CN106146387A - The preparation method of ALK inhibitor - Google Patents
The preparation method of ALK inhibitor Download PDFInfo
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- CN106146387A CN106146387A CN201510143619.2A CN201510143619A CN106146387A CN 106146387 A CN106146387 A CN 106146387A CN 201510143619 A CN201510143619 A CN 201510143619A CN 106146387 A CN106146387 A CN 106146387A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention provides the preparation method of ALK inhibitor, comprising: make compound shown in formula 4 contact with compound shown in formula 12.Utilizing the method can fast and effeciently prepare target compound, and step is simple, reaction condition is gentle, with low cost.
Description
Technical field
The present invention relates to pharmaceutical technology field, in particular it relates to the preparation method of ALK inhibitor.
Background technology
Ceritinib (Ceritinib, LDK378, compound 1) is a kind of anaplastic researched and developed by Novartis (Novartis)
Lymphoma enzyme (ALK) tyrosine kinase inhibitor, this medicine is replaced Buddhist nun by FDA approval for warp gram azoles in April, 2014
(Crizotinib) existing progression of disease or the treatment of intolerable transitivity NSCLC patient, its trade name after treatment
Zykadia.This medicine is at the non-official listing of China.
Compound 2 is the key intermediate preparing Ceritinib.
WO 2008073687 reports and prepares the route of compound 1 and be:
In this route, by the process of the synthetically prepared compound of midbody compound 42, altogether need 3 step chemical reactions, and
Reaction is used the low-temp reaction of-78 DEG C, has been unfavorable for the industrialized great production of this medicine.
Therefore, the method preparing compound 1 at present still haves much room for improvement.
Summary of the invention
It is contemplated that one of technical problem solved the most to a certain extent in correlation technique.To this end, the one of the present invention
Purpose is to propose the method for compound shown in the formula 2 that a kind of synthesis step is simple, reaction condition is gentle.
In one aspect of the invention, the invention provides a kind of method of compound shown in formula 2.According to the present invention's
Embodiment, the method includes: make compound shown in formula 4 contact with compound shown in formula 12, in order to obtain chemical combination shown in formula 2
Thing,
Inventor finds, utilizes the method for the present invention can prepare compound shown in formula 2 quickly and efficiently, and only
Needing a step can obtain target compound, synthesis step is simple, it is not necessary to carry out low-temp reaction, and reaction condition is gentle, it is easy to
Realize industrialization.
The term used in this article " contacts " and should be interpreted broadly, and it can be any to enable at least two reactant
There is the mode of chemical reaction, such as, can be that two kinds of reactants are mixed under suitable condition.As required, may be used
With under agitation, it would be desirable to the reactant carrying out contacting mixes, thus, the type of stirring is not particularly restricted, example
As being mechanical agitation, i.e. it is stirred under the effect of mechanical force.
In this article, " compound shown in formula N " is otherwise referred to as " compound N " in this article, and N is 1-12's in this article
Arbitrary integer, such as " compound shown in formula 2 " are referred to as " compound 2 " in this article.
In this article, term " first ", " second " are only used for describing purpose, and it is not intended that indicate or hint relative importance
Or the implicit quantity indicating indicated technical characteristic.Thus, define " first ", the feature of " second " can express or
Person implicitly includes one or more this feature.In describing the invention, " multiple " be meant that two or two with
On, unless otherwise expressly limited specifically.
According to embodiments of the invention, formula 4 shownization can be made under conditions of nonoxidizing atmosphere, alkali and catalyst exist
Compound contacts with compound shown in formula 12.Thereby, it is possible to react under the conditions of optimal, and response speed is very fast,
Target compound yield is higher.
According to embodiments of the invention, the concrete kind of organic solvent is not particularly limited, and those skilled in the art can basis
It is actually needed selection flexibly.In some embodiments of the invention, organic solvent can be selected from toluene, N, N-dimethyl methyl
At least one in amide (DMF), 1,4-dioxane, dimethyl sulfoxide (DMSO).Due to organic relative to other
For solvent, the toxicity of usual DMF and Isosorbide-5-Nitrae-dioxane is first to less, and it is relatively preferable to the dissolving of organic chemicals,
And boiling point is the highest, the most relatively it is not easy residual, thus, in some currently preferred embodiments of the present invention,
Organic solvent can be selected from DMF and 1,4-dioxane.Thus, be conducive to improving the efficiency of compound shown in formula 2,
And the beneficially purification of compound shown in formula 2.
According to embodiments of the invention, the concrete kind of the alkali used is not particularly limited, as long as alkalescence condition can be provided,
The most do not affect and react between compound shown in compound shown in formula 4 and formula 12.According to some embodiments of the present invention, alkali
Can be organic base or inorganic base.Preferably, inorganic base can be used.In some concrete examples of the present invention, inorganic base
Can be in potassium carbonate, cesium carbonate and potassium phosphate at least one.Thereby, it is possible to make compound and formula shown in formula 4
Shown in 12, compound reacts under the conditions of optimal, and reaction efficiency and target compound yield are higher.
According to embodiments of the invention, the nonoxidizing atmosphere used can be hydrogen, nitrogen, helium, neon, argon,
At least one in xenon, radon.According to the concrete example of the present invention, nonoxidizing atmosphere be in nitrogen and argon at least
A kind of.Thus, cost is relatively low.
According to embodiments of the invention, catalyst can be palladium catalyst.In some currently preferred embodiments of the present invention, palladium is urged
Agent is selected from tetrakis triphenylphosphine palladium (Pd (PPh3)4), 1,1'-bis-(diphenyl phosphine) ferrocene palladium chloride (Pd (dppf)2Cl2)、
Palladium (Pd (OAc)2) and three (dibenzalacetone) two palladium (Pd2dba3At least one in).Thus, response speed
Comparatively fast, reaction efficiency is higher, and is conducive to improving the productivity of target compound.
According to embodiments of the invention, can be by compound shown in compound shown in formula 4, formula 12, alkali and catalyst according to rubbing
That ratio is 1:(1～1.2): (2～3): the ratio of (0.05～0.1) mixes, thus, reactant utilization rate is higher, will not
Causing raw material, actual waste, target compound yield is higher.
According to embodiments of the invention, the ratio of compound and organic solvent shown in formula 4 can be 1g:10～30mL.Thus,
Be conducive to response speed and the reaction efficiency of compound shown in compound shown in raising formula 4 and formula 12, and then preparation can be improved
The yield of target compound and efficiency.
According to embodiments of the invention, compound shown in formula 4 and chemical combination shown in formula 12 can be made under 80～150 degrees Celsius
Thing contacts 3～7 hours.Thereby, it is possible to react under optimal temperature conditions, response speed and reaction efficiency are preferable.
If reaction temperature is too low, reaction rate is relatively slow, prepares the inefficient of target compound, if reaction temperature is too high, then
Being susceptible to side reaction, introduce impurity, target compound yield is low, and energy consumption is higher.
According to embodiments of the invention, shown in described formula 2, the method for compound may include that compound shown in formula 4
It is dissolved in organic solvent with compound shown in formula 12, under stirring condition, in the mixture obtained, adds alkali and catalyst, so
After by the mixture that obtains in nonoxidizing atmosphere, stirring reaction 3～7 hours under 80～150 degrees Celsius.
A concrete example according to the present invention, can by chloro-for compound 1-5-isopropoxy-2-methyl-4-Nitrobenzol (2.5g,
10.89mmol), 4-(4,4,5,5-tetramethyl-1,3,2-two boron penta ring-2-base)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
(3.7g, 11.97mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (30mL), be added thereto under stirring potassium carbonate (4.5g,
26.78mmol) with Pd (dppf) Cl2(398mg,0.55mmol).Nitrogen is replaced three times, under nitrogen protection atmosphere, is heated to
After 120 DEG C of stirrings are reacted 5 hours, TLC monitoring reaction is complete, and reactant liquor is cooled to room temperature, adds 100 in reactant liquor
Milliliter water dilution, is extracted with ethyl acetate three times, merges organic facies, after water and saturated aqueous common salt wash, adds anhydrous slufuric acid
Sodium is dried, and filters, solvent is evaporated off, obtains compound shown in formula 2.The method synthesis step of the present invention is simple, only needs one
Step is reacted, and reaction condition is gentle, easily realizes, is advantageously implemented industrialization.
In another aspect of this invention, the invention provides a kind of method of compound shown in formula 1.According to the present invention's
Embodiment, the method comprises the following steps:
(1) according to compound shown in foregoing method formula 2.It should be noted that shown in foregoing formula 2
All feature and advantage of the method for compound are all applicable to this step, and this is no longer going to repeat them.
(2) compound shown in formula 2 is made to carry out hydrogenation reaction, in order to obtain compound shown in formula 9.Enforcement according to the present invention
Example, can be according to the hydrogenation reaction of compound shown in any method progressive form 2 known in the art.Some realities in the present invention
Execute in example, in atmosphere of hydrogen, under conditions of palladium-carbon catalyst exists, carry out hydrogenation reaction in organic solvent.Hydrogenation is anti-
The kind of the organic solvent used in should be not particularly limited, and those skilled in the art can select the most flexibly.
A concrete example according to the present invention, can carry out described hydrogenation reaction in methanol.Specifically show at another of the present invention
In example, compound shown in formula 2 can be made to carry out hydrogenation reaction according to following steps: by molten for compound 2 (3.4g, 0.26mmol)
In methanol (50mL), (aqueous 50%, Pd contains then to add palladium-carbon catalyst (400mg) in the mixture obtained
Amount 5%), then hydrogen exchange, and the mixed solution obtained is stirred overnight under atmosphere of hydrogen, room temperature condition, then will
The reaction fluid cushion kieselguhr obtained filters, and methanol is evaporated off, and obtains compound 9 (3.3g).
(3) compound shown in formula 9 is made to contact with compound shown in formula 10, in order to obtain compound shown in formula 11.According to this
Inventive embodiment, the reaction of this step can be carried out according to any method known in the art.In some embodiments of the invention,
Can in nitrogen atmosphere, 120 degrees Celsius and at palladium, the double diphenylphosphine-9,9-dimethyl xanthene (Xantphos) of 4,5-
Under conditions of existing with cesium carbonate, compound shown in formula 9 is made to contact 10 hours with compound shown in formula 10.Thereby, it is possible to
Reacting under the conditions of optimal, reaction efficiency and target product yield are higher.
(4) compound shown in formula 11 is made to carry out deaminizating protection group reaction, in order to obtain compound shown in formula 1.According to this
Inventive embodiment, the deaminizating protection group reaction in this step can be entered according to the deaminizating protection group method that this area is conventional
OK.In some embodiments of the invention, formula 11 can be made under conditions of hydrochloric acid and ethyl acrylate (EA) exist
Shown compound carries out deaminizating protection group reaction.Thus, simple, convenient, and reaction efficiency is high.
According to embodiments of the invention, shown in formula 1, the synthetic route of compound can be as follows:
Relative to prior art, the present invention at least has the advantages that
1, the method for compound shown in formula 2 according to embodiments of the present invention, only needs single step reaction can obtain shown in formula 2
Compound, synthesis step is simple, easy to operate；
2, the method for compound shown in formula 2 according to embodiments of the present invention, it is possible to the condition realizing this reaction is numerous, instead
Answer mild condition, it is not necessary to the condition that low temperature etc. are relatively harsh, it is easy to accomplish industrialization；
3, the method for compound, used catalyst and other raw material and solvent shown in formula 2 according to embodiments of the present invention
Cheap and easy to get, cost is relatively low；
4, the method for compound shown in formula 2 according to embodiments of the present invention, experimental implementation and post-processing approach are ripe, letter
Folk prescription is just, it is easy to disposable high yield obtain product.
Detailed description of the invention
Embodiments of the invention are described below in detail.The embodiments described below is exemplary, is only used for explaining the present invention,
And be not considered as limiting the invention.Unreceipted concrete technology or condition in embodiment, according to the document in this area
Described technology or condition or carry out according to product description.Agents useful for same or instrument unreceipted production firm person, be
Can by city available from conventional products.
Embodiment
In specific embodiment described below, compound structure is by nuclear magnetic resonance, NMR (NMR) or/and LC-MS
Chromatograph (LC-MS) determines.Wherein, NMR displacement (δ) is given with the unit of 1/1000000th (ppm), the survey of NMR
Surely being to use Bruker AVANCE-400 nuclear magnetic resonance spectrometer, measuring solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chlorine
Imitative (CDCl3), deuterated methanol (CD3OD), inside it is designated as tetramethylsilane (TMS)；The survey of LC-MS chromatograph LC-MS
Surely with Agilent 1200 Infinity Series mass spectrograph.The mensuration of HPLC uses Agilent 1200DAD high-pressure liquid phase
Chromatograph (Sunfire C18 150 × 4.6mm chromatographic column)
The monitoring of the reaction process in example below uses thin layer chromatography (TLC), the body of the developing solvent that reaction is used
System has: dichloromethane and methanol system, normal hexane/petroleum ether and ethyl acetate system, and the volume ratio of solvent is according to chemical combination
The polarity of thing is different and is adjusted.Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel
Plate, the specification that the silica gel plate that thin layer chromatography (TLC) uses uses is 0.15mm～0.2mm, and thin layer chromatography separates pure
The specification changing product employing is 0.4mm～0.5mm.Column chromatography generally uses Yantai Huanghai Sea silica gel 200～300 mesh silica gel
For carrier.
The system of eluant of the column chromatography that purification compound uses and the developing solvent body of thin layer chromatography in example below
System includes: A: dichloromethane and methanol system, B: normal hexane/petroleum ether and ethyl acetate system, the volume ratio of solvent
Polarity according to compound is different and is adjusted, it is also possible to add the alkalescence such as a small amount of triethylamine and acetic acid or acid examination
Agent is adjusted.
Initiation material used in example below can use or synthesize according to methods known in the art, or can
Buy from ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, splendid remote chemistry
Science and technology (Accela ChemBio Inc), reach the companies such as auspicious chemicals.Argon atmospher or blanket of nitrogen refer to that reaction bulb connects one
The argon of about 1L volume or nitrogen balloon.
Embodiment 1: the preparation of compound shown in formula 2
By chloro-for compound 1-5-isopropoxy-2-methyl-4-Nitrobenzol (2.5g, 10.89mmol), 4-(4,4,5,5-tetramethyl
-1,3,2-two boron penta ring-2-base)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (3.7g, 11.97mmol) is dissolved in 1,4-bis-
In oxygen six ring (30mL), under stirring, it is added thereto to potassium carbonate (4.5g, 26.78mmol) and Pd (dppf) Cl2(398mg,
0.55mmol).Nitrogen is replaced three times, under nitrogen protection atmosphere, after being heated to 120 DEG C of stirring reactions 5 hours, and TLC
Monitoring reaction is complete, and reactant liquor is cooled to room temperature, adds 100 milliliters of water dilutions, use ethyl acetate in reactant liquor
Extract three times, merge organic facies, after water and saturated aqueous common salt wash, add anhydrous sodium sulfate and be dried, filter, be evaporated off
Solvent, obtains compound shown in formula 2.
LCMS:t=4.85min, 293.1 (M-t-Bu+H)+.
Embodiment 2: the preparation of compound shown in formula 2
By chloro-for compound 1-5-isopropoxy-2-methyl-4-Nitrobenzol (2.5g, 10.89mmol), 4-(4,4,5,5-tetramethyl
-1,3,2-two boron penta ring-2-base)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (3.4g, 10.89mmol) is dissolved in 1,4-
In dioxane (25mL), under stirring, it is added thereto to potassium carbonate (3.7g, 21.78mmol) and Pd (dppf) Cl2(394
mg,0.54mmol).Nitrogen is replaced three times, under nitrogen protection atmosphere, after being heated to 80 DEG C of stirring reactions 7 hours,
TLC monitoring reaction is complete, and reactant liquor is cooled to room temperature, adds 100 milliliters of water dilutions, use acetic acid in reactant liquor
Ethyl ester extracts three times, merges organic facies, after water and saturated aqueous common salt wash, adds anhydrous sodium sulfate and is dried, filters,
Solvent is evaporated off, obtains compound shown in formula 2.
Embodiment 3: the preparation of compound shown in formula 2
By chloro-for compound 1-5-isopropoxy-2-methyl-4-Nitrobenzol (2.5g, 10.89mmol), 4-(4,4,5,5-tetramethyl
-1,3,2-two boron penta ring-2-base)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (3.4g, 10.89mmol) is dissolved in 1,4-bis-
In oxygen six ring (50mL), under stirring, it is added thereto to potassium carbonate (4.6g, 27.23mmol) and Pd (dppf) Cl2(630.4mg,
0.86mmol).Nitrogen is replaced three times, under nitrogen protection atmosphere, after being heated to 90 DEG C of stirring reactions 6 hours, and TLC
Monitoring reaction is complete, and reactant liquor is cooled to room temperature, adds 100 milliliters of water dilutions, use ethyl acetate in reactant liquor
Extract three times, merge organic facies, after water and saturated aqueous common salt wash, add anhydrous sodium sulfate and be dried, filter, be evaporated off
Solvent, obtains compound shown in formula 2.
Embodiment 4: the preparation of compound shown in formula 2
By chloro-for compound 1-5-isopropoxy-2-methyl-4-Nitrobenzol (2.5g, 10.89mmol), 4-(4,4,5,5-tetramethyl
-1,3,2-two boron penta ring-2-base)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (3.4g, 10.89mmol) is dissolved in 1,4-bis-
In oxygen six ring (75mL), under stirring, it is added thereto to potassium carbonate (5.52g, 32.68mmol) and Pd (PPh3)4(1.25g,
1.08mmol).Nitrogen is replaced three times, under nitrogen protection atmosphere, after being heated to 100 DEG C of stirring reactions 5 hours, and TLC
Monitoring reaction is complete, and reactant liquor is cooled to room temperature, adds 100 milliliters of water dilutions, use ethyl acetate in reactant liquor
Extract three times, merge organic facies, after water and saturated aqueous common salt wash, add anhydrous sodium sulfate and be dried, filter, be evaporated off
Solvent, obtains compound shown in formula 2.
Embodiment 5: the preparation of compound shown in formula 2
By chloro-for compound 1-5-isopropoxy-2-methyl-4-Nitrobenzol (2.5g, 10.89mmol), 4-(4,4,5,5-tetramethyl
-1,3,2-two boron penta ring-2-base)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (3.74g, 11.98mmol) is dissolved in DMF
(25mL), in, cesium carbonate (8.88g, 27.23mmol) and Pd (PPh under stirring, it are added thereto to3)4(1.25g,1.08mmol)。
Nitrogen is replaced three times, and under nitrogen protection atmosphere, after being heated to 110 DEG C of stirring reactions 4 hours, TLC monitors reaction
Complete, reactant liquor is cooled to room temperature, in reactant liquor, adds 100 milliliters of water dilutions, be extracted with ethyl acetate three times,
Merge organic facies, after water and saturated aqueous common salt wash, add anhydrous sodium sulfate and be dried, filter, solvent is evaporated off, obtains
Compound shown in formula 2.
Embodiment 6: the preparation of compound shown in formula 2
By chloro-for compound 1-5-isopropoxy-2-methyl-4-Nitrobenzol (2.5g, 10.89mmol), 4-(4,4,5,5-tetramethyl
-1,3,2-two boron penta ring-2-base)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (3.74g, 11.98mmol) is dissolved in DMF
(50mL), in, cesium carbonate (10.65g, 32.68mmol) and Pd (OAc) under stirring, it are added thereto to2(338.4mg,
0.54mmol).Nitrogen is replaced three times, under nitrogen protection atmosphere, after being heated to 120 DEG C of stirring reactions 3 hours, and TLC
Monitoring reaction is complete, and reactant liquor is cooled to room temperature, adds 100 milliliters of water dilutions, use ethyl acetate in reactant liquor
Extract three times, merge organic facies, after water and saturated aqueous common salt wash, add anhydrous sodium sulfate and be dried, filter, be evaporated off
Solvent, obtains compound shown in formula 2.
Embodiment 7: the preparation of compound shown in formula 2
By chloro-for compound 1-5-isopropoxy-2-methyl-4-Nitrobenzol (2.5g, 10.89mmol), 4-(4,4,5,5-tetramethyl
-1,3,2-two boron penta ring-2-base)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (3.74g, 11.98mmol) is dissolved in
In DMSO (75mL), under stirring, it is added thereto to cesium carbonate (7.1g, 21.78mmol) and Pd (OAc)2(538.9mg,
0.86mmol).Nitrogen is replaced three times, under nitrogen protection atmosphere, after being heated to 130 DEG C of stirring reactions 4 hours, and TLC
Monitoring reaction is complete, and reactant liquor is cooled to room temperature, adds 100 milliliters of water dilutions, use ethyl acetate in reactant liquor
Extract three times, merge organic facies, after water and saturated aqueous common salt wash, add anhydrous sodium sulfate and be dried, filter, be evaporated off
Solvent, obtains compound shown in formula 2.
Embodiment 8: the preparation of compound shown in formula 2
By chloro-for compound 1-5-isopropoxy-2-methyl-4-Nitrobenzol (2.5g, 10.89mmol), 4-(4,4,5,5-tetramethyl
-1,3,2-two boron penta ring-2-base)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (4.04g, 13.07mmol) is dissolved in
In DMSO (25mL), under stirring, it is added thereto to potassium phosphate (6.93g, 32.68mmol) and Pd2dba3(787.5mg,
0.86mmol).Nitrogen is replaced three times, under nitrogen protection atmosphere, after being heated to 140 DEG C of stirring reactions 3.5 hours,
TLC monitoring reaction is complete, and reactant liquor is cooled to room temperature, adds 100 milliliters of water dilutions, use acetic acid in reactant liquor
Ethyl ester extracts three times, merges organic facies, after water and saturated aqueous common salt wash, adds anhydrous sodium sulfate and is dried, filters,
Solvent is evaporated off, obtains compound shown in formula 2.
Embodiment 9: the preparation of compound shown in formula 2
By chloro-for compound 1-5-isopropoxy-2-methyl-4-Nitrobenzol (2.5g, 10.89mmol), 4-(4,4,5,5-tetramethyl
-1,3,2-two boron penta ring-2-base)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (4.04g, 13.07mmol) is dissolved in toluene
(50mL), in, phosphonic acids potassium (4.62g, 21.78mmol) and Pd under stirring, it are added thereto to2dba3(989mg,1.08mmol)。
Nitrogen is replaced three times, and under nitrogen protection atmosphere, after being heated to 150 DEG C of stirring reactions 3 hours, TLC monitors reaction
Complete, reactant liquor is cooled to room temperature, in reactant liquor, adds 100 milliliters of water dilutions, be extracted with ethyl acetate three times,
Merge organic facies, after water and saturated aqueous common salt wash, add anhydrous sodium sulfate and be dried, filter, solvent is evaporated off, obtains
Compound shown in formula 2.
Embodiment 10: the preparation of compound shown in formula 2
By chloro-for compound 1-5-isopropoxy-2-methyl-4-Nitrobenzol (2.5g, 10.89mmol), 4-(4,4,5,5-tetramethyl
-1,3,2-two boron penta ring-2-base)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (4.04g, 13.07mmol) is dissolved in toluene
(75mL), in, potassium phosphate (5.77g, 27.23mmol) and Pd (dppf) Cl under stirring, it are added thereto to2(394mg,
0.54mmol).Nitrogen is replaced three times, under nitrogen protection atmosphere, after being heated to 120 DEG C of stirring reactions 3 hours, and TLC
Monitoring reaction is complete, and reactant liquor is cooled to room temperature, adds 100 milliliters of water dilutions, use ethyl acetate in reactant liquor
Extract three times, merge organic facies, after water and saturated aqueous common salt wash, add anhydrous sodium sulfate and be dried, filter, be evaporated off
Solvent, obtains compound shown in formula 2.
Embodiment 11: the preparation of compound shown in formula 9
The compound 2 (3.4g, 0.26mmol) prepared in embodiment 1 is dissolved in methanol (50mL), adds palladium carbon
(400mg) (aqueous 50%, Pd content 5%), then, hydrogen exchange, and by obtained mixture under atmosphere of hydrogen
Stirred overnight at room temperature, then filters the reaction fluid cushion kieselguhr obtained, methanol is evaporated off, obtains compound 9 (3.3g).
LCMS:t=4.16min, 349.0 (M+H+).
Embodiment 12: the preparation of compound shown in formula 11
Compound 10 (1.0g, 2.89mmol) and compound 9 (1.11g, 3.18mmol) are dissolved in 25mL dry DMF
In, and the middle palladium (32.4mg, 144 μm ol) that adds in the mixture obtained, 4,5-double diphenylphosphine-9,9-dimethyl oxygen
Miscellaneous anthracene (Xantphos) (167mg, 288 μm ol) and cesium carbonate (1.88g, 5.78mmol), add mixture after nitrogen displacement
Heat is reacted 10 hours to 120 degrees Celsius, after completion of the reaction, is cooled to room temperature, reactant liquor is diluted with water to 100mL,
Being extracted with ethyl acetate three times, merge organic facies, and have washing and saturated common salt to wash three times, anhydrous sodium sulfate is dried, mistake
Filter, rotation is evaporated off solvent, obtains compound 11 (1.03g, productivity 54%).
LCMS:t=1.02min, 658.3 (M+H+).
Embodiment 13: the preparation of compound shown in formula 1
Compound 11 (1.02g, 1.56mmol) is dissolved in 15 milliliters of HCl/EA (4mol/L), is stirred at room temperature reaction 2
Hour, after completion of the reaction, rotation is evaporated off dereaction solvent, and gained crude product obtains product Compound through column chromatography and preparation TLC purification
1 (900mg, productivity 97%).
LCMS:t=0.793min, 558.3 (M+H+)。1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.16
(d, J=7.6Hz, 1H), 7.88 (d, J=8.0Hz, 1H), 7.69 (t, J=7.6Hz, 1H), 7.48 (t, J=7.7Hz, 1H),
7.34 (s, 1H), 6.77 (s, 1H), 4.47-4.53 (m, 1H), 3.55 3.37 (m, 1H), 3.31 (d, J=12.5Hz, 2H), 3.09
2.84 (m, 3H), 2.02 (s, 3H), 1.87 (dd, J=15.8,7.5Hz, 2H), 1.75 (d, J=12.8Hz, 2H), 1.22 (d, J
=6.0Hz, 6H), 1.09 (dd, J=12.8,7.0Hz, 6H).
In the description of this specification, reference term " embodiment ", " some embodiments ", " example ", " concrete example ",
Or specific features, structure, material or the feature bag that the description of " some examples " etc. means to combine this embodiment or example describes
It is contained at least one embodiment or the example of the present invention.In this manual, to the schematic representation of above-mentioned term necessarily
It is directed to identical embodiment or example.And, the specific features of description, structure, material or feature can be arbitrary
Individual or multiple embodiment or example combine in an appropriate manner.Additionally, in the case of the most conflicting, the skill of this area
The feature of the different embodiments described in this specification or example and different embodiment or example can be combined by art personnel
And combination.
Although above it has been shown and described that embodiments of the invention, it is to be understood that above-described embodiment is exemplary,
Being not considered as limiting the invention, those of ordinary skill in the art within the scope of the invention can be to above-described embodiment
It is changed, revises, replaces and modification.
Claims (10)
1. the method for compound shown in a formula 2, it is characterised in that including:
Compound shown in formula 4 is made to contact with compound shown in formula 12, in order to obtain compound shown in described formula 2,
Method the most according to claim 1, it is characterised in that in organic solvent, in nonoxidizing atmosphere, alkali with urge
Under conditions of agent exists, compound shown in described formula 4 is made to contact with compound shown in described formula 12.
Method the most according to claim 2, it is characterised in that described organic solvent is selected from toluene, N, N-dimethyl
At least one in Methanamide, 1,4-dioxane, dimethyl sulfoxide.
Method the most according to claim 2, it is characterised in that described alkali is organic base or inorganic base, preferably inorganic base,
The most described inorganic base be in potassium carbonate, cesium carbonate and potassium phosphate at least one.
Method the most according to claim 2, it is characterised in that described nonoxidizing atmosphere is in nitrogen and argon
At least one.
Method the most according to claim 2, it is characterised in that described catalyst is palladium catalyst, the most described palladium is urged
Agent is selected from tetrakis triphenylphosphine palladium, 1,1'-bis-(diphenyl phosphine) ferrocene palladium chloride, palladium and three (dibenzylidenes
At least one acetone) in two palladiums.
Method the most according to claim 2, it is characterised in that shown in described formula 4 shown in compound, described formula 12
The mol ratio of compound, described alkali and described catalyst is 1:(1～1.2): (2～3): (0.05～0.1),
Shown in described formula 4, the ratio of compound and described organic solvent is 1g:10～30mL.
Method the most according to claim 2, it is characterised in that under 80～150 degrees Celsius, makes shown in described formula 4
Compound contacts 3～7 hours with compound shown in described formula 12.
Method the most according to claim 2, it is characterised in that including:
Compound shown in compound shown in formula 4 and formula 12 is dissolved in described organic solvent, mixed to obtain under stirring condition
Compound adds described alkali and described catalyst, then by the mixture that obtains in described nonoxidizing atmosphere, 8-～150 degrees Celsius
Lower stirring reaction 3～7 hours.
10. the method for compound shown in a formula 1, it is characterised in that including:
According to compound shown in the method formula 2 according to any one of claim 1-9；
Compound shown in formula 2 is made to carry out hydrogenation reaction, in order to obtain compound shown in formula 9；
Compound shown in formula 9 is made to contact with compound shown in formula 10, in order to obtain compound shown in formula 11；
Compound shown in formula 11 is made to carry out deaminizating protection group reaction, in order to obtain compound shown in formula 1.
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