CN105820124A - Synthesizing method for binimetinib - Google Patents
Synthesizing method for binimetinib Download PDFInfo
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- CN105820124A CN105820124A CN201610303794.8A CN201610303794A CN105820124A CN 105820124 A CN105820124 A CN 105820124A CN 201610303794 A CN201610303794 A CN 201610303794A CN 105820124 A CN105820124 A CN 105820124A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
Abstract
The invention discloses a synthesizing method for binimetinib. The method comprises the steps that 2,3,4-trifluoro-5-nitrobenzoic acid and O-(2-tert-butoxy ethyl)hydroxylamine are subjected to a condensation reaction, and obtained N-(2-tert-butoxy ethyoxyl)-2,3,4-trifluoro-5-nitrobenzamide and ammonium hydroxide are subjected to an ammonolysis reaction; obtained N-(2-tert-butoxy ethyoxyl)-2,4-diamino-3-fluoro-5-nitrobenzamide and formic acid are subjected to a ring-closure reaction in a Pearlman's catalyst; obtained N-(2-tert-butoxy ethyoxyl)-6-amino-7-fluoro-3H-benzimidazole-5-formamide and 4-bromo-2-fluoro-1-iodobenzene are subjected to a substitution reaction; obtained N-(2-tert-butoxy ethyoxyl)-6-[(4-bromo-2-fluoro-phenyl)amino]-7-fluoro-3H-benzimidazole-5-formamide is firstly subjected to a methylation reaction with methyl iodide and then subjected to a deprotection reaction with phosphoric acid, and binimetinib is obtained. The synthesizing method is short in route, operation is simplified, cost is low, and the synthesizing method is environmentally friendly and suitable for industrial production.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, be specifically related to a kind of anti-cancer agent and replace the synthetic method of Buddhist nun than Buddhist nun.
Background technology
Mitogen activated protein kinase (MEK) inhibitor replaces the chemistry entitled N-(2-of Buddhist nun (Binimetinib, MEK162) than Buddhist nun
Hydroxyl-oxethyl)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3-methyl-3H-benzimidazole-5-Methanamide, its chemical structural formula is:
The anti-cancer agent researched and developed for Ai Rui biopharmaceutical company of the Ni Shi U.S. (Array Biopharma) than Buddhist nun, for NRAS
Gene mutation body melanoma, BRAF gene mutation body melanoma and the treatment of recurrent rudimentary blood plasma ovarian cancer patients, mesh
Front clinical three phases test is successful, provides a kind of effective target therapeutic agent to patient, thereby increases and it is possible to for almost without effectively controlling
The cancer patient for the treatment of method provides a kind of new therapeutic choice.
A kind of disclosed in patent WO2014063024 prepare than Buddhist nun for the synthetic route of Buddhist nun: with 6-amino-7-fluoro-3-methyl-3H-benzene
And imidazole-5-carboxylic acid methyl ester (No. CAS is 918321-20-7) and the bromo-2-of 4-fluoro-1-iodobenzene are initiation material, by condensation, water
Solution, amidatioon, last deprotection, obtain than Buddhist nun for Buddhist nun.But 6-amino-7-fluoro-3-methyl-3H-benzimidazole-5-carboxylic acid methyl ester
Needing multistep synthetically prepared, patent WO2007002157 has specialized in its syntheti c route, and i.e. with 2,3,4-trifluoro-benzoic acids are
Initiation material, obtains this intermediate by 5 or 6 steps, and total process route is as follows:
The disclosed synthetic route replacing Buddhist nun than Buddhist nun of patent WO2013142182, is also with 2, and 3,4-trifluoro-benzoic acids are initiation material,
Through nitrification, ammonification, be esterified, be condensed, cyclization, bromination, methylate, hydrolyze, amidatioon, the step such as last deprotection,
Obtaining than Buddhist nun for Buddhist nun, process route is as follows:
Above two to be combined into the step of route the longest, and reaction condition and technique are the harshest, complicated, thus complex operation,
Relatively costly, it is unfavorable for amplifying production and Industry Promotion, it is therefore necessary to exploration technological process is short, simple to operate, low cost
Honest and clean and use the ratio Buddhist nun of the applicable industrialized production synthetic method for Buddhist nun.
Summary of the invention
For the deficiencies in the prior art and defect, it is an object of the invention to provide a kind of synthetic method replacing Buddhist nun than Buddhist nun.
In order to realize foregoing invention purpose, the technical solution used in the present invention is:
Described than Buddhist nun for the synthetic route of Buddhist nun it is
Than specifically comprising the following steps that of the synthetic method that Buddhist nun replaces Buddhist nun
(1) N-(2-tert-butoxyethoxy)-2,3,4-three fluoro-5-nitrobenzamide is prepared: by 2,3,4-tri-fluorine-5-nitro benzoic acid
In the system that condensing agent, acid binding agent alkali, solvent form, carry out condensation reaction with O-(2-t-butoxy ethyl) azanol, obtain N-(2-
Tert-butoxyethoxy)-2,3,4-three fluoro-5-nitrobenzamide；
(2) N-(2-tert-butoxyethoxy)-2,4-diaminourea-3-fluoro-5-nitrobenzamide is prepared: by N-(2-tert-butoxy second
Epoxide)-2,3,4-tri-fluoro-5-nitrobenzamides and ammonia carries out the aminating reaction that pressurizes in N-Methyl pyrrolidone, obtains N-(2-
Tert-butoxyethoxy)-2,4-diaminourea-3-fluoro-5-nitrobenzamide；
(3) N-(2-tert-butoxyethoxy)-6-amino-7-fluoro-3H-benzimidazole-5-Methanamide is prepared: by N-(2-tert-butoxy
Ethyoxyl)-2,4-diaminourea-3-fluoro-5-nitrobenzamide and formic acid carries out cyclization at palladium dydroxide carbon in the system of solvent composition
Reaction, obtains N-(2-tert-butoxyethoxy)-6-amino-7-fluoro-3H-benzimidazole-5-Methanamide；
(4) N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3H-benzimidazole-5-Methanamide is prepared:
By N-(2-the tert-butoxyethoxy)-6-amino-7-fluoro-3H-benzimidazole-5-Methanamide fluoro-1-iodobenzene of 2-bromo-with 4-at base reagent, urge
The system of agent, complexant and solvent composition carries out substitution reaction, obtains N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorobenzene
Base) amino]-7-fluoro-3H-benzimidazole-5-Methanamide；
(5) preparation replaces Buddhist nun than Buddhist nun: by N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3H-benzimidazole
-5-Methanamide carries out methylation reaction at base reagent with iodomethane in the system of solvent composition, obtains N-(tert-butoxy ethoxy
Base)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3-methyl-3H-benzimidazole-5-Methanamide, then by N-(tert-butoxy ethoxy
Base)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3-methyl-3H-benzimidazole-5-Methanamide and phosphoric acid carries out deprotection reaction, obtains
Than Buddhist nun for Buddhist nun.
Preferably, the condensing agent described in step (1) is N, N '-carbonyl dimidazoles, 1-(3-dimethylamino-propyl)-3-ethyl carbon two Asia
Amine, 1-hydroxy benzo triazole, N, N '-dicyclohexylcarbodiimide or N, N '-DIC；Described acid binding agent
Alkali is N, N-diisopropylethylamine, triethylamine, diethylamine, trimethylamine, pyridine, piperidines, DMAP, 2,6-bis-
Picoline, aniline, N, N-dimethylaniline, N, N-diethylaniline, Tris(isopropylamine)., tri-n-butylamine, tetramethyl guanidine, N-first
Base morpholine or N-ethylmorpholine；Described solvent is oxolane, dichloromethane, 1,2-dichloroethanes, chloroform, chlorobenzene, second
Nitrile, toluene, N,N-dimethylformamide, methyl tertiary butyl ether(MTBE) or 1,4-dioxane；Wherein, 2,3,4-tri-fluoro-5-Nitrobenzol
Mol ratio between formic acid, O-(2-t-butoxy ethyl) azanol, condensing agent, acid binding agent alkali, solvent is 1.0: (1.1～1.5):
(1.1～1.8): (3.5～5.5): (10.0～25.0).
Preferably, the mass percent concentration of the ammonia described in step (2) is 28%；Wherein, N-(2-tert-butoxyethoxy)-2,3,4-
Mol ratio between three fluoro-5-nitrobenzamides, ammonia, N-Methyl pyrrolidone is 1.0: (5.5～6.5): (5.0～20.0).
Preferably, the noble metal mass percentage content of the palladium dydroxide carbon described in step (3) is 20%；Described solvent is first
Alcohol, ethanol, the tert-butyl alcohol or isopropanol；Wherein, N-(2-tert-butoxyethoxy)-2,4-diaminourea-3-fluoro-5-nitrobenzamide,
Mol ratio between formic acid, palladium dydroxide carbon, solvent is 1.0: (10～20): (0.5～1.0): (50.0～80.0).
Preferably, the base reagent described in step (4) is cesium carbonate, potassium carbonate or sodium carbonate；Described catalyst is three (two benzal
Benzylacetone) two palladiums or double (tri-butyl phosphine) palladium；Described complexant is 4,5-double diphenylphosphine-9,9-dimethyl xanthene, double (2-
Diphenylphosphine phenyl) ether or 4,6-bis-(diphenylphosphine) azophenlyene；Described solvent is toluene, 1,4-dioxane or N, N-dimethyl
Methanamide；Wherein, N-(2-tert-butoxyethoxy)-6-amino-7-fluoro-3H-benzimidazole-5-Methanamide, the bromo-2-of 4-fluoro-1-iodobenzene,
Mol ratio between base reagent, catalyst, complexant, solvent is 1.0: (1.1～1.4): (2.2～2.8): (0.03～0.05):
(0.06～0.1): (10.0～50.0).
Preferably, the base reagent described in step (5) is potassium carbonate, sodium carbonate or cesium carbonate；Described solvent is N, N-dimethyl
Methanamide or DMAC N,N' dimethyl acetamide；Wherein, N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino] the fluoro-3H-of-7-
Mol ratio between benzimidazole-5-Methanamide, iodomethane, base reagent, solvent is 1.0: (1.1～1.3): (1.4～1.8):
(15.0～30.0).
Preferably, the temperature of the condensation reaction described in step (1) is 40～60 DEG C, and the response time is 4～12h；Step (2) institute
The pressure of the aminating reaction stated is 2～3 atmospheric pressure, and reaction temperature is 70～90 DEG C, and the response time is 4～8h；Step (3) is described
The temperature of ring-closure reaction be 65～100 DEG C, the response time is 16～32h；The temperature of the substitution reaction described in step (4) is
90～110 DEG C, the response time is 8～16h；The temperature of the methylation reaction described in step (5) is 50～75 DEG C, and the response time is
1～4h.
A kind of synthetic method replacing Buddhist nun than Buddhist nun of the present invention, first with 2,3,4-tri-fluorine-5-nitro benzoic acids and O-(2-tertiary fourth oxygen
Base ethyl) azanol is raw material, prepares amidatioon midbody compound, carries out aminating reaction and ring-closure reaction the most successively, so
After the more fluoro-1-iodobenzene of 2-bromo-with 4-carry out substitution reaction, obtained 5 and 6 substituted benzimidazole parent nucleus knot of target product
Structure, simplifies purification and the purity of synthetic route and optimize technological operation, beneficially intermediate, finally by methylation reaction
And deprotection, obtain finished product than Buddhist nun for Buddhist nun.
The technical scheme that the present invention provides has following technical effect that one, shortens reactions steps so that technological operation is more
The most succinct, the impurity of each step reaction is less, controlled, obtains higher yield；Its two, owing to will not produce in preparation process
Raw pollutant, thus environmental protection effect can be embodied；Its three, process route initiation material and the reagent used of the present invention are easy
, the use demand meeting crude drug can be produced in a large number, it is adaptable to industrialized production.
In a word, the inventive method process route is reasonable, operation is succinct, reagent is easy to get and total recovery is high and is satisfied industrialization and puts
Big production requirement also can embody excellent environmental protection effect.
Detailed description of the invention
Embodiment 1
A) N-(2-tert-butoxyethoxy)-2,3,4-three fluoro-5-nitrobenzamide is prepared:
2,3,4-tri-fluorine-5-nitro benzoic acid (25.0g, 0.11mol) and N, N '-carbonyl dimidazoles (22.9g, 0.14mol) are dissolved in four
Hydrogen furan (110mL), stirring, add O-(2-t-butoxy ethyl) azanol (18.1g, 0.14mol), drip N, N-diisopropyl
Base ethamine (58.5g, 0.45mol), reactant mixture 50 DEG C stirring reaction 8h, TLC point plate determines that reaction is complete, and reactant liquor revolves
Steaming is concentrated to dryness, and adds dilute hydrochloric acid and regulates to neutral, adds ethyl acetate extraction, and magnesium sulfate is dried, and concentrated by rotary evaporation is the most dry, first
Alcohol recrystallization, obtains the fluoro-5-nitrobenzamide of N-(2-tert-butoxyethoxy)-2,3,4-tri-, off-white color solid (33.5g), yield
88.0%, the reaction equation of this step is as follows:
B) N-(2-tert-butoxyethoxy)-2,4-diaminourea-3-fluoro-5-nitrobenzamide is prepared:
N-(2-tert-butoxyethoxy)-2,3,4-three fluoro-5-nitrobenzamide (33.0g, 0.10mol) is dissolved in N-Methyl pyrrolidone
(83mL), adding the ammonia (0.59mol) of mass percent concentration 28%, reactant mixture is placed in airtight stainless steel cauldron
In at 85 DEG C, stirring reaction 6h under the pressure of 2.5 atmospheric pressure, after completion of the reaction, be cooled to 40 DEG C and delivery systme pressure, slow
Slowly add water (40mL), be cooled to 10 DEG C, crystallize 3h, filters, recrystallisation from isopropanol, obtains N-(2-tert-butoxyethoxy)-2,4-
Diaminourea-3-fluoro-5-nitrobenzamide, off-white color solid (29.3g), yield 90.5%, the reaction equation of this step is as follows:
C) N-(2-tert-butoxyethoxy)-6-amino-7-fluoro-3H-benzimidazole-5-Methanamide is prepared:
N-(2-tert-butoxyethoxy)-2,4-diaminourea-3-fluoro-5-nitrobenzamide (29.0g, 0.09mol), formic acid (52.5g,
1.14mol), the palladium dydroxide carbon (28.0g, 0.05mol) of noble metal mass percentage content 20% mixes with ethanol (350mL)
Closing, reactant mixture 95 DEG C stirring reaction 16h, TLC point plate determines that reaction is complete, and reactant liquor is down to room temperature, filters, and rotation is steamed
It is concentrated to dryness, with ethyl acetate and normal hexane mixed solvent recrystallization, obtains N-(2-tert-butoxyethoxy) the fluoro-3H-of-6-amino-7-
Benzimidazole-5-Methanamide, off-white color solid (21.6g), yield 79.3%, the reaction equation of this step is as follows:
D) N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3H-benzimidazole-5-Methanamide is prepared:
N-(2-tert-butoxyethoxy)-6-amino-7-fluoro-3H-benzimidazole-5-Methanamide (21.0g, 0.07mol) is dissolved in toluene
(270mL), the bromo-2-of 4-fluoro-1-iodobenzene (24.4g, 0.08mol), cesium carbonate (52.9g, 0.16mol), three (dibenzylidenes are added
Acetone) two palladiums (2.2g, 2.4mmol), 4, double diphenylphosphine-9 of 5-, 9-dimethyl xanthene (2.7g, 4.7mmol), reactant mixture
100 DEG C of stirring reaction 12h, TLC point plates determine that reaction is complete, and reactant liquor is down to room temperature, filters, and filtrate concentrated by rotary evaporation is the most dry,
With ethyl acetate and normal hexane mixed solvent recrystallization, obtain N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-
Fluoro-3H-benzimidazole-5-Methanamide, off-white color solid (27.0g), yield 82.5%, the reaction equation of this step is as follows:
E) prepare than Buddhist nun for Buddhist nun:
N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3H-benzimidazole-5-Methanamide (27.0g,
0.06mol) it is dissolved in DMF (80mL), adds potassium carbonate (12.6g, 0.09mol), be cooled to-10 DEG C, drip
Adding iodomethane (9.5g, 0.07mol), reactant mixture 65 DEG C stirring reaction 2h, TLC point plate determines that reaction is complete, reactant liquor
Being down to room temperature, concentrated by rotary evaporation, to dry, adds ethyl acetate extraction, and magnesium sulfate is dried, and concentrated by rotary evaporation is the most dry, recrystallizing methanol,
Obtain N-(tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3-methyl-3H-benzimidazole-5-Methanamide, then
By the deprotection reaction step of patent WO2014063024, carry out deprotection reaction with phosphoric acid, through post processing and purification,
Than Buddhist nun for Buddhist nun, off-white color solid (13.8g), yield 56.0%, the reaction equation of this step is as follows:
Embodiment 2
A) N-(2-tert-butoxyethoxy)-2,3,4-three fluoro-5-nitrobenzamide is prepared:
2,3,4-tri-fluorine-5-nitro benzoic acid (30.0g, 0.14mol) and 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (27.4g,
0.18mol) it is dissolved in chloroform (240mL), stirring, add O-(2-t-butoxy ethyl) azanol (23.5g, 0.18mol), dropping
Triethylamine (61.8g, 0.61mol), reactant mixture 55 DEG C stirring reaction 9h, TLC point plate determines that reaction is complete, and reactant liquor revolves
Steaming is concentrated to dryness, and adds dilute hydrochloric acid and regulates to neutral, adds ethyl acetate extraction, and magnesium sulfate is dried, and concentrated by rotary evaporation is the most dry, first
Alcohol recrystallization, obtains the fluoro-5-nitrobenzamide of N-(2-tert-butoxyethoxy)-2,3,4-tri-, off-white color solid (39.9g), yield
87.4%, the reaction equation of this step is with embodiment 1；
B) N-(2-tert-butoxyethoxy)-2,4-diaminourea-3-fluoro-5-nitrobenzamide is prepared:
N-(2-tert-butoxyethoxy)-2,3,4-three fluoro-5-nitrobenzamide (39.0g, 0.12mol) is dissolved in N-Methyl pyrrolidone
(100mL), adding the ammonia (0.74mol) of mass percent concentration 28%, reactant mixture is placed in airtight stainless steel reaction
At 80 DEG C, stirring reaction 8h under the pressure of 3 atmospheric pressure in still, after completion of the reaction, it is cooled to 40 DEG C and delivery systme pressure, slow
Slowly add water (45mL), be cooled to 10 DEG C, crystallize 3h, filters, recrystallisation from isopropanol, obtains N-(2-tert-butoxyethoxy)-2,4-
Diaminourea-3-fluoro-5-nitrobenzamide, off-white color solid (35.4g), yield 92.5%, the same embodiment of reaction equation of this step
1；
C) N-(2-tert-butoxyethoxy)-6-amino-7-fluoro-3H-benzimidazole-5-Methanamide is prepared:
N-(2-tert-butoxyethoxy)-2,4-diaminourea-3-fluoro-5-nitrobenzamide (35.0g, 0.11mol), formic acid (73.2g,
1.59mol), the palladium dydroxide carbon (39.5g, 0.07mol) of noble metal mass percentage content 20% mixes with methanol (300mL)
Closing, reactant mixture 80 DEG C stirring reaction 18h, TLC point plate determines that reaction is complete, and reactant liquor is down to room temperature, filters, and rotation is steamed
It is concentrated to dryness, with ethyl acetate and normal hexane mixed solvent recrystallization, obtains N-(2-tert-butoxyethoxy) the fluoro-3H-of-6-amino-7-
Benzimidazole-5-Methanamide, off-white color solid (25.3g), yield 77.0%, the reaction equation of this step is with embodiment 1；
D) N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3H-benzimidazole-5-Methanamide is prepared:
N-(2-tert-butoxyethoxy)-6-amino-7-fluoro-3H-benzimidazole-5-Methanamide (25.0g, 0.08mol) is dissolved in 1,4-dioxy
Six rings (300mL), add the bromo-2-of 4-fluoro-1-iodobenzene (31.5g, 0.10mol), potassium carbonate (27.8g, 0.20mol), double (three uncles
Butyl phosphine) palladium (1.6g, 3.2mmol), double (2-diphenylphosphine phenyl) ether (3.5g, 6.4mol), reactant mixture 95 DEG C stirring is anti-
Reaction is complete to answer 14h, TLC point plate to determine, reactant liquor is down to room temperature, filters, and filtrate concentrated by rotary evaporation, to dry, uses ethyl acetate
With normal hexane mixed solvent recrystallization, obtain N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3H-benzo miaow
Azoles-5-Methanamide, off-white color solid (33.1g), yield 84.9%, the reaction equation of this step is with embodiment 1；
E) prepare than Buddhist nun for Buddhist nun:
N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3H-benzimidazole-5-Methanamide (33.0g,
0.07mol) it is dissolved in N,N-dimethylacetamide (100mL), adds sodium carbonate (11.6g, 0.11mol), be cooled to-10 DEG C,
Dropping iodomethane (12.6g, 0.09mol), reactant mixture 70 DEG C stirring reaction 3h, TLC point plate determines that reaction is complete, reaction
Liquid is down to room temperature, and concentrated by rotary evaporation, to dry, adds ethyl acetate extraction, and magnesium sulfate is dried, and concentrated by rotary evaporation is the most dry, recrystallizing methanol,
Obtain N-(tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3-methyl-3H-benzimidazole-5-Methanamide, then
By the deprotection reaction step of patent WO2014063024, carry out deprotection reaction with phosphoric acid, through post processing and purification,
Than Buddhist nun for Buddhist nun, off-white color solid (17.3g), yield 57.4%, the reaction equation of this step is with embodiment 1.
Embodiment 3
A) N-(2-tert-butoxyethoxy)-2,3,4-three fluoro-5-nitrobenzamide is prepared:
2,3,4-tri-fluorine-5-nitro benzoic acid (32.0g, 0.14mol) and 1-hydroxy benzo triazole (27.4g, 0.20mol) are dissolved in second
Nitrile (150mL), stirring, add O-(2-t-butoxy ethyl) azanol (24.1g, 0.18mol), drip DMAP
(67.2g, 0.55mol), reactant mixture 60 DEG C stirring reaction 10h, TLC point plate determines that reaction is complete, reactant liquor rotation inspissation
Being reduced to do, add dilute hydrochloric acid and regulate to neutral, add ethyl acetate extraction, magnesium sulfate is dried, and concentrated by rotary evaporation is the most dry, methanol weight
Crystallization, obtains the fluoro-5-nitrobenzamide of N-(2-tert-butoxyethoxy)-2,3,4-tri-, off-white color solid (41.8g), yield 85.8%,
The reaction equation of this step is with embodiment 1；
B) N-(2-tert-butoxyethoxy)-2,4-diaminourea-3-fluoro-5-nitrobenzamide is prepared:
N-(2-tert-butoxyethoxy)-2,3,4-three fluoro-5-nitrobenzamide (40.0g, 0.12mol) is dissolved in N-Methyl pyrrolidone
(130mL), adding the ammonia (0.69mol) of mass percent concentration 28%, reactant mixture is placed in airtight stainless steel reaction
At 90 DEG C, stirring reaction 7h under the pressure of 2 atmospheric pressure in still, after completion of the reaction, it is cooled to 40 DEG C and delivery systme pressure, slow
Slowly add water (40mL), be cooled to 10 DEG C, crystallize 3h, filters, recrystallisation from isopropanol, obtains N-(2-tert-butoxyethoxy)-2,4-
Diaminourea-3-fluoro-5-nitrobenzamide, off-white color solid (36.0g), yield 91.6%, the same embodiment of reaction equation of this step
1；
C) N-(2-tert-butoxyethoxy)-6-amino-7-fluoro-3H-benzimidazole-5-Methanamide is prepared:
N-(2-tert-butoxyethoxy)-2,4-diaminourea-3-fluoro-5-nitrobenzamide (36.0g, 0.11mol), formic acid (80.3g,
1.74mol), the palladium dydroxide carbon (46.4g, 0.09mol) of noble metal mass percentage content 20% and the tert-butyl alcohol (550mL)
Mixing, reactant mixture 100 DEG C stirring reaction 24h, TLC point plate determines that reaction is complete, and reactant liquor is down to room temperature, filters, rotation
Steaming is concentrated to dryness, and with ethyl acetate and normal hexane mixed solvent recrystallization, obtains N-(2-tert-butoxyethoxy) the fluoro-3H-of-6-amino-7-
Benzimidazole-5-Methanamide, off-white color solid (26.4g), yield 78.0%, the reaction equation of this step is with embodiment 1；
D) N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3H-benzimidazole-5-Methanamide is prepared:
N-(2-tert-butoxyethoxy)-6-amino-7-fluoro-3H-benzimidazole-5-Methanamide (26.0g, 0.08mol) is dissolved in toluene
(330mL), the bromo-2-of 4-fluoro-1-iodobenzene (34.0g, 0.11mol), sodium carbonate (23.1g, 0.22mol), three (dibenzylidenes are added
Acetone) two palladiums (3.5g, 3.8mmol), 4,6-bis-(diphenylphosphine) azophenlyene (3.7g, 6.7mmol), reactant mixture 105 DEG C stirring
Reaction 10h, TLC point plate determines that reaction is complete, and reactant liquor is down to room temperature, filters, and filtrate concentrated by rotary evaporation, to dry, uses acetic acid second
Ester and normal hexane mixed solvent recrystallization, obtain N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3H-benzo
Imidazoles-5-Methanamide, off-white color solid (33.4g), yield 82.5%, the reaction equation of this step is with embodiment 1；
E) prepare than Buddhist nun for Buddhist nun:
N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3H-benzimidazole-5-Methanamide (33.0g,
0.07mol) it is dissolved in DMF (100mL), adds cesium carbonate (34.5g, 0.11mol), be cooled to-10 DEG C,
Dropping iodomethane (12.1g, 0.09mol), reactant mixture 70 DEG C stirring reaction 4h, TLC point plate determines that reaction is complete, reaction
Liquid is down to room temperature, and concentrated by rotary evaporation, to dry, adds ethyl acetate extraction, and magnesium sulfate is dried, and concentrated by rotary evaporation is the most dry, recrystallizing methanol,
Obtain N-(tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3-methyl-3H-benzimidazole-5-Methanamide, then
By the deprotection reaction step of patent WO2014063024, carry out deprotection reaction with phosphoric acid, through post processing and purification,
Than Buddhist nun for Buddhist nun, off-white color solid (17.9g), yield 59.5%, the reaction equation of this step is with embodiment 1.
Embodiment 4
A) N-(2-tert-butoxyethoxy)-2,3,4-three fluoro-5-nitrobenzamide is prepared:
2,3,4-tri-fluorine-5-nitro benzoic acid (36.0g, 0.16mol) and N, N '-dicyclohexylcarbodiimide (50.4g, 0.24mol)
It is dissolved in toluene (200mL), stirring, add O-(2-t-butoxy ethyl) azanol (29.3g, 0.22mol), drip N, N-diformazan
Aniline (90.8g, 0.75mol), reactant mixture 45 DEG C stirring reaction 12h, TLC point plate determines that reaction is complete, and reactant liquor revolves
Steaming is concentrated to dryness, and adds dilute hydrochloric acid and regulates to neutral, adds ethyl acetate extraction, and magnesium sulfate is dried, and concentrated by rotary evaporation is the most dry, first
Alcohol recrystallization, obtains the fluoro-5-nitrobenzamide of N-(2-tert-butoxyethoxy)-2,3,4-tri-, off-white color solid (48.0g), yield
87.6%, the reaction equation of this step is with embodiment 1；
B) N-(2-tert-butoxyethoxy)-2,4-diaminourea-3-fluoro-5-nitrobenzamide is prepared:
N-(2-tert-butoxyethoxy)-2,3,4-three fluoro-5-nitrobenzamide (48.0g, 0.14mol) is dissolved in N-Methyl pyrrolidone
(135mL), adding the ammonia (0.83mol) of mass percent concentration 28%, reactant mixture is placed in airtight stainless steel reaction
At 85 DEG C, stirring reaction 8h under the pressure of 2.5 atmospheric pressure in still, after completion of the reaction, it is cooled to 40 DEG C and delivery systme pressure,
It is slowly added to water (60mL), is cooled to 10 DEG C, crystallize 3h, filters, recrystallisation from isopropanol, obtains N-(2-tert-butoxy ethoxy
Base)-2,4-diaminourea-3-fluoro-5-nitrobenzamide, off-white color solid (42.2g), yield 89.4%, the reaction equation of this step is same
Embodiment 1；
C) N-(2-tert-butoxyethoxy)-6-amino-7-fluoro-3H-benzimidazole-5-Methanamide is prepared:
N-(2-tert-butoxyethoxy)-2,4-diaminourea-3-fluoro-5-nitrobenzamide (42.0g, 0.13mol), formic acid (105.4g,
2.29mol), the palladium dydroxide carbon (60.9g, 0.11mol) of noble metal mass percentage content 20% and isopropanol (600mL)
Mixing, reactant mixture 95 DEG C stirring reaction 20h, TLC point plate determines that reaction is complete, and reactant liquor is down to room temperature, filters, rotation
Steaming is concentrated to dryness, and with ethyl acetate and normal hexane mixed solvent recrystallization, obtains N-(2-tert-butoxyethoxy) the fluoro-3H-of-6-amino-7-
Benzimidazole-5-Methanamide, off-white color solid (32.2g), yield 81.5%, the reaction equation of this step is with embodiment 1；
D) N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3H-benzimidazole-5-Methanamide is prepared:
N-(2-tert-butoxyethoxy)-6-amino-7-fluoro-3H-benzimidazole-5-Methanamide (32.0g, 0.10mol) is dissolved in N, N-bis-
Methylformamide (350mL), add the bromo-2-of 4-fluoro-1-iodobenzene (43.4g, 0.14mol), cesium carbonate (92.4g, 0.28mol),
Double (tri-butyl phosphine) palladium (2.0g, 3.9mmol), 4, double diphenylphosphine-9 of 5-, 9-dimethyl xanthene (4.5g, 7.7mol), reaction
110 DEG C of mixture stirring reaction 11h, TLC point plate determines that reaction is complete, and reactant liquor is down to room temperature, filters, filtrate concentrated by rotary evaporation
To dry, with ethyl acetate and normal hexane mixed solvent recrystallization, obtain N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) ammonia
Base]-7-fluoro-3H-benzimidazole-5-Methanamide, off-white color solid (40.0g), yield 80.0%, the reaction equation of this step is with implementing
Example 1；
E) prepare than Buddhist nun for Buddhist nun:
N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3H-benzimidazole-5-Methanamide (40.0g,
0.08mol) it is dissolved in N,N-dimethylacetamide (130mL), adds potassium carbonate (19.4g, 0.14mol), be cooled to-10 DEG C,
Dropping iodomethane (14.3g, 0.10mol), reactant mixture 55 DEG C stirring reaction 4h, TLC point plate determines that reaction is complete, reaction
Liquid is down to room temperature, and concentrated by rotary evaporation, to dry, adds ethyl acetate extraction, and magnesium sulfate is dried, and concentrated by rotary evaporation is the most dry, recrystallizing methanol,
Obtain N-(tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3-methyl-3H-benzimidazole-5-Methanamide, then
By the deprotection reaction step of patent WO2014063024, carry out deprotection reaction with phosphoric acid, through post processing and purification,
Than Buddhist nun for Buddhist nun, off-white color solid (20.3g), yield 55.5%, the reaction equation of this step is with embodiment 1.
Claims (10)
1. the synthetic method replacing Buddhist nun than Buddhist nun, it is characterised in that described method comprises the steps:
(1) N-(2-tert-butoxyethoxy)-2,3,4-three fluoro-5-nitrobenzamide is prepared: by 2,3,4-tri-fluorine-5-nitro benzoic acid
In the system that condensing agent, acid binding agent alkali, solvent form, carry out condensation reaction with O-(2-t-butoxy ethyl) azanol, obtain N-(2-
Tert-butoxyethoxy)-2,3,4-three fluoro-5-nitrobenzamide；
(2) N-(2-tert-butoxyethoxy)-2,4-diaminourea-3-fluoro-5-nitrobenzamide is prepared: by N-(2-tert-butoxy second
Epoxide)-2,3,4-tri-fluoro-5-nitrobenzamides and ammonia carries out the aminating reaction that pressurizes in N-Methyl pyrrolidone, obtains N-(2-
Tert-butoxyethoxy)-2,4-diaminourea-3-fluoro-5-nitrobenzamide；
(3) N-(2-tert-butoxyethoxy)-6-amino-7-fluoro-3H-benzimidazole-5-Methanamide is prepared: by N-(2-tert-butoxy
Ethyoxyl)-2,4-diaminourea-3-fluoro-5-nitrobenzamide and formic acid carries out cyclization at palladium dydroxide carbon in the system of solvent composition
Reaction, obtains N-(2-tert-butoxyethoxy)-6-amino-7-fluoro-3H-benzimidazole-5-Methanamide；
(4) N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3H-benzimidazole-5-Methanamide is prepared:
By N-(2-the tert-butoxyethoxy)-6-amino-7-fluoro-3H-benzimidazole-5-Methanamide fluoro-1-iodobenzene of 2-bromo-with 4-at base reagent, urge
The system of agent, complexant and solvent composition carries out substitution reaction, obtains N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorobenzene
Base) amino]-7-fluoro-3H-benzimidazole-5-Methanamide；
(5) preparation replaces Buddhist nun than Buddhist nun: by N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3H-benzimidazole
-5-Methanamide carries out methylation reaction at base reagent with iodomethane in the system of solvent composition, obtains N-(tert-butoxy ethoxy
Base)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3-methyl-3H-benzimidazole-5-Methanamide, then by N-(tert-butoxy ethoxy
Base)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3-methyl-3H-benzimidazole-5-Methanamide and phosphoric acid carries out deprotection reaction, obtains
Than Buddhist nun for Buddhist nun.
A kind of synthetic method replacing Buddhist nun than Buddhist nun the most according to claim 1, it is characterised in that the condensing agent described in step (1)
For N, N '-carbonyl dimidazoles, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, 1-hydroxy benzo triazole, N, N '-two hexamethylene
Base carbodiimide or N, N '-DIC；Described acid binding agent alkali be N, N-diisopropylethylamine, triethylamine, two
Ethamine, trimethylamine, pyridine, piperidines, DMAP, 2,6-lutidines, aniline, N, N-dimethylaniline, N, N-
Diethylaniline, Tris(isopropylamine)., tri-n-butylamine, tetramethyl guanidine, N-methylmorpholine or N-ethylmorpholine；Described solvent is four
Hydrogen furan, dichloromethane, 1,2-dichloroethanes, chloroform, chlorobenzene, acetonitrile, toluene, N,N-dimethylformamide, methyl-tert fourth
Base ether or 1,4-dioxane；Wherein, 2,3,4-tri-fluorine-5-nitro benzoic acids, O-(2-t-butoxy ethyl) azanol, condensing agent,
Mol ratio between acid binding agent alkali, solvent is 1.0: (1.1～1.5): (1.1～1.8): (3.5～5.5): (10.0～25.0).
A kind of synthetic method replacing Buddhist nun than Buddhist nun the most according to claim 1, it is characterised in that the ammonia described in step (2)
Mass percent concentration is 28%；Wherein, the fluoro-5-nitrobenzamide of N-(2-tert-butoxyethoxy)-2,3,4-tri-, ammonia,
Mol ratio between N-Methyl pyrrolidone is 1.0: (5.5～6.5): (5.0～20.0).
A kind of synthetic method replacing Buddhist nun than Buddhist nun the most according to claim 1, it is characterised in that the hydroxide described in step (3)
The noble metal mass percentage content of palladium carbon is 20%；Described solvent is methanol, ethanol, the tert-butyl alcohol or isopropanol；Wherein,
Rubbing between N-(2-tert-butoxyethoxy)-2,4-diaminourea-3-fluoro-5-nitrobenzamide, formic acid, palladium dydroxide carbon, solvent
Your ratio is 1.0: (10～20): (0.5～1.0): (50.0～80.0).
A kind of synthetic method replacing Buddhist nun than Buddhist nun the most according to claim 1, it is characterised in that the base reagent described in step (4)
For cesium carbonate, potassium carbonate or sodium carbonate；Described catalyst is three (dibenzalacetone) two palladium or double (tri-butyl phosphine) palladium；Institute
The complexant stated is the double diphenylphosphine-9,9-dimethyl xanthene of 4,5-, double (2-diphenylphosphine phenyl) ether or 4,6-bis-(diphenylphosphine)
Azophenlyene；Described solvent is toluene, 1,4-dioxane or N,N-dimethylformamide；Wherein, N-(2-tert-butoxyethoxy)-6-
Between amino-7-fluoro-3H-benzimidazole-5-Methanamide, the bromo-2-of 4-fluoro-1-iodobenzene, base reagent, catalyst, complexant, solvent
Mol ratio is 1.0: (1.1～1.4): (2.2～2.8): (0.03～0.05): (0.06～0.1): (10.0～50.0).
A kind of synthetic method replacing Buddhist nun than Buddhist nun the most according to claim 1, it is characterised in that the base reagent described in step (5)
For potassium carbonate, sodium carbonate or cesium carbonate；Described solvent is N,N-dimethylformamide or DMAC N,N' dimethyl acetamide；Wherein,
N-(2-tert-butoxyethoxy)-6-[(4-bromo-2-fluorophenyl) amino]-7-fluoro-3H-benzimidazole-5-Methanamide, iodomethane, base reagent,
Mol ratio between solvent is 1.0: (1.1～1.3): (1.4～1.8): (15.0～30.0).
A kind of synthetic method replacing Buddhist nun than Buddhist nun the most according to claim 1, it is characterised in that the condensation described in step (1) is anti-
The temperature answered is 40～60 DEG C, and the response time is 4～12h.
A kind of synthetic method replacing Buddhist nun than Buddhist nun the most according to claim 1, it is characterised in that step (2) described aminating reaction
Pressure be 2～3 atmospheric pressure, reaction temperature is 70～90 DEG C, and the response time is 4～8h.
A kind of synthetic method replacing Buddhist nun than Buddhist nun the most according to claim 1, it is characterised in that the cyclization described in step (3) is anti-
The temperature answered is 65～100 DEG C, and the response time is 16～32h.
A kind of synthetic method replacing Buddhist nun than Buddhist nun the most according to claim 1, it is characterised in that the replacement described in step (4) is anti-
The temperature answered is 90～110 DEG C, and the response time is 8～16h；The temperature of the methylation reaction described in step (5) is 50～75 DEG C,
Response time is 1～4h.
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