic acids The tert-butyl ester, off-white powder (10.9g), yield 79%.
F 6- cyano group -2- { 2- [the bromo- 3- of 4- (4- (morpholine -4- bases) piperidin-1-yl)) are prepared
4- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -3- oxopentanoates (10.0g, 19.6mmol), 3- cyanophenylhydrazines (3.3g, 24.8mmol) are mixed with trifluoroacetic acid (123.1g, 1079.6mmol), 100 DEG C of reactant mixture stirring reaction 9 hours, reaction solution is down to 60 DEG C, adds water (50mL), and insulation reaction 3 hours is rotated dense Dry, addition saturated sodium bicarbonate solution neutralization is reduced to, ethyl acetate extraction is added, magnesium sulfate is dried, and concentrated by rotary evaporation uses second to doing Acetoacetic ester and n-hexane mixed solvent recrystallization, obtain 6- cyano group -2- { 2- [the bromo- 3- of 4- (4- (morpholine -4- bases) piperidin-1-yl) benzene Base] propyl- 2- yls } -1H- indole -3-carboxylic acids, off-white powder (8.4g), yield 78%.
G) prepare 9- bromo- 6,6- dimethyl -8- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxo -6,11- dihydros - 5H- benzos [b] carbazole -3- formonitrile HCNs：
6- cyano group -2- { 2- [the bromo- 3- of 4- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- indoles -3- Carboxylic acid (8.0g, 14.5mmol), trifluoroacetic acid (9.9g, 86.8mmol) are dissolved in toluene (70mL), are heated to 110 DEG C of stirring reactions 16 hours, concentrated by rotary evaporation added saturated sodium bicarbonate solution and neutralized to dry, adds ethyl acetate extraction, and magnesium sulfate is dried, revolving It is concentrated to dryness, is recrystallized with ethyl acetate and n-hexane mixed solvent, obtain bromo- 6, the 6- dimethyl -8- of 9- [4- (morpholine -4- bases) Piperidin-1-yl] -11- oxos -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs, off-white powder (6.9g), yield 89%.
H) prepare Ai Le and replace Buddhist nun：
The bromo- 6,6- dimethyl -8- of 9- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxo -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs (6.5g, 12.2mmol) are dissolved in DMF (50mL), are cooled to -78 DEG C, are slowly added dropwise The THF solution (50mL) of n-BuLi (15mmol), -78 DEG C of stirring reactions of reactant mixture 2 hours are slowly added to connection boric acid frequency That alcohol ester (4.6g, 18.1mmol), -78 DEG C of stirring reactions of reactant mixture 1 hour rise to 20 DEG C and stirred 10 hours, delay naturally Slow to add methanol (20mL), reaction solution concentrated by rotary evaporation obtains 6,6- dimethyl -8- [4- (morpholine -4- bases) piperidines -1- to dry Base] -11- oxos -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCN -9- boric acid, addition bromoethane (1.5g, 13.8mmol), Four (triphenyl phosphorus) palladiums (0.84g, 0.73mmol), potassium carbonate (3.0g, 21.7mmol), N,N-dimethylformamide (50mL) and Water (30mL), reactant mixture is heated to 100 DEG C and reacted 18 hours, and reaction solution is down to room temperature, and concentrated by rotary evaporation adds acetic acid to dry Ethyl ester is extracted, and salt washing, magnesium sulfate is dried, and concentrated by rotary evaporation is to doing, and ethyl acetate and n-hexane mixed solvent are recrystallized, and are obtained Ai Le replaces Buddhist nun, off-white powder (4.9g), yield 83%.
Embodiment 2
A 5- [(ethoxy carbonyl) methyl] -2- bromophenyl triflates) are prepared：
2- (the bromo- 3- hydroxy phenyls of 4-) ethyl acetate (3.0g, 11.0mmol) is dissolved in N, N- diisopropylethylamine (2.4g, 18.6mmol), be slowly added dropwise trifluoromethyl sulfonic acid anhydride (4.1g, 14.5mmol), 0 DEG C of stirring reaction 4 hours, by post processing and Purifying, obtains 5- [(ethoxy carbonyl) methyl] -2- bromophenyl triflates, light yellow solid (3.4g), yield 79%.
B 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } ethyl acetate) is prepared：
5- [(ethoxy carbonyl) methyl] -2- bromophenyls triflate (3.2g, 8.2mmol) is dissolved in toluene (50mL), adds 4- (4- piperidyls) morpholine (2.6g, 15.3mmol), caustic alcohol (1.2g, 17.6mmol), reactant mixture 90 Stirring reaction 18 hours, reaction solution is down to room temperature, adds water (30mL), is cooled to 0 DEG C of crystallization 5 hours, filtering, and obtaining 2-, { 4- is bromo- 3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } ethyl acetate, white solid (2.8g), yield 83%.
C 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester) is prepared：
2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } ethyl acetate (2.8g, 6.8mmol) is dissolved in ethanol (55mL), is slowly added to caustic alcohol (0.9g, 13.2mmol), is cooled to 0 DEG C or so, and iodomethane (1.9g, 13.4mmol) is added dropwise, 60 DEG C of reactant mixture stirring reaction 6 hours, reaction solution is down to room temperature, adds watery hydrochloric acid and adjusts to neutrality, concentrated by rotary evaporation to dry, Ethyl acetate extraction is added, magnesium sulfate is dried, concentrated by rotary evaporation is to doing, and recrystallizing methanol obtains 2- { the bromo- 3- of 4- [4- (morpholine -4- Base) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester, off-white powder (2.6g), yield 87%.
D 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid) is prepared：
2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester (2.5g, 5.7mmol) Ethanol (4mL) is dissolved in, potassium hydroxide solution (KOH=0.4g is added；Water 0.7g), it is heated to 60 DEG C and reacts 12 hours, is down to room Temperature, by post-processing and purifying, obtains 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid, class White solid (2.2g), yield 94%.
E 4- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } tertiary fourth of -4- methyl -3- oxopentanoic acids) is prepared Ester：
2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid (2.0g, 4.9mmol) and third The diacid list tert-butyl ester (1.1g, 6.9mmol) is dissolved in DMF (35mL), add magnesium chloride (0.5g, 5.3mmol), DIPEA (2.6g, 20.1mmol), N, N '-dicyclohexylcarbodiimide (1.2g, 5.8mmol), It is heated to 60 DEG C to react 4 hours, is down to room temperature, is washed successively with 1N hydrochloric acid, water, saturated sodium bicarbonate solution, anhydrous magnesium sulfate is done Dry, vacuum rotary steam is to doing, and recrystallisation from isopropanol obtains 4- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- first Base -3- oxopentanoates, off-white powder (2.0g), yield 81%.
F 6- cyano group -2- { 2- [the bromo- 3- of 4- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- Yin) are prepared Diindyl -3- carboxylic acids：
4- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -3- oxopentanoates (2.0g, 3.9mmol), 3- cyanophenylhydrazines (0.6g, 4.5mmol) are mixed with acetic acid (9.4g, 156.5mmol), and 90 DEG C of reactant mixture is stirred Reaction 12 hours is mixed, reaction solution is down to 50 DEG C, add water (20mL), insulation reaction 4 hours, concentrated by rotary evaporation adds saturation to dry Sodium bicarbonate solution is neutralized, and adds ethyl acetate extraction, and magnesium sulfate is dried, and concentrated by rotary evaporation is to dry, with ethyl acetate and n-hexane Mixed solvent recrystallize, obtain 6- cyano group -2- { 2- [the bromo- 3- of 4- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } - 1H- indole -3-carboxylic acids, off-white powder (2.0g), yield 92%.
G) prepare 9- bromo- 6,6- dimethyl -8- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxo -6,11- dihydros - 5H- benzos [b] carbazole -3- formonitrile HCNs：
6- cyano group -2- { 2- [the bromo- 3- of 4- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- indoles -3- Carboxylic acid (2.0g, 3.6mmol), TFAA (1.6g, 7.6mmol) are dissolved in DMF (25mL), are heated to 100 DEG C of stirring reactions 20 hours, concentrated by rotary evaporation adds saturated sodium bicarbonate solution and neutralized to dry, adds ethyl acetate extraction, sulphur Sour magnesium is dried, and concentrated by rotary evaporation is recrystallized with ethyl acetate and n-hexane mixed solvent to dry, obtains bromo- 6, the 6- dimethyl -8- of 9- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxos -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs, off-white powder (1.6g), yield 83%.
H) prepare Ai Le and replace Buddhist nun：
The bromo- 6,6- dimethyl -8- of 9- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxo -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs (1.5g, 2.8mmol) are dissolved in tetrahydrofuran (25mL), be cooled to -78 DEG C, n-BuLi is slowly added dropwise The THF solution (11mL) of (3.1mmol), -78 DEG C of stirring reactions of reactant mixture 2 hours are slowly added to trimethylborate (0.37g, 3.6mmol), -78 DEG C of stirring reactions of reactant mixture 1 hour rise to 20 DEG C and stirred 10 hours, are slowly added to naturally Ethanol (8mL), reaction solution concentrated by rotary evaporation obtains 6,6- dimethyl -8- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxygen to dry Generation -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCN -9- boric acid, adds bromoethane (0.3g, 2.8mmol), [1,1'- is double (diphenylphosphino) ferrocene] palladium chloride (0.1g, 0.14mmol), sodium carbonate (0.44g, 4.2mmol), tetrahydrofuran (15mL) and water (10mL), reactant mixture is heated to 90 DEG C and reacted 24 hours, and reaction solution is down to room temperature, concentrated by rotary evaporation to dry, Ethyl acetate extraction is added, salt washing, magnesium sulfate is dried, concentrated by rotary evaporation is to doing, and ethyl acetate and n-hexane mixed solvent are carried out Recrystallization, get Ai Le replaces Buddhist nun, off-white powder (1.1g), yield 81%.
Embodiment 3
A 5- [(ethoxy carbonyl) methyl] -2- bromophenyl triflates) are prepared：
2- (the bromo- 3- hydroxy phenyls of 4-) ethyl acetate (2.5g, 9.2mmol) is dissolved in pyridine (1.8g, 22.8mmol), slowly Trifluoromethyl sulfonic acid anhydride (3.8g, 13.5mmol) is added dropwise, 25 DEG C of stirring reactions 1 hour, by post-processing and purifying, obtain 5- [(ethoxy carbonyl) methyl] -2- bromophenyl triflates, light yellow solid (3.5g), yield 98%.
B 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } ethyl acetate) is prepared：
5- [(ethoxy carbonyl) methyl] -2- bromophenyls triflate (3.5g, 9.0mmol) is dissolved in 1,4- dioxies six Ring (80mL), adds 4- (4- piperidyls) morpholine (4.1g, 24.1mmol), sodium isopropylate (2.2g, 26.8mmol), reaction mixing 110 DEG C of thing stirring reaction 6 hours, reaction solution is down to room temperature, adds water (55mL), is cooled to 0 DEG C of crystallization 6 hours, and filtering obtains 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } ethyl acetate, white solid (2.9g), yield 79%.
C 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester) is prepared：
2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } ethyl acetate (2.5g, 6.1mmol) is dissolved in isopropyl Alcohol (40mL), is slowly added to sodium isopropylate (1.5g, 18.3mmol), is cooled to 0 DEG C or so, be added dropwise iodomethane (2.6g, 18.3mmol), 80 DEG C of reactant mixture stirring reaction 2 hours, reaction solution is down to room temperature, adds watery hydrochloric acid and adjusts to neutrality, rotation Steaming is concentrated to dryness, and adds ethyl acetate extraction, and magnesium sulfate is dried, and concentrated by rotary evaporation is to doing, and recrystallizing methanol obtains 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester, off-white powder (2.0g), yield 75%.
D 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid) is prepared：
2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester (2.0g, 4.6mmol) Isopropanol (8mL) is dissolved in, cesium hydroxide solution (CsOH=0.9g is added；Water 0.8g), it is heated to 90 DEG C and reacts 6 hours, is down to Room temperature, by post-processing and purifying, obtains 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid, Off-white powder (1.5g), yield 80%.
E 4- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } tertiary fourth of -4- methyl -3- oxopentanoic acids) is prepared Ester：
2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid (1.5g, 3.7mmol) and third The diacid list tert-butyl ester (1.0g, 6.2mmol) is dissolved in DMA (40mL), add magnesium chloride (0.4g, 4.2mmol), pyridine (1.6g, 20.2mmol), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (0.8g, 4.2mmol), 80 DEG C are heated to react 2 hours, room temperature is down to, is washed successively with 1N hydrochloric acid, water, saturated sodium bicarbonate solution, it is anhydrous Magnesium sulfate is dried, and vacuum rotary steam is to doing, and recrystallisation from isopropanol obtains 4- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] benzene Base } -4- methyl -3- oxopentanoates, off-white powder (1.5g), yield 81%.
F 6- cyano group -2- { 2- [the bromo- 3- of 4- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- Yin) are prepared Diindyl -3- carboxylic acids：
4- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -3- oxopentanoates (1.5g, 2.9mmol), 3- cyanophenylhydrazines (0.54g, 4.1mmol) are mixed with formic acid (9.3g, 202.0mmol), 120 DEG C of reactant mixture Stirring reaction 6 hours, reaction solution is down to 70 DEG C, adds water (20mL), and insulation reaction 2 hours, concentrated by rotary evaporation adds saturation to dry Sodium bicarbonate solution is neutralized, and adds ethyl acetate extraction, and magnesium sulfate is dried, and concentrated by rotary evaporation is to dry, with ethyl acetate and n-hexane Mixed solvent recrystallize, obtain 6- cyano group -2- { 2- [the bromo- 3- of 4- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } - 1H- indole -3-carboxylic acids, off-white powder (1.3g), yield 80%.
G) prepare 9- bromo- 6,6- dimethyl -8- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxo -6,11- dihydros - 5H- benzos [b] carbazole -3- formonitrile HCNs：
6- cyano group -2- { 2- [the bromo- 3- of 4- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- indoles -3- Carboxylic acid (1.2g, 2.2mmol), acetic acid (1.3g, 21.6mmol) are dissolved in Isosorbide-5-Nitrae-dioxane (25mL), are heated to 120 DEG C of stirrings Reaction 12 hours, concentrated by rotary evaporation adds saturated sodium bicarbonate solution and neutralized to dry, adds ethyl acetate extraction, and magnesium sulfate is dried, Concentrated by rotary evaporation is recrystallized with ethyl acetate and n-hexane mixed solvent to dry, obtains bromo- 6, the 6- dimethyl -8- of 9- [4- (morpholine -4- Base) piperidin-1-yl] -11- oxos -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs, off-white powder (1.0g), yield 86%.
H) prepare Ai Le and replace Buddhist nun：
The bromo- 6,6- dimethyl -8- of 9- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxo -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs (1.0g, 1.9mmol) are dissolved in tetrahydrofuran (10mL), be cooled to -78 DEG C, n-BuLi is slowly added dropwise The THF solution (10mL) of (2.4mmol), -78 DEG C of stirring reactions of reactant mixture 2 hours are slowly added to triisopropyl borate ester (0.6g, 3.2mmol), -78 DEG C of stirring reactions of reactant mixture 1 hour rise to 20 DEG C and stirred 3 hours, are slowly added to first naturally Alcohol (10mL), reaction solution concentrated by rotary evaporation obtains 6,6- dimethyl -8- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxygen to dry Generation -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCN -9- boric acid, adds bromoethane (0.24g, 2.2mmol), two (triphenyls Phosphine) palladium chloride (0.1g, 0.14mmol), lithium chloride (0.16g, 3.8mmol), tetrahydrofuran (10mL) and water (6mL), reaction Mixture is heated to 90 DEG C and reacted 12 hours, and reaction solution is down to room temperature, and concentrated by rotary evaporation adds ethyl acetate extraction, salt solution to dry Wash, magnesium sulfate is dried, concentrated by rotary evaporation is to doing, and ethyl acetate and n-hexane mixed solvent are recrystallized, and get Ai Le replaces Buddhist nun, and class is white Color solid (0.7g), yield 77%.

Claims (10)

1. a kind of Ai Le replaces the preparation method of Buddhist nun, it is characterised in that methods described comprises the following steps：
(1) 5- [(ethoxy carbonyl) methyl] -2- bromophenyl triflates are prepared：By 2- (the bromo- 3- hydroxy phenyls of 4-) second Acetoacetic ester carries out triflated reaction with trifluoromethyl sulfonic acid anhydride in acid binding agent alkali systems, obtains 5- [(ethyoxyl carbonyls Base) methyl] -2- bromophenyl triflates；
(2) 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } ethyl acetate is prepared：By 5- [(ethoxy carbonyl) Methyl] progress in the system that acid binding agent alkali and solvent are constituted of -2- bromophenyls triflate and 4- (4- piperidyls) morpholines Substitution reaction, obtains 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } ethyl acetate；
(3) 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester is prepared：By 2-, { 4- is bromo- 3- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } progress in the system that base reagent and solvent are constituted of ethyl acetate and iodomethane Double methylation reactions, obtain 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester；
(4) 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid is prepared：By the 2- { bromo- 3- [4- of 4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester is added to the system examination being made up of base reagent, solvent and water In agent, reaction is hydrolyzed, 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid is obtained；
(5) 4- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -3- oxopentanoates are prepared：Will 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid with mono-tert-butyl malonate in magnesium chloride, tie up Sour agent alkali, condensing agent and solvent composition system in carry out condensation reaction, obtain 4- the bromo- 3- of 4- [4- (morpholine -4- bases) piperidines - 1- yls] phenyl } -4- methyl -3- oxopentanoates；
(6) prepare 6- cyano group -2- { 2- [the bromo- 3- of 4- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- indoles - 3- carboxylic acids：By 4- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -4- methyl -3- oxopentanoates and 3- Cyanophenylhydrazine carries out cyclization in the presence of acid catalyst, and reaction is then hydrolyzed, and obtains 6- cyano group -2- { 2- [4- Bromo- 3- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- indole -3-carboxylic acids；
(7) 9- bromo- 6,6- dimethyl -8- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxo -6,11- dihydro -5H- benzene is prepared And [b] carbazole -3- formonitrile HCNs：By 6- cyano group -2- { 2- [the bromo- 3- of 4- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } - 1H- indole -3-carboxylic acids carry out cyclization in the system that acid catalyst and solvent are constituted, and obtain bromo- 6, the 6- dimethyl -8- of 9- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxos -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs；
(8) prepare Ai Le and replace Buddhist nun：By the bromo- 6,6- dimethyl -8- of 9- [4- (morpholine -4- bases) piperidin-1-yl] -11- oxo -6, 11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs in the solvent reacted for boration, first with n-BuLi react, then with Organoboron reagent carries out boration reaction, then by obtained 6,6- dimethyl -8- [4- (morpholine -4- bases) piperidin-1-yl] -11- Oxo -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCN -9- boric acid and bromoethane are in metallic catalyst, inorganic salts, for urging Change in the solvent of coupling reaction and the system of water composition and carry out catalyzed coupling reaction, obtain Ai Le for Buddhist nun.
2. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that tie up acid described in step (1) Agent alkali be triethylamine, diethylamine, N, N- diisopropylethylamine, pyridine, piperidines, tri-n-butylamine, trimethylamine, tri-isopropyl amine, aniline, N, N- dimethylaniline, N, N- diethylanilines, 2,6- lutidines, DMAP, TMG, N- methylpyrroles Alkanone, N- methylmorpholines, N-ethylmorpholine, the carbon -7- alkene of 1,8- diazabicyclos [5.4.0] 11；Wherein, 2- (the bromo- 3- of 4- Hydroxy phenyl) ethyl acetate, trifluoromethyl sulfonic acid anhydride, the mol ratio between acid binding agent alkali three be 1.0: (1.2~1.5): (1.5~2.5).
3. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that tie up acid described in step (2) Agent alkali is sodium methoxide, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide or sodium isopropylate；Described solvent be N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, toluene or 1,4- dioxane；Wherein, 5- [(ethoxy carbonyl) methyl] -2- bromophenyl fluoroforms Mol ratio between sulphonic acid ester, 4- (4- piperidyls) morpholine, acid binding agent alkali is 1.0: (1.8~2.7): (2.0~3.0).
4. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that the alkali examination described in step (3) Agent is sodium methoxide, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide or sodium isopropylate；Described solvent be methanol, ethanol, the tert-butyl alcohol or Isopropanol；Wherein, between 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } ethyl acetate, iodomethane, base reagent Mol ratio be 1.0: (1.8~3.0): (1.8~3.0).
5. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that the alkali examination described in step (4) Agent is sodium hydroxide, potassium hydroxide, lithium hydroxide or cesium hydroxide；Described solvent be methanol, ethanol, isopropanol, normal propyl alcohol, The tert-butyl alcohol or n-butanol；Wherein, 2- { the bromo- 3- of 4- [4- (morpholine -4- bases) piperidin-1-yl] phenyl } -2 Methylpropionic acid ethyl ester, alkali Mol ratio between reagent, solvent, water is 1.0: (1.1~1.4): (10.0~25.0): (5.0~10.0).
6. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that tie up acid described in step (5) Agent alkali be triethylamine, diethylamine, N, N- diisopropylethylamine, pyridine, piperidines, tri-n-butylamine, trimethylamine, tri-isopropyl amine, aniline, N, N- dimethylaniline, N, N- diethylanilines, 2,6- lutidines, DMAP, TMG, N- methylpyrroles Alkanone, N- methylmorpholines, N-ethylmorpholine, the carbon -7- alkene of 1,8- diazabicyclos [5.4.0] 11；Described condensing agent is N, N '-carbonyl dimidazoles, N, N '-dicyclohexylcarbodiimide, N, N '-DIC, 1- (3- dimethylaminos third Base) -3- ethyl carbodiimides, 1- hydroxy benzo triazoles or the -7- alkene of 1,8- diazabicyclos [5.4.0]-ten one；Described is molten Agent is methyl tertiary butyl ether(MTBE), N,N-dimethylformamide or DMAC N,N' dimethyl acetamide；Wherein, 2- the bromo- 3- of 4- [4- (morpholine- 4- yls) piperidin-1-yl] phenyl -2 Methylpropionic acid, mono-tert-butyl malonate, magnesium chloride, acid binding agent alkali, rubbing between condensing agent You are than being 1.0: (1.4~1.8): (1.0~1.2): (4.0~5.6): (1.1~1.2).
7. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that the acid described in step (6) is urged Agent is trifluoroacetic acid, acetic acid, formic acid, oxalic acid, propionic acid, n-butyric acie or isobutyric acid；Wherein, 4- { the bromo- 3- of 4- [4- (morpholine -4- Base) piperidin-1-yl] phenyl } -4- methyl -3- oxopentanoates, 3- cyanophenylhydrazines, the mol ratio between acid catalyst be 1.0: (1.1~1.4): (40.0~70.0).
8. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that the acid described in step (7) is urged Agent is trifluoroacetic acid, TFAA, acetic acid, acetic anhydride, formic acid, oxalic acid, oxalyl chloride, phosphorus pentoxide, POCl3, chlorine Change sulfoxide, phosphorus pentachloride, phosphorus trichloride, polyphosphoric acids, p-methyl benzenesulfonic acid, paratoluensulfonyl chloride, methanesulfonic acid or mesyl chloride； Described solvent is toluene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or 1,4- dioxane；Wherein, 6- cyano group- 2- { 2- [the bromo- 3- of 4- (4- (morpholine -4- bases) piperidin-1-yl) phenyl] propyl- 2- yls } -1H- indole -3-carboxylic acids, acid catalyst it Between mol ratio be 1.0: (2.0~10.0).
9. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that being used for described in step (8) Boration reaction solvent be N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, tetrahydrofuran, toluene, dichloromethane, 1, 2- dichloroethanes, chloroform, methyl tertiary butyl ether(MTBE) or 1,4- dioxane；Described organoboron reagent be connection boric acid pinacol ester, Trimethylborate, triethyl borate or triisopropyl borate ester；Described metallic catalyst is four (triphenyl phosphorus) palladiums, [1,1'- is double (diphenylphosphino) ferrocene] palladium chloride or two (triphenylphosphine) palladium chlorides；Described inorganic salts are potassium carbonate, carbonic acid Sodium, potassium phosphate, lithium chloride, sodium bromide, KBr, potassium acetate, KI or potassium chloride；The described catalyzed coupling reaction that is used for Solvent be N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, tetrahydrofuran, toluene, dichloromethane, 1,2- dichloroethanes, Chloroform, methyl tertiary butyl ether(MTBE) or 1,4- dioxane；Wherein, bromo- 6, the 6- dimethyl -8- of 9- [4- (morpholine -4- bases) piperidines -1- Base] -11- oxo -6,11- dihydro -5H- benzos [b] carbazole -3- formonitrile HCNs, n-BuLi, organoboron reagent, bromoethane, metal urge Mol ratio between agent, inorganic salts is 1.0: (1.1~1.3): (1.25~1.75): and (1.0~1.2): (0.045~ 0.075): (1.45~2.00).
10. a kind of Ai Le according to claim 1 replaces the preparation method of Buddhist nun, it is characterised in that the trifluoro described in step (1) The temperature of methanesulfonic acid esterification is 0~25 DEG C, and the reaction time is 1~4 hour；The temperature of substitution reaction described in step (2) For 90~110 DEG C, the reaction time is 6~18 hours；The temperature of double methylation reactions described in step (3) is 60~80 DEG C, instead It is 2~6 hours between seasonable；The temperature of hydrolysis described in step (4) is 60~90 DEG C, and the reaction time is 6~12 hours；Step Suddenly the temperature of the condensation reaction described in (5) is 60~80 DEG C, and the reaction time is 2~4 hours；Cyclization described in step (6) Temperature be 90~120 DEG C, the reaction time be 6~12 hours；The temperature of described hydrolysis is 50~70 DEG C, reaction time For 2~4 hours；The temperature of cyclization described in step (7) is 100~120 DEG C, and the reaction time is 12~20 hours；Step (8) temperature of the boration reaction described in is -78 DEG C, and then 20~25 DEG C, the reaction time is 1~3 hour；Described catalysis is even The temperature of connection reaction is 90~120 DEG C, and the reaction time is 12~24 hours.
CN201710263682.9A 2017-04-21 2017-04-21 A kind of Ai Le replaces the preparation method of Buddhist nun Pending CN106995433A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710263682.9A CN106995433A (en) 2017-04-21 2017-04-21 A kind of Ai Le replaces the preparation method of Buddhist nun

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710263682.9A CN106995433A (en) 2017-04-21 2017-04-21 A kind of Ai Le replaces the preparation method of Buddhist nun

Publications (1)

Publication Number Publication Date
CN106995433A true CN106995433A (en) 2017-08-01

Family

ID=59435532

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710263682.9A Pending CN106995433A (en) 2017-04-21 2017-04-21 A kind of Ai Le replaces the preparation method of Buddhist nun

Country Status (1)

Country Link
CN (1) CN106995433A (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107629069A (en) * 2017-11-06 2018-01-26 中国药科大学 The preparation method of a kind of acetyl-CoA carboxylase inhibitor
WO2019008520A1 (en) * 2017-07-05 2019-01-10 Fresenius Kabi Oncology Limited A 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
CN114014825A (en) * 2021-11-10 2022-02-08 河南师范大学 Efficient synthesis method of histamine H3 receptor antagonist teloprolofen
CN115626891A (en) * 2022-10-20 2023-01-20 四川轻化工大学 Synthesis method of nilapanib key intermediate

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100197591A1 (en) * 2009-02-04 2010-08-05 Pfizer Inc 4-AMINO-7,8-DIHYDROPYRIDO[4,3-d]PYRIMIDIN-5(6H)-ONE DERIVATIVES
CN102459172A (en) * 2009-06-10 2012-05-16 中外制药株式会社 Tetracyclic compound

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100197591A1 (en) * 2009-02-04 2010-08-05 Pfizer Inc 4-AMINO-7,8-DIHYDROPYRIDO[4,3-d]PYRIMIDIN-5(6H)-ONE DERIVATIVES
CN102459172A (en) * 2009-06-10 2012-05-16 中外制药株式会社 Tetracyclic compound

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KEITH MILLS ET AL.: "Fischer lndole Synthesis of 3-Acyl- and 3-Alkoxy-carbonylindoles", 《JOURNAL OF THE CHEMICAL SOCIETY,PERKIN TRANSACTIONS 1》 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019008520A1 (en) * 2017-07-05 2019-01-10 Fresenius Kabi Oncology Limited A process for preparing alectinib or a pharmaceutically acceptable salt thereof
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
CN107629069A (en) * 2017-11-06 2018-01-26 中国药科大学 The preparation method of a kind of acetyl-CoA carboxylase inhibitor
US11014919B2 (en) 2018-12-07 2021-05-25 Fresenius Kabi Ipsum S.R.L. Process for the preparation of alectinib
CN114014825A (en) * 2021-11-10 2022-02-08 河南师范大学 Efficient synthesis method of histamine H3 receptor antagonist teloprolofen
CN115626891A (en) * 2022-10-20 2023-01-20 四川轻化工大学 Synthesis method of nilapanib key intermediate
CN115626891B (en) * 2022-10-20 2024-01-26 四川轻化工大学 Synthesis method of nilaparib key intermediate

Similar Documents

Publication Publication Date Title
CN106995433A (en) A kind of Ai Le replaces the preparation method of Buddhist nun
CN105777710B (en) A kind of Ai Le replaces the synthetic method of Buddhist nun
CN106928184B (en) A kind of Ai Le replaces the preparation method of Buddhist nun
CN102307866B (en) Method for preparing linezolid and intermediates thereof
CN107033124B (en) A kind of Ai Le replaces the preparation method of Buddhist nun
CN107129488A (en) A kind of Ai Le replaces the preparation method of Buddhist nun
CN106928185B (en) A kind of Ai Le replaces the preparation method of Buddhist nun
CN107033125B (en) A kind of Ai Le replaces the preparation method of Buddhist nun
Matache et al. Synthesis of fused dihydro-pyrimido [4, 3-d] coumarins using Biginelli multicomponent reaction as key step
CN106892860B (en) A kind of Ai Le replaces the preparation method of Buddhist nun's intermediate
CN114736191A (en) Tepritinib intermediate and preparation method and application thereof
CN105541801B (en) The synthetic method of EZH2 methyltransferase inhibitors GSK126
CN101768154A (en) New preparation method of iloperidone
CN112279838B (en) Preparation method of pyrroltinib
CN106928125A (en) A kind of Ai Le replaces the preparation method of Buddhist nun's intermediate
CN107011245A (en) A kind of Ai Le replaces the preparation method of Buddhist nun's intermediate
EP4148054A1 (en) Synthesis method for anti-tumor compound and intermediate thereof
CN107739335A (en) A kind of pleasure cuts down the synthetic method for Buddhist nun
CN104628653B (en) The method of synthesizing rosuvastatin spit of fland calcium key intermediate
WO2021045879A1 (en) Synthesis of deuterated aldehydes
EP3478684B1 (en) New processes for the preparation of vemurafenib
CN108191849B (en) Preparation method of anti-epidermal growth factor receptor drug resistance mutation inhibitor, related intermediate and application
CN112552157B (en) Preparation method of 2- (4- (2-substituted ethyl) phenyl) -2-methylpropanoic acid
CN107814757A (en) A kind of method for synthesizing polysubstituted pyrrole derivative
CN106905226A (en) A kind of Ai Le replaces the preparation method of Buddhist nun's intermediate

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
CB02 Change of applicant information
CB02 Change of applicant information

Address after: No. 1, Yong Yang Road, Liuyang high tech Industrial Development Zone, Hunan Province, Hunan

Applicant after: Hunan Boao German Pharmaceutical Co. Ltd.

Address before: 410000 Yong Yang Road, Liuyang manufacturing industrial base, Changsha, Hunan Province, No. 1

Applicant before: Hunan Boaode Biopharmaceutical Technology Development Co., Ltd.

RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20170801