CN103232406B - A kind of 1,3-thiazoles derivative - Google Patents
A kind of 1,3-thiazoles derivative Download PDFInfo
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- RGCLONGWTAZLTF-UHFFFAOYSA-N CCN(C(c(cc1)ccc1OC)=O)c1nc(-c2ccccc2)c[s]1 Chemical compound CCN(C(c(cc1)ccc1OC)=O)c1nc(-c2ccccc2)c[s]1 RGCLONGWTAZLTF-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention provides a kind of 1,3-thiazole derivative and synthetic method thereof, carbodiimide, acyl chlorides, terminal alkyne compound and elemental sulfur is utilized to prepare 2-amide thiazole derivant, productive rate is higher, synthetic method is scientific and reasonable, thus provides the universal method that a synthesis has multiple substituent 2-amide thiazole derivant.The method raw material is easy to get, applied widely, high isolated yield, experimental installation and operation is simple, is convenient to further Application and Development.
Description
Technical field
Medicinal chemistry art of the present invention, is specifically related to a kind of 1,3-thiazoles derivative, particularly relates to 2 1,3-thiazoles derivatives and synthetic method thereof be substituted.
Background technology
1,3-thiazoles derivative serves many purposes in organic synthesis field, is common synthetic intermediate.
Wherein, 2-amide thiazole compound has antibacterial, anticancer antineoplastic activity, as protein kinase inhibitors, also can be used as the antagonistic drug of Chemokine Receptors, anti-Adenosine Receptors, also have anesthetic action at field of medicaments simultaneously.
As described below, report 2-amide thiazole compound and there is antibacterial, anticancer anti-tumor application.
" Ureas of5-Aminopyrazole and2-Aminothiazole Inhibit Growth of Gram-Positive Bacteria.Bioorg.Med.Chem.Lett.2003; 13,4463 " describes the growth that 2-amide thiazole can suppress gram negative bacterium." Synthesis and Antimicrobial Activity of2-Aminothiazole Derivatives.IJPSR2010, 1, 67 ", " Microwave Mediated Cyclocondensation of2-aminothiazole into β-lactam Derivatives:Virtual Screening and In Vitro Antimicrobial Activity with Various Microorganisms.Int.J.ChemTech Res.2010, 2, 956 " and " Synthesis and Antimicrobial Activity of Some Novel2-Amino Thiazole Derivatives.J.Chem.Pharm.Res.2010, 2, 691 " all describe 2-amide thiazole and there is anti-microbial activity." Discovery of2-Aminothiazole Derivatives as Antitumor Agents.Bull.Korean Chem.Soc.2010; 31; 1463 " and " Substituted Thiazoles VI.Synthesis and Antitumor Activity of New2-Acetamido-and2or3-Propanamido-Thiazole Analogs.Eur.J.Med.Chem.2012; 54,615 " describes 2-amide thiazole and has Anticancer activity.“N-(Cycloalkylamino)acyl-2-aminothiazole Inhibitors ofCyclin-Dependent Kinase2.N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-
4-piperidinecarboxamide (BMS-387032), a Highly Efficacious and Selective Antitumor Agent.J.Med.Chem.2004,47,1719 " describe 2-amide thiazole and can be used as same cyclin-dependent kinase inhibitor.Describing 2-amide thiazole can as cyclin-denpendent kinase inhibitor for " Discovery and SAR of2-Aminothiazole Inhibitors of Cyclin-Dependent Kinase5/p25as a Potential Treatment for Alzheimer ' s Disease.Bioorg.Med.Chem.2004; 14; 5521 " and " Structure-Based Drug Design to the Discovery of New2-Aminothiazole CDK2Inhibitors.J.Mol.Graph.Model.2006; 24,341 "." Design; Synthesis; and Cytoprotective Effect of2-Aminothiazole Analogues as Potent Poly (ADP-Ribose) Polymerase-1Inhibitors.J.Med.Chem.2009; 52,718 " describes 2-amide thiazole and can be used as polyadenosine ribose phosphoric acid polysaccharase-1 inhibitor." 2-Aminothiazole Derivative as a New Class of TrkA Kinase Inhibitor.Bull.Korean Chem.Soc.2011,32,2893 " describe 2-amide thiazole and can be used as trk C kinase inhibitor." Discovery and Optimization of a Series of 2-Aminothiazole-Oxazoles as Potent Phosphoinositide3-Kinase γ Inhibitors.Bioorg.Med.Chem.Lett.2012; 22,7534 " describes 2-amide thiazole and can be used as phosphoric acid acyl inositol 3 kinase inhibitor." Screening of Thiourea Derivatives and Carbonyl-2-Aminothiazole Derivatives for Potential CCR4Antagonists Using Capillary Zone Electrophoresis.J.Chromatogr.B2011; 879,75 " describes 2-amide group and can be used as Chemokines CC-C-primitive acceptor 4 antagonistic drug." Design and Synthesis of2-Aminothiazole Based Antimicrobials Targeting MRSA.Bioorg.Med.Chem.Lett.2012; 22,7719 " describes 2-amide thiazole and can be used as anti-Adenosine Receptors A1 and muscarinic receptor M1, M2 antagonistic drug acetylcholinesterase depressant." Validated Quantitative Structure – Activity Relationship Analysis of a Series of2-Aminothiazole Based p56
lckinhibitors.Analytica Chimica Acta2009,631,29 " describing core texture is that 2-amide thiazole can be used as tyrosine protein matter kinases p56
lckinhibitor." Synthesis and Local Anaesthetic Activities of2-Aminothiazole/Thiadiazole Analogues of Lidocaine.Med.Chem.Res.2012,21,1544 " describe 2-amide thiazole and have narcotic activity.
But the synthetic method complex operation of 2-amide group-1,3-thiazoles derivative that current document provides, the kind of substituting group group is restricted.
Summary of the invention
The invention provides a kind of 1,3-thiazoles derivative, especially 2 thiazole derivatives be substituted.More specifically, a kind of 2 1,3-thiazoles derivatives replaced by amide group are provided.
The present invention also provides a kind of synthetic method of 2 1,3-thiazoles derivatives be substituted, the especially synthetic method of 2-amide thiazole.This synthetic method is from the general chemical industry Material synthesis 2-amide thiazole be cheaply easy to get, and efficiency is high, and cost is low, compared with existing method, has larger advantage.
Technical scheme of the present invention is as follows:
The compound that a kind of general formula (1) represents,
In formula,
X is S or N, Y is S or N, condition be X with Y different time be S, be N time also different,
R
0, R
1, R
2and R
3identical or different, represent hydrogen atom, hydroxyl, halogen, pseudohalogen, substituted or non-substituted C
1-12alkyl, substituted or non-substituted C
1-12alkoxyl group, substituted or non-substituted C
2-12alkoxy carbonyl, substituted or non-substituted C
6-12aryl, non-substituted C
3-7heterocyclic radical, the C be substituted on heterocycle
3-7heterocyclic radical.
Preferably, X is S, Y is N,
R
0be positioned at 5 of thiazole ring, R
1be positioned at 4 of thiazole ring ,-N (R
3) C (O) R
2be positioned at 4 of thiazole ring.
R
0for hydrogen, C
1-12alkyl, C
1-12alkoxyl group,
R
1for substituted or non-substituted C
1-12alkyl, substituted or non-substituted C
1-12alkoxyl group, substituted or non-substituted C
2-12alkoxy carbonyl, substituted or non-substituted C
6-12aryl, non-substituted C
3-7heterocyclic radical, the C be substituted on heterocycle
3-7heterocyclic radical,
R
2, R
3identical or different, represent substituted or non-substituted C
1-12alkyl, substituted or non-substituted C
1-12alkoxyl group, substituted or non-substituted C
6-12aryl, non-substituted C
3-7heterocyclic radical, the C be substituted on heterocycle
3-7heterocyclic radical.
In the present invention, the mode of connection that dotted line represents refers to and forms singly-bound or double bond.
The compounds of this invention preferably has the structure shown in formula (IV)
Wherein, R
1expression can have the one or more substituent C being selected from following A group
1-12alkyl, C
1-12alkoxyl group, C
2-12alkoxy carbonyl, C
6-12aryl and non-substituted C
3-7heterocyclic radical, on heterocycle by the substituting group of following A group replace C
3-7heterocyclic radical, preferably, R
1expression can have the one or more substituent C being selected from following A group
4-12alkyl, C
3-12cycloalkyl, C
6-12aryl and on heterocycle by the substituting group of following A group replace C
3-7heterocyclic radical, most preferably, R
1can be C
4-6alkyl, optionally by C
1-6alkyl replace phenyl, halogen atom replace phenyl, optionally by C
1-6alkyl replace cyclohexenyl, optionally by C
1-6the cyclohexyl that alkyl replaces, sulfur-bearing five yuan or hexa-member heterocycle.
R
2, R
3identical or different, represent to have the one or more substituent C being selected from following B group
1-12alkyl, C
1-12alkoxyl group, C
6-12aryl and non-substituted C
3-7heterocyclic radical, on heterocycle by the substituting group of following B group replace C
3-7heterocyclic radical, more preferably, R
2, R
3to have the one or more substituent C being selected from following B group
1-12alkyl, C
3-12cycloalkyl, C
1-12alkoxyl group, C
6-12aryl and non-substituted C
3-7heterocyclic radical, on heterocycle by the substituting group of following B group replace C
3-7heterocyclic radical, most preferably, R
2c
4-6alkyl, C
3-12cycloalkyl, optionally by C
1-6the phenyl that alkyl replaces, the phenyl optionally replaced by halogen atom, optionally by C
1-6the phenyl that alkoxyl group replaces, the benzyl optionally replaced by halogen atom, cyclohexenyl, cyclohexyl, optionally by C
1-6the cyclohexyl that alkyl replaces, R
3c
4-6alkyl, C
3-12cycloalkyl, optionally by C
1-6the phenyl that alkyl replaces.
The substituting group of A group refers to halogen atom, cyano group, C
1-6alkoxyl group, C
1-6carbalkoxy, C
1-6alkyl, C
1-6haloalkyl, C
2-6alkylidene group, the substituting group of A group is more preferably halogen atom, C
1-6alkyl, C
2-6alkylidene group,
The substituting group of B group refers to halogen atom, cyano group, C
1-6alkoxyl group, C
1-6alkyl, C
1-6haloalkyl, C
2-6alkylidene group, the substituting group of B group is more preferably halogen atom, C
1-6alkoxyl group, C
1-6alkyl, C
1-6haloalkyl, C
2-6alkylidene group.
The synthetic method of the compounds of this invention, comprises the following steps:
A) compound shown in formula (I) and alkide are reacted, then add sulphur simple substance;
B) carbodiimide shown in the acyl chlorides shown in formula (II) and formula (III) is reacted;
C) by step b) reaction mixture add in step reaction mixture a), then improve temperature of reaction;
D) to step c) reaction mixture carry out aftertreatment;
Wherein,
R
1represent substituted or non-substituted C
1-12alkyl, substituted or non-substituted C
1-12alkoxyl group, substituted or non-substituted C
2-12alkoxy carbonyl, substituted or non-substituted C
6-12aryl, non-substituted C
3-7heterocyclic radical, the C be substituted on heterocycle
3-7heterocyclic radical,
R
2, R
3identical or different, represent substituted or non-substituted C
1-12alkyl, substituted or non-substituted C
1-12alkoxyl group, substituted or non-substituted C
6-12aryl, non-substituted C
3-7heterocyclic radical, the C be substituted on heterocycle
3-7heterocyclic radical,
R
4represent substituted or non-substituted C
1-12alkyl.
About the solvent that synthetic method is used, preferred steps a) is reacted in ether solvent one; Step b) react in ether solvent two; Described ether solvent one and ether solvent two identical or different, they are selected from organic ether compounds independently of one another; Further preferably, described step temperature of reaction a) is between the zero pour of described ether solvent one and 0 DEG C; Described step b) temperature of reaction between 25 DEG C and the boiling point of described ether solvent two; More preferably, described ether solvent one and ether solvent two identical or different, they are selected from alkyl oxide, aryl oxide or cyclic ethers, sherwood oil or their mixture independently of one another; Most preferably, described ether solvent one and ether solvent two are selected from ether, tetrahydrofuran (THF), methyltetrahydrofuran or their mixture independently of one another.
About alkide used in synthetic method, be preferably containing lithium alkyl compound, more preferably, be selected from n-Butyl Lithium or tert-butyl lithium.
Synthetic method of the present invention, preferred described step is warming up to room temperature after a) adding sulphur simple substance continuation reaction naturally.
Synthetic method of the present invention, preferred described step c) in temperature of reaction is risen to 60-100 DEG C.
Synthetic method of the present invention, the mol ratio of preferred described carbodiimide, acyl chlorides, formula (I) compound, alkide, sulphur simple substance is 1:(1-1.2): (1-1.2): (1-1.2): (0.125-0.15).
Synthetic method of the present invention, preferred described aftertreatment comprises reaction solution and concentrates, and concentration process adopts air distillation, underpressure distillation or evaporates with Rotary Evaporators.
Synthetic method of the present invention, by chromatographic column separation and purification product in preferred last handling process, eluent is sherwood oil and methylene dichloride mixed solvent, more preferably, sherwood oil and the methylene dichloride mixed solvent of eluent to be volume ratio be 1:1.
2-amide thiazole synthetic method of the present invention, comprises the following steps:
A) terminal alkyne compound shown in formula (I) and alkide are reacted in ether solvent one, temperature of reaction is between the zero pour of described ether solvent one and 0 DEG C; Add sulphur simple substance and continue reaction, be naturally warming up to room temperature;
B) reacted in ether solvent two by the carbodiimide shown in the acyl chlorides shown in formula (II) and formula (III), temperature of reaction is between 25 DEG C and the boiling point of described ether solvent two;
C) reaction solution b) is added in reaction solution a), temperature of reaction is risen to 60-100 DEG C;
D) reaction solution obtains the polysubstituted 2-amide thiazole shown in formula (IV) through aftertreatment;
The primitive reaction formula of above-mentioned reaction process is as follows:
Wherein:
R
1represent:
Carbonatoms is the alkyl of 1-12 or more, such as: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-..., undecyl, dodecyl, tridecyl ..., octadecyl etc., be more preferably C
1-6alkyl;
Carbonatoms is the cycloalkyl of 3-6, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
Carbonatoms is the thiazolinyl of 1-12, such as propenyl, cyclohexenyl etc.;
Carbonatoms is the aryl of 6-12, such as phenyl, xenyl, naphthyl etc.;
Or carbonatoms is the heterocyclic aryl of 2-5, such as thienyl, thiazolyl, pyridyl etc.
Above-mentioned group can be substituted base and replaced, and described substituting group can be common C
1-4alkyl or alkoxyl group, C
4-6cycloalkyl, halogen atom etc.
R
2represent:
Carbonatoms is the alkyl of 1-12 or more, such as: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-..., undecyl, dodecyl, tridecyl ..., octadecyl etc., be more preferably C
1-6alkyl;
Carbonatoms is the cycloalkyl of 3-6, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
Carbonatoms is the thiazolinyl of 1-12, such as propenyl, styryl etc.;
Carbonatoms is the aryl of 6-12, such as phenyl, xenyl, naphthyl etc.;
Or carbonatoms is the heterocyclic aryl of 2-5, such as thienyl, thiazolyl, pyridyl etc.
Above-mentioned group can be substituted base and replaced, and described substituting group can be common C
1-4alkyl or alkoxyl group, C
4-6cycloalkyl, halogen atom etc.
R
3represent:
Carbonatoms is the alkyl of 1-12 or more, such as: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-..., undecyl, dodecyl, tridecyl ..., octadecyl etc., be more preferably C
1-6alkyl;
Carbonatoms is the cycloalkyl of 3-6, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
Carbonatoms is the aryl of 6-12, such as phenyl, xenyl, naphthyl etc.;
Or carbonatoms is the heterocyclic aryl of 2-5, such as thienyl, thiazolyl, pyridyl etc.
Above-mentioned group can be substituted base and replaced, and described substituting group can be common C
1-4alkyl or alkoxyl group, C
4-6cycloalkyl, halogen atom etc.
R
4represent:
Carbonatoms is the alkyl of 4-12 or more, such as: the tertiary butyl, tert-pentyl, tertiary hexyl, tertiary heptyl, tertiary octyl group, tertiary nonyl, tertiary decyl etc.
The preferred n-Butyl Lithium of alkide RM used in the present invention or tert-butyl lithium, useful commercial reagent, without the need to special processing.
Ether solvent used in the present invention, i.e. ether solvent one and ether solvent two can be alkyl oxide, aryl oxide or cyclic ethers, can be a kind of ether, and also can be the mixture of multiple ether, conventional ether solvent is ether, tetrahydrofuran (THF), methyltetrahydrofuran etc. such as.This ether solvent useful commercial reagent, is back to mazarine steams through sodium-benzophenone before using.Described ether solvent one can be identical with the moiety of ether solvent two, also can be different, and have no special requirements.
The mol ratio preferable range of various reaction raw materials of the present invention or reagent is as shown in table 1:
The preferred molar ratio of the various reaction raw materials of table 1. or reagent
| Raw material or reagent | Carbodiimide | Acyl chlorides | Terminal alkyne compound | Alkide | Ether solvent | S 8 |
| Molar equivalent | 1 | 1-1.2 | 1-1.2 | 1-1.2 | Arbitrarily | 0.125-0.15 |
The ratio of the inventive method to terminal alkyne compound and ether solvent is not particularly limited, as long as can make reaction solution uniform stirring, the terminal alkyne compound of preferred 1mmol is dissolved in the ether solvent that volume is greater than 2mL.
It is how many slightly different according to different raw materials that the inventive method respectively walks the reaction times, detects disappearance and be as the criterion, general 10-12 hour with raw material.
Step d) of the present invention can adopt oil bath (such as silicone oil, paraffin wet goods) or other modes to heat, as long as maintain temperature of reaction.
The normally simple reaction solution of aftertreatment concentrates, and reaction solution concentration process can adopt the method such as air distillation, underpressure distillation, or such as concentrates with Rotary Evaporators.
In order to obtain more highly purified product, preferably carry out purifying to the product after aftertreatment, described purge process can make eluent with the solvent of certain polarity, and chromatographic column is separated.Selected eluent has different according to the opposed polarity of product.Generally, eluent selects volume ratio to be sherwood oil: methylene dichloride=1:1.Use chromatographic column such as laboratory to commonly use silicagel column or high performance liquid chromatography etc.
On the other hand, present invention also offers the application of the compounds of this invention in preparation antibacterials or antitumor drug.
The compounds of this invention 1,3-thiazoles derivative serves many purposes in organic synthesis field, can be used as synthetic intermediate, in order to synthesize known compound.
Wherein, the application 2-amide thiazole compound has antibacterial, anticancer antineoplastic activity, as protein kinase inhibitors, also can be used as the antagonistic drug of Chemokine Receptors, anti-Adenosine Receptors, also have anesthetic action at field of medicaments simultaneously.
The present invention utilizes carbodiimide, acyl chlorides, terminal alkyne compound and elemental sulfur to prepare 2-amide thiazole derivant, and productive rate is higher, and synthetic method is scientific and reasonable, thus provides the universal method that a synthesis has multiple substituent 2-amide thiazole derivant.The method raw material is easy to get, applied widely, high isolated yield, experimental installation and operation is simple, is convenient to further Application and Development.
Embodiment
The present invention is further described below in conjunction with embodiment, but the scope do not limited the present invention in any way.
Embodiment 1---preparation formula IVa(R
1=Ph, R
2=4-CF
3-Ph, R
3=Et) compound:
IVa
Under nitrogen protection, to be equipped with 2mL ether 20mL reaction tubes in add 1mmol phenylacetylene, adopt dry ice-propanone bath by constant for temperature of reaction at-78 DEG C, drip 1mmol n-Butyl Lithium, add rear reaction half an hour, add 0.125mmol S
8, be naturally warming up to 25 DEG C, magnetic agitation reacts two hours.Under nitrogen protection, to be equipped with 3mL ether 20mL reaction tubes in add the 1mmol N-tertiary butyl-N-ethyl carbodiimide and 1mmol to trifluoromethyl benzoyl chloride, 25 DEG C of reaction 48h.By above-mentioned two kinds of reaction solns mixing, 80 DEG C are reacted 10 hours.Reaction solution concentrates, silicagel column decolouring is separated, with sherwood oil: the mixed solvent of methylene dichloride=1:1 makees eluent, obtain thiazole derivative N-ethyl-N-(4-phenyl-2-thiazole)-4-trifluoromethyl benzamide 305mg(purity >98%, yellow solid), isolated yield 81%.The nuclear magnetic data of this compound is as follows:
1h NMR (300MHz, CDCl
3): δ 1.38 (t, J=6.9Hz, 3H, CH
3), 4.21 (q, J=6.9Hz, 2H, CH
2), 7.25-7.44 (m, 4H, CH), 7.63 (d, J=8.0Hz, 2H, CH), 7.75 (d, J=8.0Hz, 2H, CH) 7.90-7.92 (m, 2H, CH);
13c NMR (75MHz, CDCl
3): δ 14.12,45.12,109.36,123.54 (q, J=272.2Hz), 125.75 (q, J=3.5Hz), 125.93,126.95,128.63,128.99,133.12 (q, J=33.4Hz), 134.44,138.57,149.50,158.36,169.03.
Embodiment 2---preparation formula IVb(R
1=2-Me-Ph, R
2=4-CF
3-Ph, R
3=Et) compound:
IVb
Under nitrogen protection, to be equipped with 2mL ether 20mL reaction tubes in add 1mmol o-methyl-benzene acetylene, adopt dry ice-propanone bath by constant for temperature of reaction at-78 DEG C, drip 1mmol n-Butyl Lithium, add rear reaction half an hour, add 0.125mmol S
8, be naturally warming up to 25 DEG C, magnetic agitation reacts two hours.Under nitrogen protection, to be equipped with 3mL ether 20mL reaction tubes in add the 1mmol N-tertiary butyl-N-ethyl carbodiimide and 1mmol to trifluoromethyl benzoyl chloride, 25 DEG C of reaction 48h.By above-mentioned two kinds of reaction solns mixing, 60 DEG C are reacted 10 hours.Reaction solution concentrates, silicagel column decolouring is separated, with sherwood oil: the mixed solvent of methylene dichloride=1:1 makees eluent, obtain thiazole derivative N-ethyl-N-(4-(o-methyl-phenyl-)-2-thiazole)-4-trifluoromethyl benzamide 222mg(purity >98%, yellow solid), isolated yield 57%.The nuclear magnetic data of this compound is as follows:
1h NMR (400MHz, CDCl
3, Me
4si): δ 1.35 (t, J=6.9Hz, 3H, CH
3), 2.46 (s, 3H, CH
3), 4.19 (q, J=6.9Hz, 2H, CH
2), 7.06 (s, 1H, CH), 7.25-7.27 (m, 3H, CH), 7.59-7.60 (m, 1H, CH), 7.65 (d, J=8.0Hz, 2H, CH), 7.76 (d, J=8.0Hz, 2H, CH);
13cNMR (100MHz, CDCl
3, Me
4si): δ 14.13,21.25,45.14,112.76,123.57 (q, J=272.4Hz), 125.79 (q, J=3.7Hz), 125.89,127.07,128.03,128.99,129.61,130.92,132.25 (q, J=32.9Hz), 134.73,136.12,138.73,150.31,169.04.
Embodiment 3---preparation formula IVc(R
1=3-Cl-Ph, R
2=4-CF
3-Ph, R
3=Et) compound:
IVc
Under nitrogen protection, to be equipped with 2mL ether 20mL reaction tubes in add 1mmol m-chloro phenylacetylene, adopt dry ice-propanone bath by constant for temperature of reaction at-78 DEG C, drip 1mmol n-Butyl Lithium, add rear reaction half an hour, add 0.125mmol S
8, be naturally warming up to 25 DEG C, magnetic agitation reacts two hours.Under nitrogen protection, to be equipped with 3mL ether 20mL reaction tubes in add the 1mmol N-tertiary butyl-N-ethyl carbodiimide and 1mmol to trifluoromethyl benzoyl chloride, 25 DEG C of reaction 48h.By above-mentioned two kinds of reaction solns mixing, 100 DEG C are reacted 10 hours.Reaction solution concentrates, silicagel column decolouring is separated, with sherwood oil: the mixed solvent of methylene dichloride=1:1 makees eluent, obtain thiazole derivative N-ethyl-N-(4-(chloro-phenyl-)-2-thiazole)-4-trifluoromethyl benzamide 320mg(purity >98%, yellow solid), isolated yield 78%.The nuclear magnetic data of this compound is as follows:
1h NMR (400MHz, CDCl
3, Me
4si): δ 1.38 (t, J=6.7Hz, 3H, CH
3), 4.22 (q, J=6.7Hz, 2H, CH
2), 7.27-7.33 (m, 3H, CH), 7.64-7.66 (m, 2H, CH), 7.76-7.77 (m, 3H, CH), 7.90 (s, 1H, CH);
13c NMR (100MHz, CDCl
3, Me
4si): δ 14.04,45.13,110.35,123.52 (q, J=270.7Hz), 123.98,125.80 (q, J=3.7Hz), 126.11,126.99,127.82,129.87,132.30 (q, J=33.0Hz), 134.62,136.25,138.48,148.13,158.61,169.12.
Embodiment 4---preparation formula IVd(R
1=3-thienyl, R
2=4-CF
3-Ph, R
3=Et) compound:
IVd
Synthetic route is substantially with embodiment 1, and aftertreatment is identical.The raw material that sets out of this synthesis is the 2-acetylene thiophene of 1.1mmol, the N-tertiary butyl-N-the ethyl carbodiimide of 1mmol, 1.1mmol to trifluoromethyl benzoyl chloride, use 1mmol n-Butyl Lithium, obtain straight product N-ethyl-N-(4-(3-thienyl)-2-thiazole)-4-trifluoromethyl benzamide 256mg(purity >98%, red solid), isolated yield 67%.The nuclear magnetic data of this compound is as follows:
1h NMR (400MHz, CDCl
3, Me
4si): δ 1.36 (t, J=6.9Hz, 3H, CH
3), 4.21 (q, J=6.9Hz, 2H, CH
2), 7.10 (s, 1H, CH), 7.34-7.36 (m, 1H, CH), 7.46-7.54 (m, 2H, CH), 7.63-7.77 (m, 4H, CH);
13c NMR (100MHz, CDCl
3, Me
4si): δ 14.02,45.13,108.96,121.63,123.56 (q, J=272.5Hz), 125.42 (q, J=3.7Hz), 125.76,126.16,127.05,128.79,132.27 (q, J=33.0Hz), 136.85,138.63,145.84,169.05.
Embodiment 5---preparation formula IVe(R
1=cyclohexenyl, R
2=4-CF
3-Ph, R
3=Et) compound:
IVe
Synthetic route is substantially with embodiment 1, and aftertreatment is identical.The raw material that sets out of this synthesis is the cyclohexenyl acetylene of 1.1mmol, the N-tertiary butyl-N-the ethyl carbodiimide of 1mmol, 1.1mmol to trifluoromethyl benzoyl chloride, use 1mmol n-Butyl Lithium, obtain straight product 258mg(purity >98%, red solid), isolated yield 68%.The nuclear magnetic data of this compound is as follows:
1h NMR (400MHz, CDCl
3, Me
4si): δ 1.33 (t, J=6.9Hz, 3H, CH
3), 1.66-1.80 (m, 4H, CH
2), 2.24-2.39 (m, 4H, CH
2), 4.16 (q, J=6.9Hz, 2H, CH
2), 6.72-6.76 (m, 2H, CH), 7.62 (d, J=8.0Hz, 2H, CH), 7.74 (d, J=8.0Hz, 2H, CH);
13c NMR (75MHz, CDCl
3, Me
4si): δ 14.00,22.26,22.60,25.47,25.49,45.09,107.49,123.58 (q, J=272.5Hz), 125.73 (q, J=3.7Hz), 126.27,127.10,128.81,131.08,132.18 (q, J=32.8Hz), 138.85,151.52,169.02.
Embodiment 6---preparation formula IVf(R
1=
nbu, R
2=4-CF
3-Ph, R
3=Et) compound:
iVf
Synthetic route is substantially with embodiment 1, and aftertreatment is identical.The raw material that sets out of this synthesis is the 1-pentyne of 1.1mmol, the N-tertiary butyl-N-ethyl carbodiimide of 1mmol, 1.1mmol to trifluoromethyl benzoyl chloride, use 1mmol n-Butyl Lithium, obtain straight product 232mg(purity >98%, red oil), isolated yield 65%.The nuclear magnetic data of this compound is as follows:
1h NMR (400MHz, CDCl
3, Me
4si): δ 0.93 (t, J=7.3Hz, 3H, CH
3), 1.29 (t, J=7.0Hz, 3H, CH
3), 1.34-1.42 (m, 2H, CH
2), 1.63-1.65 (m, 2H, CH
2), 2.69 (t, J=7.3Hz, 2H, CH
2), 4.13 (q, J=7.0Hz, 2H, CH
2), 6.64 (s, 1H, CH), 7.61 (d, J=7.8Hz, 2H, CH), 7.72 (d, J=7.8Hz, 2H, CH);
13c NMR (100MHz, CDCl
3, Me
4si): δ 13.84,13.92,22.22,31.14,31.37,44.99,109.62,123.58 (q, J=272.5Hz), 125.63 (q, J=3.3Hz), 127.14,129.89,132.07 (q, J=33.0Hz), 138.99,152.54,168.74.
Embodiment 7---preparation formula IVg(R
1=Cy, R
2=4-CF
3-Ph, R
3=Et) compound:
IVg
Synthetic route is substantially with embodiment 1, and aftertreatment is identical.The raw material that sets out of synthesis is the cyclohexyl-acetylene of 1mmol, the N-tertiary butyl-N-the ethyl carbodiimide of 1mmol, 1mmol to trifluoromethyl benzoyl chloride, use 1.2mmol n-Butyl Lithium, the straight product finally obtained is 206mg(purity >98%, yellow solid), isolated yield 54%.
Embodiment 8---preparation formula IVh(R
1=Ph, R
2=2-Me-Ph, R
3=Et) compound:
IVh
Synthetic route is substantially with embodiment 1, and aftertreatment is identical.The raw material that sets out of synthesis is the phenylacetylene of 1mmol, the N-tertiary butyl-N-ethyl carbodiimide of 1mmol, the o-methyl-benzene formyl chloride of 1mmol, use 1.2mmol n-Butyl Lithium, the straight product finally obtained is 178mg(purity >98%, yellow solid), isolated yield 55%.
Embodiment 9---preparation formula IVi(R
1=Ph, R
2=3-Me-Ph, R
3=Et) compound:
IVi
Synthetic route is substantially with embodiment 1, and aftertreatment is identical.The raw material that sets out of synthesis is the phenylacetylene of 1mmol, the N-tertiary butyl-N-ethyl carbodiimide of 1mmol, the m-methyl benzoyl formyl chloride of 1mmol, use 1.2mmol n-Butyl Lithium, the straight product finally obtained is 200mg(purity >98%, yellow solid), isolated yield 65%.
Embodiment 10---preparation formula IVj(R
1=Ph, R
2=4-MeO-Ph, R
3=Et) compound:
IVj
Synthetic route is substantially with embodiment 1, and aftertreatment is identical.The raw material that sets out of synthesis is the phenylacetylene of 1mmol, the N-tertiary butyl-N-ethyl carbodiimide of 1mmol, the anisoyl chloride of 1mmol, use 1.2mmol n-Butyl Lithium, the straight product finally obtained is 217mg(purity >98%, yellow solid), isolated yield 64%.
Embodiment 11---preparation formula IVk(R
1=Ph, R
2=4-F-Ph, R
3=Et) compound:
IVk
Synthetic route is substantially with embodiment 1, and aftertreatment is identical.The raw material that sets out of synthesis is the phenylacetylene of 1mmol, the N-tertiary butyl-N-ethyl carbodiimide of 1mmol, 1mmol to fluorobenzoyl chloride, use 1.2mmol n-Butyl Lithium, the straight product finally obtained is 269mg(purity >98%, yellow solid), isolated yield 84%.
Embodiment 12---preparation formula IVl(R
1=Ph, R
2=styrenyl, R
3=Et) compound:
IVl
Synthetic route is substantially with embodiment 1, and aftertreatment is identical.The raw material that sets out of synthesis is the phenylacetylene of 1mmol, the N-tertiary butyl-N-ethyl carbodiimide of 1mmol, the 3-phenyl-2-acrylate chloride of 1mmol, use 1.2mmol n-Butyl Lithium, the straight product finally obtained is 217mg(purity >98%, yellow solid), isolated yield 65%.
Embodiment 13---preparation formula IVm(R
1=Ph, R
2=Et, R
3=Et) compound:
IVm
Synthetic route is substantially with embodiment 1, and aftertreatment is identical.The raw material that sets out of synthesis is the phenylacetylene of 1mmol, the N-tertiary butyl-N-ethyl carbodiimide of 1mmol, the propionyl chloride of 1mmol, use 1.2mmol n-Butyl Lithium, the straight product finally obtained is 135mg(purity >98%, yellow solid), isolated yield 52%.
Embodiment 14---preparation formula IVn(R
1=Ph, R
2=cyclopropyl, R
3=Et) compound:
IVn
Synthetic route is substantially with embodiment 1, and aftertreatment is identical.The raw material that sets out of synthesis is the phenylacetylene of 1mmol, the N-tertiary butyl-N-ethyl carbodiimide of 1mmol, the Cyclopropyl carbonyl chloride of 1mmol, use 1.2mmol n-Butyl Lithium, the straight product finally obtained is 142mg(purity >98%, yellow oily liquid), isolated yield 52%.
Embodiment 15---preparation formula IVo(R
1=Ph, R
2=4-CF
3-Ph, R
3=
nhex) compound:
IVo
Synthetic route is substantially with embodiment 1, and aftertreatment is identical.The raw material that sets out of synthesis is the phenylacetylene of 1mmol, the N-tertiary butyl-N-n-hexyl the carbodiimide of 1mmol, 1mmol to trifluoromethyl benzoyl chloride, use 1.2mmol n-Butyl Lithium, the straight product finally obtained is 226mg(purity >98%, yellow oily liquid), isolated yield 65%.
Embodiment 16---preparation formula IVp(R
1=4-MeO-Ph, R
2=4-CF
3-Ph, R
3=Bn) compound:
IVp
Synthetic route is substantially with embodiment 1, and aftertreatment is identical.Synthesis the raw material that sets out be 1mmol to Methoxy-phenylacetylene, the N-tertiary butyl-N-benzyl the carbodiimide of 1mmol, 1mmol to trifluoromethyl benzoyl chloride, use 1.2mmol n-Butyl Lithium, the straight product finally obtained is 286mg(purity >98%, yellow oily liquid), isolated yield 61%.
Active example:
The inhibit activities of 5-lipoxygenase albumen in the arachidonic acid metabolism network that the rough determination Iva compound N-ethyl-N-shown in example 1 (4-phenyl-2-thiazole)-4-trifluoromethyl benzamide is relevant to inflammatory protein, external 503nhibiting concentration is 50 μm of ol/L, shows good anti-inflammatory anti-microbial activity.
Claims (6)
1. a synthetic method for 1,3-thiazoles derivative, is characterized in that, comprises the following steps:
A) compound shown in formula (I) and alkide RM are reacted, then add sulphur simple substance;
B) carbodiimide shown in the acyl chlorides shown in formula (II) and formula (III) is reacted;
C) by step b) reaction mixture add in step reaction mixture a), then improve temperature of reaction;
D) to step c) reaction mixture carry out aftertreatment and obtain the compound that general formula (IV) represents;
Wherein,
R
1represent phenyl, methyl substituted phenyl, the phenyl of methoxy substitution, thienyl, cyclohexenyl, butyl, cyclohexyl,
R
2represent the phenyl of methyl substituted phenyl, methoxy substitution, styryl, ethyl, cyclopropane base,
R
3represent ethyl or C6 alkyl,
R
4represent the tertiary butyl, R
4in the carbon atom that is connected with nitrogen-atoms in carbodiimide be quaternary carbon,
Described alkide RM is selected from n-Butyl Lithium or tert-butyl lithium.
2. synthetic method as claimed in claim 1, is characterized in that, step a) is reacted in ether solvent one; Step b) react in ether solvent two; Described ether solvent one and ether solvent two identical or different, they are selected from alkyl oxide, aryl oxide or cyclic ethers or their mixture independently of one another.
3. synthetic method as claimed in claim 2, is characterized in that, described step temperature of reaction a) is between the zero pour of described ether solvent one and 0 DEG C; Described step b) temperature of reaction between 25 DEG C and the boiling point of described ether solvent two; Described step is warming up to room temperature after a) adding sulphur simple substance continuation reaction naturally; Described step c) in temperature of reaction is risen to 60-100 DEG C.
4. synthetic method as claimed in claim 1, it is characterized in that, the mol ratio of described carbodiimide, acyl chlorides, formula (I) compound, alkide, sulphur simple substance is 1:1-1.2:1-1.2:1-1.2:0.125-0.15.
5. synthetic method as claimed in claim 1, it is characterized in that, described aftertreatment comprises reaction solution and concentrates, concentration process adopts air distillation, underpressure distillation or evaporates with Rotary Evaporators, described aftertreatment also comprises by chromatographic column separation and purification product, sherwood oil and the methylene dichloride mixed solvent of eluent to be volume ratio be 1:1.
6. the application of the compound shown in formula Iva in preparation antibacterials,
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