CN106414414A - Method for manufacturing triketone compound - Google Patents

Method for manufacturing triketone compound Download PDF

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CN106414414A
CN106414414A CN201580028166.7A CN201580028166A CN106414414A CN 106414414 A CN106414414 A CN 106414414A CN 201580028166 A CN201580028166 A CN 201580028166A CN 106414414 A CN106414414 A CN 106414414A
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alkyl
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ketone
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formula
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CN106414414B (en
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平野裕贵
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Kumiai Chemical Industry Co Ltd
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Ihara Chemical Industry Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A manufacturing method for a triketone compound represented by general formula (1), the method being characterised by comprising a rearrangement reaction step in which an enol ester compound represented by general formula (2) is subjected to a rearrangement reaction using a base in conditions that do not contain a cyanide, thereby obtaining the triketone compound represented by general formula (1). [Effect] It is possible to manufacture a high yield of a triketone compound that is a useful agricultural compound, in mild conditions and without using highly toxic cyanides, and without requiring a specific solvent.

Description

The manufacture method of 3 ketone
Technical field
The present invention relates to having the manufacture method of the 3 ketone of Oxopyrazine ring, more particularly to pass through rearrangement reaction The method manufacturing 3 ketone by enol ester compounds.
Background technology
As described in Patent Document 1, the 3 ketone with Oxopyrazine ring is many institutes as herbicide Known.In the manufacture method of the 3 ketone recorded in the publication, first, make to close as the Oxopyrazine cyclisation of raw material Thing is reacted in a solvent in the presence of base, manufactures the enol ester compounds (operation 1) as reaction intermediate.Or, Can also make to be reacted in the presence of dehydrating condensation agent in a solvent as the compound of raw material, manufacture enol ester compounds (operation 2).Then, the enol ester compounds obtained by making and cyanogen compound carry out rearrangement reaction in the presence of base, manufacture and make 3 ketone (operation 3) for target compound.Herein, cyanogen compound refers to discharge the compound of cyanide ion (i.e., Cyanogen compound), specifically can exemplify potassium cyanide, Cyanogran. .alpha.-hydroxyisobutyronitrile. etc., employ .alpha.-hydroxyisobutyronitrile. in an embodiment.
Below, operation 3 is described in detail.In operation 3, by cyanogen compound (being .alpha.-hydroxyisobutyronitrile. in embodiment 1) Produce cyanide ion.Herein, this reaction is balancing response, and balance moves right in the basic conditions.Therefore, in embodiment 1 In, add triethylamine as alkali (the 0161st section).
Produced cyanide ion carries out nucleophilic addition to the carbonyl carbon of ester, generates cyaniding acidifying through electron transfer Compound.Then, carbon-carbon bond is formed by the nucleophilic addition of the carbonyl carbon to cyaniding acid compound for the α carbon from cyclohexanedione, warp Cross electron transfer and obtain target 3 ketone.Herein, the cyanide ion required for rearrangement reaction can be regenerated, thus For catalytic amount.It should be noted that with regard to its reaction mechanism, such as may be referred to Tet Lett (Tetrahedron Lett., 1996, volume 37,1007) etc..
In the past, in there is the manufacture method of 3 ketone of Oxopyrazine ring, in order to object is obtained with high yield, It is believed that the interpolation of cyanogen compound is necessary as shown in patent documentation 1.That is, in the reaction using cyanogen compound, such as Shown on, the cyaniding acid compound as intermediate is generated by cyanide ion, thus expeditiously carrying out rearrangement reaction.But It is that the use of cyanogen compound has problems in terms of toxicity, in order to manufacture 3 ketone on an industrial scale it is desirable to avoid using Cyanogen compound.
The autofrettage developing the 3 ketone not using cyanogen compound is key subjects to be solved, so far This is attempted.For example, patent documentation 2 has been recorded a kind of manufacture method of the 3 ketone with phenyl ring, its Benzoyl compound is used as raw material, is manufactured under the conditions of cyanogen compound is non-existent.In the document, it is only limitted to solvent It is defined to the situation of 55 DEG C～57 DEG C of condition using acetonitrile, alkali using sodium carbonate, reaction temperature, yield is than for reaching 82% relatively High yield (embodiment 1).But, do not record the manufacture method of the higher yield more than 82%, and, except embodiment 1 Beyond condition, it is 54% (embodiment 2), the low yield of 45% (embodiment 3).Additionally, for having Oxopyrazine in the literature The 3 ketone of ring is not recorded and is implied.
In addition, having recorded a kind of manufacture method of the 3 ketone with pyridine ring in patent documentation 3, it is by pyridine Carboxylic acid compounds be used as raw material, in the presence of cyanogen compound or in the absence of manufactured.But, with more than 70% yield The embodiment obtaining object only with the addition of the condition of cyanogen compound.Additionally, for having Oxopyrazine ring in the literature 3 ketone also recorded and implied.
Prior art literature
Patent documentation
Patent documentation 1：No. 2009/016841 publication of International Publication (section such as the 0111st, 0116,0117)
Patent documentation 2：Japanese Kohyo 10-512874 publication (claim 1 etc.)
Patent documentation 3：Japanese Unexamined Patent Publication 2-78662 publication (claim 1 etc.)
Content of the invention
Invention problem to be solved
It is an object of the invention to provide a kind of manufacture method of the 3 ketone with Oxopyrazine ring, it is not being deposited Under conditions of having problematic cyanogen compound in terms of toxicity, target compound can be obtained with high yield.
For solving the scheme of problem
In view of the foregoing, the present inventor is repeated to the method manufacturing the 3 ketone with Oxopyrazine ring Further investigation, result is it was unexpectedly observed that can obtain target compound with high yield under conditions of there is not cyanogen compound.Base Complete the present invention in this technological thought.
That is, the present invention solves above-mentioned problem by the invention described in the item of offer following [1] to [11].
[1] a kind of manufacture method of 3 ketone, it is formula (1)：
[changing 1]
In formula, X1Represent oxygen atom or sulphur atom,
X2Represent that (this carbon atom can be by R for carbon atom5Replace) or nitrogen-atoms (this nitrogen-atoms can be with oxygen atom one similar shape Become N- oxide),
R1Represent：Hydrogen atom；C1～C12Alkyl；C2～C6Thiazolinyl；C2～C6Alkynyl；C3～C8Cycloalkyl；C1～C6Alkyl halide Base；C2～C6Haloalkenyl group；C1～C6Alkylthio group C1～C6Alkyl；C1～C6Alkoxy C1～C6Alkyl；C1～C6Alkoxy carbonyl group C1 ～C6Alkyl；C6～C10Aryl C1～C6(aryl of this group can be by 1 or more than 2 identical or different R for alkyl6Taken Generation)；There is the heterocycle C that in oxygen atom, sulphur atom and nitrogen-atoms 1～5 heteroatomic carbon numbers are 2～101 ～C6(1 had in oxygen atom, sulphur atom and nitrogen-atoms～5 heteroatomic carbon numbers of this group are 2 to alkyl ～10 heterocycle can be by 1 or more than 2 identical or different R7Replaced)；C6～C10(this group can be by 1 for aryl Or more than 2 identical or different R6Replaced)；Or there are 1～5 in oxygen atom, sulphur atom and nitrogen-atoms Heteroatomic carbon number is that (this group can be by 1 or more than 2 identical or different R for 2～10 heterocyclic radical7Taken Generation),
R2～R5Can be identical or different, represent hydrogen atom, halogen atom, nitro, C1～C6Alkyl, C1～C6Haloalkyl, C1～C6Alkoxyl, C1～C6Alkylthio group, C1～C6Alkyl sulphinyl, C1～C6Alkyl sulphonyl or C1～C6Alkoxy C1～C6 Alkyl,
R6Represent hydrogen atom, halogen atom, C1～C6Alkyl, C1～C6Haloalkyl, C1～C6Alkoxyl, C1～C6Alkyl halide Epoxide, C1～C6Alkoxy carbonyl group or C1～C6Alkoxy C1～C6Alkyl,
R7Represent hydrogen atom, oxo base, halogen atom, C1～C6Alkyl, C1～C6Haloalkyl, C1～C6Alkoxyl, C1～C6 Halogenated alkoxy, C1～C6Alkoxy carbonyl group or C1～C6Alkoxy C1～C6Alkyl.}
The manufacture method of represented 3 ketone,
This manufacture method is characterised by, including following rearrangement reaction operations：Right under conditions of not comprising cyanogen compound Following formulas (2)：
[changing 2]
In formula, R1～R4、X1And X2As above-mentioned formula (1) defines.}
Represented enol ester compounds carry out the rearrangement reaction using alkali, obtain the triketone represented by above-mentioned formula (1) Compound.
[2] manufacture method of the 3 ketone as described in [1] is it is characterised in that above-mentioned alkali is triethylamine, diisopropyl Ethamine, pyridine, N, accelerine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or its mixture.
[3] 3 ketone as described in [2] manufacture method it is characterised in that above-mentioned alkali be triethylamine, sodium carbonate, Potassium carbonate or its mixture.
[4] manufacture method of the 3 ketone as any one of [1]～[3] is it is characterised in that above-mentioned formula (2) the enol ester compounds represented by are by making following formulas (3)：
[changing 3]
In formula, R1～R4、X1And X2As above-mentioned formula (1) defines,
Y represents halogen atom.}
Represented acid halide compound and following formulas (4)：
[changing 4]
The intermediate manufacturing process of represented cyclohexanedione compound reaction and manufacture.
[5] manufacture method of the 3 ketone as described in [4] is it is characterised in that above-mentioned intermediate manufacturing process and upper State rearrangement reaction operation to carry out in the presence of identical or different alkali.
[6] manufacture method of the 3 ketone as any one of [1]～[5] is it is characterised in that above-mentioned intermediate The reaction of manufacturing process and above-mentioned rearrangement reaction operation is carried out using identical or different solvent.
[7] 3 ketone as described in [6] manufacture method it is characterised in that above-mentioned solvent be chlorobenzene, dichloro-benzenes, Toluene, dimethylbenzene or its mixed solvent.
[8] manufacture method of the 3 ketone as any one of [1]～[7] is it is characterised in that more than 0 DEG C Carry out at a temperature of in less than 80 DEG C of scope.
[9] 3 ketone as described in [8] manufacture method it is characterised in that more than 10 DEG C less than 50 DEG C of model Carry out at a temperature of in enclosing.
[10] manufacture method as any one of [1]～[9], wherein,
In above-mentioned formula (1),
X1For oxygen atom,
X2For carbon atom, (this carbon atom can be by R5Replaced),
R1For phenyl, (this group can be by 1 or more than 2 identical or different R6Replaced),
R2～R5Can be identical or different, it is hydrogen atom, halogen atom, C1～C6Alkyl or C1～C6Alkoxyl,
R6By hydrogen atom, halogen atom, C1～C6Alkyl, C1～C6Represented by alkoxyl.
[11] manufacture method as any one of [1]～[9], wherein,
In above-mentioned formula (1),
X1For oxygen atom,
X2For carbon atom, (this carbon atom can be by R5Replaced),
R1For phenyl, (this group can be by 1 or more than 2 identical or different R6Replaced),
R2～R5Can be identical or different, it is hydrogen atom, halogen atom,
R6By hydrogen atom, C1～C6Represented by alkoxyl.
The effect of invention
In accordance with the invention it is possible to be obtained with high yield under conditions of having problematic cyanogen compound in terms of there is not toxicity There is the 3 ketone of Oxopyrazine ring.
Specific embodiment
Symbol described in this specification and term are illustrated.
Halogen atom refers to fluorine atom, chlorine atom, bromine atoms or atomic iodine.
C1～C3Etc represent that first prime number of subsequently described group is based on the statement of the symbol of element and index number Scope represented by index number.For example, represent in the case of being somebody's turn to do that carbon number is 1～3, C1～C6Statement represent carbon number For 1～6, C1～C12Statement represent that carbon number is 1～12.
C1～C6Alkyl represents the alkyl of the straight or branched that carbon number is 1～6.
As C1～C6Alkyl, for example, can enumerate methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl Base, the tert-butyl group, n-pentyl, 1- methyl butyl, 2- methyl butyl, 3- methyl butyl, 1- ethyl propyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, neopentyl, n-hexyl, 1- methyl amyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 1- second Base butyl, 2- ethyl-butyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 1,3- dimethylbutyl, 2,2- dimethyl butyrate Base, 2,3- dimethylbutyl, 3,3- dimethylbutyl, 1,1,2- thmethylpropyl, 1,2,2- thmethylpropyl, 1- ethyl -1- The groups such as methyl-propyl, 1- Ethyl-2-Methyl propyl group, but it is not limited to these.
As preferred C1～C6Alkyl, for example, can enumerate the alkyl of the straight or branched that carbon number is 1～4, more The alkyl of the straight or branched that carbon number is 1～3 preferably can be enumerated.
As preferred C1～C6Alkyl, specifically, for example, can enumerate methyl, ethyl, n-pro-pyl, isopropyl, positive fourth Base, sec-butyl, isobutyl group, the tert-butyl group, more preferably can enumerate the groups such as methyl, ethyl, n-pro-pyl, isopropyl.
C1～C12Alkyl represents the alkyl of the straight or branched that carbon number is 1～12.
As C1～C12Alkyl, for example, except the above-mentioned C illustrating1～C6Outside the illustration of alkyl, n-heptyl, 1- can be enumerated Methylhexyl, 5- methylhexyl, 1,1- dimethyl amyl group, 2,2- dimethyl amyl group, 4,4- dimethyl amyl group, 1- ethyl pentyl group, 2- ethyl pentyl group, 1,1,3- trimethyl butyl, 1,2,2- trimethyl butyl, 1,3,3- trimethyl butyl, 2,2,3- trimethyl fourth Base, 2,3,3- trimethyl butyl, 1- butyl, 1,1,2,2- tetramethyl propyl group, n-octyl, 1- methylheptyl, 3- methyl heptan Base, 6- methylheptyl, 2- ethylhexyl, 5,5- dimethylhexanyl, 2,4,4- tri-methyl-amyl, 1- ethyl -1- methyl amyl, just Nonyl, 1- Methyl Octyl, 2- Methyl Octyl, 3- Methyl Octyl, 7- Methyl Octyl, 1- ethylheptyl, 1,1- dimethyl heptyl, 6, 6- dimethyl heptyl, positive decyl, 1- Nonyl, 2- Nonyl, 6- Nonyl, 1- ethyloctanyl, 1- propylheptyl, just The groups such as undecyl, dodecyl, but it is not limited to these.
As preferred C1～C12Alkyl, for example, it is possible to enumerate the alkane of the straight or branched that carbon number is 1～10 Base, more preferably can enumerate the alkyl of the straight or branched that carbon number is 1～8, further preferably can enumerate carbon atom The alkyl of the straight or branched for 1～6 for the number.
As preferred C1～C12Alkyl, specifically, for example, can enumerate methyl, ethyl, n-pro-pyl, isopropyl, just Butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, 1- methyl butyl, 1- ethyl propyl, 1,1- dimethyl propyl, neopentyl, N-hexyl, 1- methyl amyl, 1- ethyl-butyl, 1,1- dimethylbutyl, n-heptyl, 1- methylhexyl, 1,1- dimethyl amyl group, 4,4- dimethyl amyl group, 1- ethyl pentyl group, 1- butyl, n-octyl, 1- methylheptyl, 5,5- dimethylhexanyl, n-nonyl, 1- Methyl Octyl, 1- ethylheptyl, 1,1- dimethyl heptyl, 6,6- dimethyl heptyl, positive decyl, 1- Nonyl, 1- ethyl Octyl group, 1- propylheptyl, more preferably can enumerate methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, uncle Butyl, n-pentyl, 1- methyl butyl, 1- ethyl propyl, 1,1- dimethyl propyl, neopentyl, n-hexyl, 1- methyl amyl, 1- Ethyl-butyl, 1,1- dimethylbutyl, n-heptyl, 1- methylhexyl, 1,1- dimethyl amyl group, 4,4- dimethyl amyl group, 1- second Base amyl group, 1- butyl, n-octyl, 1- methylheptyl, 5,5- dimethylhexanyl, further preferably can enumerate methyl, second Base, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, 1- methyl butyl, 1- ethyl propyl, 1, The groups such as 1- dimethyl propyl, neopentyl, n-hexyl, 1- methyl amyl, 1- ethyl-butyl, 1,1- dimethylbutyl.
C2～C6Thiazolinyl represents the thiazolinyl of the straight or branched that carbon number is 2～6.
As C2～C6Thiazolinyl, for example, it is possible to enumerate vinyl, 1- acrylic, isopropenyl, 2- acrylic, 1-butylene Base, 1- methyl-1-propylene base, crotyl, 1- methyl -2- acrylic, 3- cyclobutenyl, 2- methyl-1-propylene base, 2- methyl - 2- acrylic, 1,3- butadienyl, 1- pentenyl, 1- ethyl -2- acrylic, pentenyl, 1- methyl isophthalic acid-cyclobutenyl, 3- penta Thiazolinyl, 1- methyl-2-butene base, 4- pentenyl, 1- methyl -3- cyclobutenyl, 3-methyl-1-butene base, 1,2- dimethyl -2- third Thiazolinyl, 1,1- dimethyl -2- acrylic, 2- methyl-2-butene base, 3- methyl-2-butene base, 1,2- dimethyl -1- acrylic, 2- methyl -3- cyclobutenyl, 3- methyl -3- cyclobutenyl, 1,3- pentadienyl, 1- vinyl -2- acrylic, 1- hexenyl, 1- third Base -2- acrylic, 2- hexenyl, 1- methyl-1-pentene thiazolinyl, 1- ethyl-crotyl, 3- hexenyl, 4- hexenyl, 5- hexene Base, 1- methyl -4- pentenyl, 1- ethyl -3- cyclobutenyl, 4-methyl-1-pentene -2- base, 1- ethyl -1- methyl -2- acrylic, 1- Ethyl-2-Methyl -2- acrylic, 4-methyl-1-pentene -3- base, 2- methyl-pentenyl, 3- methyl-3-pentenyl, 4- Methyl-3-pentenyl, 1,3- dimethyl-crotyl, 1,1- dimethyl -3- cyclobutenyl, 3- methyl -4- pentenyl, 4- methyl - 4- pentenyl, 1,2- dimethyl -3- cyclobutenyl, 1,3- dimethyl -3- cyclobutenyl, 1,1,2- trimethyl -2- acrylic, 1,5- are own The groups such as dialkylene, 1- vinyl -3- cyclobutenyl, 2,4- hexadienyl, but it is not limited to these.
As preferred C2～C6Thiazolinyl, for example, it is possible to enumerate the thiazolinyl of the straight or branched that carbon number is 2～4.
As preferred C2～C6Thiazolinyl, specifically, for example, can enumerate vinyl, 1- acrylic, isopropenyl, 2- Acrylic, 1-butylene base, 1- methyl-1-propylene base, crotyl, 1- methyl -2- acrylic, 3- cyclobutenyl, 2- methyl isophthalic acid-the third The groups such as thiazolinyl, 2- methyl -2- acrylic, 1,3- butadienyl.
C2～C6Alkynyl represents the alkynyl of the straight or branched that carbon number is 2～6.
As C2～C6Alkynyl, for example, can enumerate acetenyl, 1- propinyl, 2-propynyl, ethyl acetylene base, 1- methyl -2- Propinyl, 2-butyne base, 3- butynyl, 1- pentynyl, 1- ethyl -2-propynyl, valerylene base, 3- pentynyl, 1- methyl -2- Butynyl, 4- pentynyl, 1- methyl -3- butynyl, 2- methyl -3- butynyl, 1- hexin base, 1- (n-pro-pyl) -2-propynyl, 2- hexin base, 1- ethyl -2-butyne base, 3- hexin base, 1- methyl-valerylene base, 1- methyl -3- pentynyl, 4- methyl-1-pentene Alkynyl, 3- methyl-1-pentene alkynyl, 5- hexin base, 1- ethyl -3- butynyl, 1- ethyl -1- methyl -2-propynyl, 4- methyl - The groups such as 1- pentyne -3- base, 1,1- dimethyl -2-butyne base, 2,2- dimethyl -3- butynyl, but it is not limited to these.
As preferred C2～C6Alkynyl, for example, it is possible to enumerate the alkynyl of the straight or branched that carbon number is 2～4.
As preferred C2～C6Alkynyl, specifically, for example, can enumerate acetenyl, 1- propinyl, 2-propynyl, 1- The groups such as butynyl, 1- methyl -2-propynyl, 2-butyne base, 3- butynyl.
C3～C8Cycloalkanes basis representation carbon number is 3～8 cycloalkyl.
As C3～C8Cycloalkyl, for example, can enumerate cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl Deng group, but it is not limited to these.
As preferred C3～C8Cycloalkyl, for example, can enumerate the cycloalkyl that carbon number is 3～6.
As preferred C3～C8Cycloalkyl, specifically, for example, can enumerate cyclopropyl, cyclobutyl, cyclopenta, hexamethylene The groups such as base.
C1～C6Haloalkyl represents that the carbon number being replaced by identical or different 1～13 halogen atoms is 1～6 Straight or branched alkyl.
As C1～C6Haloalkyl, for example can enumerate methyl fluoride, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, Trifluoromethyl, trichloromethyl, chlorodifluoramethyl-, bromine difluoro methyl, 2- fluoro ethyl, 1- chloroethyl, 2- chloroethyl, 1- bromoethyl, 2- bromoethyl, 2,2- bis- fluoro ethyl, 1,2- Dichloroethyl, 2,2- Dichloroethyl, 2,2,2- trifluoroethyl, 2,2,2- tri- chloroethene Base, 1,1,2,2- tetra- fluoro ethyl, pentafluoroethyl group, 2- bromo- 2- chloroethyl, the chloro- 1,1,2,2- of 2- tetra- fluoro ethyl, 1- chloro- 1,2,2, 2- tetra- fluoro ethyl, 1- chloropropyl, 2- chloropropyl, 3- chloropropyl, 2- bromopropyl, 3- bromopropyl, 2- bromo- 1- Methylethyl, 3- iodine Propyl group, 2,3- bis- chloropropyl, 2,3- dibromopropyl, 3,3,3- trifluoro propyl, 3,3,3- tri- chloropropyl, 3- bromo- 3,3- difluoro third Base, the chloro- 3- fluoropropyl of 3,3- bis-, 2,2,3,3- tetra- fluoropropyl, 1- bromo- 3,3,3- trifluoro propyl, 2,2,3,3,3- five fluoropropyl, The fluoro- 1- trifluoromethyl ethyl of 2,2,2- tri-, heptafluoropropyl, the fluoro- 1- trifluoromethyl ethyl of 1,2,2,2- tetra-, 2,3- bis- chloro- 1,1, 2,3,3- five fluoropropyl, 2- chlorobutyl, 3- chlorobutyl, 4- chlorobutyl, 2- chloro- 1- methyl-propyl, 4- brombutyl, 3- bromo- 2- first Base propyl group, 2- bromo- 1- methyl-propyl, the chloro- 1- methyl-propyl of 2,2- bis-, 2- chloro- 1- chloromethyl propyl group, 4,4,4- triRuorobutyl, The fluoro- 1- methyl-propyl of 3,3,3- tri-, the fluoro- 2- methyl-propyl of 3,3,3- tri-, 2,3,4- tri- chlorobutyl, the chloro- 1,1- bis- of 2,2,2- tri- Methylethyl, 4- chloro- 4,4- difluorobutyl groups, the chloro- 4- fluorine butyl of 4,4- bis-, 4- bromo- 4,4- difluorobutyl groups, the bromo- 4,4- of 2,4- bis- Difluorobutyl groups, the chloro- 3,4,4- triRuorobutyl of 3,4- bis-, the chloro- 4,4,4- triRuorobutyl of 3,3- bis-, 4- bromo- 3,3,4,4- tetrafluoro fourth The bromo- 3- of base, 4- chloro- 3,4,4- triRuorobutyl, 2,2,3,3,4,4- hexafluoro butyl, 2,2,3,4,4,4- hexafluoro butyl, 2,2,2- Three fluoro- 1- methyl isophthalic acid-trifluoromethyl ethyls, the fluoro- 2- trifluoromethylpropyl of 3,3,3- tri-, 2,2,3,3,4,4,4- seven fluorine butyl, The fluoro- 2- trifluoromethylpropyl of 2,3,3,3- tetra-, 1,1,2,2,3,3,4,4- octafluoro butyl, 1,1,2,2,3,3,4,4,4- nine fluorine fourth Base, 4- chloro- 1,1,2,2,3,3,4,4- octafluoro butyl, 5- fluorine amyl group, 5- chlorine amyl group, 5,5- bis- fluorine amyl group, 5,5- dichloro amyl group, The groups such as 5,5,5- tri- fluorine amyl groups, 6,6,6- trifluoro hexyls, 5,5,6,6,6- five fluorine hexyls, but it is not limited to these.
As preferred C1～C6Haloalkyl, for example, it is possible to enumerate be taken by identical or different 1～7 halogen atoms The carbon number in generation is the alkyl of 1～3 straight or branched.
As preferred C1～C6Haloalkyl, specifically, for example can enumerate methyl fluoride, chloromethyl, bromomethyl, two Methyl fluoride, dichloromethyl, trifluoromethyl, trichloromethyl, chlorodifluoramethyl-, bromine difluoro methyl, 2- fluoro ethyl, 1- chloroethyl, 2- Chloroethyl, 1- bromoethyl, 2- bromoethyl, 2,2- bis- fluoro ethyl, 1,2- Dichloroethyl, 2,2- Dichloroethyl, 2,2,2- trifluoro second Base, 2,2,2- trichloroethyl, 1,1,2,2- tetra- fluoro ethyl, pentafluoroethyl group, 2- bromo- 2- chloroethyl, 2- chloro- 1,1,2,2- tetrafluoro second The chloro- 1,2,2,2- of base, 1- tetra- fluoro ethyl, 1- chloropropyl, 2- chloropropyl, 3- chloropropyl, 2- bromopropyl, 3- bromopropyl, the bromo- 1- of 2- Methylethyl, 3- iodine propyl group, 2,3- bis- chloropropyl, 2,3- dibromopropyl, 3,3,3- trifluoro propyl, 3,3,3- tri- chloropropyl, 3- Bromo- 3,3- bis- fluoropropyl, the chloro- 3- fluoropropyl of 3,3- bis-, 2,2,3,3- tetra- fluoropropyl, 1- bromo- 3,3,3- trifluoro propyl, 2,2,3, 3,3- five fluoropropyl, the fluoro- 1- trifluoromethyl ethyl of 2,2,2- tri-, heptafluoropropyl, the fluoro- 1- trifluoromethyl ethyl of 1,2,2,2- tetra-, The groups such as chloro- 1,1,2,3,3- five fluoropropyl of 2,3- bis-.
C2～C6Haloalkenyl group represents that the carbon number being replaced by identical or different 1～11 halogen atoms is 1～6 Straight or branched thiazolinyl.
As C2～C6Haloalkenyl group, for example, it is possible to it is chloro- to enumerate 2- chlorovinyl, 2- bromo vinyl, 2- iodoethylene base, 3- 2- acrylic, 3- bromo- 2- acrylic, 1- chloromethyl vinyl base, 2- bromo- 1- methyl ethylene, 1- trifluoromethyl vinyl, 3,3, 3- trichloro-1-propene base, the fluoro- 1- acrylic of the bromo- 3,3- of 3- bis-, the chloro- 1- acrylic of 2,3,3,3- tetra-, 1- trifluoromethyl -2,2- Difluoroethylene base, 2- chloro-2-propene base, the fluoro- 2- acrylic of 3,3- bis-, the chloro- 2- acrylic of 2,3,3- tri-, the bromo- 3- of 4- chloro- 3,4, The fluoro- 1-butylene base of 4- tri-, 1- bromomethyl -2- acrylic, the chloro- crotyl of 3-, the fluoro- crotyl of 4,4,4- tri-, the bromo- 4,4- of 4- Difluoro-2-butene base, 3- bromo- 3- cyclobutenyl, the fluoro- 3- cyclobutenyl of 3,4,4- tri-, the bromo- 3- cyclobutenyl of 3,4,4- tri-, 3- bromo- 2- first Base -2- acrylic, the fluoro- 2- methyl -2- acrylic of 3,3- bis-, the fluoro- 2- methylpropenyl of 3,3,3- tri-, 3- chloro- 4,4,4- tri- are fluoro- Crotyl, the fluoro- 1- methyl-1-propylene base of 3,3,3- tri-, the fluoro- 1,3- butadienyl of 3,4,4- tri-, the bromo- 1- amylene of 3,4- bis- Base, the fluoro- 3- methyl -3- cyclobutenyl of 4,4- bis-, the fluoro- 1- pentenyl of 3,3,4,4,5,5,5- seven, the fluoro- 4- pentenyl of 5,5- bis-, 4, The fluoro- 4- pentenyl of 5,5- tri-, the fluoro- 3- Trifluoromethyl-1-cyclobutenyl of 3,4,4,4- tetra-, the fluoro- 3- methyl-2-butene of 4,4,4- tri- Base, the fluoro- 2,4- pentadienyl of 3,5,5- tri-, the fluoro- 2- hexenyl of 4,4,5,5,6,6,6- seven, 3,4,4,5,5,5- hexafluoro -4- three Methyl fluoride -1- pentenyl, the fluoro- 4- trifluoromethyl-pentenyl of 4,5,5,5- tetra- or the fluoro- 4- trifluoromethyl of the bromo- 4,5,5- of 5- tri- - The groups such as pentenyl, but it is not limited to these.
As preferred C2～C6Haloalkenyl group, for example, it is possible to enumerate be taken by identical or different 1～5 halogen atoms The carbon number in generation is the thiazolinyl of 1～3 straight or branched.
As preferred C2～C6Haloalkenyl group, specifically, for example, can enumerate 2- chlorovinyl, 2- bromo vinyl, 2- Iodoethylene base, 3- chloro-2-propene base, 3- bromo- 2- acrylic, 1- chloromethyl vinyl base, 2- bromo- 1- methyl ethylene, 1- trifluoro Methyl ethylene, 3,3,3- trichloro-1-propene base, the fluoro- 1- acrylic of the bromo- 3,3- of 3- bis-, the chloro- 1- acrylic of 2,3,3,3- tetra-, 1- trifluoromethyl -2,2- difluoroethylene base, 2- chloro-2-propene base, the fluoro- 2- acrylic of 3,3- bis-, the chloro- 2- acrylic of 2,3,3- tri- Deng group.
C1～C6Alcoxyl basis representation carbon number is the alkoxyl of 1～6 straight or branched.
As C1～C6Alkoxyl, for example, it is possible to enumerate methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, uncle The groups such as butoxy, amoxy, hexyloxy, but it is not limited to these.
As preferred C1～C6Alkoxyl, for example, it is possible to enumerate the alcoxyl of the straight or branched that carbon number is 1～3 Base.
As preferred C1～C6Alkoxyl, specifically, for example, can enumerate methoxyl group, ethyoxyl, propoxyl group, isopropyl The groups such as epoxide.
C1～C6Alkylthio group represents (alkyl)-S- base that the carbon number that moieties are above-mentioned implication is 1～6.
As C1～C6Alkylthio group, for example, can enumerate methyl mercapto, ethylmercapto group, positive rosickyite base, isopropyisulfanyl, butylthio, uncle The groups such as butylthio, penta sulfenyl, own sulfenyl, but it is not limited to these.
As preferred C1～C6Alkylthio group, for example, it is possible to enumerate the alkane sulfur of the straight or branched that carbon number is 1～3 Base.
As preferred C1～C6Alkylthio group, specifically, for example, can enumerate methyl mercapto, ethylmercapto group, positive rosickyite base, different The groups such as rosickyite base.
C1～C6Alkyl sulfenyl basis representation moieties be above-mentioned implication carbon number be 1～6 (alkyl)-SO- Base.
As C1～C6Alkyl sulphinyl, for example, it is possible to enumerate methylsulfinyl, ethylsulfinyl, n-pro-pyl Asia Sulfonyl, isopropylsulphinyl, butylsulfinyl, terf-butylsulfinyl, pentylsulfinyl, hexylsulfinyl etc. Group, but it is not limited to these.
As preferred C1～C6Alkyl sulphinyl, for example, it is possible to enumerate the straight or branched that carbon number is 1～3 Alkyl sulphinyl.
As preferred C1～C6Alkyl sulphinyl, specifically, for example, can enumerate methylsulfinyl, ethyl Asia The groups such as sulfonyl, n-pro-pyl sulfinyl, isopropylsulphinyl.
C1～C6Alkyl sulfonyl basis representation moieties be above-mentioned implication carbon number be 1～6 (alkyl)-SO2- base.
As C1～C6Alkyl sulphonyl, for example, it is possible to enumerate methyl sulphonyl, ethylsulfonyl, n-pro-pyl sulfonyl, The groups such as isopropelsulfonyl, butyl sulfonyl, tert. butylsulfonyl, pentylsulfonyl, hexyl sulfonyl, but it is not limited to this A bit.
As preferred C1～C6Alkyl sulphonyl, for example, it is possible to enumerate the straight or branched that carbon number is 1～3 Alkyl sulphonyl.
As preferred C1～C6Alkyl sulphonyl, specifically, for example can enumerate methyl sulphonyl, ethylsulfonyl, The groups such as n-pro-pyl sulfonyl, isopropelsulfonyl.
C1～C6Haloalkoxy basis representation haloalkyl moiety have above-mentioned implication, by identical or different 1～13 The carbon number that halogen atom is replaced is (alkyl)-O- base of 1～6 straight or branched.
As C1～C6Halogenated alkoxy, for example, it is possible to enumerate chloromethane epoxide, difluoro-methoxy, chlorine difluoro-methoxy, three Fluorine methoxyl group, 2,2,2- trifluoro ethoxy, 3,3,3- trifluoro propoxyl group, seven fluoro- 2- propoxyl group, 4,4,4- trifluoro butoxy, 5, The groups such as 5,5- trifluoro amoxys, 6,6,6- trifluoro hexyloxy, but it is not limited to these.
As preferred C1～C6Halogenated alkoxy, for example, it is possible to enumerate the straight or branched that carbon number is 1～3 Halogenated alkoxy.
As preferred C1～C6Halogenated alkoxy, specifically, for example, can enumerate chloromethane epoxide, difluoro-methoxy, chlorine The groups such as difluoro-methoxy, trifluoromethoxy, 2,2,2- trifluoro ethoxy, 3,3,3- trifluoro propoxyl group, seven fluoro- 2- propoxyl group.
C1～C6Alkoxy C1～C6Alkyl represents moieties and alkoxy portion have above-mentioned implication, by carbon atom The carbon number that the alkoxyl by 1～6 for the number is replaced is 1～6 alkyl.
As C1～C6Alkoxy C1～C6Alkyl, for example, it is possible to enumerate methoxy, ethoxyl methyl, propoxyl group first Base, i-propoxymethyl, butoxymethyl, t-butoxymethyl, amoxy methyl, hexoxymethyl, methoxy ethyl, methoxy The groups such as base propyl group, methoxybutyl, methoxypentyl, methoxyethyl, but it is not limited to these.
As preferred C1～C6Alkoxy C1～C6Alkyl, for example, it is possible to enumerate by carbon number be 1～3 straight chain or The carbon number that the alkoxyl of branched is replaced is the alkyl of 1～3 straight or branched.
As preferred C1～C6Alkoxy C1～C6Alkyl, specifically, for example, can enumerate methoxy, ethoxy The groups such as ylmethyl, propoxy methyl, i-propoxymethyl, methoxy ethyl, methoxy-propyl.
C1～C6Alkylthio group C1～C6Alkyl represents that moieties and the moieties of alkylthio group have above-mentioned implication, quilt The carbon number that the alkylthio group by 1～6 for the carbon number is replaced is 1～6 alkyl.
As C1～C6Alkylthio group C1～C6Alkyl, for example, it is possible to enumerate methylthiomethyl, Ethylsulfanylmethyl, rosickyite Ji Jia Base, isopropylthiomethyl, Butylthiomethyl, tertiary butylthio methyl, penta sulfenyl methyl, own butylthiomethyl, methylmercaptoethyl, first sulfur The groups such as base propyl group, methylthiobutyl, methyl mercapto amyl group, methyl mercapto hexyl, but it is not limited to these.
As preferred C1～C6Alkylthio group C1～C6Alkyl, for example, it is possible to enumerate by carbon number be 1～3 straight chain or The carbon number that the alkylthio group of branched is replaced is the alkyl of 1～3 straight or branched.
As preferred C1～C6Alkylthio group C1～C6Alkyl, specifically, for example, can enumerate methylthiomethyl, second sulfur The groups such as ylmethyl, propylsulfanylmethyl, isopropylthiomethyl, methylmercaptoethyl, methylthio.
C1～C6Alkoxy carbonyl group represents (alkoxyl)-C that the carbon number that alkoxy portion has above-mentioned implication is 1～6 (=O)-base.
As C1～C6Alkoxy carbonyl group, for example, it is possible to enumerate methoxycarbonyl, ethoxy carbonyl, positive propoxy carbonyl, different The groups such as propoxycarbonyl, butoxy carbonyl, tert-butoxycarbonyl, pentyloxy carbonyl, hexyloxy carbonyl, but it is not limited to this A bit.
As preferred C1～C6Alkoxy carbonyl group, for example, it is possible to enumerate the alkane of the straight or branched that carbon number is 1～3 Oxygen carbonyl.
As preferred C1～C6Alkoxy carbonyl group, specifically, for example, can enumerate methoxycarbonyl, ethoxy carbonyl, just The groups such as propoxycarbonyl, isopropoxy carbonyl.
C1～C6Alkoxy carbonyl group C1～C6Alkyl represents alkoxy portion and moieties have above-mentioned implication, former by carbon The carbon number that the alkoxy carbonyl group by 1～6 for the subnumber is replaced is 1～6 alkyl.
As C1～C6Alkoxy carbonyl group C1～C6Alkyl, for example, it is possible to enumerate 2- methoxyl group -2- oxoethyl, 2- ethoxy Base -2- oxoethyl, 2- propoxyl group -2- oxoethyl, 2- isopropoxy -2- oxoethyl, 2- butoxy -2- oxoethyl, 2- tert-butoxy -2- oxoethyl, 2- amoxy -2- oxoethyl, 2- hexyloxy -2- oxoethyl, 3- methoxyl group -3- oxo The groups such as propyl group, 4- methoxyl group -4- oxo butyl, 5- methoxyl group -5- oxopentyl, 6- methoxyl group -6- oxo-hexyl, but do not limit Due to these.
As preferred C1～C6Alkoxy carbonyl group C1～C6Alkyl, for example, it is possible to enumerate the straight chain being 1～3 by carbon number Or the alkyl of the straight or branched that the carbon number that replaced of the alkoxy carbonyl group of branched is 1～3.
As preferred C1～C6Alkoxy carbonyl group C1～C6Alkyl, specifically, for example, can enumerate 2- methoxyl group -2- oxygen For ethyl, 2- ethyoxyl -2- oxoethyl, 2- propoxyl group -2- oxoethyl, 2- isopropoxy -2- oxoethyl, 3- methoxy The groups such as base -3- oxopropyl, 4- methoxyl group -4- oxo butyl.
As C6～C10Aryl, for example, can enumerate the groups such as phenyl or naphthyl.
C6～C10Aryl C1～C6Alkyl represents aryl moiety and moieties have above-mentioned implication, be 6 by carbon number The carbon number that～10 aryl is replaced is 1～6 alkyl.
As C6～C10Aryl C1～C6Alkyl, for example, it is possible to enumerate benzyl, phenethyl, 1- phenylethyl, 3- phenyl third Base, 4- phenyl butyl, 5- phenylpentyl, 6- Phenylhexyl, naphthalene -1- ylmethyl, naphthalene -2- ylmethyl, 1- (naphthalene -1- base) ethyl, 2- (naphthalene -1- base) ethyl, 1- (naphthalene -2- base) ethyl, 2- (naphthalene -2- base) ethyl, 3- (naphthalene -1- base) propyl group, 3- (naphthalene -2- base) third Base, 4- (naphthalene -1- base) butyl, 4- (naphthalene -2- base) butyl, 5- (naphthalene -1- base) amyl group, 5- (naphthalene -2- base) amyl group, 6- (naphthalene -1- Base) group such as hexyl, 6- (naphthalene -2- base) hexyl, but it is not limited to these.
As preferred C6～C10Aryl C1～C6Alkyl, for example, it is possible to enumerate the aryl institute being 6～10 by carbon number The carbon number replacing is the alkyl of 1～3 straight or branched.
As preferred C6～C10Aryl C1～C6Alkyl, specifically, for example, can enumerate benzyl, phenethyl, 1- phenyl The groups such as ethyl, 3- phenyl propyl.
Have in oxygen atom, sulphur atom and nitrogen-atoms 1～5 heteroatomic carbon numbers be 2～10 miscellaneous Ring group represents 1～5 heteroatomic binary～ten yuan having selected from the group of oxygen atom, sulphur atom and nitrogen-atoms composition Monocyclic, polycycle or condensed ring formula the univalent perssad that constituted of heterocycle.
It is 2～10 as 1 having in oxygen atom, sulphur atom and nitrogen-atoms～5 heteroatomic carbon numbers Heterocyclic radical, for example, it is possible to enumerate oxirane, oxolane, pyrrolidine, Tetramethylene sulfide, Tetramethylene sulfide dioxide, tetrahydrochysene Thiapyran, tetrahydric thiapyran dioxide, 4,5- dihydro isoxazole, piperidines, piperazine, morpholine, furan, thiophene, pyrroles, pyrazoles, imidazoles, Azoles, isoxazole, thiazole, isothiazole, 1,3,4- diazole, 1,3,4- thiadiazoles, 1,3,4- triazole, 1,2,4- diazole, 1, 2,4- thiadiazoles, 1,2,4- triazole, 1,2,3- diazole, 1,2,3- thiadiazoles, 1,2,3- triazole, tetrazolium, pyridine, pyrimidine, pyrrole Piperazine, pyridazine, 1,3,5- triazine, 1,2,4- triazine, benzothiophene, benzofuran, indole, benzothiazole, benzothiazole, benzo miaow Azoles, benzo isoxazole, benzisothiazole, indazole, 1,3- benzodioxole, phendioxin, 4- dioxane, 2,3- dihydrobenzo furan The group such as mutter, but be not limited to these.
As 1 preferably having in oxygen atom, sulphur atom and nitrogen-atoms～5 heteroatomic carbon numbers it is 2～10 heterocyclic radical, for example, it is possible to enumerate have selected from 1～3 in the group of oxygen atom, sulphur atom and nitrogen-atoms composition The univalent perssad that the heterocycle of individual heteroatomic five yuan～seven yuan of monocyclic, polycycle or condensed ring formula is constituted.
As 1 preferably having in oxygen atom, sulphur atom and nitrogen-atoms～5 heteroatomic carbon numbers it is 2～10 heterocyclic radical, specifically, for example, can enumerate oxolane, pyrrolidine, 4,5- dihydro isoxazole, thiophene, different The groups such as azoles, pyridine, pyrimidine, pyrazine, pyridazine, 1,3,5- triazine, 1,2,4- triazine.
Have in oxygen atom, sulphur atom and nitrogen-atoms 1～5 heteroatomic carbon numbers be 2～10 miscellaneous Ring C1～C6Alkyl represents：Being had 1～5 heteroatomic carbon numbers in oxygen atom, sulphur atom and nitrogen-atoms is 2～10 heterocycle and C1～C6The carbon number that alkyl has that the heterocycle of above-mentioned implication replaced is 1～6 alkyl.
It is 2～10 as 1 having in oxygen atom, sulphur atom and nitrogen-atoms～5 heteroatomic carbon numbers Heterocycle C1～C6Alkyl, for example, it is possible to enumerate (oxolane -2- base) methyl, (4,5- dihydro isoxazole -5- base) methyl, The groups such as (isoxazole -5- base) methyl, (thiophene -2- base) methyl, but it is not limited to these.
As cyanogen compound, for example, can enumerate the cyaniding alkali metal class such as Cyanogran., potassium cyanide；.alpha.-hydroxyisobutyronitrile., Blausure (German), Maintain polymer of Blausure (German) etc..
Below, describe the present invention in detail.
1. the manufacture method of 3 ketone
In the present invention, the 3 ketone (hereinafter referred to as " 3 ketone ") with Oxopyrazine ring of manufacture is Compound represented by formula (1).
[changing 5]
In formula, X1Represent oxygen atom or sulphur atom,
X2Represent that (this carbon atom can be by R for carbon atom5Replace) or nitrogen-atoms (this nitrogen-atoms can be with oxygen atom one similar shape Become N- oxide),
R1Represent：Hydrogen atom；C1～C12Alkyl；C2～C6Thiazolinyl；C2～C6Alkynyl；C3～C8Cycloalkyl；C1～C6Alkyl halide Base；C2～C6Haloalkenyl group；C1～C6Alkylthio group C1～C6Alkyl；C1～C6Alkoxy C1～C6Alkyl；C1～C6Alkoxy carbonyl group C1 ～C6Alkyl；C6～C10Aryl C1～C6(aryl of this group can be by 1 or more than 2 identical or different R for alkyl6Taken Generation)；There is the heterocycle C that in oxygen atom, sulphur atom and nitrogen-atoms 1～5 heteroatomic carbon numbers are 2～101 ～C6(1 had in oxygen atom, sulphur atom and nitrogen-atoms～5 heteroatomic carbon numbers of this group are 2 to alkyl ～10 heterocycle can be by 1 or more than 2 identical or different R7Replaced)；C6～C10(this group can be by 1 for aryl Or more than 2 identical or different R6Replaced)；Or there are 1～5 in oxygen atom, sulphur atom and nitrogen-atoms Heteroatomic carbon number is that (this group can be by 1 or more than 2 identical or different R for 2～10 heterocyclic radical7Taken Generation),
R2～R5Can be identical or different, represent hydrogen atom, halogen atom, nitro, C1～C6Alkyl, C1～C6Haloalkyl, C1～C6Alkoxyl, C1～C6Alkylthio group, C1～C6Alkyl sulphinyl, C1～C6Alkyl sulphonyl or C1～C6Alkoxy C1～C6 Alkyl,
R6Represent hydrogen atom, halogen atom, C1～C6Alkyl, C1～C6Haloalkyl, C1～C6Alkoxyl, C1～C6Alkyl halide Epoxide, C1～C6Alkoxy carbonyl group or C1～C6Alkoxy C1～C6Alkyl,
R7Represent hydrogen atom, epoxide, halogen atom, C1～C6Alkyl, C1～C6Haloalkyl, C1～C6Alkoxyl, C1～C6Halogen For alkoxyl, C1～C6Alkoxy carbonyl group or C1～C6Alkoxy C1～C6Alkyl.}
It is a feature of the present invention that including following rearrangement reaction operations (ii)：Right under conditions of not comprising cyanogen compound Enol ester compounds represented by following formulas (2) carry out the rearrangement reaction using alkali, obtain three represented by above-mentioned formula (1) Assimilation compound.
[changing 6]
In formula, R1～R4、X1And X2As above-mentioned formula (1) defines.}
The intermediate that the present invention preferably further includes manufacturing the enol ester compounds represented by above-mentioned formula (2) manufactures work Sequence (i).That is, after preferably manufacturing enol ester compounds in intermediate manufacturing process (i), in above-mentioned rearrangement reaction operation (ii) The middle 3 ketone manufacturing formula (1).Hereinafter, each operation is described in detail.
2. intermediate manufacturing process (i)
Intermediate manufacturing process (i) is the operation of the enol ester compounds manufacturing above-mentioned formula (2).The enol of formula (2) Ester compounds can be manufactured using known method.As such method, (i-1) specifically can be enumerated with acid halide Compound is the reaction of raw material；(i-2) reaction with carboxylic acid compound as raw material.Hereinafter, illustrate respectively.
(i-1) reaction with acid halide compound as raw material
Reaction with acid halide compound as raw material refers to make acid halide compound be esterified and make in the presence of base The method making the enol ester compounds of formula (2).Specifically, for making following formulas (3)：
[changing 7]
In formula, R1～R4、X1、X2For example above-mentioned formula (1) is defined with Y.}
Represented acid halide compound and following formulas (4)：
[changing 8]
The method of represented cyclohexanedione compound reaction.
(starting compound)
It is acid halide compound and formula (4) institute table represented by formula (3) as the compound that starting compound uses The cyclohexanedione compound showing.The acid halide compound of formula (3) can be manufactured by the method described in patent documentation 1. It should be noted that in the following description, for example sometimes " compound represented by formula (1) " is referred to as " formula (1) ". Also identical with regard to other formulas.
As long as reaction is carried out, then the consumption of formula (4) can be measured for arbitrary, and those skilled in the art can suitably adjust. From yield, the suppression aspect such as by-product and business efficiency, the consumption of formula (4) is 0.5 for example with respect to 1 mole of formula (3) Mole～10.0 moles in the range of, in the range of preferably 0.9 mole～1.5 moles, more preferably 1.0 moles～1.2 rub In the range of you.
(alkali)
Formula (2) can be reacted and be obtained by making above-mentioned formula (3) and formula (4) in the presence of base.Middle system Make alkali used in operation (i-1) can use and the different alkali of alkali used in rearrangement reaction operation (ii) described later, also may be used With using identical alkali.That is, used in intermediate manufacturing process (i-1), alkali can with alkali used in rearrangement reaction operation (ii) With identical can also be different.As long as in addition, the consumption that reaction carries out alkali used in then intermediate manufacturing process (i) can be for appointing The amount of meaning, those skilled in the art can suitably adjust.From yield, the suppression aspect such as by-product and business efficiency, alkali Consumption for example suitably selects from the scope of 1 equivalent～5 equivalent with respect to formula (3), preferably 1 equivalent～2 equivalent, more preferably For 1.0 equivalent～1.5 equivalents.
(solvent)
The reaction of intermediate manufacturing process (i-1) preferably uses solvent and carries out.Make as in intermediate manufacturing process (i-1) Solvent, it is possible to use from the different solvent of solvent used in rearrangement reaction operation (ii) described later, it is possible to use phase Same solvent.That is, used in intermediate manufacturing process (i-1), solvent is permissible with solvent used in rearrangement reaction operation (ii) Identical can also be different.In addition, as long as reaction is carried out, used in intermediate manufacturing process (i-1), the consumption of solvent can be Arbitrary amount, for example, with respect to 1 mole of formula (3), be 0.01L～50L (liter), be preferably 0.1L～10L, more preferably 0.1L～5L.
(reaction temperature)
Reaction temperature is usually in less than more than 0 DEG C 80 DEG C of scope, in the range of preferably 5 DEG C～50 DEG C, more preferably In the range of 10 DEG C～35 DEG C.
(response time)
Response time is different according to reaction temperature, reaction substrate, response magnitude etc., usually 10 minutes～48 hours.
(i-2) reaction with carboxylic acid compound as raw material
Then, the intermediate manufacturing process (i-2) with carboxylic acid compound as raw material is illustrated.This reaction is in dehydration The method making carboxylic acid compound carry out dehydrating condensation in the presence of condensing agent and manufacturing the enol ester compounds of formula (2).Specifically Ground is said, is to make following formulas (5)：
[changing 9]
In formula, R1～R4、X1、X2As formula (1) defines }
The method that represented carboxylic acid compound and formula (4) are reacted.
(starting compound)
It is represented by carboxylic acid compound and formula (4) represented by formula (5) as the compound that starting compound uses Cyclohexanedione compound.
(dehydrating condensation agent)
As dehydrating condensation agent, it is possible to use dicyclohexyl carbodiimide (DCC), N- (3- dimethylamino-propyl)-N '- Ethylcarbodiimine (EDC or WSC), N, N '-carbonyl dimidazoles, 2- chloro- 1,3- dimethylimidazolinium chloride, iodate -2- Chloro- 1- pyridine etc..
(other composition)
This reaction can be carried out in the presence of base it is also possible to carry out under the conditions of alkali is non-existent.As used The species of alkali and consumption, can be the condition same with above-mentioned " (i-1) reaction with acid halide compound as raw material ".Need Illustrate, used in intermediate manufacturing process (i-2), alkali can be identical with alkali used in rearrangement reaction operation (ii) Can be different.As long as in addition, the consumption that reaction carries out alkali used in then intermediate manufacturing process (i-2) can be arbitrary Amount, those skilled in the art can suitably adjust.From yield, the suppression aspect such as by-product and business efficiency, for example, relative Suitably select from the scope of 1 equivalent～5 equivalent in formula (3), preferably 1 equivalent～2 equivalent, more preferably 1.0 equivalents～ 1.5 equivalent.
(solvent)
In addition, this reaction is preferably carried out in the presence of the solvent.The species of the solvent being used and amount can be with above-mentioned " (i-1) reaction with acid halide compound as raw material " same condition.
(reaction temperature)
As long as it can be arbitrary temperature that reaction carries out then reaction temperature, those skilled in the art can suitably adjust.From Yield, suppression the aspect such as by-product and business efficiency set out, as reaction temperature, generally can exemplify -20 DEG C (minus 20 DEG C) with In scope below the upper and boiling point of solvent that used, it is preferably in less than more than -10 DEG C 100 DEG C of scope, is more preferably 0 In less than 80 DEG C of scope more than DEG C, in more preferably less than more than 10 DEG C 50 DEG C of scope.
(response time)
Response time is not particularly limited, and those skilled in the art can suitably adjust.From yield, suppression by-product and warp The Ji aspect such as efficiency is set out, as the response time of intermediate manufacturing process (i-2), can exemplify 0.5 hour～48 hours, excellent Elect 1 hour～36 hours, the scope of more preferably 1 hour～24 hours as.
3. the separation (an operation two-step) of intermediate
Enol ester compounds in intermediate manufacturing process (i), represented by production (2).The present invention can be carried out Can not carry out as the separation of the enol ester compounds of intermediate implementing, all can be obtained with high yield in any case and make The 3 ketone of the formula (1) for target.That is, the 3 ketone of formula (1) can be by following manufacture methods (A) and manufacturer Method (B) being manufactured, in the case of with the carboxylic acid compound of the acid halide compound of formula (3) or formula (5) as initial substance, Manufacture method (A) be do not carry out intermediate separation and continuously carry out subsequent rearrangement reaction operation (ii) based on an operation Manufacture method；Manufacture method (B) be underway mesosome separation after carry out after rearrangement reaction operation (ii) based on The manufacture method of two-step.Below, illustrate to the manufacture method based on an operation with based on the manufacture method of two-step.
(A) manufacture method based on an operation
In the present invention, conduct can be manufactured in the case of not separating as the enol ester compounds of the formula (2) of intermediate The 3 ketone of the formula (1) of target.Therefore, it can to carry out intermediate manufacture work by an operation (one step, a step) Both sequence (i) and rearrangement reaction operation (ii).Intermediate manufacturing process (i) is being carried out by an operation (step) and is resetting In the case of both reaction process (ii), the enol ester compounds as intermediate remain in intermediate manufacturing process in advance In the generation mixture (reactant mixture) obtaining in (i), and add additional alkali, thus carry out rearrangement reaction operation (ii).Or it is also possible to when starting intermediate manufacturing process (i), by intermediate manufacturing process (i) and rearrangement reaction operation (ii) the alkali more than total amount (whole amount) of alkali used in adds to reaction system.In the case of being somebody's turn to do, intermediate manufacture sometimes The reaction of operation (i) is carried out with the reaction of rearrangement reaction operation (ii) simultaneously.
In addition, with regard to the whole, reagent, solvent etc. used in the present invention, those skilled in the art are permissible Suitably selection is added in the lump, is added batch-wise, Deca, independent Deca, the method such as being simultaneously added dropwise.These put into and the method for importing can Suitably to be selected and adjusted by those skilled in the art.
(B) manufacture method based on two-step
As other methods, intermediate manufacturing process (i) and rearrangement reaction operation (ii) can be carried out independently of one another.Change Yan Zhi, can carry out intermediate manufacturing process (i) and rearrangement reaction operation (ii) by two-step (two steps, two steps). In the case of to carry out intermediate manufacturing process (i) and rearrangement reaction operation (ii) by two-step (two steps), in intermediate In manufacturing process (i), the enol ester compounds of the formula (2) as intermediate are separated.Those skilled in the art utilize known skill Art carries out suitable post processing to the generation mixture (reactant mixture) of intermediate manufacturing process (i), such that it is able to will as in The enol ester compounds of mesosome separate.
The enol ester compounds of formula (2) can be in the generation mixture (reactant mixture) from intermediate manufacturing process (i) In be kept completely separate after purification be used for rearrangement reaction operation (ii).Or, enol ester compounds can also be from intermediate manufacturing process I the generation mixture (reactant mixture) of () is used with the state being dissolved in solvent after separating as the solution of suitable solvent In rearrangement reaction operation (ii).In addition, enol ester compounds can suitably be dried.For example, it is possible to using acid The generation mixture (reactant mixture) of intermediate manufacturing process (i) is carried out, and is dried using desiccant etc..
As the example of this acid, the mineral acids such as hydrochloric acid, hydrobromic acid, sulphuric acid can be enumerated；Acetic acid, trifluoroacetic acid etc. are organic Acid；And the acid by these sour dilute with waters.The preferred concrete example of these acid is 1%～20% hydrochloric acid and 1%～20% Sulphuric acid etc., more preferably 5%～15% hydrochloric acid.In addition, as the example of desiccant, anhydrous sodium sulfate, anhydrous sulfur can be enumerated Sour magnesium, molecular sieve 3a and molecular sieve 4A etc., preferably can enumerate anhydrous sodium sulfate.This by two-step come the manufacturer carrying out Method solvent used in the such as reaction of rearrangement reaction operation (ii) is used molten with the reaction of intermediate manufacturing process (i) It is particularly advantageous when agent is preferably different.
It is believed that the 3 ketone of formula (1) is from the generation mixture of rearrangement reaction operation (ii), (reaction mixes in addition Thing) in generate in its salt form.The salt of this 3 ketone can separate in its salt form, or can also be by acidity Change and separated using the extraction of suitable solvent.In other words, for the 3 ketone of formula (1), in rearrangement reaction work After the reaction of sequence (ii) terminates, make generation mixture (reactant mixture) be acidity, can be carried out by conventional method afterwards Separate.Herein, the example of the acid using to be acid can enumerate the mineral acids such as hydrochloric acid, hydrobromic acid, sulphuric acid；Second The organic acid such as acid, trifluoroacetic acid；And the acid by these sour dilute with waters.As the preferred concrete example of these acid, permissible Enumerate 1%～20% hydrochloric acid and 1%～20% sulphuric acid etc., more preferably 5%～15% hydrochloric acid.Additionally, formula (1) as needed 3 ketone can also operate to carry out purification by column chromatography and/or recrystallization etc..
4. rearrangement reaction operation (ii)
For the enol ester compounds of formula (2), in subsequent rearrangement reaction operation (ii), carry out rearrangement reaction, system The 3 ketone of the affected formula (1) for target.In rearrangement reaction operation (ii), under conditions of without cyanogen compound, excellent Choosing carries out the rearrangement reaction using alkali in the presence of the solvent.
Herein, cyanogen compound refers to discharge the compound of cyanide ion as mentioned above, can enumerate inorganic cyaniding and close Thing, organic cyanogen compound.As inorganic cyanogen compound, specifically, potassium cyanide, Cyanogran., lithium cyanide, cyaniding can be exemplified Caesium, magnesium cyanide, Cyanogas (Am. Cyanamid)., nickel cyanide, copper cyanider, zinc cyanide etc..As organic cyanogen compound, specifically, third can be exemplified Ketone cyanalcohol, trimethylsilyl cyanide, triethyl group cyanogen silane, tetrabutyl ammonium cyanide, tetraethyl ammonium cyanide etc..
In addition, the condition without cyanogen compound refers to be substantially free of the condition of cyanogen compound in reaction system, specifically Say, refer to contained cyanogen compound in reaction system be below 10ppm, be preferably below 5ppm, more preferably 1ppm with Under.
(alkali)
As alkali used in rearrangement reaction operation (ii), for example, it is possible to enumerate organic amine；Metal carbonate salt；Gold Belong to bicarbonate salts；Carboxylic acid metal's salt；With its mixture.Among these, more preferably can enumerate organic amine；Metal carbonate Salt；With its mixture.
As the concrete example of these alkali, organic amine (for example, triethylamine, diisopropylethylamine, pyridine, 4- can be enumerated Dimethylamino naphthyridine (DMAP), N, accelerine, 1,8- diazabicyclo [5.4.0] 11 carbon -7- alkene (DBU) etc.)；Gold Belong to carbonate (for example, sodium carbonate, potassium carbonate, magnesium carbonate, Calcium Carbonate etc.)；Metal bicarbonate salt (for example, sodium bicarbonate, Potassium bicarbonate etc.)；Carboxylic acid metal's salt (for example, the metal acetate class such as sodium acetate, potassium acetate, calcium acetate, magnesium acetate)；Metal Alkoxide (for example, Feldalat NM, Sodium ethylate, sodium tert-butoxide, Feldalat KM, potassium tert-butoxide etc.)；Metal hydroxidess (for example, hydroxide Sodium, potassium hydroxide, calcium hydroxide, magnesium hydroxide etc.)；Metal hydride (for example, lithium hydride, sodium hydride, hydrofining, calcium hydride) Deng；And the mixture of its arbitrary proportion, but it is not limited to these.
In the alkali that these exemplify, as preferred concrete example, can enumerate triethylamine, diisopropylethylamine, pyridine, DMA, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and its mixture, more preferably can enumerate three second Amine, pyridine, sodium carbonate, potassium carbonate and its mixture, further preferably can enumerate triethylamine, sodium carbonate and potassium carbonate.
As long as the form that reaction carries out then this alkali can be arbitrary form.The form of this alkali can be by people in the art Member suitably selects.
(consumption of alkali)
As long as the consumption that reaction carries out the alkali in then rearrangement reaction operation (ii) can be measured for arbitrary, people in the art Member can suitably adjust.From yield, the suppression aspect such as by-product and business efficiency, the use of the alkali of rearrangement reaction operation (ii) Amount for example suitably select from the scope of 1 equivalent～5 equivalent with respect to formula (2), preferably 1 equivalent～2 equivalent, be more preferably 1.0 equivalent～1.5 equivalents.
In addition, with regard to total consumption of the alkali in whole intermediate manufacturing process (i) and rearrangement reaction operation (ii), example As, in the case of and carrying out above by two-step in the case of carrying out above by an operation in either case under, phase Formula (2) is suitably selected from the scope of 1 equivalent～10 equivalent, preferably 2 equivalent～4 equivalents, more preferably 2.0 equivalents ～3.0 equivalents.
(solvent)
The reaction of rearrangement reaction operation (ii) preferably uses solvent and carries out.As solvent, for example, it is possible to enumerate nitrile (for example, acetonitrile etc.)；Ethers (for example, diethyl ether, diisopropyl ether, cyclopentyl methyl ether (CPME), oxolane (THF), two Alkane, glycol dimethyl ether, diethylene glycol dimethyl ether etc.)；Halogenated hydrocarbon (for example, dichloromethane, chloroform, carbon tetrachloride, four chloroethenes Alkane etc.)；Aromatic hydrocarbon (for example, benzene, chlorobenzene, dichloro-benzenes, nitro benzene,toluene,xylene etc.)；Amide-type (for example, N, N- bis- Methylformamide (DMF), DMAC N,N' dimethyl acetamide (DMAC), N-Methyl pyrrolidone (NMP) etc.)；Imidazolone type (example As DMI (DMI) etc.)；Sulfoxide type (for example, dimethyl sulfoxide (DMSO) etc.)；And its arbitrarily than The mixed solvent of example, but it is not limited to these.
As the preference of these solvents, acetonitrile, oxolane (THF), dioxane, dichloromethane, benzene, chlorine can be enumerated Benzene, dichloro benzene,toluene,xylene, N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMAC) and its mixing are molten Agent.
If considering the recirculation of solvent in industry manufacture, environment aspect and cost etc., as this solvent particularly preferred Example, chlorobenzene, dichloro benzene,toluene,xylene and its mixed solvent can be enumerated.The ratio of any mixed solvent is not had yet There is restriction.
In the past, (for example, in patent documentation 2 it was acetonitrile) only in the case of using specific solvent, and can be obtained with high yield Obtain the 3 ketone as target, in the present invention, be not limited to specific solvent and species can be realized with high yield extensive Solvent.
(consumption of solvent)
As long as the consumption that reaction carries out the solvent in then rearrangement reaction operation (ii) can be measured for arbitrary.In the present invention The consumption of solvent suitably can be adjusted by those skilled in the art.From yield, the suppression aspect such as by-product and business efficiency, As the consumption of solvent, for example, be 0.01L～50L (liter) with respect to 1 mole of formula (2), preferably 0.1L～10L, more preferably For 0.1L～5L.
It should be noted that carrying out in the case of the manufacture carrying out 3 ketone by an operation and by two-step Under either case in the case of the manufacture of 3 ketone, as intermediate manufacturing process (i) and/or rearrangement reaction operation (ii) consumption of solvent, for example, is 0.01L～50L (liter), is preferably 0.1L～10L, more with respect to 1 mole of formula (2) It is preferably 0.1L～5L.
(reaction temperature)
As long as the reaction temperature that reaction is carried out in the then present invention can be arbitrary temperature.Reaction temperature in the present invention can Suitably to be adjusted by those skilled in the art.From yield, the suppression aspect such as by-product and business efficiency, as reaction temperature Degree, generally can exemplify in the scope of below more than -20 DEG C (minus 20 DEG C) and the boiling point of solvent that used, be preferably -10 DEG C In above less than 100 DEG C of scope, in more preferably less than more than 0 DEG C 80 DEG C of scope, it is more preferably more than 10 DEG C 50 In scope below DEG C.
It should be noted that carrying out in the case of the manufacture carrying out 3 ketone by an operation and by two-step Under either case in the case of the manufacture of 3 ketone, as intermediate manufacturing process (i) and/or rearrangement reaction operation (ii) reaction temperature, by, in the scope more than -20 DEG C (minus 20 DEG C) and below the boiling point of solvent that used, preferably illustrating Go out in less than more than -10 DEG C 100 DEG C of scope, in more preferably less than more than 0 DEG C 80 DEG C of scope, be more preferably 10 DEG C In above less than 50 DEG C of scope.
In the past, in the case of higher reaction temperature (for example, being 55 DEG C～57 DEG C in patent documentation 2), can be with High yield obtains the 3 ketone as target, but, it is not limited to such high reaction temperature in the present invention, can be to wrap Include low temperature and realize high yield in interior extensive reaction temperature.
(response time)
Response time in the present invention is not particularly limited.Response time in the present invention can be by people in the art Member suitably adjusts.From yield, suppression the aspect such as by-product and business efficiency, as rearrangement reaction operation (ii) reaction when Between, can exemplify 0.5 hour～48 hours, be preferably 1 hour～36 hours, the scope of more preferably 1 hour～24 hours.
It should be noted that in the case of the manufacture carrying out 3 ketone by two-step, as described above, in conduct The response time of mesosome manufacturing process (i), can exemplify 0.5 hour～48 hours, be preferably 1 hour～36 hours, more preferably For the scope of 1 hour～24 hours.From same aspect, as carried out by two-step 3 ketone manufacture when The response time of rearrangement reaction operation (ii), can exemplify 0.5 hour～48 hours, be preferably 1 hour～36 hours, more preferably For the scope of 1 hour～24 hours.
In addition, in both situations carrying out intermediate manufacturing process (i) and rearrangement reaction operation (ii) by an operation Under, the reaction of intermediate manufacturing process (i) is also carried out sometimes with the reaction of rearrangement reaction operation (ii) simultaneously.Therefore, from yield, The suppression aspect such as by-product and business efficiency is set out, and in the case of carrying out by an operation, can exemplify 0.5 hour～48 little When, be preferably 1 hour～36 hours, be preferably the scope of 1 hour～24 hours.
5. the yield of 3 ketone
In the present invention, carry out the rearrangement reaction using alkali under conditions of without cyanogen compound, therefore, it is possible to very high Yield obtain as target formula (1) 3 ketone.Such high yield is that the 3 ketone of formula (1) is distinctive, Existing other 3 ketone is unable to reach such high yield.The reasons why formula (1) can be manufactured with high yield is not clear, But think that the characteristic of the framing structure or substituent R 1 with quinoxaline ring of compound creates impact.Hereinafter, to this click-through Row explanation.
In embodiment described later, the compound of comparative example 1 is the structure close with the 3 ketone of formula (1), but with The ring of Oxopyrazine cyclic condensation has the nitrogen-atoms of alkalescence, and it is possible to suppress rearrangement reaction.Compound with regard to patent documentation 3 Also identical.
In addition, for the compound of comparative example 2 described later, under the reaction conditions the stability of ring low it is possible to hold Easily decompose.Due to this reason it is believed that yield is low.
The compound of patent documentation 2 is existing 3 ketone, and yield is 82% to the maximum, but this is at 55 DEG C～57 DEG C Heating condition under yield, it is therefore envisaged, yield is lower in the case of being reacted under room temperature (10 DEG C～35 DEG C).
Thus, as obtaining the condition of high yield by not using the rearrangement reaction of cyanogen compound, can enumerate：For Heterocycle；There is no basic nitrogen；Ring is stablized it may be said that the 3 ketone of the formula (1) of the present invention is special conjunction at reaction conditions Suitable.
As described above, according to the present invention, under conditions of there is not cyanogen compound, by easy operation, at room temperature Temperate condition under it is not necessary to specific solvent, can be with high yield and industry rule while the by-product suppressing garbage is raw Molding makes this 3 ketone.Additionally, additionally provide being not limited to what reaction at a temperature of the broad range of room temperature was also carried out Option.And then, additionally provide as recirculation easily and low cost solvent, i.e. as industrial preferred solvent, The option also carrying out is reacted with high yield in the case that chlorobenzene and toluene etc. are aromatic hydrocarbon.Therefore, the present invention can provide work In industry preferably and economically it is also preferred that 3 ketone manufacture method.
Embodiment
Then, enumerate embodiment that the manufacture method of the present invention is specifically described, but the present invention is not implemented by these Any restriction of example.
Below in an example, room temperature is usually 10 DEG C～35 DEG C of scope.
(high performance liquid chromatography (HPLC) analysis method)
With regard to HPLC analysis method, it is referred to following document as needed.
(a)：(society) Japanization association compile, " new experimental chemistry lecture 9 analytical chemistry II ", page 86～112 (1977), Publisher's meal spring new I, Wan Shan Co., Ltd. (for example, with regard to can be used in the combination of the filler-mobile phase of post, are referred to Page 93～96.)
(b)：(society) Japanization association volume, " experimental chemistry lecture 20-1 analytical chemistry " the 5th edition, page 130～151 (2007), publisher village Tian Chengsi youth, Wan Shan Co., Ltd. are (for example, with regard to the specifically used method of reverse-phase chromatography analysis And condition, it is referred to page 135～137.)
(assay method of pH)
PH is measured using glass electrode formula hydrogen ion concentration indicating gage.Refer to as glass electrode formula hydrogen ion concentration Show meter, it is, for example possible to use the model that DKK-TOA CORPORATION manufactures：HM-20P.
(embodiment 1)
3- (2- hydroxyl -6- oxo -1- cyclohexene carbonyl) -1- (4- methoxyphenyl) quinoxaline -2 (1H) -one (1a) Manufacture
[changing 10]
At room temperature to the dichloromethane 10mL of hydroresorcinol 2.6g (23mmol) and triethylamine 2.1g (21mmol) The dichloromethane of Deca 1- (4- methoxyphenyl) -2- oxo -1,2- dihydro-quinoxaline -3- carboxyl acyl chloride 5.0g (16mmol) in solution Alkane 10mL solution.At room temperature reactant mixture is stirred 2 hours, be carried out with 10% hydrochloric acid afterwards, use anhydrous sodium sulfate Organic layer after point liquid is dried.Leach inorganic matters, add triethylamine 2.1g (21mmol) in obtained solution, Stir 3 hours under room temperature.After reactant mixture being carried out with 10% hydrochloric acid, with anhydrous sodium sulfate to the organic layer after point liquid It is dried.Leach inorganic matters, after solvent being distilled off under reduced pressure, make residue recrystallization with methanol, obtain as yellow powder 3- (2- hydroxyl -6- oxo -1- cyclohexene carbonyl) -1- (4- methoxyphenyl) quinoxaline -2 (1H) -one 5.5g at end.(yield 88%)
Fusing point：112-114℃
1H-NMR(300MHz,CDCl3)δ:16.29(brs,1H),7.86-7.88(m,1H),7.41-7.08(m,6H), 6.79-6.82(m,1H),3.88(s,3H),2.76(m,2H),2.44(m,2H),2.06(m,2H)
In embodiment 1, after intermediate manufacturing process, the enol ester compounds as intermediate were once dried, then Carry out rearrangement reaction in rearrangement reaction operation it is known that, can be obtained with high yield in the manufacture method of such two-step 3 ketone as target.
(embodiment 2)
The chloro- 3- of 5- (2- hydroxyl -6- oxo -1- cyclohexene carbonyl) -1- (4- methoxyphenyl) quinoxaline -2 (1H) -one (1b) manufacture
[changing 11]
Molten to the chlorobenzene 8mL of hydroresorcinol 1.7g (15.0mmol) and triethylamine 3.2g (31.5mmol) at room temperature The chloro- 1- of Deca 5- (4- methoxyphenyl) -2- oxo -1,2- dihydro-quinoxaline -3- carboxyl acyl chloride 5.0g (14.3mmol) in liquid Chlorobenzene 18mL solution.At room temperature by reactant mixture stir 2 hours, backward reactant mixture in add chlorobenzene 22mL, use 10% hydrochloric acid is carried out.With anhydrous sodium sulfate, the organic layer after point liquid is dried, solvent is distilled off under reduced pressure.With Acetone is carried out to residue, obtains the chloro- 3- of 5- (2- hydroxyl -6- oxo -1- cyclohexene the carbonyl) -1- as yellow powder (4- methoxyphenyl) quinoxaline -2 (1H) -one 4.9g.(yield 81%)
Fusing point：249-251℃
1H-NMR(300MHz,CDCl3)δ:16.22(brs,1H),7.39(m,2H),7.17-7.30(m,2H),7.07- 7.10 (m, 2H), 6.70 (d, J=8.4Hz, 1H), 3.87 (s, 3H), 2.75 (t, J=12.6Hz, 2H), 2.43 (brs, 2H), 2.05 (t, J=12.9Hz, 2H)
In example 2 it is known that different from the framing structure of embodiment 1, but can be obtained as target using high yield 3 ketone.In addition, in example 2, on the way post processing is not carried out to intermediate as in Example 1, but continuously Ground carries out intermediate manufacturing process and rearrangement reaction operation, but understands that the manufacture method by such operation also can be with height Yield obtains the 3 ketone as target.
(embodiment 3)
The chloro- 3- of 5- (2- hydroxyl -6- oxo -1- cyclohexene carbonyl) -1- (4- methoxyphenyl) quinoxaline -2 (1H) -one (1b) manufacture
Molten to the toluene 5mL of hydroresorcinol 1.7g (15.0mmol) and triethylamine 1.6g (15.7mmol) at room temperature The chloro- 1- of Deca 5- (4- methoxyphenyl) -2- oxo -1,2- dihydro-quinoxaline -3- carboxyl acyl chloride 5.0g (14.3mmol) in liquid Toluene 17mL solution.Add triethylamine 1.6g (15.7mmol) further in reactant mixture, stir 2 hours at 60 DEG C.To Add toluene 11mL in reactant mixture, be carried out with 10% hydrochloric acid.With anhydrous sodium sulfate, the organic layer after point liquid is carried out It is dried, solvent is distilled off under reduced pressure.With acetone, water, residue is carried out, obtains the chloro- 3- of 5- as yellow powder (2- hydroxyl -6- oxo -1- cyclohexene carbonyl) -1- (4- methoxyphenyl) quinoxaline -2 (1H) -one 4.9g.(yield 81%)
In embodiment 3, reacted it is known that can be obtained with high yield at the temperature (60 DEG C) higher than embodiment 2 3 ketone as target.In addition we know, even with toluene as solvent, yield is also high.
(embodiment 4)
The chloro- 3- of 5- (2- hydroxyl -6- oxo -1- cyclohexene carbonyl) -1- (4- methoxyphenyl) quinoxaline -2 (1H) -one (1b) manufacture
Molten to the acetonitrile 8mL of hydroresorcinol 0.40g (3.6mmol) and triethylamine 0.76g (7.5mmol) at room temperature The chloro- 1- of Deca 5- (4- methoxyphenyl) -2- oxo -1,2- dihydro-quinoxaline -3- carboxyl acyl chloride 1.05g (3.0mmol) in liquid Acetonitrile 5.0mL solution, is stirred at room temperature 2 hours afterwards.The chloro- 3- of 5- (2- hydroxyl -6- oxo -1- cyclohexene carbonyl) -1- (4- Methoxyphenyl) yield of quinoxaline -2 (1H) -one analyzed by the HPLC of reaction solution, counted using absolute standard curve Calculate.(yield 92%)
In example 4, it is used acetonitrile as solvent it is known that high income.
(embodiment 5)
The chloro- 3- of 5- (2- hydroxyl -6- oxo -1- cyclohexene carbonyl) -1- (4- methoxyphenyl) quinoxaline -2 (1H) -one (1b) manufacture
Molten to the acetonitrile 5mL of hydroresorcinol 0.37g (3.3mmol) and potassium carbonate 1.0g (7.2mmol) at room temperature The second of the chloro- 1- of Deca 5- (4- methoxyphenyl) -2- oxo -1,2- dihydro-quinoxaline -3- carboxyl acyl chloride 1.0g (2.9mmol) in liquid Nitrile 5.0mL solution.After being stirred at room temperature 2 hours, 10% hydrochloric acid is added to make pH be acid, in decompression in reactant mixture Under solvent is distilled off.Leach separated out solid, with acetone, water, solid is carried out, obtain the 5- as yellow powder Chloro- 3- (2- hydroxyl -6- oxo -1- cyclohexene carbonyl) -1- (4- methoxyphenyl) quinoxaline -2 (1H) -one 1.1g.(yield 91%)
In embodiment 5, it is used potassium carbonate as alkali it is known that high income.
(embodiment 6)
3- (2- hydroxyl -6- oxo -1- cyclohexene carbonyl) -1- (4- methoxyphenyl) quinoxaline -2 (1H) -one (1a) Manufacture
At room temperature to the dichloromethane of hydroresorcinol 0.37g (3.3mmol) and potassium carbonate 1.00g (7.2mmol) Deca 1- (4- methoxyphenyl) -2- oxo -1,2- dihydro-quinoxaline -3- carboxyl acyl chloride 1.0g (3.2mmol) in 5.0mL solution Dichloromethane 5.0mL solution, is stirred at room temperature 24 hours afterwards.3- (2- hydroxyl -6- oxo -1- cyclohexene carbonyl) -1- (4- Methoxyphenyl) yield of quinoxaline -2 (1H) -one analyzed by the HPLC of reaction solution, counted using absolute standard curve Calculate.(yield 95%)
In embodiment 6, potassium carbonate is used as alkali, is used dichloromethane as solvent it is known that yield is very high.
(comparative example 1)
3- (2- hydroxyl -6- oxo -1- cyclohexene carbonyl) -1- (3,4- difluorophenyl) pyrido [2,3-b] pyrazine -2 (1H) manufacture of -one (1c)
[changing 12]
At room temperature to the acetonitrile 10mL solution of hydroresorcinol 1.3g (12mmol) and potassium carbonate 2.8g (20mmol) Middle Deca 1- (3,4- difluorophenyl) -2- oxo -1,2- dihydro pyrido [2,3-b] pyrazine -3- carboxyl acyl chloride 3.0g (9.4mmol) Acetonitrile 10mL solution.Reactant mixture was stirred at room temperature after 3 hours, adds 10% hydrochloric acid to make in reactant mixture PH is acidity, is extracted with ethyl acetate.With anhydrous sodium sulfate, the organic layer after point liquid is dried, distills under reduced pressure Remove solvent.Make residue recrystallization with methanol, obtain 3- (2- hydroxyl -6- oxo -1- cyclohexene carbonyl) as yellow powder - 1- (3,4- difluorophenyl) pyrido [2,3-b] pyrazine -2 (1H) -one 1.5g.(yield 40%)
Fusing point：226-228℃
1H-NMR(300MHz,CDCl3)δ:16.05(brs,1H),8.46(m,1H),8.19(m,1H),7.12-7.40(m, 4H),2.78(m,2H),2.46(m,2H),2.09(m,2H)
(comparative example 2)
6- (2- hydroxyl -6- oxo -1- cyclohexene carbonyl) -2- methyl 4-phenyl -1,2,4- triazine -3,5 (2H, 4H)-two The manufacture of ketone (1d)
[changing 13]
Molten to the acetonitrile 10mL of hydroresorcinol 0.63g (5.6mmol) and potassium carbonate 1.56g (11mmol) at room temperature Lentamente Deca 2- methyl -3,5- dioxo -4- phenyl -2,3,4,5- tetrahydrochysene -1,2,4- triazine -6- carboxyl acyl chloride 1.0g in liquid (3.8mmol) acetonitrile 10mL solution.Reactant mixture is stirred at room temperature after 2 hours, adds in reactant mixture 10% hydrochloric acid and make pH be acid, extracted with ethyl acetate.After the organic layer after point liquid being carried out with water, with anhydrous Sodium sulfate is dried, and solvent is distilled off under reduced pressure.Make residue recrystallization with methanol, obtain the 6- as colourless crystallization (2- hydroxyl -6- oxo -1- cyclohexene carbonyl) -2- methyl 4-phenyl -1,2,4- triazine -3,5 (2H, 4H)-diketone 0.72g. (yield 56%)
Fusing point：182-185℃
1H-NMR(300MHz,CDCl3)δ:16.00(brs,1H),7.26-7.64(m,5H),3.70(s,3H),2.76(t, J=12.6Hz, 2H), 2.46 (t, J=13.2Hz, 2H), 2.05 (brs, 2H)
Industrial applicibility
According to the present invention, provide the new industrial autofrettage of the 3 ketone with Oxopyrazine ring.
In the inventive method, do not use toxicity aspect cyanogen compound of problems, can under mild conditions, pass through Easy operation manufactures this 3 ketone.
In addition, it is not necessary to specific solvent in the inventive method, can be received with high while suppressing the generation of by-product Rate and commercial scale manufacture this 3 ketone highly purified.
The 3 ketone represented by above-mentioned formula (3) being obtained by the inventive method is useful as pesticide.Example As the chloro- 3- of 5- (2- hydroxyl -6- oxo -1- cyclohexene carbonyl) -1- (4- methoxyphenyl) quinoline manufacturing in embodiment 2～5 Quinoline -2- (1H) -one has excellent activity of weeding as described in No. 2009/016841 publication of International Publication No., in industry Upper useful.Therefore, the inventive method has very high industrial utility value.

Claims (11)

1. a kind of manufacture method of 3 ketone, it is the manufacture method of the 3 ketone represented by formula (1),
[changing 1]
In formula, X1Represent oxygen atom or sulphur atom,
X2Represent carbon atom or nitrogen-atoms, this carbon atom can be by R5Replace, this nitrogen-atoms can together form N- oxygen with oxygen atom Compound,
R1Represent：Hydrogen atom；C1～C12Alkyl；C2～C6Thiazolinyl；C2～C6Alkynyl；C3～C8Cycloalkyl；C1～C6Haloalkyl；C2 ～C6Haloalkenyl group；C1～C6Alkylthio group C1～C6Alkyl；C1～C6Alkoxy C1～C6Alkyl；C1～C6Alkoxy carbonyl group C1～C6Alkane Base；C6～C10Aryl C1～C6Alkyl, the aryl of this group can be by 1 or more than 2 identical or different R6Replaced；Tool There is the heterocycle C that in oxygen atom, sulphur atom and nitrogen-atoms 1～5 heteroatomic carbon numbers are 2～101～C6Alkane Base, 1 had in oxygen atom, sulphur atom and nitrogen-atoms～5 heteroatomic carbon numbers of this group are 2～10 Heterocycle can be by 1 or more than 2 identical or different R7Replaced；C6～C10Aryl, this group can by 1 or 2 with Upper identical or different R6Replaced；Or 1～5 had in oxygen atom, sulphur atom and nitrogen-atoms heteroatomic Carbon number is 2～10 heterocyclic radical, and this group can be by 1 or more than 2 identical or different R7Replaced,
R2～R5Can be identical or different, represent hydrogen atom, halogen atom, nitro, C1～C6Alkyl, C1～C6Haloalkyl, C1～C6 Alkoxyl, C1～C6Alkylthio group, C1～C6Alkyl sulphinyl, C1～C6Alkyl sulphonyl or C1～C6Alkoxy C1～C6Alkyl,
R6Represent hydrogen atom, halogen atom, C1～C6Alkyl, C1～C6Haloalkyl, C1～C6Alkoxyl, C1～C6Halogenated alkoxy, C1～C6Alkoxy carbonyl group or C1～C6Alkoxy C1～C6Alkyl,
R7Represent hydrogen atom, oxo base, halogen atom, C1～C6Alkyl, C1～C6Haloalkyl, C1～C6Alkoxyl, C1～C6Halo Alkoxyl, C1～C6Alkoxy carbonyl group or C1～C6Alkoxy C1～C6Alkyl,
This manufacture method is characterised by, including following rearrangement reaction operations：To following under conditions of not comprising cyanogen compound Enol ester compounds represented by formula (2) carry out the rearrangement reaction using alkali, obtain three assimilations represented by described formula (1) Compound,
[changing 2]
In formula, R1～R4、X1And X2As above-mentioned formula (1) defines.
2. the manufacture method of 3 ketone as claimed in claim 1 is it is characterised in that described alkali is triethylamine, diisopropyl Base ethamine, pyridine, N, accelerine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or its mixture.
3. 3 ketone as claimed in claim 2 manufacture method it is characterised in that described alkali be triethylamine, sodium carbonate, Potassium carbonate or its mixture.
4. the manufacture method of the 3 ketone as any one of claims 1 to 3 is it is characterised in that described formula (2) Represented enol ester compounds are by making the acid halide compound represented by following formulas (3) and following formula (4) institutes table Show cyclohexanedione compound reaction intermediate manufacturing process and manufacture,
[changing 3]
In formula, R1～R4、X1And X2As above-mentioned formula (1) defines,
Y represents halogen atom,
[changing 4]
5. the manufacture method of 3 ketone as claimed in claim 4 is it is characterised in that described intermediate manufacturing process and institute State rearrangement reaction operation to carry out in the presence of identical or different alkali.
6. the manufacture method of the 3 ketone as any one of Claims 1 to 5 is it is characterised in that described intermediate The reaction of manufacturing process and described rearrangement reaction operation is carried out using identical or different solvent.
7. 3 ketone as claimed in claim 6 manufacture method it is characterised in that described solvent be chlorobenzene, dichloro-benzenes, Toluene, dimethylbenzene or its mixed solvent.
8. the manufacture method of the 3 ketone as any one of claim 1～7 is it is characterised in that 80 more than 0 DEG C Carry out at a temperature of in scope below DEG C.
9. 3 ketone as claimed in claim 8 manufacture method it is characterised in that more than 10 DEG C less than 50 DEG C of model Carry out at a temperature of in enclosing.
10. the manufacture method of the 3 ketone as any one of claim 1～claim 9, wherein,
In described formula (1),
X1For oxygen atom,
X2For carbon atom, this carbon atom can be by R5Replaced,
R1For phenyl, this group can be by 1 or more than 2 identical or different R6Replaced,
R2～R5Can be identical or different, it is hydrogen atom, halogen atom, C1～C6Alkyl or C1～C6Alkoxyl,
R6By hydrogen atom, halogen atom, C1～C6Alkyl, C1～C6Represented by alkoxyl.
The manufacture method of 11. 3 ketones as any one of claim 1～claim 9, wherein,
In described formula (1),
X1For oxygen atom,
X2For carbon atom, this carbon atom can be by R5Replaced,
R1For phenyl, this group can be by 1 or more than 2 identical or different R6Replaced,
R2～R5Can be identical or different, it is hydrogen atom, halogen atom,
R6By hydrogen atom, C1～C6Represented by alkoxyl.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113233998A (en) * 2021-05-24 2021-08-10 浙江新安化工集团股份有限公司 Preparation method of mesotrione
CN114450261A (en) * 2019-10-01 2022-05-06 株式会社德山 Process for producing trione compound

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1039808A (en) * 1988-07-25 1990-02-21 希巴-盖吉股份公司 New herbicides
CN1169140A (en) * 1995-01-25 1997-12-31 曾尼卡有限公司 Process for prodn. of 2-(substd. benzoyl)-1,3-cyclohexanediones
JPH10265432A (en) * 1997-03-25 1998-10-06 Sds Biotech Kk Production of 2benzoylcyclic 1,3diketone derivative
CN1272837A (en) * 1997-11-27 2000-11-08 曾尼卡有限公司 Process for preparation of acylated cyclic 1,3-dicarbonyl compounds
CN1368947A (en) * 1999-08-10 2002-09-11 辛根塔参与股份公司 Process for preparation of acylated 1,3-dicarbonyl compounds
CN101778832A (en) * 2007-08-01 2010-07-14 组合化学工业株式会社 Oxopyrazine derivative and weedicide
WO2012148622A1 (en) * 2011-04-28 2012-11-01 E. I. Du Pont De Nemours And Company Herbicidal pyrazinones
CN103772243A (en) * 2013-12-30 2014-05-07 北京英力精化技术发展有限公司 Preparation method of mesotrione

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1039808A (en) * 1988-07-25 1990-02-21 希巴-盖吉股份公司 New herbicides
CN1169140A (en) * 1995-01-25 1997-12-31 曾尼卡有限公司 Process for prodn. of 2-(substd. benzoyl)-1,3-cyclohexanediones
JPH10265432A (en) * 1997-03-25 1998-10-06 Sds Biotech Kk Production of 2benzoylcyclic 1,3diketone derivative
CN1272837A (en) * 1997-11-27 2000-11-08 曾尼卡有限公司 Process for preparation of acylated cyclic 1,3-dicarbonyl compounds
CN1368947A (en) * 1999-08-10 2002-09-11 辛根塔参与股份公司 Process for preparation of acylated 1,3-dicarbonyl compounds
CN101778832A (en) * 2007-08-01 2010-07-14 组合化学工业株式会社 Oxopyrazine derivative and weedicide
WO2012148622A1 (en) * 2011-04-28 2012-11-01 E. I. Du Pont De Nemours And Company Herbicidal pyrazinones
CN103772243A (en) * 2013-12-30 2014-05-07 北京英力精化技术发展有限公司 Preparation method of mesotrione

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114450261A (en) * 2019-10-01 2022-05-06 株式会社德山 Process for producing trione compound
CN113233998A (en) * 2021-05-24 2021-08-10 浙江新安化工集团股份有限公司 Preparation method of mesotrione
CN113233998B (en) * 2021-05-24 2021-12-28 浙江新安化工集团股份有限公司 Preparation method of mesotrione

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