CN107641099A - The preparation method of 4 oxinoid compounds of substitution - Google Patents

The preparation method of 4 oxinoid compounds of substitution Download PDF

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Publication number
CN107641099A
CN107641099A CN201710586902.1A CN201710586902A CN107641099A CN 107641099 A CN107641099 A CN 107641099A CN 201710586902 A CN201710586902 A CN 201710586902A CN 107641099 A CN107641099 A CN 107641099A
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alkylidene
formula
compound
preparation
heterocyclic radical
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习宁
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Sunshine Lake Pharma Co Ltd
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Add And Open Up Scientific Co
Guangdong HEC Pharmaceutical
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Abstract

The present invention relates to the preparation method of 4 substituted oxinoid compounds, such compound is the intermediate for preparing the protein tyrosine kinase for the treatment of cancer (PTK) inhibitor.

Description

The preparation method of substituted 4- oxinoid compounds
Technical field
The present invention relates to chemicals preparation field, more particularly to the extensive 4- hydroxyquinoline class chemical combination for preparing substitution The method of thing, such compound are the intermediates for preparing the protein tyrosine kinase for the treatment of cancer (PTK) inhibitor.
Background technology
Substituted 4- oxinoid compounds are protein tyrosine kinase (PTK) inhibitor for preparing treating cancer Conventional intermediate.Protein tyrosine kinase be protein kinase subfamily, its propagation to cell, differentiation, metabolism, migration and existence There is critically important adjustment effect.They can be further divided into acceptor histidine kinase (such as：Axl,VEGFR,c-Met(HGFR), Ron, EGFR, PDGFR and FGFR) and non-acceptor is (such as：C-src and bcr-abl) kinases.Receptor tyrosine kinase is cross-film egg In vain, growth factor can be made to keep extracellular calmodulin binding domain CaM, transmembrane region and intracellular portion as having kinases across cell membrane Function, phosphorylation is in a specific protein-tyrosine residue, so as to influence cell propagation.Abnormal expression or protein kinase Activity directly involves the pathogenesis of numerous human cancers.
Patent application WO 2012/118632, WO 2013/180949 and WO 2014/022128 individually disclose formula (I) The preparation method of the laboratory level of shown compound：
The preparation method of compound shown in formula (I) disclosed in 1.WO 2012/118632：
The preparation method of compound shown in formula (I) disclosed in 2.WO 2013/180949：
The preparation method of compound shown in formula (I) disclosed in 3.WO 2014/022128：
WO 2013/086229 also discloses that the microwave synthesis method of compound shown in formula (I)：
The synthetic method of compound is all the preparation method of laboratory level shown in formula (I) described above, and reaction condition is not It is adapted to the industrial mass production being amplified to.Preparation method disclosed in WO 2013/086229 needs microwave condition, and this is difficult reality Existing technical grade production.
The substituted 4- oxinoid compounds intermediate universal as protein tyrosine kinase (PTK) inhibitor, It is badly in need of having a kind of simple, conveniently, economic technical grade preparation method in this area.
The purpose of the present invention aims to provide the side of compound shown in a kind of simple preparation and purification formula (I) of technical grade Method, avoid producing excessive isomers and other impurities in the process, improve the yield and purity of product.
Brief summary of the invention
On the one hand, the present invention provides a kind of preparation method of compound shown in formula (I),
Wherein：Each R independently is F, Cl, Br, I, CN, C1-6Alkyl, ORaOr NRbRc；
N is 0,1,2,3 or 4；
Ra、RbAnd RcIt is each independently H, C1-6Alkyl, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-4Alkylidene, 3-6 atom The heterocyclic radical of composition, (3-6 former molecular heterocyclic radical)-C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, 5- The molecular heteroaryl of 10 originals or (5-10 former molecular heteroaryl)-C1-4Alkylidene, wherein the C1-6Alkyl, C3-6 Cycloalkyl, C3-6Cycloalkyl-C1-4Alkylidene, 3-6 former molecular heterocyclic radical, (3-6 former molecular heterocyclic radical)-C1-4 Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 original is molecular miscellaneous Aryl)-C1-4Alkylidene is unsubstituted independently of one another or is substituted by 1,2,3 or 4 substituent, and the substituent is independently Selected from F, Cl, CN, N3、OH、C1-6Alkyl, C1-6Haloalkyl or C1-6Alkoxy；
Compound is not compound set forth below wherein shown in formula (I)：
Its described preparation method comprises the steps of：Compound shown in formula (II)
Reaction obtains compound shown in formula (I) in dichloro-benzenes (III)；
Wherein described dichloro-benzenes (III) is structure as shown below
In some embodiments, each R independently is F, I, CN, methyl, ethyl, n-propyl, isopropyl, normal-butyl, different Butyl, the tert-butyl group, ORaOr NRbRc。
In other embodiments, Ra、RbAnd RcIt is each independently H, methyl, ethyl, n-propyl, isopropyl, positive fourth Base, isobutyl group, the tert-butyl group, C5-6Cycloalkyl, C5-6Cycloalkyl-C1-2Alkylidene, 5-6 former molecular heterocyclic radical, (5-6 former Molecular heterocyclic radical)-C1-2Alkylidene, phenyl, phenyl-C1-2Alkylidene or 5-6 former molecular heteroaryl, wherein described Methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, C5-6Cycloalkyl, C5-6Cycloalkyl-C1-2Alkylidene, 5- The molecular heterocyclic radical of 6 originals, (5-6 former molecular heterocyclic radical)-C1-2Alkylidene, phenyl, phenyl-C1-2Alkylidene and 5- 6 molecular heteroaryls of original are unsubstituted independently of one another or substituted by 1,2,3 or 4 substituent, and the substituent is only On the spot it is selected from F, Cl, CN, N3、OH、C1-3Alkyl or C1-3Alkoxy.
In some embodiments, compound shown in formula (I) is structure shown in formula (Ia)
Wherein RaWith defining as described herein.
In other embodiments, compound shown in formula (II) is structure shown in formula (IIa)
Wherein RaWith defining as described herein.
In some embodiments, reaction of the compound in dichloro-benzenes (III) shown in formula (II) is 160 DEG C~220 DEG C carry out.
In other embodiments, reaction of the compound in dichloro-benzenes (III) shown in formula (II) be 170 DEG C~ 190 DEG C progress.
In some embodiments, molar concentration of the compound in dichloro-benzenes (III) shown in formula (II) be 0.05M~ 0.45M。
In other embodiments, molar concentration of the compound in dichloro-benzenes (III) shown in formula (II) be 0.10M~ 0.25M。
On the other hand, the present invention provides the purifying of compound shown in the formula (I) that a kind of preparation method of the present invention obtains Method, the purification process comprise the steps of：
(a) reaction solution that is concentrated under reduced pressure obtains solid；
(b) solid obtained by dichloromethane washing step (a)；
(c) solid after step (b) washing is isolated by filtration out；
(d) the separating obtained solid of step (c) is washed with water；
(e) solid after step (d) washing is filtered to isolate；
(f) the separating obtained solid of drying steps (e).
In some embodiments, solid masses (g) obtained by step (a) and methylene chloride volume used in step (b) (mL) ratio is 0.4~0.8.
In other embodiments, the quality (g) of solid obtained by step (a) and dichloromethane body used in step (b) The ratio of product (mL) is 0.5~0.7.
In some embodiments, the mixture of solid obtained by step (a) and dichloromethane stirs at 45 DEG C in step (b) 2 hours.
In other embodiments, the mixture of the separating obtained solid of step (c) and water stirs at 100 DEG C in step (d) Mix 2 hours.
In some embodiments, when filtering in step (e) mixture temperature of water and gained solid remain 25 DEG C~ 60℃。
Compound can be prepared according to the method described in patent document WO 2012/118632 shown in formula (II).
Detailed description of the invention book
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation enclosed.This Invention is intended to cover all replacement, modification and equivalent technical solutions, and they are included in the present invention defined such as claim In the range of.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method described herein and material Trample the present invention.The present invention is not limited to method described herein and material.The one of document, patent and the similar material combined Or more it is different from the application or in the case of contradicting it is (including but not limited to defined term, term application, described Technology, etc.), be defined by the application.
It will further be appreciated that some features of the present invention, are clearly visible, are carried out in multiple independent embodiments Description, but can also be provided in combination in single embodiment.Conversely, the various features of the present invention, for brevity, It is described, but can also be provided individually or with arbitrarily suitable sub-portfolio in single embodiment.
Unless otherwise noted, technology used in the present invention and scientific terminology and the technical field of the invention technical staff It is conventional understand that there is identical implication, unless otherwise noted, all patents public affairs cited in full content are disclosed in the present invention Open publication and be integrally incorporated the present invention by reference.
The present invention will apply defined below unless other aspects show.According to the purpose of the present invention, chemical element is according to member Plain periodic table, CAS versions and chemicals handbook, 75,thEd, 1994 define.In addition, organic chemistry General Principle is shown in “Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999, and“March's Advanced Organic Chemistry”,by Michael B.Smith and Jerry March, John Wiley&Sons,New York:2007, therefore all contents of the invention have all merged bibliography.
Many different aspects and embodiment disclosed by the invention, and each aspect and each implementation is described below Scheme is not restricted for scope disclosed by the invention.Term " aspect " and " embodiment " are intended to non-limiting , no matter the term " aspect " or " embodiment " in this manual from anywhere in occur.As used herein with " wrapping Include ", " containing " or " being characterised by " synonymous transitional term "comprising" be inclusive or open, and be not excluded in addition , unrequited key element.
In the context of the present invention, all numerals being disclosed that are approximation.Each digital numerical value has It is possible that the difference such as 1%, 2%, 5%, 7%, 8% or 10%.Whenever a numeral with N values is disclosed, any tool There is the numeral within the value of N+/- 1%, N+/- 2%, N+/- 3%, N+/- 5%, N+/- 7%, N+/- 8% or N+/- 10% can be bright It is really open, wherein " +/- " refers to add deduct.Whenever disclosing a lower limit in a number range, DL, and a upper limit, DU, when, any numerical value within the scope of the disclosed can be specifically disclosed.
All reactions steps reaction of the present invention is more than to a certain extent as consumption of raw materials is approximately greater than 70% 80%, more than 90%, more than 95%, or post-processed after reaction raw materials have been exhausted after testing, such as cooled down, collected, Extraction, filter, separation, purified treatment or its combination.Conventional method such as TLC (TLC), efficient liquid phase can be passed through The methods of chromatography (HPLC), gas chromatography (GC), detects the extent of reaction.Conventional method can be used to enter reaction solution Row post processing, for example, by collecting crude product after reduction vaporization or conventional distil-lation reaction dissolvent, direct plunge into and react in next step； Or crude product is directly filtrated to get, direct plunge into and react in next step；Or after standing, pour out supernatant liquor and obtain crude product, directly Input is connect to react in next step；Or select appropriate organic solvent or its combination to be extracted, distill, crystallization, column chromatography, rinse, The purification steps such as mashing.
Each dropwise addition process of the present invention and the reaction of described each step are carried out under the conditions of certain temperature, Ren Heshi Conjunction is used in each dropwise addition process or the temperature of each course of reaction is included in the present invention.In addition, many of this area similar change It is dynamic, equivalent substitution, or it is equal to temperature and temperature range described in the invention, it is accordingly to be regarded as the scope of the present invention.This hair It is bright to give the preferable temperature of each dropwise addition process or temperature range, and respectively react preferable reaction temperature.
Solvent used in each reactions steps of the present invention is not particularly limited, any to dissolve to a certain extent Initiation material and do not suppress reaction solvent be included in the present invention.In addition, many similar changes of this area, are equally replaced Change, or be equal to the different proportion of solvent described in the invention, solvent combination, and solvent combination, be accordingly to be regarded as the bag of the present invention Containing scope.The present invention gives preferable solvent used in each reactions steps.
" room temperature " refers to temperature by about 10 DEG C to about 40 DEG C in the present invention.In certain embodiments, " room temperature " refers to Be temperature by about 20 DEG C to about 30 DEG C；In other embodiment, " room temperature " refers to 20 DEG C, 22.5 DEG C, 25 DEG C, 27.5 DEG C etc..
Term " alkali " includes organic base and inorganic base.Described organic base includes, but are not limited to triethylamine, trimethylamine, N, N- diisopropylethylamine, N- methylmorpholines, N- methyl piperidines, or pyridine.Described inorganic base includes, but are not limited to alkali metal Or the carbonate or bicarbonate of alkaline earth metal hydroxide, alkali metal or alkaline-earth metal alkyl oxide, alkali metal or alkaline-earth metal Salt or phosphate or hydrophosphate or ammonia.In certain embodiments, alkali of the present invention is organic base；In certain embodiments, The alkali is inorganic base.In certain embodiments, the alkali is triethylamine, trimethylamine, DIPEA, N- methyl Coffee quinoline, N- methyl piperidines, pyridine, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, saleratus, bicarbonate Sodium, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate or combinations thereof.In certain embodiments, it is of the present invention First alkali is sodium hydroxide, potassium hydroxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, saleratus, sodium acid carbonate, sodium phosphate, phosphorus Sour potassium, disodium hydrogen phosphate, or dipotassium hydrogen phosphate.
This term can exchange use to " optionally substituting " this term with " substituted or non-substituted ".Term is " optionally Ground ", " optional " or " optional " refer to then described event or situation can with but may not occur, and the description is including wherein The situation of the event or situation occurs, and the situation of the event or situation does not occur wherein.In general, term " optionally " Whether it is located at before term " substituted ", all represents to give one or more of structure hydrogen atom by specific substituent institute Substitution.Unless otherwise indicated, an optional substituted radical can be substituted in each commutable position of group.When More than one position can be substituted by one or more substituents selected from specific group in given structural formula, then substitution Base with identical or different can substitute in each position.Wherein described substituent can be, but be not limited to, F, Cl, Br, I, CN、N3、OH、ORa、NRbRc、C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxy C3-6Cycloalkyl, C3-6Cycloalkyl-C1-4Alkylidene, 3-6 former molecular heterocyclic radical, (3-6 former molecular heterocyclic radical)-C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4 Alkylidene, 5-10 former molecular heteroaryl or (5-10 former molecular heteroaryl)-C1-4Alkylidene, wherein, Ra、RbWith RcWith defining as described herein.
Terminology used in the present invention " alkyl " or " alkyl group ", represent saturated straight chain or side chain containing 1-20 carbon atom Monovalence hydrocarbon atomic group.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom, and some of them are implemented Example is that alkyl group contains 1-10 carbon atom, and other embodiment is that alkyl group contains 1-8 carbon atom, in addition one A little embodiments are that alkyl group contains 1-6 carbon atom, and other embodiment is that alkyl group contains 1-4 carbon atom, Other embodiment is that alkyl group contains 1-3 carbon atom.
The example of alkyl group includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (n- Pr ,-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,- CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2- amyl groups (- CH (CH3)CH2CH2CH3), 3- amyl groups (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl isophthalic acids-butyl (- CH2CH2CH(CH3)2), 2- first Base -1- butyl (- CH2CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyls (- CH (CH3) CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyl groups (- C (CH3)2CH2CH2CH3), 3- first Base -2- amyl groups (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyl groups (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- penta Base (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl groups (- CH (CH2CH3)CH(CH3)2), 2,3- dimethyl -2- butyl (- C (CH3)2CH(CH3)2), 3,3- dimethyl -2- butyl (- CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc., wherein described Alkyl group can be independently unsubstituted or substituted by one or more substituents described in the invention.
Term " alkyl " used in the present invention and its prefix " alkane ", the saturated carbon chains all comprising straight chain and side chain.
Term " alkylidene " represents to remove from the saturated hydrocarbyl of straight or branched the saturation obtained by two hydrogen atoms Bivalent hydrocarbon radical group.Unless otherwise detailed instructions, alkylidene group contains 1-10 carbon atom, and other embodiment is, sub- Alkyl group contains 1-6 carbon atom, and other embodiment is that alkylidene group contains 1-4 carbon atom, and other is real Applying example is, alkylidene group contains 1-2 carbon atom.Such example includes methylene (- CH2-), ethylidene (- CH2CH2-), Isopropylidene (- CH (CH3)CH2-) etc., wherein the alkylidene group can be independently unsubstituted or one or more Substituent described in the invention is substituted.
Term " alkoxy " represents that alkyl group is connected by oxygen atom with molecule remainder, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-20 carbon atom, some of real Applying example is, alkoxy base contains 1-10 carbon atom, and other embodiment is that alkoxy base contains 1-8 carbon atom, Other embodiment is that alkoxy base contains 1-6 carbon atom, and other embodiment is that alkoxy base contains 1-4 Individual carbon atom, other embodiment are that alkoxy base contains 1-3 carbon atom.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1- propoxyl group (n-PrO, n- propoxyl group ,-OCH2CH2CH3), 2- propoxyl group (i-PrO, i- propoxyl group ,-OCH (CH3)2), 1- butoxy (n-BuO, n- butoxy ,-OCH2CH2CH2CH3), 2- methyl-l- propoxyl group (i-BuO, i- fourth oxygen Base ,-OCH2CH(CH3)2), 2- butoxy (s-BuO, s- butoxy ,-OCH (CH3)CH2CH3), 2- methyl -2- propoxyl group (t- BuO, t- butoxy ,-OC (CH3)3), 1- amoxys (n- amoxys ,-OCH2CH2CH2CH2CH3), 2- amoxys (- OCH (CH3) CH2CH2CH3), 3- amoxys (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl -2- fourths Epoxide (- OCH (CH3)CH(CH3)2), 3- methyl-l- butoxy (- OCH2CH2CH(CH3)2), 2- methyl-l- butoxy (- OCH2CH(CH3)CH2CH3), etc., wherein the alkoxy base can be independently unsubstituted or by this one or more hair Bright described substituent is substituted.
Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represent alkyl, and alkenyl or alkoxy base are by one Individual or multiple halogen atoms are substituted, and such example includes, but is not limited to, trifluoromethyl, trifluoromethoxy etc..
Term " cycloalkyl " refers to the remainder for having one or more tie points to be connected to molecule, saturation, contains 3- Monocyclic, the bicyclic or three-ring system of 12 carbon atoms.This bicyclic system includes that spiral shell is bicyclic and condensed-bicyclic.Some of them are implemented Example, cycloalkyl is the member ring systems containing 3-10 carbon atom；Other embodiment, cycloalkyl are the ring bodies containing 3-8 carbon atom System；Other embodiment, cycloalkyl are the member ring systems containing 3-6 carbon atom；Other embodiment, cycloalkyl are to contain 5-6 The member ring systems of individual carbon atom；The example of group of naphthene base includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, Suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, etc..And the group of naphthene base can be only It is on the spot unsubstituted or substituted by one or more substituents described in the invention.
Term " cycloalkyl alkylidene " represents that alkyl group can be substituted by one or more groups of naphthene base, wherein alkane Base and group of naphthene base have implication as described in the present invention.Some of embodiments are, cycloalkyl alkylidene group refer to " compared with Rudimentary cycloalkyl alkylidene " group, i.e. group of naphthene base are connected to C1-6Alkyl group on.Other embodiment is ring Alkyl group is connected to C1-4Alkyl group on.Other embodiment is that group of naphthene base is connected to C1-3Alkyl group On.Other embodiment is that group of naphthene base is connected to C1-2Alkyl group on.Such example includes, but and unlimited In, cyclopropylethyl, cyclopentyl-methyl, cyclohexyl methyl etc..The cycloalkyl alkylidene group can not taken independently In generation, is substituted by one or more substituents described in the invention.
Term " heterocyclic radical " and " heterocycle " are used interchangeably here, all referring to the saturation comprising 3-12 annular atom or portion Point undersaturated, nonaromatic monocyclic, bicyclic or tricyclic system, wherein at least one annular atom is selected from nitrogen, sulphur and oxygen atom, And this member ring systems has one or more tie points to be connected with the remainder of molecule.Unless otherwise indicated, heterocyclic radical can be carbon Base or nitrogen base, and-CH2- group can be optionally by-C (=O)-replacement.The sulphur atom of ring can optionally be oxidized to S- oxygen Compound.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compounds.The example of heterocyclic radical includes, but are not limited to：Epoxy second Alkyl, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidinyl, 2- pyrrolinyls, 3- pyrrolinyls, pyrazoline Base, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1, 3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranoses, 4H- pyranoses, tetrahydro thiapyran base, Piperidyl, morpholinyl, thio-morpholinyl, piperazinyl , alkyl dioxins, dithiane base , thioxane bases, homopiperazine base, homopiperidinyl, Oxepane alkyl, thia cycloheptyl alkyl, oxygen azepineBase, diazaBase, sulphur azepineBase, indoline base, 1,2,3,4- Tetrahydro isoquinolyl, 1,3- Ben Bing bis- Evil cyclopentadienyls, 2- oxa- -5- azabicyclos [2.2.1] hept- 5- bases.- CH in heterocyclic radical2- base Group includes, but not limited to 2- oxo-pyrrolidine bases, oxo -1,3-thiazoles alkyl, 2- piperidones by the example of-C (=O)-substitution Base, 3,5- dioxy piperazine piperidinyls, hybar X base.The oxidized example of sulphur atom includes, but not limited to sulfolane in heterocyclic radical Base and 1,1- dioxothiomorpholinyls.Described heterocyclyl groups can be optionally by one or more described in the invention Substituent is substituted.
In some embodiments, heterocyclic radical is 3-6 former molecular heterocyclic radical, refers to include 3-6 annular atom Saturation or part are undersaturated monocyclic, and wherein at least one annular atom is selected from nitrogen, sulphur and oxygen atom.Unless otherwise indicated, 3-6 Former molecular heterocyclic radical can be carbon-based or nitrogen base, and-CH2- group can be optionally by-C (=O)-replacement.The sulphur of ring is former Son can optionally be oxidized to S- oxides.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compounds.3-6 atom The example of the heterocyclic radical of composition includes, but are not limited to：Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, Pyrrolidinyl, 2- pyrrolinyls, 3- pyrrolinyls, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuran Base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3- dioxy cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro Pyranose, 2H- pyranoses, 4H- pyranoses, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl , dioxanes Base, dithiane base , thioxane bases.- CH in heterocyclic radical2- group includes, but not limited to 2- oxygen by the example of-C (=O)-substitution For pyrrolidinyl, oxo -1,3-thiazoles alkyl, 2- piperidone bases and 3,5- dioxy piperazine piperidinyl.Sulphur atom is by oxygen in heterocyclic radical The example of change includes, but not limited to sulfolane base and 1,1- dioxothiomorpholinyl.Described 3-6 is former molecular miscellaneous Cyclic groups optionally can be substituted by one or more substituents described in the invention.
In some embodiments, heterocyclic radical is 5-6 former molecular heterocyclic radical, refers to include 5-6 annular atom Saturation or part are undersaturated monocyclic, and wherein at least one annular atom is selected from nitrogen, sulphur and oxygen atom.Unless otherwise indicated, 5-6 Former molecular heterocyclic radical can be carbon-based or nitrogen base, and-CH2- group can be optionally by-C (=O)-replacement.The sulphur of ring is former Son can optionally be oxidized to S- oxides.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compounds.5-6 atom The example of the heterocyclic radical of composition includes, but are not limited to：Pyrrolidinyl, 2- pyrrolinyls, 3- pyrrolinyls, pyrazolinyl, pyrazoles Alkyl, imidazolinyl, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3- dioxy ring Amyl group, two sulphur cyclopenta, THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranoses, 4H- pyranoses, tetrahydro thiapyran base, piperidyl, Morpholinyl, thio-morpholinyl, piperazinyl , alkyl dioxins, dithiane base , thioxane bases.- CH in heterocyclic radical2- group quilt-C (= O the example of)-substitution includes, but not limited to 2- oxo-pyrrolidine bases, oxo -1,3-thiazoles alkyl, 2- piperidone bases and 3,5- Dioxy piperazine piperidinyl.The oxidized example of sulphur atom includes, but not limited to 1,1- dioxothiomorpholinyls in heterocyclic radical.Institute The 5-6 former molecular heterocyclyl groups stated optionally can be taken by one or more substituents described in the invention Generation.
In other embodiments, heterocyclic radical is 5 molecular heterocyclic radicals of original, is referred to full comprising 5 annular atoms And/or part is undersaturated monocyclic, wherein at least one annular atom is selected from nitrogen, sulphur and oxygen atom.Unless otherwise indicated, 5 atoms The heterocyclic radical of composition can be carbon-based or nitrogen base, and-CH2- group can be optionally by-C (=O)-replacement.The sulphur atom of ring can To be optionally oxidized to S- oxides.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compounds.5 originals are molecular The example of heterocyclic radical includes, but are not limited to：Pyrrolidinyl, 2- pyrrolinyls, 3- pyrrolinyls, pyrazolinyl, pyrazolidinyl, miaow Oxazoline base, imidazolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3- dioxy cyclopenta, two Sulphur cyclopenta.- CH in heterocyclic radical2- group by-C (=O)-substitution example include, but not limited to 2- oxo-pyrrolidines base and Oxo -1,3- thiazolidinyls.The oxidized example of sulphur atom includes, but not limited to sulfolane base in heterocyclic radical.Described 5 Former molecular heterocyclyl groups optionally can be substituted by one or more substituents described in the invention.
In other embodiments, heterocyclic radical is 6 molecular heterocyclic radicals of original, is referred to full comprising 6 annular atoms And/or part is undersaturated monocyclic, wherein at least one annular atom is selected from nitrogen, sulphur and oxygen atom.Unless otherwise indicated, 6 atoms The heterocyclic radical of composition can be carbon-based or nitrogen base, and-CH2- group can be optionally by-C (=O)-replacement.The sulphur atom of ring can To be optionally oxidized to S- oxides.The nitrogen-atoms of ring can optionally be oxidized to N- oxygen compounds.6 originals are molecular The example of heterocyclic radical includes, but are not limited to：THP trtrahydropyranyl, dihydro pyranyl, 2H- pyranoses, 4H- pyranoses, tetrahydric thiapyran Base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl , alkyl dioxins, dithiane base , thioxane bases.- CH in heterocyclic radical2- base Group includes, but not limited to 2- piperidone bases and 3,5- dioxy piperazine piperidinyl by the example of-C (=O)-substitution.Sulphur is former in heterocyclic radical The oxidized example of son includes, but not limited to 1,1- dioxothiomorpholinyls.The described molecular heterocyclic radical base of 6 originals Group optionally can be substituted by one or more substituents described in the invention.
Term " heterocycloalkylene " represents that alkyl group can be substituted by one or more heterocyclyl groups, wherein alkane Base and heterocyclyl groups have implication as described in the present invention.Some of embodiments are, heterocycloalkylene group refer to " compared with Rudimentary heterocycloalkylene " group, i.e. heterocyclyl groups are connected to C1-6Alkyl group on.Other embodiment is, miscellaneous Cyclic groups are connected to C1-4Alkyl group on.Other embodiment is that heterocyclyl groups are connected to C1-2Alkyl group On.Such example includes, but is not limited to, 2- pyrrolidines ethyls, 3- azetidine methyl etc..The heterocyclic radical alkylene Base group can be independently unsubstituted or substituted by one or more substituents described in the invention.
Term " n former molecular ", wherein n is integer, the number of ring member nitrogen atoms in molecule is typically described, described The number of ring member nitrogen atoms is n in molecule.For example, piperidyl is 6 molecular heterocyclic radicals of original, and 1,2,3,4- tetralyl is The molecular carbocylic radical group of 10 originals.
Term " hetero atom " refers to O, S, N, P and Si, including the form of N, S and any oxidation state of P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the form that the hydrogen in heterocycle on nitrogen-atoms is substituted, for example, N is (as in 3,4- dihydro-2 h-pyrrole bases N), NH (as the NH in pyrrolidinyl) or NR (NR in the pyrrolidinyl substituted as N-).
Term " halogen " refers to F, Cl, Br or I.
Term " aryl " can be used alone or as " aralkyl ", a big portion of " aralkoxy " or " aryloxy alkyl " Point, expression contains 6-14 annular atom, or 6-12 annular atom, or 6-10 annular atom is monocyclic, bicyclic, and the carbocyclic ring of three rings System, wherein, at least one member ring systems are aromatic, and each of which member ring systems include 3-7 former molecular ring, and have One or more attachment points are connected with the remainder of molecule.Term " aryl " can be exchanged with term " aromatic rings " and used, such as Aromatic rings can include phenyl, naphthyl and anthryl.The aromatic yl group can be independently unsubstituted or by one or more sheet The described substituent of invention is substituted.
Term " aryl alkylene " represent alkyl group can be substituted by one or more aromatic yl groups, wherein alkyl and Aromatic yl group has implication as described in the present invention, and some of embodiments are that arylalkylene groups refer to the " virtue of lower level Base alkylidene " group, i.e. aromatic yl group are connected to C1-6Alkyl group on.Other embodiment is arylalkylene groups Refer to contain C1-4Alkyl " benzene alkylene ".Other embodiment is that arylalkylene groups refer to that aromatic yl group is connected to C1-2Alkyl group on.Wherein instantiation includes benzyl, diphenyl methyl, phenethyl etc..The arylalkylene groups Can be independently unsubstituted or be substituted by one or more substituents described in the invention.
Term " heteroaryl " can be used alone or as most of " heteroaryl alkyl " or " heteroarylalkoxy ", Expression contains 5-14 annular atom, or 5-12 annular atom, or 5-10 annular atom, or 5-6 annular atom is monocyclic, bicyclic, And three-ring system, wherein at least one member ring systems are aromatic, and at least one member ring systems include one or more hetero atoms, Each of which member ring systems include 5-7 former molecular ring, and have one or more attachment points to be connected with molecule remainder. Term " heteroaryl " can exchange use with term " hetero-aromatic ring " or " heteroaromatics ".In some embodiments, heteroaryl Base is comprising 1,2,3 or 4 former molecular heteroaryl of be independently selected from O, S and N heteroatomic 5-12.In other implementations In scheme, heteroaryl is comprising 1,2,3 or 4 former molecular heteroaryl of be independently selected from O, S and N heteroatomic 5-10. In other embodiments, heteroaryl is to include 1,2,3 or 4 heteroatomic 5-6 atom group for being independently selected from O, S and N Into heteroaryl.In other embodiments, heteroaryl is to be independently selected from heteroatomic the 5 of O, S and N comprising 1,2,3 or 4 The individual molecular heteroaryl of original.In other embodiments, heteroaryl is to be independently selected from O, S and N comprising 1,2,3 or 4 The molecular heteroaryl of heteroatomic 6 originals.
Other embodiment is that heteroaryl includes following monocyclic groups, but is not limited to these monocyclic groups：2- furans Mutter base, 3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5- is different Oxazolyl, 2- oxazolyls, 4- oxazolyls, 5- oxazolyls, N- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridine radicals, 3- pyridines Base, 4- pyridine radicals, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, pyridazinyl (such as 3- pyridazinyls), 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, tetrazole radical (such as 5H- tetrazole radicals, 2H- tetrazole radicals), triazolyl (such as 2- triazolyls, 5- triazolyls, 4H-1,2,4- tri- Oxazolyl, 1H-1,2,4- triazolyls, 1,2,3-triazoles base), 2- thienyls, 3- thienyls, pyrazolyl (e.g., 2- pyrazolyls and 3- pyrroles Oxazolyl), isothiazolyl, 1,2,3- oxadiazolyl, 1,2,5- oxadiazolyl, 1,2,4- oxadiazolyl, 1,3,4- oxadiazolyl, 1, 2,3- thio biphosphole bases, 1,3,4- thio biphosphole base, 1,2,5- thio biphosphole base, pyrazinyl, 1,3,5-triazines base；Also include with Under bicyclic radicals, but be not limited to these bicyclic radicals：Benzimidazolyl, benzofuranyl, benzothienyl, indyl (such as 2- indyls), purine radicals, quinolyl (such as 2- quinolyls, 3- quinolyls, 4- quinolyls), and isoquinolyl (such as 1- isoquinolines Quinoline base, 3- isoquinolyls or 4- isoquinolyls).The heteroaryl groups optionally described in the invention are taken by one or more Substituted for base.
Term " heteroarylalkylenyl " represents that alkyl group can be substituted by one or more heteroaryl groups, wherein alkane Base and heteroaryl groups have implication as described in the present invention, and some of embodiments are, heteroarylalkylenyl group refer to " compared with Rudimentary heteroarylalkylenyl " group, i.e. heteroaryl groups are connected to C1-6Alkyl group on.Other embodiment is, miscellaneous Aromatic yl group is connected to C1-4Alkyl group on.Other embodiment is that heteroaryl groups are connected to C1-2Alkyl group On.Wherein instantiation includes 2- picolyls, 3- furylethyls etc..The heteroarylalkylenyl group can independently not It is substituted or is substituted by one or more substituents described in the invention.
Term " alkyl amino " includes " N- alkyl aminos " and " N, N- dialkyl amido ", wherein amino group independently Ground is substituted by one or two alkyl group.Some of embodiments are that alkyl amino is one or two C1-6Alkyl connects The alkylamino group of lower level on to nitrogen-atoms.Other embodiment is that alkyl amino is C1-3Lower level alkyl Amino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but not It is limited to, N- methylaminos, N- ethylaminos, N, N- dimethylaminos, N, N- lignocaines etc..
Used term is " undersaturated " in the present invention represents to contain one or more degrees of unsaturation in group.
Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded from otherwise Content.
As described in the invention, the member ring systems formed in substituent one key connection of picture to the ring at center are (such as formula a institutes Show) represent substituent any commutable position on ring and can substitute.For example, to represent substituent R any on A rings by formula a The position that may be substituted, as shown in formula b-1, b-2, b-3 and b-4：
The detailed description of compounds process for production thereof shown in formula (I) of the present invention
On the one hand, the present invention provides a kind of preparation method of compound shown in formula (I),
Wherein：Each R independently is F, Cl, Br, I, CN, C1-6Alkyl, ORaOr NRbRc；
N is 0,1,2,3 or 4；
Ra、RbAnd RcIt is each independently H, C1-6Alkyl, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-4Alkylidene, 3-6 atom The heterocyclic radical of composition, (3-6 former molecular heterocyclic radical)-C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, 5- The molecular heteroaryl of 10 originals or (5-10 former molecular heteroaryl)-C1-4Alkylidene, wherein the C1-6Alkyl, C3-6 Cycloalkyl, C3-6Cycloalkyl-C1-4Alkylidene, 3-6 former molecular heterocyclic radical, (3-6 former molecular heterocyclic radical)-C1-4 Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 original is molecular miscellaneous Aryl)-C1-4Alkylidene is unsubstituted independently of one another or is substituted by 1,2,3 or 4 substituent, and the substituent is independently Selected from F, Cl, CN, N3、OH、C1-6Alkyl, C1-6Haloalkyl or C1-6Alkoxy；
Compound is not compound set forth below wherein shown in formula (I)：
Its described preparation method comprises the steps of：Compound shown in formula (II)
Reaction obtains compound shown in formula (I) in dichloro-benzenes (III)；
Wherein described dichloro-benzenes (III) is structure as shown below
In some embodiments, each R independently is F, I, CN, methyl, ethyl, n-propyl, isopropyl, normal-butyl, different Butyl, the tert-butyl group, ORaOr NRbRc。
In other embodiments, Ra、RbAnd RcIt is each independently H, methyl, ethyl, n-propyl, isopropyl, positive fourth Base, isobutyl group, the tert-butyl group, C5-6Cycloalkyl, C5-6Cycloalkyl-C1-2Alkylidene, 5-6 former molecular heterocyclic radical, (5-6 former Molecular heterocyclic radical)-C1-2Alkylidene, phenyl, phenyl-C1-2Alkylidene or 5-6 former molecular heteroaryl, wherein described Methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, C5-6Cycloalkyl, C5-6Cycloalkyl-C1-2Alkylidene, 5- The molecular heterocyclic radical of 6 originals, (5-6 former molecular heterocyclic radical)-C1-2Alkylidene, phenyl, phenyl-C1-2Alkylidene and 5- 6 molecular heteroaryls of original are unsubstituted independently of one another or substituted by 1,2,3 or 4 substituent, and the substituent is only On the spot it is selected from F, Cl, CN, N3、OH、C1-3Alkyl or C1-3Alkoxy.
In some embodiments, compound shown in formula (I) is structure shown in formula (Ia)
Wherein RaWith defining as described herein.
In other embodiments, compound shown in formula (II) is structure shown in formula (IIa)
Wherein RaWith defining as described herein.
In some embodiments, reaction of the compound in dichloro-benzenes (III) shown in formula (II) is 160 DEG C~220 DEG C carry out.
In other embodiments, reaction of the compound in dichloro-benzenes (III) shown in formula (II) be 170 DEG C~ 190 DEG C progress.
In some embodiments, molar concentration of the compound in dichloro-benzenes (III) shown in formula (II) be 0.05M~ 0.45M。
In other embodiments, molar concentration of the compound in dichloro-benzenes (III) shown in formula (II) be 0.10M~ 0.25M。
On the other hand, the present invention provides the purifying of compound shown in the formula (I) that a kind of preparation method of the present invention obtains Method, the purification process comprise the steps of：
(a) reaction solution that is concentrated under reduced pressure obtains solid；
(b) solid obtained by dichloromethane washing step (a)；
(c) solid after step (b) washing is isolated by filtration out；
(d) the separating obtained solid of step (c) is washed with water；
(e) solid after step (d) washing is filtered to isolate；
(f) the separating obtained solid of drying steps (e).
In some embodiments, solid masses (g) obtained by step (a) and methylene chloride volume used in step (b) (mL) ratio is 0.4~0.8.
In other embodiments, the quality (g) of solid obtained by step (a) and dichloromethane body used in step (b) The ratio of product (mL) is 0.5~0.7.
In some embodiments, the mixture of solid obtained by step (a) and dichloromethane stirs at 45 DEG C in step (b) 2 hours.
In other embodiments, the mixture of the separating obtained solid of step (c) and water stirs at 100 DEG C in step (d) Mix 2 hours.
In some embodiments, when filtering in step (e) mixture temperature of water and gained solid remain 25 DEG C~ 60℃。
Compound can be prepared according to the method described in patent document WO 2012/118632 shown in formula (II).
General building-up process
The embodiments described below, unless otherwise indicated, all temperature are degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, unless otherwise indicated, using when all without by not being further purified, unless other aspects show.In general is tried Agent is from Shantou Xi Long chemical plant, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, and Tianjin is resided well the limited public affairs of space chemicals Department, Tianjin good fortune morning chemical reagent factory, Wuhan Xin Huayuan developments in science and technology Co., Ltd, Qingdao Teng Long chemical reagent Co., Ltd, It is commercially available with Haiyang Chemical Plant, Qingdao.
The glassware reacted below is all dried.
The test condition of proton nmr spectra is：Under room temperature condition, Brooker (Bruker) 400MHz or 600MHz core Magnetic instrument, with CDC13、DMSO-d6、CD3OD or acetone-d6For solvent (in units of ppm), with TMS (0ppm) or chloroform (7.26ppm) is used as reference standard.When there is multiplet, following abbreviation will be used：S (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, double triplets).Coupling constant, use J Represent, unit is hertz (Hz).
The test condition of Algorithm (MS) data is：Agilent 6120Quadrupole HPLC-MS (pillars Model：Zorbax SB-C18,2.1 × 30mm, 3.5 μm, 6min, flow velocity 0.6mL/min, mobile phase：5%-95% (contains The CH of 0.1% formic acid3CN) (H of 0.1% formic acid is being contained2O the ratio in)), detected in 210nm/254nm with UV, use electron spray Ionization pattern (ESI).
The characteristic manner of compound purity and content is：Preparative high performance liquid chromatography (the Pre- of Agilent 1260 ) or Calesep Pump250 preparative high performance liquid chromatographies (Pre-HPLC) (pillar model HPLC：NOVASEP,50/80mm, DAC), detected in 210nm/254nm with UV.
The use of brief word below is through the present invention：
BiCl3Bismuth chloride
CH2Cl2, DCM dichloromethane
DMF N,N-dimethylformamides
DMSO dimethyl sulfoxide (DMSO)s
Eq, eq. equivalent
H hours
H2SO4Sulfuric acid
HPLC high performance liquid chromatographies
L, l liters
M mass
M molal weights
Pre-HPLC preparative high performance liquid chromatographies
TsOH p-methyl benzenesulfonic acids
T temperature
V volumes
ZnCl2Zinc chloride
Following synthetic schemes lists the experimental procedure for preparing compound shown in formula (I).Wherein, R and n has such as the present invention The definition.
In a heated condition, compound(1)In solvent(2)Middle reaction obtains compound(3)。
Embodiment
Following examples are used to illustrate the present invention, but are not limited to the scope of the present invention.
The synthesis of the 4- hydroxyl -7- methoxy quinolines of embodiment 1
The addition 4L o-dichlorohenzenes into 5L four-necked bottles, the lower addition 5- (((3- methoxyphenyls) amino) methylene) of stirring- 2,2- dimethyl-1,3-dioxane -4,6- diketone (110.8g, 400mmol), 180 DEG C are warming up to, keep solvent refluxing state Reaction 3 hours.After reaction terminates, 3.5L o-dichlorohenzene is evaporated under reduced pressure out, residual reaction liquid left at room temperature over night, separates out yellow Solid, filter, obtain crude product.Crude product is added to CH2Cl2(mCrude product/VCH2Cl2=0.5 (g/mL)) in, gained mixture exists Stirred 2 hours at 45 DEG C, wash partial solvent (o-dichlorohenzene) and impurity off, if it is desired, can operated with repeated washing (general common Need three times), suction filtration obtains solid, and water (m is added in the solid after vacuum dryingSolid/VWater=0.45 (g/mL)), gained mixing Thing stirs 2 hours at 100 DEG C, is cooled to 30 DEG C~50 DEG C, filters, and removes water, if it is desired, above-mentioned plus water washing process (general to need altogether twice) can be repeated, gained solid is dried in vacuo to obtain light yellow solid (36.2g, yield：51.8%, purity (HPLC)：96.4%).
MS(ESI,pos.ion)m/z:176.1[M+H]+；
1H NMR(400MHz,DMSO-d6)δ(ppm):11.54 (s, 1H), 7.98 (d, J=9.5Hz, 1H), 7.85-7.76 (m, 1H), 6.95-6.86 (m, 2H), 5.94 (d, J=7.4Hz, 1H), 3.84 (s, 3H).
The screening and optimization of reaction condition：
1. solvent, catalyst and the optimization in reaction time
The influence of the solvent of table 1.1, catalyst and reaction time to synthesis 4- hydroxyl -7- methoxy quinolines (P)
NP represents to be not present, and content (%) refers to the HPLC contents of the material in the mixture.
Compound I as follows is caused isomeric compound in reaction：
The experimental data of table 1.1 is shown：It is undesirable that dimethylbenzene, DMF, DMSO make solvent effect；Catalyst Z nCl2、 TsOH、H2SO4And BiCl3Also without positive effect；It is best that pseudocumene makees solvent effect, but the reaction time is longer, at 180 DEG C Reaction 12 hours or more long, this is higher to equipment requirement, there is certain risk, so to be also not suitable for technical grade other for pseudocumene Production process.
The o-dichlorohenzene of table 1.2 is influence of the solvent to synthesis 4- hydroxyl -7- methoxy quinolines (P)
Content (%) refers to the HPLC contents of the material in the mixture.
Influence of the solvent specification of table 1.3 to product P/ isomers I mol ratios
ND：It is uncertain
The experimental result of table 1.2 and 1.3 is shown：O-dichlorohenzene is best as reaction dissolvent effect, it is not required that addition is urged Agent；Using fresh and recovery o-dichlorohenzene on product P/ isomers I ratio without too big influence；But as in solvent Water content>1%, under the same terms, raw material conversion is endless, and obtained reactant mixture color is partially black.
2. the selection of molar reactive concentration
The influence of the molar reactive concentrations on product P/ isomers I mol ratios of table 2
Sequence number Molar reactive concentration (M) Reaction time (h) Product P/ isomers I (mol ratio)
1 0.10 5 5.89
2 0.15 5 5.06
3 0.20 5 4.71
Experimental result is shown：As reaction density increases, product P/ isomers I ratios gradually reduce, and consider yield With the complexity of purifying, select molar reactive concentration optimal for 0.10~0.12M.
3. the selection of reaction temperature
The influence of the reaction temperature of table 3
Sequence number Temperature (DEG C) Reaction time (h) Feed stock conversion (%)
1 176 5 More than 99
2 180 3 More than 99
Feed stock conversion=[molal weight of (molal weight of yield/product of product) × raw material]/raw material feeds intake Quality
Experimental result is shown：Between 176 DEG C~180 DEG C, the reaction time can reach very reaction temperature at 3~5 hours Good effect.
4. the optimization of post-processing approach
Influence of the dosage of the dichloromethane of table 4.1 to product P and isomers I contents
R*=crude product quality (g)/methylene chloride volume (mL)；Content (%) refers to the material in the mixture HPLC contents.
As R*=0.5, although product assay is relatively low, suspending system stirring is easier；But as R* >=0.6, place When managing large-tonnage product, very little, system is difficult to stir to quantity of dichloromethane, may so make washing insufficient.Consider, Selection R*=0.5 washs to product at present.
Influence of the washing sequence of table 4.2 to product
Content (%) refers to the HPLC contents of the material in the mixture.
Experimental result is shown：Product crude product is first washed through dichloromethane, after this post processing mode is washed with water, obtain Product purity and yield it is higher, and product color is preferable.
Influence of the mixture temperature to product when the water-washing process of table 4.3 filters operation
Content (%) and purity (%) refer to the HPLC contents of the material in the mixture.
Experimental result is shown：When being filtered in water-washing process, mixture temperature is maintained at 30 DEG C~50 DEG C, and product purity becomes Change little.

Claims (15)

  1. A kind of 1. preparation method of compound shown in formula (I)
    Wherein：Each R independently is F, Cl, Br, I, CN, C1-6Alkyl, ORaOr NRbRc；
    N is 0,1,2,3 or 4；
    Ra、RbAnd RcIt is each independently H, C1-6Alkyl, C3-6Cycloalkyl, C3-6Cycloalkyl-C1-4Alkylidene, 3-6 atom composition Heterocyclic radical, (3-6 former molecular heterocyclic radical)-C1-4Alkylidene, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, 5-10 Former molecular heteroaryl or (5-10 former molecular heteroaryl)-C1-4Alkylidene, wherein the C1-6Alkyl, C3-6Cycloalkanes Base, C3-6Cycloalkyl-C1-4Alkylidene, 3-6 former molecular heterocyclic radical, (3-6 former molecular heterocyclic radical)-C1-4Alkylene Base, C6-10Aryl, C6-10Aryl-C1-4Alkylidene, 5-10 former molecular heteroaryl and (5-10 former molecular heteroaryl Base)-C1-4Alkylidene is unsubstituted independently of one another or is substituted by 1,2,3 or 4 substituent, and the substituent independently selects From F, Cl, CN, N3、OH、C1-6Alkyl, C1-6Haloalkyl or C1-6Alkoxy；
    Compound is not compound set forth below wherein shown in formula (I)：
    Its described preparation method comprises the steps of：Compound shown in formula (II)
    Reaction obtains compound shown in formula (I) in dichloro-benzenes (III)；
    Wherein described dichloro-benzenes (III) is structure as shown below
  2. 2. preparation method according to claim 1, wherein each R independently be F, I, CN, methyl, ethyl, n-propyl, Isopropyl, normal-butyl, isobutyl group, the tert-butyl group, ORaOr NRbRc。
  3. 3. preparation method according to claim 1, wherein the Ra、RbAnd RcIt is each independently H, methyl, ethyl, just Propyl group, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, C5-6Cycloalkyl, C5-6Cycloalkyl-C1-2Alkylidene, 5-6 atom composition Heterocyclic radical, (5-6 former molecular heterocyclic radical)-C1-2Alkylidene, phenyl, phenyl-C1-2Alkylidene or 5-6 atom composition Heteroaryl, wherein the methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, C5-6Cycloalkyl, C5-6Ring Alkyl-C1-2Alkylidene, 5-6 former molecular heterocyclic radical, (5-6 former molecular heterocyclic radical)-C1-2Alkylidene, phenyl, Phenyl-C1-2The former molecular heteroaryl of alkylidene and 5-6 is unsubstituted independently of one another or by 1,2,3 or 4 substituent institute Substitution, the substituent is independently selected from F, Cl, CN, N3、OH、C1-3Alkyl or C1-3Alkoxy.
  4. 4. compound shown in preparation method according to claim 1, wherein formula (I) is structure shown in formula (Ia)
  5. 5. compound shown in preparation method according to claim 1, wherein formula (II) is structure shown in formula (IIa)
  6. 6. preparation method according to claim 1, wherein compound is anti-in dichloro-benzenes (III) shown in the formula (II) Should be in 160 DEG C~220 DEG C progress.
  7. 7. preparation method according to claim 1, wherein compound is anti-in dichloro-benzenes (III) shown in the formula (II) Should be in 170 DEG C~190 DEG C progress.
  8. 8. preparation method according to claim 1, wherein compound rubbing in dichloro-benzenes (III) shown in the formula (II) Your concentration is 0.05M~0.45M.
  9. 9. preparation method according to claim 1, wherein compound rubbing in dichloro-benzenes (III) shown in the formula (II) Your concentration is 0.10M~0.25M.
  10. 10. the purification process of compound, institute shown in the formula (I) that preparation method described in a kind of claim 1 to 9 any one obtains Purification process is stated to comprise the steps of：
    (a) reaction solution that is concentrated under reduced pressure obtains solid；
    (b) solid obtained by dichloromethane washing step (a)；
    (c) solid after step (b) washing is isolated by filtration out；
    (d) the separating obtained solid of step (c) is washed with water；
    (e) solid after step (d) washing is filtered to isolate；
    (f) the separating obtained solid of drying steps (e).
  11. 11. purification process according to claim 10, wherein in solid masses (g) and step (b) obtained by the step (a) The ratio of methylene chloride volume (mL) used is 0.4~0.8.
  12. 12. purification process according to claim 10, wherein the quality (g) of solid obtained by the step (a) and step (b) In methylene chloride volume (mL) used ratio be 0.5~0.7.
  13. 13. purification process according to claim 10, wherein solid and dichloromethane obtained by step (a) in the step (b) The mixture of alkane stirs 2 hours at 45 DEG C.
  14. 14. purification process according to claim 10, wherein the separating obtained solid of step (c) and water in the step (d) Mixture 100 DEG C stir 2 hours.
  15. 15. purification process according to claim 10, wherein when being filtered in the step (e) water and gained solid mixing Thing temperature remains 25 DEG C~60 DEG C.
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