CN103951635B - A kind of synthetic method being used as the thiazole compound of Neurology Department pharmaceutical intermediate - Google Patents
A kind of synthetic method being used as the thiazole compound of Neurology Department pharmaceutical intermediate Download PDFInfo
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- CN103951635B CN103951635B CN201410157911.5A CN201410157911A CN103951635B CN 103951635 B CN103951635 B CN 103951635B CN 201410157911 A CN201410157911 A CN 201410157911A CN 103951635 B CN103951635 B CN 103951635B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The present invention relates to a kind of synthetic method of thiazolium compounds being used as the intermediate of Neurology Department medicine, described method comprises in the presence of a catalyst, and mercaptoaniline compound and halogenated aromatic compound react, a step and obtain object product.Meanwhile, when adding auxiliary agent, find the productive rate that can further improve product.This synthetic method of the present invention has simple to operate, object product purity advantages of higher, can be the cheap thiazole compound intermediate that pharmaceutical industries provides a large amount of, has good market-oriented prospect and industrial value.
Description
Technical field
The present invention relates to a kind of synthetic method of heterogeneous ring compound, relate more particularly to a kind of synthetic method being used as the thiazolium compounds of the intermediate of Neurology Department medicine, belong to the synthesis field of medicine intermediate.
Background technology
At field of medicaments, thiazole compound is the very important medicine of a class, medicine intermediate, basic material etc., has pharmaceutical activity and the physiologically active of Mutiple Targets, has important researching value and application prospect at field of medicaments.
More specifically, thiazole compound tool neuroprotective system, antianaphylaxis, anti-inflammatory, antitumor, anticonvulsion, immunomodulatory, the various active such as antibacterial.
Such as, alzheimer's disease (Alzheimer ' sdisease, AD) be a kind of nerve degenerative diseases, especially common in the elderly, bring heavy economical load and mental burden to society, patient, become the first illness of world's senile dementia at present.
The people such as Zhou Lin (" benzothiazole schiff base compounds conformed with once and with the research of amyloid-beta bonding properties ", " Acta Pharmaceutica Sinica ", 2012,47 (5), 685-688) disclose benzothiazole compounds, it can be used as the molecular image probe of AD, thus provides medical evidence and foundation for the detection of AD, and this compounds wherein can be following thiazole compound:
Wherein, R can be dimethylamino, nitro, methoxyl group, Br, I or hydroxyl.
CN103435571A discloses a kind of tetrahydro benzothiazol compounds of following formula, and it can be used for treating nervous system disorders:
WO2007019346A discloses a kind of as the benzothiazole of SIRTUNIN conditioning agent and the medical compounds of thiazolopyridin, and it can be used to treat nerve degenerative diseases, and its structural formula is as follows:
WO2006008040A discloses a kind of benzothiazole compound of replacement, and it can be used to treat alzheimer's disease, and has the effect of neuroprotective, and the structural formula of this compound is as follows:
Just based on the great potential of thiazole compound in nervous system disease treatment field, people have carried out a large amount of synthetic methods and have explored, have developed many synthetic routes, such as, in above-mentioned listed multiple prior art document and/or patent, all disclose different preparation methods.
But for the synthesis of thiazole compound, still there is the necessity continuing to improve, this is the basis that is accomplished of the present invention and power just also.
Summary of the invention
The present inventor has carried out large quantifier elimination to the synthetic method of thiazole compound, through exploring, completes the present invention.
Technical scheme of the present invention and content relate to the synthetic method of thiazole compound shown in following formula (I), described method comprises: under the existence of catalyzer and alkali reaction auxiliary agent, formula (II) compound and formula (III) compound react, thus obtain the thiazole compound of described formula (I):
R
1be selected from H, C
1-C
6alkyl, C
1-C
6alkoxyl group, halogen, halo C
1-C
6alkyl or halo C
1-C
6alkoxyl group;
R
2be selected from H, C
1-C
6alkyl, C
1-C
6alkoxyl group, cyano group, nitro, halogen, halo C
1-C
6alkyl or halo C
1-C
6alkoxyl group;
X is halogen.
Wherein, C
1-C
6the implication of alkyl refers to the straight or branched alkyl with 1-6 carbon atom, such as can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl or n-hexyl etc. in non-limiting manner.
Wherein, C
1-C
6alkoxyl group refers to " C defined above
1-C
6alkyl " be connected with O atom after group.
Wherein, the implication of halogen refers to haloid element, non-exclusively such as can be F, Cl, Br or I.
Wherein, halo C
1-C
6the implication of alkyl refers to the " C defined above be optionally substituted by halogen
1-C
6alkyl ", be such as trifluoromethyl, pentafluoroethyl group, difluoromethyl, chloromethyl etc. in non-limiting manner.
Wherein, halo C
1-C
6the implication of alkoxyl group refers to the " C defined above be optionally substituted by halogen
1-C
6alkoxyl group ", be such as trifluoromethoxy, five fluorine oxyethyl groups, difluoro-methoxy, chlorine methoxyl group etc. in non-limiting manner.
Wherein, described catalyzer is inorganic nickel or organic nickel salt, such as, can be NiCl
2, NiBr
2, NiSO
4, NiNO
3, any one in tosic acid nickel, most preferably be tosic acid nickel.
Wherein, described alkali reaction auxiliary agent is alkali metal alcoholates, organic amine compound.Such as can be any one in sodium methylate, potassium methylate, sodium tert-butoxide, potassium tert.-butoxide, triethylamine, trolamine or pyridine or any multiple mixture, be preferably triethylamine, trolamine or pyridine, most preferably be pyridine.
Wherein, the mol ratio of formula (II) compound and formula (III) compound is 1:1-3, such as, can be 1:1,1:1.5,1:2,1:2.5 or 1:3.
Wherein, the mol ratio of formula (II) compound and catalyzer is 1:0.1-0.2, such as, can be 1:0.1,1:0.15 or 1:0.2.
Wherein, the mol ratio of formula (II) compound and alkali reaction auxiliary agent is 1:1-3, such as, can be 1:1,1:1.5,1:2,1:2.5 or 1:3.
Wherein, temperature of reaction is 60-100 DEG C, such as, can be 60 DEG C, 70 DEG C, 80 DEG C, 90 DEG C or 100 DEG C.
Wherein, the reaction times is 5-12 hour, such as, can be 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours or 12 hours.
Wherein, the method of the invention can be carried out in organic solvent, described organic solvent can be alcohols, ethers, alkane, halogenated alkane, aromatic hydrocarbons, halogenated aryl hydrocarbon, acid amides, ester class, sulfone class etc., such as, can be any one in methyl alcohol, ethanol, propyl alcohol, ether, tetrahydrofuran (THF), normal hexane, methylene dichloride, carbon trichloride, tetracol phenixin, benzene,toluene,xylene, chlorobenzene, dichlorobenzene, dimethyl formamide (DMF), ethyl acetate, dimethyl sulfoxide (DMSO) (DMSO) or multiple mixture.
Wherein, aftertreatment after reaction terminates processes by chromatography over CC, such as can be: after completion of the reaction, filtered while hot, regulates pH to acid filtrate with aqueous hydrochloric acid, then washes, by the organic phase rotary evaporation after washing except desolventizing, residue is purified by column chromatography, and wherein elutriant is the mixture of acetone, ethyl acetate and sherwood oil, and three's volume ratio is 1-3:1:2-4.
In sum, the present invention is reacted by mercaptoaniline compounds and halogen benzyl compound, thus obtains a class thiazolium compounds.Product yield and the purity of described synthetic method gained are higher, and have good researching value and industrial potential, the synthesis for field of medicaments intermediate provides new synthetic method.Compared with prior art, beneficial effect of the present invention is:
1, by adopting unique catalyst system and alkaline assistant system, object product is obtained with high yield and high purity.
2, determine optimum alkaline assistant, find the use by auxiliary agent, product can be improved by rate, prove that itself and catalyzer have played synergy.
Embodiment
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary embodiments and object are only used for exemplifying the present invention; not any type of any restriction is formed to real protection scope of the present invention, more non-protection scope of the present invention is confined to this.
Embodiment 1
First in reactor, add 500ml methylene chloride, then add the adjacent mercaptoaniline of 1mol, 1mol to the tosic acid nickel of fluorine bromobenzyl, 0.2mol and the pyridine of 1mol, raised temperature to 90 DEG C, stirring reaction 7 hours.
After completion of the reaction, filtered while hot, regulate pH to acid filtrate with aqueous hydrochloric acid, then wash, by the organic phase rotary evaporation after washing except desolventizing, residue is purified by column chromatography, wherein elutriant is the mixture of acetone, ethyl acetate and sherwood oil, and three's volume ratio is 1:1:4, obtains target product 2-to fluorophenyl benzothiazole, productive rate 98.1%
Purity 98.9% (HPLC).
1HNMR(400MHz,DMSO)δ8.02-7.98(m,3H),7.83(d,J=7.5Hz,1H),7.45(t,J=8.0Hz,1H),7.36(t,J=8.0Hz,1H),7.16-7.07(m,2H)。
Embodiment 2
First in reactor, add 500ml etoh solvent, then add the pyridine of the adjacent mercaptoaniline of 1mol, the bromobenzyl of 1mol, the tosic acid nickel of 0.1mol and 1mol, raised temperature to 60 DEG C, stirring reaction 12 hours.
After completion of the reaction, filtered while hot, regulate pH to acid filtrate with aqueous hydrochloric acid, then wash, by the organic phase rotary evaporation after washing except desolventizing, residue is purified by column chromatography, wherein elutriant is the mixture of acetone, ethyl acetate and sherwood oil, and three's volume ratio is 1:1:2, obtains 2-phenylbenzothiazol, productive rate 98.3%, purity 98.9% (HPLC).
1HNMR(400MHz,DMSO)δ8.08-8.03(m,3H),7.85(d,J=8.0Hz,1H),7.49-7.43(m,4H),7.34-7.30(m,1H)。
Embodiment 3
First in reactor, add 500ml solvent hexane, then add the adjacent mercaptoaniline of 1mol, 2mol to the tosic acid nickel of methyl bromobenzyl, 0.15mol and the pyridine of 2mol, raised temperature to 70 DEG C, stirring reaction 10 hours.
After completion of the reaction, filtered while hot, regulate pH to acid filtrate with aqueous hydrochloric acid, then wash, by the organic phase rotary evaporation after washing except desolventizing, residue is purified by column chromatography, wherein elutriant is the mixture of acetone, ethyl acetate and sherwood oil, and three's volume ratio is 2:1:3, obtains target product 2-p-methylphenyl benzothiazole, productive rate 98.5%, purity 99.1% (HPLC).
1HNMR(400MHz,DMSO)δ8.03(d,J=8.5Hz,1H),7.91(d,J=8.5Hz,2H),7.84(d,J=8.0Hz,1H),7.42-7.37(m,1H),7.32-7.25(m,1H),7.22(d,J=8.0Hz,2H),2.39(s,3H)。
Embodiment 4
First in reactor, add 500ml solvent toluene, then add the adjacent mercaptoaniline of 1mol, 3mol to the tosic acid nickel of methoxyl group bromobenzyl, 0.2mol and the pyridine of 3mol, raised temperature to 80 DEG C, stirring reaction 8 hours.
After completion of the reaction, filtered while hot, regulates pH to acid filtrate with aqueous hydrochloric acid, then washes, by the organic phase rotary evaporation after washing except desolventizing, residue is purified by column chromatography, and wherein elutriant is the mixture of acetone, ethyl acetate and sherwood oil, and three's volume ratio is 3:1:4, obtain target product 2-p-methoxyphenyl benzothiazole, productive rate 97.6%, purity 98.5% (HPLC).
1HNMR(400MHz,DMSO)δ8.00-7.96(m,3H),7.81(d,J=8.5Hz,1H),7.42(t,J=7.0Hz,1H),7.31(t,J=7.0Hz,1H),6.95(d,J=9.0Hz,2H),3.84(s,3H)。
Embodiment 5
First in reactor, add 500ml solvents tetrahydrofurane, then add the 2-sulfydryl-5-chloroaniline of 1mol, 3mol to the tosic acid nickel of methoxyl group bromobenzyl, 0.2mol and the pyridine of 2.5mol, raised temperature to 90 DEG C, stirring reaction 8 hours.
After completion of the reaction, filtered while hot, regulate pH to acid filtrate with aqueous hydrochloric acid, then wash, by the organic phase rotary evaporation after washing except desolventizing, residue is purified by column chromatography, wherein elutriant is the mixture of acetone, ethyl acetate and sherwood oil, and three's volume ratio is 2:1:4, obtains target product 5-chloro-2-p-methoxyphenyl benzothiazole, productive rate 92.7%, purity 98.9% (HPLC).
1HNMR(400MHz,DMSO)δ7.95-7.88(m,3H),7.71(d,J=8.5Hz,1H),7.26(dd,J=2.0,8.0Hz,1H),6.97-6.92(m,2H),3.87(s,3H)。
Embodiment 6
First in reactor, add 500ml solvent ethyl acetate, then add the adjacent mercaptoaniline of 1mol, 1.5mol to the tosic acid nickel of cyano-benzyl bromide, 0.15mol and the pyridine of 1.5mol, raised temperature to 100 DEG C, stirring reaction 5 hours.
After completion of the reaction, filtered while hot, regulate pH to acid filtrate with aqueous hydrochloric acid, then wash, by the organic phase rotary evaporation after washing except desolventizing, residue is purified by column chromatography, wherein elutriant is the mixture of acetone, ethyl acetate and sherwood oil, and three's volume ratio is 2:1:3, obtains target product 2-to cyano-phenyl benzothiazole, productive rate 92.8%, purity 98.4% (HPLC).
1HNMR(400MHz,DMSO)δ8.13(d,J=8.5Hz,2H),8.02(d,J=8.5Hz,1H),7.90(d,J=8.0Hz,1H),7.71(d,J=8.5Hz,2H),7.48(d,J=8.0Hz,1H),7.39(d,J=8.0Hz,1H)。
Embodiment 7-12
Except replacing with except following nickel compound by the catalyzer tosic acid nickel in embodiment 1-6, implement embodiment 7-12 with the identical embodiment with embodiment 1-6 respectively, result is as following table:
As can be seen here, only have tosic acid nickel to have best catalytic effect, and other nickel compound all cause productive rate decrease to some degree, demonstrates catalysis specificity and the specificity of tosic acid nickel.
Embodiment 13-18
Replace with except following basic cpd except by the pyridine in embodiment 1-6, implement embodiment 13-18 with the identical embodiment with embodiment 1-6 respectively, result is as following table:
As can be seen here, pyridine has best with concerted catalysis effect that is tosic acid nickel, and other basic cpd all can not obtain synergy so with tosic acid nickel.
Embodiment 19-24
Do not comprise except pyridine except in embodiment 1-6, implement embodiment 19-24 with the identical embodiment with embodiment 1-6 respectively, result is as following table:
As can be seen here, when not comprising pyridine, productive rate has and to a certain degree reduces, but productive rate is still greater than productive rate when comprising other basic cpds, this demonstrate that when comprising other basic cpds outside pyridine, products collection efficiency lower than productive rate when not comprising any basic cpd, will further demonstrate the concerted catalysis effect of pyridine on the contrary thus.
Should be appreciated that the purposes of these embodiments is only not intended to for illustration of the present invention limit the scope of the invention.In addition; also should understand; after having read technology contents of the present invention, those skilled in the art can make various change, amendment and/or modification to the present invention, and these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.
Claims (6)
1. the synthetic method of thiazole compound shown in a following formula (I), described method comprises: under the existence of catalyzer and alkali reaction auxiliary agent, formula (II) compound and formula (III) compound react, thus obtain the thiazole compound of described formula (I):
R
1be selected from H or halogen;
R
2be selected from H, C
1-C
6alkyl, C
1-C
6alkoxyl group, cyano group or halogen;
X is halogen;
Described catalyzer is tosic acid nickel;
Described alkali reaction auxiliary agent is pyridine.
2. synthetic method as claimed in claim 1, is characterized in that: the mol ratio of formula (II) compound and formula (III) compound is 1:1-3.
3. synthetic method as claimed in claim 1, is characterized in that: the mol ratio of formula (II) compound and catalyzer is 1:0.1-0.2.
4. synthetic method as claimed in claim 1, is characterized in that: the mol ratio of formula (II) compound and alkali reaction auxiliary agent is 1:1-3.
5. synthetic method as claimed in claim 1, is characterized in that: temperature of reaction is 60-100 DEG C; Reaction times is 5-12 hour.
6. the synthetic method as described in any one of claim 1-5, it is characterized in that: described method is carried out in organic solvent, described organic solvent is any one in methyl alcohol, ethanol, propyl alcohol, ether, tetrahydrofuran (THF), normal hexane, methylene dichloride, carbon trichloride, tetracol phenixin, benzene,toluene,xylene, chlorobenzene, dichlorobenzene, dimethyl formamide, ethyl acetate, dimethyl sulfoxide (DMSO) or multiple mixture.
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