CN1471506A - Method for preparing carbonyl alpha-substituted nitrogen compounds - Google Patents

Method for preparing carbonyl alpha-substituted nitrogen compounds Download PDF

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CN1471506A
CN1471506A CNA018179630A CN01817963A CN1471506A CN 1471506 A CN1471506 A CN 1471506A CN A018179630 A CNA018179630 A CN A018179630A CN 01817963 A CN01817963 A CN 01817963A CN 1471506 A CN1471506 A CN 1471506A
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low grade
alkyl
phenyl
substituent
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罗必奎
张立塔
尹应武
文成贵
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Insight High Technology Beijing Co Ltd
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07C337/00—Derivatives of thiocarbonic acids containing functional groups covered by groups C07C333/00 or C07C335/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
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    • C07C337/06—Compounds containing any of the groups, e.g. thiosemicarbazides
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07C2601/14—The ring being saturated

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Abstract

The present invention relates to a process of producing carbonyl alpha-substituted nitrogen-containing compounds, which comprises reacting a halo-ketone or a-halo-aldehyde with primary amine, secondary amine or heterocycle compound containing nitrogen atome in the presence of Lewis acid and in the presence of absence of solvent. This process has the advantages of simple and easy-to-operate procedure, mild reacting condition, low energy-consumption, high yield, etc. thus improves efficiently the utilization and productivity of the equipment.

Description

Method for preparing carbonyl alpha-substituted nitrogen compounds
The preparation method technical field of carbonyl "-substitution nitrogen-containing compound
Novel prepare carbonyl the present invention relates to a kind of " method of-substitution nitrogen-containing compound; this method includes; in the presence of a lewis acid; there is solvent or in the absence of solvent in the case of, make -1 generation ketone or-| the heterocyclic compound for aldehyde and primary amine, secondary amine or containing nitrogen-atoms reacts.Background technology
At present, usually using for ketone or | the heterocyclic compound for aldehyde and primary amine, secondary amine or containing nitrogen-atoms reacts, and prepares carbonyl, and "-substitution nitrogen-containing compound, its preparation method mainly has direct method and epoxy intermediate method.
Wherein direct method is-halogenated ketone or " -1 generation aldehyde and primary amine, secondary amine or the heterocyclic compound containing nitrogen-atoms directly react generation carbonyl《- substitution nitrogen-containing compound.Both with the halogen on 2-position substitution reaction can occur for heterocyclic compound of this method due to primary amine, secondary amine or containing nitrogen-atoms, it can also be reacted with the carbonyl carbon on 1-position, and temperature is higher, with the easier progress of carbonyl carbon reaction on 1- positions, i.e., accessory substance is more.
Such as Japan Patent JP 10114736 is reported by the chloro- 2-methyl isophthalic acids of 2--(4-methyl mercapto phenyl）- 1- acetone directly with morpholine react, under 130 °C flow back 10 hours, obtain 2- methyl isophthalic acids-（4-methyl mercapto phenyl）- 2-morpholine-1- acetone, reaction yield is 87 .9%.Its reaction sees below formula：
Figure IMGF000002_0001
Epoxy intermediate method is more general method, first-halogenated ketone or "-halogenated aldehyde elder generation With sodium methoxide reaction generation oxirane compound intermediate, the intermediate again with primary amine, secondary amine or the heterocyclic compound containing nitrogen-atoms reaction generation carbonyl-substitution nitrogen-containing compound.This method easily hydrolyzes generation hydroxy compounds due to -1 generation ketone or ^ -1 generations aldehyde, epoxide is unstable, to raw material | for ketone or | need absolute for aldehyde, sodium methoxide and nitrogen-containing compound, and strictly to control reaction condition, so reaction yield fluctuation is larger, product quality is difficult to ensure that.
For example United States Patent (USP) US-A- 2,827,460 is reported by 2- chlorine-2-methyl-1-(4-chlorophenyl）- 1- acetone and sodium methoxide reaction generation epoxide-2-methoxyl group of 3,3-dimethyl-2- (4- chlorophenyls）Polyethylene oxide intermediate, the intermediate reacts 22 hours at a reflux temperature with morpholine again, obtains 2- methyl isophthalic acids-(4- chlorophenyls）- 2- morpholine -1- acetone.Its
Reaction scheme sees below formula：
Figure IMGF000003_0001
Because the patent does not report yield, inventor proves by experiment：As free alkali in sodium methoxide is too high, in morpholine, water content is too high can all have a significant impact to reaction；In the case of the raw material absolute of reaction, epoxide reacts 22 hours at a reflux temperature with morpholine can then generate more accessory substance.
In addition, Japan Patent JP 63,192,744th, United States Patent (USP) US 3,465,039th, US 3,314,970, former Soviet Union's patent SU 225,203, SU 230,827. ZA 6801749, Stefanescu, Paul is in Rev. Chim. (Bucharest) (1968), 19 (11), 639 and Hahn, Hob- Gyu et al. report such reaction in Han'guk Nonghwa Hakhoechi (1997), 40 (2) 139.
In summary, carbonyl is prepared using direct method or epoxy intermediate method《- substitution nitrogen-containing compound, which all exists, to be selected feed quality requirements height, reaction temperature height, reaction time length, reaction orientation Selecting property difference and the defect such as yield is relatively low.The disclosure of invention
The present invention is on the basis of above method Shortcomings are summarized, to be found by substantial amounts of experiment and dynamic trace analysis, in the presence of having lewis acid, for ketone or《- halogenated aldehyde first can form complex compound with lewis acid, and under very low Warm degree, the complex compound can also be generated.Due to "-halogenated ketone or《- halogenated aldehyde and lewis acid formation complex compound, and make-position!The reactivity of atom is greatly increased, so as to improve "-| the selectivity of the heterocyclic compound reaction for ketone or-halogenated aldehyde with primary amine, secondary amine or containing nitrogen-atoms, extraordinary effect is achieved, so as to complete the present invention.
Specifically, following formulas are prepared the present invention relates to one kind（I) the method for compound,
RlR2 -C(Q)-C0R5 (I)
In formula：
R1And R2Hydrogen is represented alone；C foretells23Straight or branched alkyl or replaced by one or more substituents _23Straight or branched alkyl, the substituent is selected from hydroxyl, element, low Grade alkoxies and low Grade alkylthio groups；Five yuan or hexa-atomic cyclic hydrocarbon radical or heterocycle alkyl；Aryl or the aryl replaced by one or more substituents, the substituent are selected from 1 element, hydroxyl, sulfydryl, low Grade alkyl, low Grade alkoxies, low Grade alkylthio groups, phenoxy group, thiophenyl and benzylthio；Or R1And R2It is connected to form five yuan or hexa-atomic cyclic hydrocarbon radical or heterocycle alkyl；
R5Hydrogen is represented alone； ^—23Straight or branched alkyl or replaced by one or more substituents-23Straight or branched alkyl, the substituent is selected from halogen, hydroxyl, low Grade alkoxies, low Grade alkylthio groups, the alkyl-substituted phenylsulfonyl-amidos of paper Grade and benzyl；Five yuan or hexa-atomic cyclic hydrocarbon radical or heterocycle alkyl；Aryl or the aryl replaced by one or more substituents, the substituent be selected from halogen, hydroxyl, sulfydryl, _12Alkyl, _12Alkoxy or alkenyloxy group, C3— 12Cycloalkyloxy or cyclenes epoxide, alkylthio group or alkenylthio group, C3 _12Cycloalkylthio or cyclenes dredge base, by the substitution of hydroxyl, low Grade alkyl or low Grade alkoxies（^ mono- ^ alkylthio groups, replaced by the alkyl-substituted amino of low Grade（^_12Alkylthio group, C2Alkyl-dithio or alkene disulfide group, C ,-12 Alkane sulfonyl or alkene sulfonyl, _12Alkane sulfinyl or alkene sulfinyl, phenoxy group, thiophenyl, base dredged by the alkyl-substituted thiophenyls of low Grade, phenyl disulfide group, phenyl sulfonyl, phenylsulfmyl and benzyl；
Or R R2With R5It is joined directly together to form five yuan to octatomic ring ketone；
Q representatives-NR3R4,
Wherein R3And R4Hydrogen is represented alone； ς_23Straight or branched alkyl or replaced by one or more substituents _23Straight or branched alkyl, the substituent is selected from hydroxyl, low Grade alkoxies and low Grade alkylthio groups；Aryl or the aryl replaced by one or more substituents, the substituent are selected from halogen, hydroxyl, sulfydryl, low Grade alkyl, low Grade alkoxies, low Grade alkylthio groups, phenoxy group, thiophenyl and benzylthio；
Or R3And R4Formed together with connected nitrogen-atoms containing 1 to 3 nitrogen, five yuan of oxygen heteroatom or hexa-member heterocycle base；
Characterized in that, in the presence of a lewis acid, there is solvent or in the absence of solvent in the case of, make formula（II) α -1 generations ketone or α -] for aldehyde and formula（III) amines is reacted,
R^^CX'COR5 (II)
Wherein R1、 R2And R5As defined above,
X1Represent fluorine, chlorine or bromine；
Q— H (III)
Q is as defined above in formula.
According to preparation method of the present invention, in a preferred embodiment of the invention, in formula (I) compound：
R1And R2Hydrogen is represented alone； _12Straight or branched alkyl or replaced by one or more substituents _12Straight or branched alkyl, wherein described substituent is selected from hydroxyl, element, low Grade alkoxies and low Grade alkylthio groups；Five yuan or hexa-atomic cycloalkyl or Heterocyclylalkyl；Phenyl, benzyl, pyridine radicals or pyrimidine radicals；The phenyl replaced by one or more substituents, the substituent Xuan Zi Halogen elements, hydroxyl, sulfydryl, low Grade alkyl, lower alkoxy, low Grade alkane dredge base, phenoxy group, thiophenyl and benzylthio；Or R1And R2It is connected to form five yuan or hexa-atomic cycloalkyl or Heterocyclylalkyl； R5Hydrogen is represented alone； (：Foretell12Straight or branched alkyl or replaced by one or more substituents _12Straight or branched alkyl, described substituent is selected from 1 element, hydroxyl, low Grade alkoxies, low Grade alkylthio groups, the alkyl-substituted phenylsulfonyl-amidos of paper Grade and benzyl；Five yuan or hexa-atomic cycloalkyl or Heterocyclylalkyl；Phenyl, naphthyl or anthryl；The phenyl replaced by one or more substituents, the substituent Xuan Zi Halogen elements, hydroxyl, sulfydryl,8Alkyl,8Alkoxy or _4Alkenyloxy group, c3 _8Cycloalkyloxy,（^ _8Alkylthio group or alkene ^ i bases, c3— 8Cycloalkylthio, the low Grade alkylthio groups replaced by hydroxyl, low Grade alkyl or low Grade alkoxies, the low Grade alkylthio groups replaced by the alkyl-substituted amino of low Grade, low Grade alkyl-dithios, low Grade alkyl sulfonyl, low Grade Alkylsulfinyls, phenoxy group, benzene dredge base, by the alkyl-substituted benzene ^ ^ bases of low Grade, phenyl disulfide group, phenyl sulfonyl, phenylsulfmyl and benzylthio；
Or R R2With R5It is joined directly together to form five to octatomic ring, ketone；
Q representatives-NR3R4,
Wherein R3And R4Hydrogen is represented alone；C foretells12Straight or branched alkyl is replaced by one or more substituents<^ _12Straight or branched alkyl, described substituent is selected from hydroxyl, low Grade alkoxies and low Grade alkylthio groups；Phenyl, benzyl, pyridine radicals or pyrimidine radicals；The phenyl replaced by one or more substituents, the substituent is selected from 1 element, hydroxyl, sulfydryl, low Grade alkyl, lower alkoxy, low Grade alkylthio groups, phenoxy group, thiophenyl and benzylthio；
Or R3And R4Formed together with connected nitrogen-atoms containing 1 to 3 nitrogen, five yuan of oxygen heteroatom or hexa-member heterocycle base.
According to preparation method of the present invention, in the present invention more preferably embodiment, in formula（I in),
R1And R2Hydrogen is represented alone；Low Grade straight or brancheds alkyl or the low Grade straight or brancheds alkyl by one or two substituent substitution, described substituent are selected from hydroxyl, element, low Grade alkoxies and low Grade alkylthio groups；Five yuan or hexa-atomic cycloalkyl；Phenyl or benzyl；By the phenyl of one or two substituent substitution, the substituent is selected from 1 element, hydroxyl, sulfydryl, low Grade alkyl, low Grade alkoxies, low Grade alkylthio groups, phenoxy group, thiophenyl and benzylthio；Or R1And R2Five yuan of the form that is connected or hexa-atomic cycloalkyl or Heterocyclylalkyl； R5Hydrogen is represented alone；Low Grade straight or brancheds alkyl or the low Grade straight or brancheds alkyl by one or two substituent substitution, described substituent are selected from 1 element, hydroxyl, low Grade alkoxies, low Grade alkylthio groups, the alkyl-substituted phenylsulfonyl-amidos of low Grade and benzyl；Five yuan or hexa-atomic cycloalkyl or Heterocyclylalkyl；Phenyl or naphthyl；By one or the phenyl of two substituents substitution, the substituent be selected from halogen, hydroxyl, sulfydryl, _8Alkyl, _8Alkoxy or（：Foretell alkenyloxy group, c6_ 8Cycloalkyloxy,8Alkylthio group or _4Alkenylthio group, c6_8Cycloalkylthio, the low Grade alkylthio groups replaced by hydroxyl, low Grade alkyl or low Grade alkoxies, the low Grade alkylthio groups replaced by the alkyl-substituted amino of low Grade, low Grade alkyl-dithios, low Grade alkyl sulfonyl, low Grade Alkylsulfinyls, phenoxy group, thiophenyl, by the alkyl-substituted thiophenyls of low Grade, phenyl disulfide group, phenyl a word used in place name acyl group, phenyl Asia comb acyl group and benzylthio；
Or R1、 R2With R5It is joined directly together to form five yuan to octatomic ring ketone；
Q representatives-NR3R4,
Wherein R3And R4Hydrogen is represented alone；Low Grade straight or brancheds alkyl or by one or disubstituted substituted low Grade straight or brancheds alkyl, the substituent is selected from hydroxyl, lower alkoxy and low Grade alkylthio groups；Phenyl or benzyl；By the phenyl of one or two substituent substitution, the substituent is selected from 1 element, hydroxyl, sulfydryl, low Grade alkyl, lower alkoxy, low Grade alkylthio groups, phenoxy group, benzene and dredges base and benzylthio；
Or R3And R4Formed together with connected nitrogen-atoms containing 1 to 3 nitrogen, five yuan of oxygen heteroatom or hexa-member heterocycle base.
According to preparation method of the present invention, in most preferably a kind of embodiment of the invention, in formula（I in),
R1And R2Hydrogen is represented alone；Low Grade straight or branched alkyls or the low Grade straight or branched alkyls by one or two substituent substitution, described substituent are selected from hydroxyl, element, low Grade alkoxies and low Grade alkylthio groups；Five yuan or hexa-atomic cycloalkyl；Phenyl or benzyl；By the phenyl of one or two substituent substitution, the substituent is selected from！Element, hydroxyl, sulfydryl, low Grade alkyl, lower alkoxy, low Grade alkylthio groups, phenoxy group, thiophenyl and benzylthio；Or R1And R2It is connected to form five yuan or hexa-atomic cycloalkyl； R5Hydrogen is represented alone；Low Grade straight or branched alkyls or the low Grade straight or branched alkyls by one or two substituent substitution, described substituent are selected from element, hydroxyl, low Grade alkoxies, low Grade alkylthio groups, the alkyl-substituted phenylsulfonyl-amidos of paper Grade and benzyl；Five yuan or hexa-atomic cycloalkyl；Phenyl or naphthyl；By the phenyl of one or two substituent substitution, the substituent is selected from halogen, hydroxyl, sulfydryl, low Grade alkyl, low Grade alkoxies, low Grade alkylthio groups, phenoxy group and benzene and dredges base；
Or R R2With R5It is joined directly together to form five yuan to octatomic ring ketone；
Q representatives-NR3R4 ,
Wherein R3And R4Hydrogen is represented alone；Low Grade straight or branched alkyls or the low Grade straight or branched alkyls by one or two substituent substitution, the substituent are selected from hydroxyl, low Grade alkoxies and low Grade alkylthio groups；Phenyl or benzyl；By the phenyl of one or two substituent substitution, the substituent is selected from i elements, hydroxyl, sulfydryl, low alkyl group, lower alkoxy, low Grade alkylthio groups, phenoxy group, thiophenyl and benzylthio；
Or R3And R4Formed together with connected nitrogen-atoms containing 1 to 3 nitrogen, five yuan of oxygen heteroatom or hexa-member heterocycle base.
According to preparation method of the present invention, in most preferably another embodiment of the invention, in formula（I in),
R R2、 R3、 R4And R5Representative low Grade straight or brancheds alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, vinyl, pi-allyl, acrylic, acetenyl, propargyl or propinyl；For described for the low Grade straight or brancheds alkyl of one or two substituent substitution, wherein described substituent is selected from fluorine, chlorine, bromine, hydroxyl, methoxyl group, ethyoxyl, methyl mercapto and ethylmercapto group；
R 1And R2It is connected to form five yuan or hexa-atomic cycloalkyl or Heterocyclylalkyl is that ring defends base, cyclohexyl, tetrahydrochysene and calls out mutter base or tetrahydro-thienyl；
R5Five yuan represented or hexa-atomic cycloalkyl or Heterocyclylalkyl are cyclopenta, cyclohexyl, tetrahydrofuran base or tetrahydro-thienyl；
For R R2、 R3And R4Represent by the phenyl of one or the substitution of two substituents Speech, wherein described substituent is selected from fluorine, chlorine, bromine, hydroxyl, sulfydryl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, methyl mercapto, ethylmercapto group, positive rosickyite base, isopropyisulfanyl, positive butylthio, phenoxy group, thiophenyl and benzylthio；
For R5For the phenyl replaced by one or two substituents represented, wherein described substituent is selected from fluorine, chlorine, Australia, hydroxyl, sulfydryl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, positive epoxide in heptan, n-octyloxy, allyloxy, cyclopentyloxy, cyclohexyl epoxide, methyl mercapto, ethylmercapto group, positive third ^ ^ bases, isopropyisulfanyl, positive butylthio, positive sulfenyl in heptan, just pungent sulfenyl, allyl sulfenyl, cyclopentylthio, cyclohexyl dredges base, 2- hydroxyeththylthios, methyl disulfide group, ethyoxyl ethylmercapto group, dimethylamino methyl mercapto, first sulfonyl, methyl sulfinyl, phenoxy group, thiophenyl, to methylphenyl-sulfanyl, phenyl disulfide group, phenoxy group, thiophenyl and benzylthio；
R3And R4It is pyrrole radicals, pyridine radicals, imidazole radicals, triazolyl, tetrazole radical, isoxazolyl, ^ oxazolyl, bis- oxazolyls, piperidyl, morpholinyl, indyl, indazolyl, benzimidazolyl or carbazyl to be formed together with connected nitrogen-atoms containing 1 to 3 nitrogen, five yuan of oxygen heteroatom or hexa-member heterocycle base.
According to preparation method of the present invention, in most preferably another embodiment of the invention, in formula（I in),
R1 . R2、 R3、 R4And R5Representative low Grade straight or branched alkyls are methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group；
R1And R2It is connected to form cyclohexyl；
R R2、 R3And R4For phenyl or benzyl；
R5For phenyl or naphthyl, the representative substituent on the phenyl of one or two substituent substitution is chlorine, methyl mercapto or thiophenyl；
R1 . R2With R5It is joined directly together to form hexa-atomic cyclic ketones；
R3And R4Pyrrole radicals, pyrazolyl, imidazole radicals, piperidyl or morpholinyl are formed together with connected nitrogen-atoms.
According to preparation method of the present invention, wherein prepared compound is following compounds： 2- methyl -1- (4- methyl mercapto phenyl）- 2--1-acetone of morpholine；
1- Ν, Ν-methylbenzylamino-8,9-dichloro- heptadecyl 4-Phenylsulfanylphenyl ketone；
1- piperidines butylcyclohexyl 4- chlorphenyl ketones；
1- (Ν, Ν-di-n-butyl amino）- 1- phenyl -2- acetone；
2- methyl -2- imidazole radicals -2- propionic aldehyde；
1- (1- naphthyls）- 2- pyrrole miaow base ethyl ketones；
2- Ν, Ν-diphenyl amino cyclohexanone；
L-1-N- NSC 77136 base amino -3- (4- methylphenylsulfonyl amino）- 4- phenyl -2- butanone.
Term " low Grade alkyl ", " lower alkoxy " or " low Grade alkylthio groups " of the present invention refer to containing " _6Alkyl ", " _6Alkoxy " or "-6Alkylthio group ".
Reaction can be without using solvent above, but use solvent sometimes to improve the mixed effect of reaction, applicable solvent have ketone, nitrile, fat hydrocarbon, for hydro carbons, ethers, esters, it is preferred that acetone, butanone, acetonitrile, n-hexane, petroleum ether, dichloromethane, chloroform, 1,2- dichloroethanes, 1,1,2,2- tetrachloroethanes, 1,1,2- trichloro ethylene, ether, ethyl acetate.
Operating process of the present invention is：Under the conditions of having solvent or be solvent-free, formula（II) halogenated ketone or " -1 generation aldehyde and formula（III) amines（Primary amine, secondary amine or the heterocyclic compound containing nitrogen-atoms）Mix, reacted under 0 °C-120 °C, raw material can be converted completely typically within 0.2-20 hour with lewis acid, in-situ transesterification rate is post-treated, carry product is obtained after Pure close to 100%.
In the methods of the invention, lewis acid is selected from boron trifluoride, alchlor, zinc chloride, ferric trichloride, stannic chloride, copper chloride, antimony chloride, titanium tetrachloride and polyphosphoric acids etc..Preferably alchlor or zinc chloride.
, can be as needed being selected raw material with lewis acidic mol ratio when carrying out present invention reaction.During reaction, the formula that can be used（II)-halogenated ketone or halogenated aldehyde, formula（III) mol ratio between compound and lewis acid is 1： 0.2-30 ：0.01-10, preferred molar ratio is 1： 0.5—5 ： 0.1—2. The inventive method can be reacted within the scope of relatively wide temperature, the temperature reacted can be 0 °C -120 °C, preferably 10 °C -60 °C, the time reacted is 0.2-20 hours, and general 0 .5- can react complete for 5 hours.
The inventive method has following features：
1st, operation is simple for present invention process, to equipment without particular/special requirement, it is easy to industrialized production；
2nd, the reaction condition of the invention compared with other methods is gentle.It is general only to need 10 °C -60 °C and just be reacted well, Cong Er Minus lacks side reaction, meanwhile, reached energy-saving purpose；
3rd, it is of the invention compared with other methods, in the great great Shrink short reaction time, add raw material and typically only need to react within 0.5-5 hours complete, be effectively improved utilization rate of equipment and installations and production capacity；
4th, the present invention is by selecting lewis acid to be used as reaction promoter, raw material is changed into the in-situ transesterification rate of product close to 100%, so as to be effectively improved reaction yield；
5th, it is of the invention because the impurity produced in reaction is less, it can save and post-process some steps, so as to simplify operating procedure；
6th, the present invention few can be used as the case may be or even without solvent, so as to reduce cost of material.Realize the best mode of the present invention
The present invention will be also further described by following examples and comparative examples, but these embodiments should not be understood as limitation of the present invention.
Embodiment 1
2-methyl isophthalic acid-（4- methyl mercapto phenyl）The preparation of -2- morpholine -1- acetone
Figure IMGF000011_0001
The preparation of 1 isobutyryl chloride
176g (2mol) isobutyric acid is weighed, 137g (lmol) phosphorus trichloride is added in above-mentioned solution, reaction separates upper strata , Minus pressure distillations and obtains isobutyryl chloride after 8 hours, static 0.5 hour.
2. 2- methyl-1- (4-methyl mercapto phenyl）The preparation of -1- acetone
Weigh 248g (2mol) thioanisole, 250ml nitrobenzene, add after 267g (2mol) alchlor and stir 1 hour, isobutyryl chloride is added to react 1 hour, first washed with acidic aqueous solution, alkali liquid washing is used again, layering, obtain after organic phase desolventizing 2-methyl isophthalic acid-（4- methyl mercapto phenyl）- 1- acetone.
3. 2- bromo- 2- methyl -1- (4- methyl mercapto phenyl）The preparation of-1-acetone
By 386g (2mol) 2- methyl-1- (4-methyl mercapto phenyl）- 1- acetone solutions are in 400ml carbon tetrachloride, and Slow is added drop-wise in the solution configured above slowly after 320g (2mol) bromines are diluted with 270ml carbon tetrachloride, and stirring makes reaction complete in 1 hour after completion of dropping.Nitrogen blowing drives the bromination hydrogen dissolved in solution away, is evaporated off obtaining the above-mentioned products of 524g after solvent, content 97.8%, above three step total recoverys be 93.8%.
4. 2- methyl -1- (4- methyl mercapto phenyl）The preparation of-2-morpholine-1-acetone
Weighing 143g (98.7% content,.^！The bromo- ^- methyl of ^ Shang ^--：！- ^- first ^^ base phenyl）- 1- acetone and 500ml petroleum ethers, add 174g (2mol) beautiful jade, add the g of alchlor 13., back flow reaction 5 hours.Add hydrochloric acid and adjust pH value 2 or so, aqueous phase is added drop-wise in 30% sodium hydroxide solution after layering, separate out faint yellow solid, crude product is obtained after filtering, the purpose compound of pale white crystals is obtained after being recrystallized with mixed solvent, filtering is weighed as 130g, content 99.4%, yield 927% after drying.
Embodiment 2
The preparation of 1-Ν, Ν-methylbenzylamino-8,9-dichloro- heptadecyl 4- Phenylsulfanylphenyl ketones
Figure IMGF000012_0001
1. the preparation of cis -9- octadecylenes acid chloride
13.1g (0.11mol) thionyl chloride is weighed, is added drop-wise under 40-50 °C in 28.2g (0.1mol) oleic acid solutions, is reacted 6 hours.Unreacted thionyl chloride is sloughed in heating.
The preparation of the cis alkenyl 4- Phenylsulfanylphenyl ketones of -9- 17 of 2-
Weigh 20.5g (0.11mol) diphenyl sulfide, 80mll, 2- dichloroethanes, stirred 1 hour after 16.0g (0.12mol) alchlor is added under 5 °C of 0-, solution of acid chloride prepared above is added dropwise, time for adding is 1 hour, continue to be warming up to 30-35 °C of insulated and stirred after stirring 2 hours 0.5 hour, then dilute hydrochloric acid solution washing is added, it is washed with water to neutrality, obtain 1, the 2- dichloroethane solutions of cis-9-ten seven alkenyl 4- Phenylsulfanylphenyl ketone crude products.
3. the preparation of the chloro heptadecyl 4- Phenylsulfanylphenyl ketones of 2,8,9- tri-
To the 1 of the above-mentioned alkenyl 4- Phenylsulfanylphenyl ketone crude products of cis -9- 17,30ml acetic acid is added in 2- dichloroethane solutions, it is cooled to 25 °C of 10-, Slow is passed through 27.3g (0.3mol) chlorine slowly, logical chlorine time control was at 1.5 hours or so, continue to stir 1 hour, then pass to nitrogen bubble, drive chlorine and hydrogen chloride gas excessive in system away, solvent is evaporated off, is recrystallized with ethyl acetate, the crystallization of 45.5g grey sheets is obtained, content 98.6%, above three step total recoverys be 80.7%.
The preparation of 4- 1-N, N-methylbenzylamino-8,9- dichloro- heptadecyl 4-Phenylsulfanylphenyl ketone
80gN- methylbenzylamines are weighed, 45.5g (98.6% content, 0.08mol) 2,8,9- tri- chloro heptadecyl 4- Phenylsulfanylphenyls ketones and 15.6g (0.10mol) iron chloride are added at room temperature, are reacted 5 hours at 50 °C.Adding 10% sodium hydroxide solution adjusts pH value to 13-14, separates out white solid, and white crystals are obtained after being recrystallized after filtering with methanol solvate, and filtering is weighed as 46.8g, content 99,5, yield 90.8% after drying.
Embodiment 3
The preparation of 1- piperidines butylcyclohexyl 4-chlorphenyl ketones
Figure IMGF000014_0001
1. the preparation of cyclohexanecarbonyl chloride
Weigh 13.1g (0.22mol) thionyl chloride, Slow is added drop-wise in 25.6g (0.2mol) cyclohexanecarboxylic acid solution slowly at room temperature, continue to stir 2 hours after completion of dropping, then temperature rising reflux 1 hour, then be down to room Warm.
2. the preparation of cyclohexyl 4- chlorphenyl ketones
80ml carbon tetrachloride and 24.8g (0.22mol) chlorobenzene are added in solution of acid chloride prepared above, add after 32.0g (0.24mol) alchlor and stir 3 hours under 5-1CTC, 20 °C of 15- insulated and stirreds 0.5 hour are warming up to again, then dilute hydrochloric acid solution washing is added, it is washed with water to neutrality, obtains the carbon tetrachloride solution of cyclohexyl 4-chlorphenyl ketone crude product.
3. the preparation of 1- chlorocyclohexyl 4- chlorphenyl ketones
20ml acetic acid is added to the carbon tetrachloride solution of above-mentioned cyclohexyl 4- chlorphenyls ketone crude product, 10 °C of Warm to 5- drops, Slow is passed through 35.5g (0.5mol) chlorine slowly, logical chlorine time control continued to stir 2 hours at 2 hours or so, and solvent is evaporated off in Sheng Wen Minus pressures, recrystallized with methanol, obtain 45.7g white crystals, content 99.6%, above three step total recoverys be 88.5%.
4. the preparation of 1- piperidines butylcyclohexyl 4- chlorphenyl ketones
Weigh 100ml ethyl acetate, 45.7g (99.6% contents are added under the Warm of room, 0.18mol) 1-chlorocyclohexyl 4- chlorphenyls ketone, stirring complete molten rear addition 15.3g (0.18mol) piperidines and 6.8g (0.10mol) boron trifluoride, react 5 hours at 50 °C.Adding 10% sodium hydroxide solution adjusts pH value to 13-14, and upper strata You Xiang Minus pressure-offs are gone into solvent after layering, and white crystals are obtained after being recrystallized with methanol solvate, and filtering is weighed as 51.6g, content 99.4%, yield 93.3% after drying.
Embodiment 4
1- (the n-butyl amine bases of N, N- bis-）The preparation of -1- phenyl -2- acetone
Figure IMGF000015_0001
1. the preparation of the bromo- 1- phenyl -2- acetone of 1-
80ml sulfuric acid is added into 80ml acetic acid, benzyl methyl ketone 26.8g (0.2mol) is added dropwise at room temperature, 20 °C of 15- is cooled to again, the lower Slow of stirring is added dropwise Slow after 32.0g (0.2mol) bromine, completion of dropping and is warming up to 50-60 °C slowly slowly, continues to stir 3.5 hours, stop stirring, in 50-, 60 °C stand 0.5 hour, and layering, upper oil phase directly carries out next step reaction.
2. the preparation of 1- N, N- di-n-butyl amino -1- phenyl -2- acetone
Weigh 80ml dichloroethanes, bromo- 1- phenyl -2- acetone crude products of 1- prepared above at room temperature, stirring is lower to add 14.4g (0.2mol) di-n-butyl amine, and 47.4g (0.25mol) titanium tetrachloride is added dropwise in Slow slowly, is reacted 5 hours at 50 °C.It is cooled to 15 °C of 10-, Slow adds 10% sodium hydroxide solution and adjusts pH value to 13-14 , Minus pressure-offs to go to obtain pale white crystals after being recrystallized with methanol solvate after dichloroethanes slowly, and filtering is weighed as 39.5g after drying, content 99.1%, yield 95.8%.
- 2-imidazole radicals of 2- methyl of embodiment 5-2- propionic aldehyde
Figure IMGF000015_0002
The chloro- 2 methyl propanals of 36.0g (0.5mol) 2- and 50ml petroleum ethers are weighed, 47.6g (0.7mol) imidazoles is added, zinc chloride 25.4g (0.2mol) is added, 60 °C are reacted 5 hours.Dilute hydrochloric acid solution is added, pH=l 2 is adjusted, 30% sodium hydroxide solution is added dropwise to aqueous phase in static layering, pH=8 9 are adjusted, oily liquids , Minus pressure distillations is separated out and obtains pale yellow oily liquid, it is weighed as 63.2g, content 98.7%, yield 90.4%.
Embodiment 6 1- (1-naphthyls） -2The preparation of-pyrazolyl ethyl ketone
Figure IMGF000016_0001
By 12.5g (0.05mol) 1- (1-naphthyls）- 2-bromo ethyl ketone, 6.8g (0. Imol) pyrazoles are added in 30ml petroleum ethers, then add alchlor 6.7g (0.05mol), are reacted 4 hours under 45 °C.10% sodium hydroxide solution is added, pH=13 14, static layering, upper oil phase adds 0.5g activated carbons, it is heated to reflux decolourizing 0.5 hour, decrease temperature crystalline after heat filtering obtains white solid, ll.lg, content 99.4%, yield 93.8% are weighed as after drying.
Embodiment 7
The preparation of 2-N, N- diphenyl amino cyclohexanone
Figure IMGF000016_0002
17.7g (0.1mol) 2- bromos cyclohexanone, 16.9g (0. Imol) diphenylamines are added in 60ml dichloroethanes, zinc chloride 13.6g is then added, reacted 3 hours under 40 °C.Dilute hydrochloric acid solution is added, pH=l 2 is adjusted, static layering is added dropwise 30% sodium hydroxide solution to aqueous phase, adjusts pH=8 9, separates out yellow solid, 25.7g, content 99.5%, yield 96.6% are weighed as after drying.
The L- 1-N- NSC 77136 base amino-3- of embodiment 8-methylphenyl-sulfonamido）The preparation of -4- phenyl -2- butanone
Figure IMGF000016_0003
By 35.2g (0.1mol) L-l- chloro- 3- (4- methylphenyl-sulfonamidos）- 4-phenyl-2-butanone is added to 50ml carbon tetrachloride, adds 28.4g (0.1mol) positive 19 amine, adds zinc chloride 14.0g (0.11mol), back flow reaction 4 hours.10% sodium hydroxide solution is added, pH=13 14 are adjusted, static layering, lower floor's You Xiang Minus pressure-offs are molten, are solvent recrystallization with ethyl acetate, orange-yellow pulverulent solids are obtained, 57.7g, content 98.5%, yield 94.8% are weighed as after drying.
Comparative examples 1
Direct method preparation 2- methyl isophthalic acids-（4- methyl mercapto phenyl）- 2- morpholine -1- acetone
1. the bromo- 2-methyl-1- of 2-（4-methyl mercapto phenyl）The preparation of-1-acetone
2-bromo- 2- methyl-1-（4- methyl mercapto phenyl）The preparation be the same as Example 1 of -1- acetone.2- 2- methyl-1-（4-methyl mercapto phenyl）The preparation of-2--1-acetone of morpholine
Weigh 143g (98.7 contents, 0.5mol) 2-bromo- 2-methyl isophthalic acid-(4- methyl mercapto phenyl）- 1-acetone, power σ enters to react 10 hours under 200ml dimethylbenzene and 174g (2mol) p woodss, reflux state.Add hydrochloric acid and adjust pH value 2 or so, with xylene extraction twice, aqueous phase is added into 30% liquid caustic soda after layering and adjusts pH value to alkalescence, separate out faint yellow solid, crude product is obtained after filtering, pale white crystals are obtained after being recrystallized with mixed solvent, filtering is weighed as 92.2g after drying, content 98.9%, yield 65.3%.
Comparative examples 2
Using epoxy intermediate method prepare 2- methyl isophthalic acids-（4- methyl mercapto phenyl）- 2--1-acetone of morpholine
The bromo- 2- methyl isophthalic acids of 1-2--(4-methyl mercapto phenyl）The preparation of-1-acetone
The bromo- 2- methyl isophthalic acids of 2--(4- methyl mercapto phenyl）The preparation be the same as Example 1 of -1- acetone.2- 3,3- dimethyl -2- methoxyl groups -2- (4- methyl mercapto phenyl）29.7g (0.55mol) sodium methoxide is dissolved in 150ml methanol by the preparation of oxirane, is heated with stirring to backflow, weighs 143g (98.7% content, 0.5mol) 2- bromo-2- methyl -1- (4- methyl mercapto phenyl）- 1-acetone solution is in 100ml methanol, solution after dissolving is added drop-wise in sodium methoxide solution, stirred at reflux 1 hour after completion of dropping, distillating carbinol solvent, residue is poured into frozen water, ether layer is washed after being extracted with ether once, and anhydrous sodium sulfate drying , Nong Shrink Hou Minus pressure distillation coolings are obtained Epoxide 3,3- dimethyl-2- methoxyl groups-2-（4- methyl mercapto phenyl）The crystal sterling of oxirane.
3,2- methyl -1-（4-methyl mercapto phenyl）The preparation of-2-morpholine-1-acetone
To 3,3--2-methoxyl groups of dimethyl-2- (4- methyl mercapto phenyl）348g (4mol) morpholine is added in oxirane, reflux state is heated to and reacts 15 hours.It is evaporated off after morpholine being extracted with ether, extract adds 10% aqueous hydrochloric acid solution and adjusts pH value 2 or so, aqueous phase is added into 30% liquid caustic soda after layering and adjusts pH value 13 or so, again Hou Nong Shrink are extracted with ether, then ethyl alcohol recrystallization is used, pale white crystals are obtained, filtering is weighed as 101g after drying, content 98.3%, two step total recoverys are 71 .6%.
Be not difficult to find out by the above embodiments 1-5 and comparative examples -2, the method for the invention have simplify reactions steps, that reaction condition is gentle, the reaction time is short, conversion ratio is high etc. is excellent/,, ° industrial applicability
Formula of the present invention（I) the method for compound, it uses lewis acid as reaction promoter, can greatly improve the conversion ratio of raw material, simplify reactions steps, and reaction condition is become Warm and reaction time shortening, so as to save the energy, improve utilization rate of equipment and installations and yield.Due to present invention process, operation is simple, therefore is easy to industrialized production.

Claims (1)

  1. Wooden fork profit is required
    1, one kind prepares following formula（I) the method for compound,
    R1R2-C(Q)-C0R5(I) in formula：
    R1And R2Hydrogen is represented alone；（^ _23Straight or branched alkyl is replaced by one or more substituents23Straight or branched alkyl, the substituent is selected from hydroxyl, 1 plain, low Grade alkoxies and low Grade alkylthio groups；Five yuan or hexa-atomic cyclic hydrocarbon radical or heterocycle alkyl；Aryl or the aryl replaced by one or more substituents, the substituent are selected from element, hydroxyl, sulfydryl, low Grade alkyl, low Grade alkoxies, low Grade alkane coloured glaze base, phenoxy group, thiophenyl and benzylthio；Or R1And R2It is connected to form five yuan or hexa-atomic cyclic hydrocarbon radical or heterocycle alkyl；
    R5Hydrogen is represented alone；（^ _23Straight or branched alkyl is replaced by one or more substituents23Straight or branched alkyl, the substituent is selected from element, hydroxyl, low Grade alkoxies, low Grade alkylthio groups, the alkyl-substituted phenylsulfonyl-amidos of paper Grade and benzyl；Five yuan or hexa-atomic cyclic hydrocarbon radical or heterocycle alkyl；Aryl or the aryl replaced by one or more substituents, the substituent Xuan Zi Halogen elements, hydroxyl, sulfydryl, C foretell12Alkyl,（：Foretell12Alkoxy or alkenyloxy group, C3— 12Cycloalkyloxy or cyclenes epoxide, _12Alkylthio group or alkenylthio group, C3 12Cycloalkylthio or cyclenes sulfenyl, replaced by hydroxyl, low Grade alkyl or low Grade alkoxies（：Foretell12Alkylthio group, replaced by the alkyl-substituted amino of low Grade（Foretell12Alkylthio group, C foretell12Alkyl-dithio or alkene disulfide group ,-12Alkane sulfonyl or alkene sulfonyl,12Alkane sulfinyl or alkene sulfinyl, phenoxy group, thiophenyl, by the alkyl-substituted thiophenyls of low Grade, phenyl disulfide group, phenyl sulfonyl, the thin acyl group in phenyl Asia and benzylthio；
    Or R1、 R2With R5It is joined directly together to form five yuan to octatomic ring ketone；
    Q representatives-NR3R4,
    Wherein R3And R4Hydrogen is represented alone；（^ _23Straight or branched alkyl or replaced by one or more substituents _23Straight or branched alkyl, the substituent is selected from hydroxyl, low Grade alkoxies and low Grade alkylthio groups；Aryl or the aryl replaced by one or more substituents, the substituent choosing From halogen, hydroxyl, sulfydryl, low alkyl group, low Grade alkoxies, low Grade alkylthio groups, phenoxy group, thiophenyl and benzylthio；
    Or R3And R4Formed together with connected nitrogen-atoms containing 1 to 3 nitrogen, five yuan of oxygen heteroatom or hexa-member heterocycle base；
    Characterized in that, in the presence of a lewis acid, there is solvent or in the absence of solvent in the case of, make formula（II) a-l is for ketone or (1-1 is for aldehyde and formula（Π Ι) amines reacted,
    RiR2 - CX OR5 (II)
    Wherein R R2And R5As defined above,
    X1Represent fluorine, chlorine or bromine；
    Q— H (III)
    Q is as defined above in formula.
    Methods of the 2- according to wooden fork profit requires 1,
    Characterized in that,
    In formula（I) in compound：
    R1And R2Hydrogen is represented alone； ς_12Straight or branched alkyl or replaced by one or more substituents _12Straight or branched alkyl, described substituent is selected from hydroxyl, element, low Grade alkoxies and low Grade alkylthio groups；Five yuan or hexa-atomic cycloalkyl or Heterocyclylalkyl；Phenyl, benzyl, pyridine radicals or pyrimidine radicals；The phenyl replaced by one or more substituents, the substituent is selected from halogen, hydroxyl, sulfydryl, low alkyl group, lower alkoxy, low Grade alkylthio groups, phenoxy group, thiophenyl and benzylthio；Or R1And R2It is connected to form five yuan or hexa-atomic cycloalkyl or Heterocyclylalkyl；
    R5Hydrogen is represented alone； (^—12Straight or branched alkyl is replaced by one or more substituents（：Foretell12Straight or branched alkyl, described substituent is selected from halogen, hydroxyl, low Grade alkoxies, low Grade alkylthio groups, the alkyl-substituted phenylsulfonyl-amidos of paper Grade and benzyl；Five yuan or hexa-atomic cycloalkyl or Heterocyclylalkyl；Phenyl, naphthyl or anthryl；The phenyl replaced by one or more substituents, the substituent be selected from halogen, hydroxyl, sulfydryl,8Alkyl,（^_8Alkoxy or4Alkenyloxy group, C3 _8Cycloalkyloxy,8Alkylthio group or4Alkenylthio group, C3 8Cycloalkylthio, the low Grade alkylthio groups, alkyl-substituted by low Grade replaced by hydroxyl, low Grade alkyl or low Grade alkoxies Low Grade alkylthio groups that amino is replaced, low Grade alkyl-dithios, low Grade alkyl sulfonyl, low Grade Alkylsulfinyls, phenoxy group, thiophenyl, by the alkyl-substituted thiophenyls of low Grade, phenyl disulfide group, phenyl sulfonyl, phenylsulfmyl and benzylthio；
    Or R1、 R2With R5It is joined directly together to form five to octatomic ring ketone；
    Q representatives-NR3R4 ,
    Wherein R3And R4Hydrogen is represented alone；C foretells12Straight or branched alkyl is replaced by one or more substituents12Straight or branched alkyl, described substituent is selected from hydroxyl, low Grade alkoxies and low Grade alkane and dredges base；Phenyl, benzyl, pyridine radicals or pyrimidine radicals；The phenyl replaced by one or more substituents, the substituent is selected from 1 element, hydroxyl, sulfydryl, lower alkyl bases, low Grade alkoxies, low Grade alkylthio groups, phenoxy group, thiophenyl and benzyl and dredges base；
    Or R3And R4Formed together with connected nitrogen-atoms containing 1 to 3 nitrogen, five yuan of oxygen heteroatom or hexa-member heterocycle base.
    Methods of 3, according to wooden fork profit requires 2,
    Characterized in that, in formula（I in),
    R1And R2Hydrogen is represented alone；Lower straight or branched hydrocarbyl or by one or the low Grade straight or brancheds alkyl of two substituents substitution, described substituent are selected from hydroxyl, from plain, low Grade alkoxies and low Grade alkylthio groups；Five yuan or hexa-atomic cycloalkyl；Phenyl or benzyl；By the phenyl of one or two substituent substitution, the substituent is selected from 1 element, hydroxyl, sulfydryl, low Grade alkyl, low Grade alkoxies, low Grade alkylthio groups, phenoxy group, thiophenyl and benzylthio；Or R1And R2It is connected to form five yuan or hexa-atomic cycloalkyl or Heterocyclylalkyl；
    R5Hydrogen is represented alone；Low Grade straight or brancheds alkyl or the low Grade straight or brancheds alkyl by one or two substituent substitution, described substituent are selected from element, hydroxyl, low Grade alkoxies, low Grade alkylthio groups, the phenylsulfonyl-amido and benzyl of low alkyl group substitution；Five yuan or hexa-atomic cycloalkyl or Heterocyclylalkyl；Phenyl or naphthyl；By one or the phenyl of two substituents substitution, the substituent be selected from halogen, hydroxyl, sulfydryl, _8Alkyl, _8Alkoxy or4Alkenyloxy group,
    。6 _ 8Cycloalkyloxy,（^ _8Alkylthio group or4Alkenylthio group, c6 _ 8Cycloalkylthio, by hydroxyl, low Grade alkyl or low Grade alkoxies replace low Grade alkylthio groups, by the alkyl-substituted amino institutes of low Grade Substitution low Grade alkane υ bases, low Grade alkyl-dithios, low Grade alkyl ^ I acyl groups, low Grade Alkylsulfinyls, phenoxy group, thiophenyl, by the alkyl-substituted thiophenyls of low Grade, phenyl disulfide group, phenyl ^<The sub- a word used in place name acyl group of acyl group, phenyl and benzyl coloured glaze base；
    Or R1、 R2With R5It is joined directly together to form five yuan to octatomic ring ketone；
    Q representatives-NR3R4,
    Wherein R3And R4Hydrogen is represented alone；Low Grade straight or brancheds alkyl or the lower straight replaced by one or two substituents or branched hydrocarbyl, the substituent are selected from hydroxyl, low Grade alkoxies and lower alkylthio；Phenyl or benzyl；By the phenyl of one or two substituent substitution, the substituent is selected from element, hydroxyl, sulfydryl, low Grade alkyl, low Grade alkoxies, low Grade alkylthio groups, phenoxy group, thiophenyl and benzylthio；
    Or R3And R4Formed together with connected nitrogen-atoms containing 1 to 3 nitrogen, five yuan of oxygen heteroatom or hexa-member heterocycle base.
    Methods of 4, according to wooden fork profit requires 3,
    Characterized in that, in formula（I in),
    R1And R2Hydrogen is represented alone；Low Grade straight or branched alkyls or the lower straight replaced by one or two substituents or branched alkyl, described substituent are selected from hydroxyl, element, low Grade alkoxies and low Grade alkylthio groups；Five yuan or hexa-atomic cycloalkyl；Phenyl or benzyl；By the phenyl of one or two substituent substitution, the substituent is selected from element, hydroxyl, sulfydryl, low Grade alkyl, low Grade alkoxies, low Grade alkylthio groups, phenoxy group, thiophenyl and benzylthio；Or R1And R2It is connected to form five yuan or hexa-atomic cycloalkyl；
    R5Hydrogen is represented alone；Low Grade straight or branched alkyls or the low Grade straight or branched alkyls by one or two substituent substitution, described substituent are selected from element, hydroxyl, low Grade alkoxies, low Grade alkane and dredge base, the alkyl-substituted phenylsulfonyl-amidos of paper Grade and benzyl；Five yuan or hexa-atomic cycloalkyl；Phenyl or naphthyl；By the phenyl of one or two substituent substitution, the substituent is selected from！Element, hydroxyl, sulfydryl, low Grade alkyl, low Grade alkoxies, low Grade alkylthio groups, phenoxy group and thiophenyl；Or R R2With R5It is joined directly together to form five yuan to octatomic ring ketone；
    Q representatives-NR3R4, Wherein R3And R4Hydrogen is represented alone；Low Grade straight or branched alkyls or the low Grade straight or branched alkyls by one or two substituent substitution, the substituent are selected from hydroxyl, low Grade alkoxies and low Grade alkylthio groups；Phenyl or benzyl；By the phenyl of one or two substituent substitution, the substituent is selected from | | element, hydroxyl, sulfydryl, low Grade alkyl, low Grade alkoxies, low Grade alkylthio groups, phenoxy group, benzene dredge base and benzylthio；
    Or R3And R4Formed together with connected nitrogen-atoms containing 1 to 3 nitrogen, five yuan of oxygen heteroatom or hexa-member heterocycle base.
    Methods of 5, according to wooden fork profit requires 3,
    Characterized in that, in formula（I in),
    R1 . R2 R3、 R4And R5Representative low Grade straight or brancheds alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, vinyl, pi-allyl, acrylic, acetenyl, propargyl or propinyl；For described for the low Grade straight or brancheds alkyl of one or two substituent substitution, wherein described substituent is selected from fluorine, chlorine, bromine, hydroxyl, methoxyl group, ethyoxyl, methyl mercapto and ethylmercapto group；
    R1And R2It is that ring defends base, cyclohexyl, tetrahydrofuran base or tetrahydro-thienyl to be connected to form five yuan or hexa-atomic cycloalkyl or Heterocyclylalkyl；
    R5Five yuan represented or hexa-atomic cycloalkyl or Heterocyclylalkyl defend base, cyclohexyl, tetrahydrofuran base or tetrahydro-thienyl as ring；
    For R R R3And R4For the phenyl replaced by one or two substituents represented, wherein described substituent is selected from fluorine, chlorine, bromine, hydroxyl, sulfydryl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, methyl mercapto, ethylmercapto group, positive rosickyite base, isopropyl a word used in place name υ bases, positive butylthio, phenoxy group, thiophenyl and benzylthio；
    For R5For the benzene replaced by one or two substituents represented, wherein described substituent, which is selected from fluorine, chlorine, bromine, hydroxyl, sulfydryl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, positive epoxide in heptan, n-octyloxy, allyloxy, ring, defends base epoxide, cyclohexyl epoxide, methyl mercapto, ethylmercapto group, positive rosickyite base, isopropyisulfanyl, positive butylthio, positive sulfenyl in heptan, just pungent sulfenyl, allyl sulfenyl, cyclopentylthio, cyclohexylthio, 2- hydroxyl second Dredge base, methyl disulfide group, ethyoxyl ethylmercapto group, two Yue amino methyl mercaptos, first sulfonyl, methyl sulfinyl, phenoxy group, thiophenyl, to methylphenyl-sulfanyl, phenyl disulfide group, phenoxy group, benzene coloured glaze base and the thin base of virtue；
    R3And R4It is pyrrole radicals, pyridine radicals, imidazole radicals, triazolyl, tetrazole radical, different fish sticking its mouth out of the water oxazolyl, oxazolyls, di azoly, piperidyl, morpholinyl, indyl, indazolyl, benzimidazolyl or carbazyl to be formed together with connected nitrogen-atoms containing 1 to 3 nitrogen, five yuan of oxygen heteroatom or hexa-member heterocycle base.
    Methods of 6, according to wooden fork profit requires 4,
    Characterized in that, in formula（I in),
    R2、 R3、 R4And R5Representative low Grade straight or branched alkyls are methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group；
    R1And R2It is connected to form cyclohexyl；
    R R2、 R3And R4For phenyl or benzyl；
    R5For phenyl or naphthyl, the representative substituent on the phenyl of one or two substituent substitution is chlorine, methyl mercapto or thiophenyl；
    R R2With R5It is joined directly together to form hexa-atomic cyclic ketones；
    R3And R4Pyrrole radicals, pyrazolyl, imidazole radicals, piperidyl or morpholinyl are formed together with connected nitrogen-atoms.
    7th, the method according to wooden fork profit requires 1,
    Characterized in that, prepared compound is following compounds：
    2- methyl-1-（4- methyl mercapto phenyl）- 2-morpholine-1- acetone；
    1- Ν, Ν-methylbenzylamino-8,9-dichloro- heptadecyl 4-Phenylsulfanylphenyl ketone；
    1- piperidines butylcyclohexyl 4-chlorphenyl ketones；
    1- (Ν, Ν-di-n-butyl amino）- 1- phenyl -2- acetone；
    2- methyl -2- imidazole radicals -2- propionic aldehyde；
    1- (1- naphthyls）- 2-pyrrole miaow base ethyl ketone；
    2-Ν, Ν-diphenyl amino cyclohexanone； L-l- N- NSC 77136 base amino -3- (4- methylphenylsulfonyl amino) -4- phenyl -2_ butanone.
    8. the method according to any one of wooden fork profit requires 1 to 7,
    Characterized in that, described lewis acid is selected from boron trifluoride, alchlor, zinc chloride, ferric trichloride, stannic chloride, copper chloride, antimony chloride, titanium tetrachloride and polyphosphoric acids.
    9. the method according to wooden fork profit requires 8,
    Characterized in that, described lewis acid is selected from alchlor and zinc chloride.
    10. the method according to any one of wooden fork profit requires 1 to 7,
    Characterized in that, described formula（II) α -!For ketone or α-for aldehyde, formula（Ι Π) mol ratio between amines and lewis acid is 1： 0.2—30： 0.01— 10.
    11. the method according to wooden fork profit requires 10,
    Characterized in that, described formula（II) α-for ketone or α-！For aldehyde, formula（III) mol ratio between amines and lewis acid is 1： 0.5—5: 0.1— 2.
    12. the method according to any one of wooden fork profit requires 1 to 7,
    Its special ￡ is that the temperature reacted is 0 °C -120 °C.
    13. the method according to wooden fork profit requires 12,
    Characterized in that, the temperature reacted is io ° of c -6o ° of c.
    14. the method according to any one of wooden fork profit requires 1 to 7,
    Characterized in that, the time reacted is 0.2-20 hours.
    15. the method according to wooden fork profit requires 14,
    Characterized in that, the time reacted is 0.5-5 hours.
    16. the method according to any one of wooden fork profit requires 1 to 7,
    Characterized in that, when the reaction is using solvent, suitable solvent is ketone, nitrile, fat hydrocarbon, 1 generation hydro carbons, ethers or esters.
    17. the method according to wooden fork profit requires 16,
    Characterized in that, suitable solvent is acetone, butanone, acetonitrile, n-hexane, petroleum ether, dichloromethane, chloroform, 1,2-dichloroethanes, 1,1,2,2- tetrachloroethanes, 1,1,2- trichloro ethylene, ether or ethyl acetate.
CNA018179630A 2000-11-21 2001-11-21 Method for preparing carbonyl alpha-substituted nitrogen compounds Pending CN1471506A (en)

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CN101659644B (en) * 2008-08-26 2011-04-20 天津英力科技发展有限公司 Method for synthesizing 2-methyl-1-[4-(methylthio)phenyl]-2-(4-morpholinyl)-1-propanon
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