CN106674228B - Multicomponent heterocycle compound and its preparation method and application - Google Patents
Multicomponent heterocycle compound and its preparation method and application Download PDFInfo
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- CN106674228B CN106674228B CN201611131478.3A CN201611131478A CN106674228B CN 106674228 B CN106674228 B CN 106674228B CN 201611131478 A CN201611131478 A CN 201611131478A CN 106674228 B CN106674228 B CN 106674228B
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- 0 *C(C(*)N(C(*)C(*)C1=C)N2C(*)C1=C)C2=O Chemical compound *C(C(*)N(C(*)C(*)C1=C)N2C(*)C1=C)C2=O 0.000 description 1
- LUPWMCXCGFTJMT-UHFFFAOYSA-N CCCC([NH+](C)[O-])=O Chemical compound CCCC([NH+](C)[O-])=O LUPWMCXCGFTJMT-UHFFFAOYSA-N 0.000 description 1
- NDGRWYRVNANFNB-UHFFFAOYSA-O O=C1[NH2+]NCC1 Chemical compound O=C1[NH2+]NCC1 NDGRWYRVNANFNB-UHFFFAOYSA-O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2282—Unsaturated compounds used as ligands
- B01J31/2291—Olefins
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2282—Unsaturated compounds used as ligands
- B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
- B01J31/2461—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as ring members in the condensed ring system or in a further ring
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/824—Palladium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The present invention relates to multicomponent heterocycle compounds and its preparation method and application, belong to bioactive compound synthesis technology field, more particularly to multicomponent heterocycle compound, preparation method and use shown in a kind of formula (I), and the catalyst system suitable for the preparation method
Description
Technical field
The invention belongs to bioactive compound synthesis technology fields, and in particular to a kind of multicomponent heterocycle compound, its system
Preparation Method and purposes, and the catalyst system suitable for the preparation method.
Background technique
Heterocyclic organic agricultural chemicals is a kind of pesticide with the fastest developing speed in recent years.It is mainly used as Insecticides (tech) & Herbicides (tech)
And fungicide, also have as acaricide, rat poison and plant growth regulator.Heterocycle insecticides mainly include pyridine, piperazine,
Imidazoles, diazine, triazines, phenthazine, carbazoles, Buprofezin etc..Heterocycle herbicide mainly includes such as 5-member heterocyclic ring containing nitrogen
Compound, such as Amrol, pyrazoles, imidazolone type；Hexa-atomic cycle compound, as bipyridyliums compound and other hexa-atomic contain
Nitrogen compound etc..Heterocyclic nitrogen-group fungicide mainly has vinclozolin, tridemorph, tricyclazole, triadimefon etc..Nitrogen heterocyclic
Usually there is multifarious bioactivity, there is great researching value in fields such as medicine, pesticides.Nitrogen-containing heterocycle is to deposit extensively
It is one of the important segment of natural products and organic compound, how efficiently constructs nitrogen-containing heterocycle, and how by this class
Heterocyclic derivatives have provided the active compound of good biological, have respectively for reactive compound exploitation and synthesis technology industrialization
It is significant.
Summary of the invention
Based on the above issues, the present invention provides a kind of lower formula (I) compound represented:
Wherein, R1、R2、R3、R4、R5Can be mutually the same or different, independently selected from H or inertia group, preferably not
Group with carbon-carbon double bond or triple carbon-carbon bonds.It, can be selected from H, unsubstituted or optionally by one or more R as examplea
Substituted following groups: alkyl, alkoxy, alkylthio group, naphthenic base, cycloalkyl oxy, cycloalkylsulfanyl, heterocycle, heterocycle
Oxygroup, heterocyclic thio, aryl, aryloxy, heteroaryl, heteroaryl oxygroup, nitro, halogen ,-NRdReRf、-C(O)Rg、-C
(O)ORg、-S(O)ORg；
Each RaIt is independently from each other halogen, hydroxyl, sulfydryl, nitro, carbonyl, alkyl, naphthenic base, heterocycle, virtue
Base, heteroaryl, alkyl oxy, cycloalkyl oxy, heterocycle oxygroup, aryloxy, heteroaryl oxygroup ,-NRdReRf、-C(O)
Rg、-C(O)ORg、-S(O)ORg；
Rd、Re、RfIt is independently from each other hydrogen or optionally by one or more RbSubstituted following groups: alkyl, alkenyl,
Naphthenic base, heterocycle, aryl, heteroaryl；
RgIndependently selected from negative oxygen ion, hydroxyl or optionally by one or more RbSubstituted following groups: alkyl, aryl,
Heteroaryl, naphthenic base, heterocycle, alkyl oxy, cycloalkyl oxy, heterocycle oxygroup, aryloxy, heteroaryl oxygroup；
Each RbIndependently there is such as RaDefined meaning.
As example, formula (I) compound can be selected from following compounds:
The present invention also provides the preparation methods of formula (I) compound, including chemically react as follows:
Wherein, group R1、R2、R3、R4、R5With definition described above.
According to the present invention, the preparation method can carry out in a solvent.
According to the present invention, the solvent can be organic solvent.The organic solvent is not particularly limited, as long as its
It is inert to reaction condition.Preferably, the solvent can be polar aprotic solvent, such as selected from hydrocarbon solvent,
One of amide solvent, sulfone class solvent, sulfoxide type solvents, heterocyclic solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent are more
Kind.As example, the solvent can be selected from DMF (n,N-Dimethylformamide), DMSO (dimethyl sulfoxide), NMP (N- methyl pyrrole
Pyrrolidone), DCE (1,2- dichloroethanes), one of chloroform or a variety of.
Alternatively, the reaction can carry out in the presence of metal halide.The metal halide can be selected from
One of the fluoride of alkali metal, chloride, bromide, iodide are a variety of.As illustrative example, the metal halogen
Compound can be selected from one of LiF, KF, KCl, KBr, NaF, NaCl, NaBr or a variety of.Preferably, the metal halide
For anhydrous compound.
Preferably, the reaction carries out in the presence of a catalyst.The catalyst is in palladium complex, phosphine composition
It is one or more.
As example, the palladium complex can be the complex of 0 ,+2 ,+3 or+4 valence palladiums, such as 0 valence palladium complex.Example
Such as, the palladium complex can be allyl palladium chloride, cyclopentadienyl group Allylpalladium, Pd (OAc)2、Pd2(dba)3、PdCl2、
Pd(PPh3)4One of or it is a variety of；
As example, the phosphine composition can be aryl phosphine complex, such as selected from monodentate phosphine ligand triphenylphosphine, double
Tooth Phosphine ligands DPPE and DPPF, three isopropoxy phosphine of electron deficient phosphine oxygen ligand, one of aminophosphine ligand (S) -3-36 or a variety of.
The molar ratio of preparation method according to the present invention, formula (A) compound and formula (B) compound can be 4:1~1:1,
Such as 3:1~2:1.
The molar ratio of preparation method according to the present invention, formula (B) compound and catalyst can be 1:0.15~1:0.01,
Such as 1:0.1~1:0.05.
Preparation method according to the present invention, when catalyst is the mixture of palladium complex and phosphine composition, molar ratio
It can be palladium complex: phosphine composition=1:1~2, such as 1:1~1.5, such as 1:1~1.25.
The ratio between the volume of preparation method according to the present invention, the mole of formula (B) compound and solvent (mol:L) can be
1:5~1:50, such as 1:10~1:30, such as 1:15~1:20.
The molar ratio of preparation method according to the present invention, formula (B) compound and metal halide is 1:1~1:10, such as
1:1.2~1:4.8, such as 1:2~1:2.4.
Preferably, it is described reaction carried out under the conditions of anhydrous and oxygen-free, such as can under inert atmosphere (such as nitrogen atmosphere) into
Row.
Preferably, the reaction time of the synthetic method is 2 hours or more.As illustrative example, can for 3,
3.5,4,5,6 or 12 hours.
Preferably, the temperature of the reaction is 40 DEG C or more.It can be 40 DEG C, 50 DEG C, 60 as illustrative example
℃,70℃,80℃,90℃.It is further preferred that reaction temperature is 70 DEG C.
The present invention provides a kind of carbon monoxide-olefin polymeric, including palladium complex and phosphine composition, wherein the palladium complex and
Phosphine composition has meaning defined above and ratio.
Purposes the present invention also provides formula (I) compound as intermediate, such as it is used to prepare lower formula (III) compound
Purposes:
Wherein R1、R2、R3、R4、R5With meaning described above.
As example, formula (III) compound can be selected from following compounds:
The present invention also provides the methods of preparation formula (III) compound, including chemically react as follows:
Wherein, R6And R7It is mutually the same or different, it is taken independently selected from H, halogen, hydroxyl, sulfydryl, cyano, nitro, nothing
Generation or optionally by one or more RaSubstituted following groups: alkyl, alkoxy, alkylthio group, naphthenic base, cycloalkyl oxy, ring
Alkyl sulfenyl, heterocycle, heterocycle oxygroup, heterocyclic thio, aryl, aryloxy, heteroaryl, heteroaryl oxygroup, nitro, halogen
Element ,-NRdReRf、-C(O)Rg、-C(O)ORg、-S(O)ORg、-(O-(CH2)x-O)yH；
Representative forms singly-bound or double bond；
Representative forms double or triple bonds；
R1、R2、R3、R4、R5、Rd、Re、Rf、RgWith meaning described above；
X, y is independently from each other 1 or more integer.
The method of formula (III) compound produced according to the present invention, can be under the conditions of anhydrous and oxygen-free, such as inert atmosphere
Under, formula (I) compound reacts preparation formula (III) compound with formula (II) compound in organic solvent.It is described to have as example
Solvent can be selected from polar aprotic solvent described above, such as acetone.
The temperature of the reaction is 40 DEG C or more, such as 40 DEG C, 50 DEG C, 60 DEG C, 70 DEG C, 80 DEG C, 90 DEG C or reflux temperature.
Reaction time can be 1 hour or more, such as 2~24 hours, and such as 6~12 hours.
The method of formula (III) compound produced according to the present invention, the reaction are that Diels-Alder reacts.
The molar ratio of preparation method according to the present invention, formula (I) compound and formula (II) compound can be 1:1~1:3,
Such as 1:1.2~1:2.
The present invention also provides acceptable salt in formula (III) compound represented or its pharmacy or Pesticide Science.
The present invention also provides the formula of crystal form (III) compounds.For example, the present invention provides the compound 3- of crystal form
36, with following crystal parameters:
。
Further, the present invention also provides a kind of composition pesticide, comprising formula (III) compound represented or its pharmacy or
Acceptable salt and auxiliary material in Pesticide Science.
The composition pesticide can management of weeds, such as herba digitariae, rape and barnyard grass can be prevented and kill off etc..
The present invention also provides compounds shown in formula (III) to prepare the purposes in drug or pesticide.
Term and definition
Unless otherwise indicated, group and the term definition recorded in present specification and claims, including its work
For recorded in the definition of example, illustrative definition, preferred definition, table definition, particular compound determines in embodiment
Justice etc., can any combination and combination each other.Group definition and compound structure after such combination and combination, should
Belong in the range of the application protection.
The numberical range that present specification and claims are recorded, when the numberical range is defined as " integer ",
Two endpoints and each integer within the scope of this that should be understood as describing the range.For example, " 0~10 integer " is answered
When each integer for being interpreted as describing 0,1,2,3,4,5,6,7,8,9 and 10.When the numberical range is defined as " counting ",
It should be understood as that two endpoints, each integer within the scope of this and each within the scope of this that describe the range are small
Number.For example, " 0~10 number " should be understood as not only describing 0,1,2,3,4,5,6,7,8,9 and 10 each integer, also
At least describe wherein each integer respectively with 0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9 and.
" halogen " that the present invention uses refers to fluorine, chlorine, bromine and iodine.
The present invention is used alone or " alkyl " as suffix or prefix is intended to include having 1 to 20, preferably 1-6 carbon
The branch and linear saturation aliphatic hydrocarbyl of atom (if or provide the specific number of carbon atom, refer to the specific number).For example,
“C1-6Alkyl " indicates the straight chain and branched alkyl with 1,2,3,4,5 or 6 carbon atom.The example of alkyl includes but is not limited to
Methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, amyl and hexyl.
The present invention is used alone or " halogenated alkyl " or " alkyl halide " as suffix or prefix is intended to include having
At least one halogenic substituent and there is 1-20, preferably 1-6 carbon atom (if or provide the specific number of carbon atom,
Refer to the specific number) branch and linear saturation aliphatic hydrocarbyl.For example, " C1-10Halogenated alkyl " indicate have 0,1,2,3,4,5,
6, the halogenated alkyl of 7,8,9,10 carbon atoms.The example of halogenated alkyl includes but is not limited to methyl fluoride, difluoromethyl, fluoroform
Base, chlorine methyl fluoride, 1- fluoro ethyl, 3- fluoropropyl, 2- chloropropyl, 3,4- difluorobutyl groups etc..
The present invention is used alone or " alkenyl " as suffix or prefix is intended to include having 2 to 20, preferably 2-6 carbon
The branch and straight chain rouge comprising alkenyl or alkene of atom (if or provide the specific number of carbon atom, refer to the specific number)
Race's alkyl.For example, " C2-6Alkenyl " indicates the alkenyl with 2,3,4,5 or 6 carbon atoms.The example of alkenyl includes but is not limited to
Vinyl, allyl, 1- acrylic, 1- cyclobutenyl, 2- cyclobutenyl, 3- cyclobutenyl, 2- methyl but-2-ene base, 3- methyl butyl- 1-
Alkenyl, 1- pentenyl, 3- pentenyl and 4- hexenyl.
The present invention is used alone or " alkynyl " as suffix or prefix is intended to include having 2 to 20, preferably 2-6 carbon
The branch and straight chain rouge comprising alkynyl or alkynes of atom (if or provide the specific number of carbon atom, refer to the specific number)
Race's alkyl.Such as acetenyl, propinyl (such as l- propinyl, 2-propynyl), 3- butynyl, pentynyl, hexin base and 1- first
The amyl- 2- alkynyl of base.
Terminology used in the present invention " aryl " refers to the aromatic ring structure being made of 5 to 20 carbon atoms.Such as: comprising 5,6,
The aromatic ring structure of 7 and 8 carbon atoms can be mono-cyclic aromatic group such as phenyl；Include 8,9,10,11,12,13 or 14
The ring structure of carbon atom can be polycyclic such as naphthalene.Aromatic ring can replace in one or more ring positions those described above substitution
Base.Term " aryl " further includes the polycyclic ring system with two or more rings, and two of them or more carbon is two adjacent
(ring is " condensed ring ") common to ring, wherein at least one ring is aromatics and other rings for example can be naphthenic base, cyclenes
Base, cycloalkynyl radical, aryl and/or heterocycle.Polycyclic example includes but is not limited to 2,3- dihydro -1,4- benzo dioxa hexamethylene two
Alkene and 2,3- dihydro -1- benzofuran.
Terminology used in the present invention " naphthenic base " is intended to include the saturation ring group with carbon atom is specified number.These terms
It may include condensed or bridge joint multi-loop system.Naphthenic base has 3 to 40 carbon atoms in its ring structure.In an embodiment
In, naphthenic base has 3,4,5 or 6 carbon atoms in its ring structure.For example, " C3-6Naphthenic base " indicates such as cyclopropyl, ring fourth
The group of base, cyclopenta or cyclohexyl.
" heteroaryl " that the present invention uses refers to the heteroaromatic miscellaneous of at least one ring hetero atom (such as sulphur, oxygen or nitrogen)
Ring.Heteroaryl includes single loop system and multi-loop system (such as with 2,3 or 4 condensed ring).The example of heteroaryl includes but unlimited
In pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, triazine radical, furyl, quinolyl, isoquinolyl, thienyl, imidazole radicals, thiophene
Oxazolyl, indyl, pyrrole radicals, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, three
Oxazolyl, tetrazole radical, indazolyl, 1,2,4- thiadiazolyl group, isothiazolyl, benzothienyl, purine radicals, carbazyl, benzimidazole
Base, benzoxazolyl, azepine benzoxazolyl, Imidazothiazole base, benzo [1,4] dioxine base, benzo [1,3] two
Oxole base etc..In some embodiments, heteroaryl has 3 to 40 carbon atoms and has in other embodiments
3 to 20 carbon atoms.In some embodiments, heteroaryl includes that 3 to 14,4 to 14,3 to 7 or 5 to 6 cyclization are former
Son.In some embodiments, heteroaryl has 1 to 4,1 to 3 or 1 to 2 hetero atom.In some embodiments, miscellaneous
Aryl has 1 hetero atom.
Unless otherwise indicated, terminology used in the present invention " heterocycle " refer to the saturation comprising 3 to 20 atoms, insatiable hunger and/or
The monocyclic, bicyclic or tricyclic of fractional saturation, wherein 1,2,3,4 or 5 annular atom is selected from nitrogen, sulphur or oxygen, unless otherwise indicated,
It can be connected by carbon or nitrogen, wherein-CH2Group is optionally replaced by-C (O)-；And wherein unless otherwise indicated, ring nitrogen
Atom or ring sulfur atom are optionally oxidized to form N- oxide or S- oxide or theheterocyclic nitrogen atom and optionally be quaternized；Its middle ring
In-NH optionally replaced by acetyl group, formoxyl, methyl or mesyl；And ring is optionally replaced by one or more halogens.It answers
It should be appreciated that these hetero atoms are not adjacent to each other when the sum of S atom in heterocycle and O atom is more than 1.If described miscellaneous
Ring group is two rings or tricyclic, then at least one ring may optionally be heteroaromatic rings or aromatic ring, and condition is that at least one ring is non-miscellaneous
Aromatics.It is not centainly aromatics if the heterocycle is monocycle.The example of heterocycle include but is not limited to piperidyl,
N- acetylpiperidinyl, N- methyl piperidine base, N- formyl piperazine base, N- mesylpiperazinyl, high piperazine base, piperazinyl,
Azetidinyl, oxetanyl, morpholinyl, tetrahydro isoquinolyl, tetrahydric quinoline group, indolinyl, oxinane
Base, dihydro -2H- pyranose, tetrahydrofuran base, tetrahydro thiapyran base, tetrahydric thiapyran -1- oxide, tetrahydric thiapyran -1,1- titanium dioxide
Object, 1H- pyridin-2-ones and 2,5- dioxoimidazolidin alkyl.
Terminology used in the present invention " protecting group " refers to interim substituent group, protect the functional group with potential reaction and
So as not to which undesirable chemical conversion occurs.The example of the protecting group includes the silyl ether and aldehyde of the ester of carboxylic acid, alcohol
Corresponding acetal and ketal with ketone.
According to the position of different substituents and property, the compound of the present invention can also be additionally comprising one or more not right
Title center.Asymmetric carbon atom can (R) or (S) configuration exist, when an only asymmetric center, generate racemic mixing
Object obtains non-enantiomer mixture when containing multiple asymmetric centers.In some cases, due to around particular key
There is likely to be asymmetry for blocked rotation, such as two substituted aromatic rings of center key connection specific compound.And
And substituent group can exist in the form of cis or trans isomery.
The compounds of this invention further includes its respectively all possible stereoisomer, is single stereoisomers or described
Any mixing of the arbitrary proportion of stereoisomer (such as R- isomers or S- isomers or E- isomers or Z- isomers)
The form of object.This can be realized by any suitable art methods (such as chromatography, especially such as chiral chromatography)
The separation of the single stereoisomers (such as single enantiomter or single diastereoisomer) of the compound of invention.
In addition, the compound can exist in the form of tautomer.The compounds of this invention includes all possible
Tautomer is the form of any mixture of the arbitrary proportion of single tautomer or the tautomer.
All these isomers and their mixture are included in the present invention.
Acceptable salt can be in the pharmacy or Pesticide Science of the compounds of this invention has nitrogen-atoms for example in chain or ring
The compound of the present invention with enough alkalinity acid-addition salts, such as with following inorganic acid formed acid-addition salts: for example
Hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or the acid-addition salts formed with following organic acid: such as
Formic acid, acetic acid, acetoacetate, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, enanthic acid, hendecanoic acid, lauric acid, benzene first
Acid, salicylic acid, 2- (4- hydroxy benzoyl) benzoic acid, camphoric acid, cinnamic acid, pentamethylene propionic acid, didextrose acid, 3- hydroxyl-
2- naphthoic acid, niacin flutter acid, pectinic acid, persulfuric acid, 3- phenylpropionic acid, picric acid, pivalic acid, 2- ethylenehydrinsulfonic acid, clothing health
Acid, sulfamic acid, trifluoromethanesulfonic acid, dodecyl sulphate, ethanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, 2- naphthalene sulfonic acids,
Naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid,
Alginic acid, maleic acid, fumaric acid, D- gluconic acid, mandelic acid, ascorbic acid, glucoheptose, phosphoglycerol, aspartic acid, sulfosalisylic
Acid, hemisulfic acid or thiocyanic acid.
In addition, the pharmaceutically acceptable salt that the another kind of the compound of the present invention with enough acidity is suitble to is alkali gold
Belong to salt (such as sodium salt or sylvite), alkali salt (such as calcium salt or magnesium salts), ammonium salt, or with provide the acceptable sun of physiology
The salt that the organic base of ion is formed, such as the salt formed with following substance: N-METHYL-ALPHA-L-GLUCOSAMINE, dimethyl aminoglucose, ethyl Portugal
Osamine, lysine, dicyclohexylamine, 1,6- hexamethylene diamine, ethanol amine, aminoglucose, sarcosine, serinol, trihydroxy methyl amino
Methane, amino-propanediol, 1- amino -2,3,4- butantriol.In addition, Basic nitrogen-containing groups can be used following reagent quaternized: rudimentary
Alkyl halide, such as methyl, ethyl, propyl and butyl chloride compound, bromide and iodide；Dialkyl sulfate, such as sulphur
Dimethyl phthalate, dithyl sulfate, dibutyl sulfate and diamyl sulfates；Long chain halide, such as decyl, lauryl, nutmeg
Base and stearyl chlorides, bromide and iodide；Aralkyl halide such as benzyl and phenylethyl bromide etc..
Also, acceptable salt should also include the medicine for the compound that part is inner salt form in the pharmacy or Pesticide Science
Acceptable salt on.
Skilled persons will also appreciate that the acid-addition salts of compound claimed can pass through a variety of known formulas
Any one in method makes the compound with inorganic acid appropriate or organic acid reaction to prepare.Alternatively, acidity of the invention
The alkali metal salt and alkali salt of compound react the compound of the present invention with alkali appropriate by various known methods
To prepare.
Term " auxiliary material " refer to it is pharmaceutically acceptable or can pesticide inert fraction.The example of categories of excipients is wrapped without limitation
Include adhesive, disintegrating agent, lubricant, glidant, stabilizer, filler and diluent etc..Excipient can enhance pharmaceutical preparation
Operating characteristic makes preparation be more suitable for directly compressing by increasing mobility and/or adherence.Typical case suitable for above-mentioned preparation
Pharmaceutically acceptable carrier example are as follows: carbohydrate, such as lactose, sucrose, mannitol and sorbierite；Starch, for example, it is beautiful
Rice starch, tapioca and potato starch；Cellulose and its derivates, such as sodium carboxymethylcellulose, ethyl cellulose and first
Base cellulose；Calcium phosphate, such as Dicalcium Phosphate and tricalcium phosphate；Sodium sulphate；Calcium sulfate；Polyvinylpyrrolidone；Polyethylene
Alcohol；Stearic acid；Alkali earth metal stearate, such as magnesium stearate and calcium stearate；Stearic acid；Plant oil, such as peanut oil,
Cottonseed oil, sesame oil, olive oil and corn oil；Nonionic, cation and anionic surfactant；Ethylene glycol polymer；β-
Cyclodextrin；Fatty alcohols；With hydrolyzed cereal solids and other nontoxic compatible fillers, adhesive, disintegrating agent, slow
The commonly used auxiliary material in pharmaceutical preparation such as electuary, preservative, antioxidant, lubricant, colorant.
Beneficial effect
Formula (I) compound provided by the invention can be used as intermediate synthesis can biologically active nitrogen-containing heterocycle chemical combination
Object.Preparation method disclosed by the invention is easy to operate, and reaction efficiency is higher, can efficiently construct five yuan or more of polynary nitrogen-containing hetero
Cyclics can and cycle compound synthesis polynary with easy realization by designed synthon.
Detailed description of the invention
Fig. 1 is the mono-crystalline structures figure of compound 3-36.
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.After having read documented content of the invention, those skilled in the art can be right
The present invention carries out various variations or modifications, and such equivalent forms are equally fallen in the scope of protection of the invention.
Reagent and instrument
Unless otherwise indicated, all reagents directly use after buying from Reagent Company without any purification process.DMF nitrogen
The lower hydrogenation Calcium treatment of protection newly distills.Other solvents are all to remove water to use after purification under nitrogen protection.
Unless otherwise indicated, the operation of following embodiments is that anhydrous and oxygen-free carries out under nitrogen protection.
The 200-300 mesh silica gel that rapid column chromatography uses Haiyang Chemical Plant, Qingdao to produce.1H NMR(300MHz)、13C NMR
(50MHz) and13C NMR (75MHz) is with tetramethylsilane (TMS) for internal standard, deuterated chloroform (CDCl3) it is solvent, it uses
VarianCXR300, VarianCXR200, Bruker-400 type nmr determination.1H H NMR spectroscopy, chemical shift δ unit are
Ppm, tetramethylsilane (TMS) is in unimodal, its chemical shift is as measuring basis, it is specified that δTMS=0ppm；Coupling constant (J
Value) as unit of Hz.13C H NMR spectroscopy, chemical shift δ unit are ppm, deuterated chloroform (CDCl3) it is in triplet, its chemical potential
It moves as measuring basis, it is specified that δCDCl3=77ppm.Infrared spectroscopy is by Thermo Electron Corporation
The measurement of Nicolet AVATAR 330FT-IR spectrometer.Mass spectrometric data is by GC-MS Aglient-Technologies 6890N-
5973 and Institute of Analysis of Peking University high-resolution mass spectrometer VG-ZAB-HS measurement.
* compound (A) preparation example
Synthesize compound 3-30: magnesium chips (7.2g), HgCl2(90mg), 80% propargyl bromide toluene solution (1mL) and 50mL
Anhydrous ether (the new distillation of Na processing) is added in 1000mL there-necked flask stirs under nitrogen protection, is slowly heated to reaction and starts to put
Heat reflux adds 100mL ether for system and is cooled to -20 DEG C, keeps -20 DEG C of 80% propargyl bromide toluene solutions of dropwise addition
The mixed solution of (32mL) and 150mL ether are warming up to 0 DEG C of reaction 2h after being added dropwise.It is kept for 0 DEG C, trimethylchloro-silicane is added dropwise
The mixed solution of alkane (38mL) and 110mL ether are warmed to room temperature reaction 4h in 0 DEG C of reaction 0.5h after being added dropwise.System generates
A large amount of magnesium salts, filtering, filtrate first use a large amount of ether solvents of rectifying post separation, and 90-92 DEG C of fraction is collected in redistillation.GC-MS detection
For the mixture of propargyl trimethyl silane and toluene, propargyl trimethyl silane 3-30 content 80%, yield about 66%.
Synthesis compound 3-31: the anhydrous second of 100mL is added in propargyl trimethyl silicane 3-30 (5.6g) under nitrogen protection
In ether, -78 DEG C are slowly added dropwise 2.5M n-BuLi (20mL), in -78 DEG C of reaction 0.5h after being added dropwise, rise to 0 DEG C of stirring 1h,
Paraformaldehyde (5.76g) 0 DEG C of stirring 0.5h is added, is warmed to room temperature reaction 12h.Saturated aqueous ammonium chloride quenching reaction, ether
Extraction three times (50mL/ times), merges organic phase, anhydrous Na2SO4It is dry, it is spin-dried for obtaining yellow oil, (be washed through silica gel column chromatography
De- agent: petrol ether/ethyl acetate=4/1) product Compound 3-31, colorless oil, 6.39g, yield 90% are obtained after purification.
It synthesizes compound 3-32: compound 3-31 (4.26g, 30mmol) is added in 200mL there-necked flask, 100mL dichloro
Methane, triethylamine (4.0g, 40mmol), DMAP (0.2g) are stirred, and chloroacetic chloride (2.59g, 33mmol) is added dropwise at 0 DEG C, drips
0 DEG C of reaction 0.5h after finishing is warmed to room temperature reaction 2h.Water washing three times (50mL/ times), merges organic phase, anhydrous Na2SO4It is dry,
It is spin-dried for obtaining yellow oil, obtains product after purification through silica gel column chromatography (eluant, eluent: petrol ether/ethyl acetate=25/1)
Close object 3-32, colorless oil, 4.69g, yield 85%.
Synthesize compound (A): under ethylene balloon atmosphere, by 4- trimethyl silicon substrate -2- butine acetate 3-32 (9.2g,
50mol), Grubbs II (2.2g, 2.5mmol, 5mol%) and methylene chloride (200mL) are added in 250mL there-necked flask, in room
12h is stirred to react under temperature.Methylene chloride is spin-dried for obtain dark brown oil, through silica gel column chromatography (eluant, eluent: petroleum ether/second
Acetoacetic ester=50/1) colorless oil product (A), 7.95g, yield 75% are obtained after purification.
* compound (B) preparation example
The preparation of 3- pyrazolidone 3-33: hydrazine hydrate (0.14mol) is added in 75mL ethyl alcohol, propylene is added dropwise at room temperature
The mixed solution of acetoacetic ester (0.125mol) and 50mL ethyl alcohol are stirred at room temperature reaction 1h, reheat reflux after being added dropwise
4h, concentration, obtains light yellow oil product through silica gel column chromatography [eluant, eluent: methanol/chloroform=15/85 (V/V)] after purification
3-33,2.56g, yield 24%.
The preparation of azomethine imines: by 3- pyrazolidone 3-33 (1.0equiv, 4mmol), aldehyde (1.1equiv,
It 4.4mmol) is added in 2mL methanol and 0.5-3h is stirred at room temperature, 5-20mL ether is added and is largely precipitated, product idol is obtained by filtration
Nitrogen methine imines (B).
Embodiment 1
The compound 3-35a of synthesis such as following formula
By compound (A) (0.4mmol), 1- phenyl -3- carbonyl-azomethine imines (0.2mmol, 34.8mg), Pd
(PPh3)4(18.5mg, 0.016mmol), PPh3(5.2mg, 0.02mmol) and anhydrous K F (27.8mg, 0.48mmol) are added dry
It in dry reaction tube, vacuumizes and is then charged with nitrogen, this process was repeated three times.Then DMF (1mL) is added.Reaction system is 70
3.5h is stirred to react at DEG C.Ethyl acetate extraction, water washing merge organic phase, anhydrous Na2SO4It is dry, it is spin-dried for obtaining yellow oil
Shape object obtains compound 3-35a through silica gel column chromatography (eluant, eluent: ethyl acetate/petroleum ether=1/2) after purification, is in nothing
Color grease, 38.1mg, yield 75%.1H NMR (CDCl3,300MHz): 7.38-7.28 (m, 5H), 5.38 (d, 1H, J=
0.75Hz), 5.33 (s, 1H), 5.02 (s, 1H), 4.90 (s, 1H), 4.77 (d, 1H, J=8.1Hz), 4.16 (d, 1H, J=
7.2Hz),3.82-3.80(m,1H),3.35-3.24(m,1H),2.97-2.70(m,3H),2.58-2.53(m,1H),2.26-
2.18(m,1H)；13C NMR(CDCl3,75MHz):171.4,145.8,144.9,142.2,128.2,127.9,127.1,
114.8,110.6,74.3,49.7,48.6,44.8,29.2；MS(C16H18N2O):254(M+).HRMS(EI):
Anal.Calcd.(M+H+)255.14919,Found:255.14925.
Embodiment 2
The compound 3-35b of synthesis such as following formula
By compound (A) (0.4mmol), 1- p-trifluoromethyl phenyl -3- carbonyl-azomethine imines (0.2mmol,
48.4mg)、Pd(PPh3)4(18.5mg, 0.016mmol), PPh3(5.2mg, 0.02mmol) and anhydrous K F (27.8mg,
It 0.48mmol) is added in dry reaction tube, vacuumizes and be then charged with nitrogen, this process was repeated three times.Then DMF is added
(1mL).Reaction system is stirred to react 2.5h at 70 DEG C.Ethyl acetate extraction, water washing merge organic phase, anhydrous Na2SO4It is dry
It is dry, it is spin-dried for obtaining yellow oil, be obtained after purification through silica gel column chromatography (eluant, eluent: ethyl acetate/petroleum ether=1/2)
Compound 3-35b, light yellow oil, 56.7mg, yield 88%.1H NMR(CDCl3, 300MHz): 7.64 (d, 2H, J=
4.1Hz), 7.51 (d, 2H, J=3.9Hz), 5.39 (s, 1H), 5.34 (s, 1H), 5.02 (s, 1H), 4.90 (s, 1H), 4.77
(d, 1H, J=8.0Hz), 4.15 (d, 1H, J=8.0Hz), 3.90-3.86 (m, 1H), 3.38-3.27 (m, 1H), 2.89-2.66
(m,3H),2.56-2.51(m,1H),2.30-2.21(m,1H)；13C NMR(CDCl3,75MHz):171.2,146.0,145.1,
144.5,130.4,129.9,127.4,125.8,125.7,122.0,115.0,110.8,73.9,49.8,44.6,30.0；MS
(C17H17F3N2O):322(M+)；HRMS(EI):Anal.Calcd.(M+H+)323.13657,Found:323.13726.
Embodiment 3
It is the compound 3-36 of Material synthesis such as following formula using the compound 3-35a in embodiment 1
Compound 3-35a (40.6mg, 0.16mmol) and dimethyl butyn (27.3mg, 0.192mmol) are added
In acetone (2mL), 12h is reacted in return stirring, is spin-dried for, through silica gel column chromatography (eluant, eluent: petrol ether/ethyl acetate=1/2)
White solid product 3-36,54.5mg, yield 86% are obtained after purification.1H NMR(CDCl3,400MHz):7.36-7.30(m,
5H), 4.42 (d, 1H, J=6.0Hz), 3.96-3.88 (m, 2H), 3.78 (s, 3H), 3.75 (s, 3H), 3.36-3.23 (m,
2H),3.18-2.97(m,2H),2.90-2.79(m,3H),2.71-2.63(m,1H),2.34-2.19(m,2H)；13C NMR
(CDCl3,100MHz):171.1,168.0,167.8,132.3,132.2,129.1,128.9,128.7,128.0,127.5,
127.0,69.2,52.3,49.2,49.0,48.7,46.7,34.7,32.4,29.1；MS(C22H24N2O5):369(M+)；HRMS
(EI):Anal.Calcd.(M+H+)397.17508,Found:397.17603.
4 crystal structure determination of embodiment
The crystal parameters and test condition of compound 3-36 are shown in table 1.
The single crystal data and structural parameters of 1 compound 3-36 of table
The test of 5 activity of weeding of embodiment
0.01g compound 3-36 is added in 2mL volumetric flask, obtaining concentration with acetone solution constant volume is the molten of 5mg/mL
Liquid.Solution 1.0mL is taken, the solution that 1mg/mL is made in agar water is added to.After tested, formula 3-36 compound has good
Activity of weeding, such as can be more than 20% for the inhibiting rate of barnyard grass.
Embodiments of the present invention are illustrated above.But the present invention is not limited to above embodiment.It is all
Within the spirit and principles in the present invention, any modification, equivalent substitution, improvement and etc. done should be included in protection of the invention
Within the scope of.
Claims (11)
- Formula 1. (I) compound represented:Wherein, R1、R2、R4、R5Can be mutually the same or different, independently selected from H or C1-6Alkyl；R3Selected from unsubstituted or optionally by one or more RaSubstituted phenyl；Each RaIt is independently from each other halogen, hydroxyl, sulfydryl, nitro, C1-6Alkyl, C1-6Alkyl oxy.
- 2. the preparation method of compound as described in claim 1, including chemically react as follows:Wherein, group R1、R2、R3、R4、R5With definition described in claim 1；The preparation method carries out in a solvent, and the solvent is selected from n,N-Dimethylformamide, dimethyl sulfoxide, N- methylpyrrole One of alkanone, 1,2- dichloroethanes, chloroform are a variety of；The reaction carries out in the presence of metal halide, the metal halide be selected from LiF, KF, KCl, KBr, NaF, One of NaCl, NaBr or a variety of；The reaction carries out in the presence of a catalyst, and the catalyst is selected from one of palladium complex, phosphine composition or more Kind；The palladium complex is allyl palladium chloride, cyclopentadienyl group Allylpalladium, Pd (OAc)2、Pd2(dba)3、PdCl2、Pd (PPh3)4One of or it is a variety of；The phosphine composition is selected from monodentate phosphine ligand triphenylphosphine, bidentate phosphine ligands DPPE and DPPF, electron deficient phosphine oxygen ligand three Isopropoxy phosphine, one of aminophosphine ligand (S) -3-36 or a variety of:
- 3. preparation method as claimed in claim 2, in which:The molar ratio of formula (A) compound and formula (B) compound is 4:1~1:1；The molar ratio of formula (B) compound and catalyst is 1:0.15~1:0.01；When catalyst is the mixture of palladium complex and phosphine composition, molar ratio is palladium complex: phosphine composition=1:1~ 2；The ratio between the mole of formula (B) compound and the volume of solvent mol:L are 1:5~1:30；The molar ratio of formula (B) compound and metal halide is 1:1~1:10；The reaction carries out under the conditions of anhydrous and oxygen-free.
- 4. preparation method as claimed in claim 3, in which:The molar ratio of formula (A) compound and formula (B) compound is 3:1~2:1；The molar ratio of formula (B) compound and catalyst is 1:0.1~1:0.05；When catalyst is the mixture of palladium complex and phosphine composition, molar ratio is palladium complex: phosphine composition=1:1~ 1.5；The ratio between the mole of formula (B) compound and the volume of solvent mol:L are 1:15~1:20；The molar ratio of formula (B) compound and metal halide is 1:2~1:4.8；The reaction carries out under inert atmosphere under the conditions of anhydrous and oxygen-free；The reaction time of the synthetic method is 2 hours or more；The temperature of the reaction is 40 DEG C or more.
- 5. the preparation method of compound shown in lower formula (III), including chemically react as follows:Wherein, R6And R7It is mutually the same or different, independently selected from-C (O) ORg；Representative forms double bond；It represents and forms three keys；R1、R2、R3、R4、R5、RgWith meaning described in claim 1；RgIndependently selected from C1-6Alkyl.
- 6. preparation method described in claim 5, in which:Under the conditions of anhydrous and oxygen-free, formula (I) compound reacts preparation formula (III) chemical combination with formula (II) compound in organic solvent Object；The organic solvent is selected from polar aprotic solvent.
- 7. preparation method as claimed in claim 6, in which:Under an inert atmosphere, formula (I) compound reacts preparation formula (III) compound with formula (II) compound in organic solvent；The organic solvent is selected from acetone；The temperature of the reaction is 40 DEG C or more；Reaction time is 1 hour or more；The molar ratio of formula (I) compound and formula (II) compound is 1:1~1:3.
- 8. acceptable salt in formula (III) compound represented or its Pesticide Science, wherein formula (III) compound represented has power Benefit requires structure shown in formula described in 5 (III).
- 9. acceptable salt in compound as claimed in claim 8 or its Pesticide Science, wherein formula (III) compound represented is
- 10. acceptable salt in compound as claimed in claim 9 or its Pesticide Science, wherein formula (III) compound represented For crystal formIt is with following crystal parameters:Crystallographic system and Space group Monoclinic system, P2 (1)/nCell parameterα=90 °β=102.379 (8) °γ=90 °.
- 11. composition pesticide, comprising such as acceptable salt on the described in any item compounds of claim 8-10 or its Pesticide Science And auxiliary material.
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