CN105503771A - Synthesis method of medical intermediate fused ring thiazole compound - Google Patents
Synthesis method of medical intermediate fused ring thiazole compound Download PDFInfo
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- CN105503771A CN105503771A CN201610085894.8A CN201610085894A CN105503771A CN 105503771 A CN105503771 A CN 105503771A CN 201610085894 A CN201610085894 A CN 201610085894A CN 105503771 A CN105503771 A CN 105503771A
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- synthetic method
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- alkali
- following formula
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- HVBHHTFBYMSBQB-HMMKTVFPSA-N C/C=C1/N=C(C2=CC=CCC2)S/C1=C/C Chemical compound C/C=C1/N=C(C2=CC=CCC2)S/C1=C/C HVBHHTFBYMSBQB-HMMKTVFPSA-N 0.000 description 1
Classifications
-
- 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
Abstract
The invention relates to a synthesis method of a fused ring thiazole compound which is shown in a following formula (III) and capable of being used as a medical intermediate. The method comprises the steps that in organic solvent, a reaction is conducted on a compound in the following formula (I) and a compound in the following formula (II) under the action of a catalyst, ligand, alkali and a promoter, and therefore the compound shown in the formula (III) is obtained, and please see the formula in the description, wherein R1, R2 and R3 are independently selected from H or C1-C6 alkyl or C1-C6 alkoxy or halogen, X adopts halogen, and M adopts an alkali metal atom. According to the synthesis method of the fused ring thiazole compound, by means of use of a suitable substrate, a composite reaction system composed of the catalyst, the ligant, the alkali, the promoter and the organic solvent is selected in a combined mode, therefore, a target product can be obtained at high yield, and the good application prospect and wide industrial production potential can be achieved in the technical field of medical intermediate synthesis.
Description
Technical field
The present invention relates to a kind of synthetic method of thiazole compound, relate more specifically to a kind of synthetic method that can be used as the condensed ring thiazole compound of medicine intermediate, belong to medicine intermediate synthesis field.
Background technology
And thiazole compound is as a kind of important heterogeneous ring compound, usually be present in medicine, dyestuff and natural active matter, it usually as intermediate or active group construction unit, is usually exist as active group in the synthesis of organic synthesis especially medical compounds in final product.
Up to now, the synthetic method of multiple condensed ring thiazole compound has been reported in prior art:
1, reaction is condensed; this reaction normally carries out annelation reaction with corresponding aryl compound and aryl phenyl-sulfhydrate compounds; thus obtain object product; such as FanXuesen etc. (" Anovelandpracticalsynthesisof2-benzoylbenzothiazolesand2-benzylbenzothiazoles "; TetrahedronLetters; 2011; 52; 899-902) report and react by 2-aminothiophenol and phenylacetic aldehyde the method preparing 2-aroyl benzothiazole compound, its reaction formula is as follows:
And for example Chinese patent application CN201510679742.6 discloses following annelation reaction, formula (I) compound and the reaction of formula (II) compound, thus obtains the benzothiazole compound of formula (III),
2, the edge base group modification reaction of thiazole compound, such as LeiWang etc. (" Base-PromotedFormalArylationofBenzo [d] oxazoleswithAcylChloride ", J.Org.Chem.2013,78,12076-12081) report benzothiazole and acyl chloride reaction, thus obtain the benzothiazole of aryl replacement, its reaction formula is as follows:
Although disclose the multiple method of this compounds of synthesis in prior art, but its productive rate is general lower, therefore for the novel method for synthesizing of this compounds of exploitation synthesis, and realize the object of high yield, still need further to further investigate, this is the dynamic foundation that is accomplished of the present invention just.
Summary of the invention
In order to seek the novel method for synthesizing of the thiazole compound that can be used as medicine intermediate, and realizing the object improving productive rate, present inventor has performed deep research and exploration, after having paid enough creative works, thus completing the present invention.
Specifically, technical scheme of the present invention and content relate to the synthetic method of condensed ring thiazole compound shown in a kind of following formula (III), described method comprises: in organic solvent, following formula (I) compound and following formula (II) compound react under catalyzer, part, alkali and promotor effect, thus obtain described formula (III) compound
Wherein, R
1-R
3be selected from H, C independently of one another
1-C
6alkyl, C
1-C
6alkoxy or halogen;
X is halogen;
M is alkali metal atom.
In described synthetic method of the present invention, described 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.
In described synthetic method of the present invention, described C
1-C
6the implication of alkoxyl group refers to the C with above-mentioned implication
1-C
6the group obtained after alkyl is connected with Sauerstoffatom.
In described synthetic method of the present invention, described halogen is haloid element, such as, can be F, Cl, Br or I.
In described synthetic method of the present invention, described alkali metal atom such as can be Li, Na or K etc.
In described synthetic method of the present invention, described catalyzer is Pd (PPh
3)
2cl
2(two (triphenylphosphine) palladium chloride), Pd (dpbpf) Cl
2(1,1 '-bis-(two-tertiary butyl phosphine) ferrocene dichloro closes palladium), PdCl
2(CH
3cN)
2(two (cyanogen methyl) palladium chloride), dppePdCl
2(the two diphenyl phosphine oxide Palladous chloride of 1,2-) or Pd (PhCN)
2cl
2any one in (two (cyano group benzene) palladium chloride), most preferably is dppePdCl
2(the two diphenyl phosphine oxide Palladous chloride of 1,2-).
In described synthetic method of the present invention, described part is following formula L1 or L2,
Described part most preferably is L1.
In described synthetic method of the present invention, described alkali is Tetramethyl Ethylene Diamine (TMEDA), N, N'-dimethyl-ethylenediamine (DMEDA), N, N-diisopropylethylamine (DIPEA), N, any one in N-dimethylethanolamine (DMEA) or triethylamine, most preferably be N, N-dimethylethanolamine (DMEA).
In described synthetic method of the present invention, described promotor is copper trifluoromethanesulfcomposite (Cu (OTf)
2).
In described synthetic method of the present invention, described organic solvent is the mixture of Isosorbide-5-Nitrae-dioxane and DMF (DMF), and wherein the volume ratio of Isosorbide-5-Nitrae-dioxane and DMF (DMF) is 1:3.
Wherein, the consumption of described organic solvent strict restriction, and those skilled in the art can carry out suitable selection according to practical situation and determine, such as its consumption size is carried out and aftertreatment to facilitate reaction, is no longer described in detail at this.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and formula (II) compound for being 1:0.5-1, such as, can be 1:0.5,1:0.7,1:0.9 or 1:1.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and catalyzer is 1:0.08-0.12, such as, can be 1:0.08,1:0.1 or 1:0.12.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and part is 1:0.1-0.2, such as, can be 1:0.1,1:0.15 or 1:0.2.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and alkali is 1:1-1.6, such as, can be 1:1,1:1.3 or 1:1.6.
In described synthetic method of the present invention, the mol ratio of described formula (I) compound and promotor is 1:0.1-0.15, such as, can be 1:0.1,1:0.12,1:0.14 or 1:0.15.
In described synthetic method of the present invention, temperature of reaction is 80-100 DEG C, such as, can be 80 DEG C, 90 DEG C or 100 DEG C.
In described synthetic method of the present invention, the reaction times is 6-9 hour, such as, can be 6 hours, 7 hours, 8 hours or 9 hours.
In described synthetic method of the present invention, after formula (I) compound and formula (II) compound react and terminate, can be passed through conventional aftertreatment and obtain object product, such as can be passed through pillar layer separation, more such as can be specific as follows: after reaction terminates, filter, be neutral by filtrate hydrochloric acid soln adjust ph, then fully vibrate with saturated sodium bicarbonate aqueous solution, add extraction into ethyl acetate 2-3 time again, isolate organic phase and merge organic phase, concentrating under reduced pressure, residue crosses silica gel column chromatography, wash-out is carried out with the equal-volume mixture of acetone and sherwood oil, thus obtain described formula (III) compound.
In sum, the invention provides a kind of synthetic method that can be used as the condensed ring thiazole compound of medicine intermediate, described method is by the use of suitable substrates, and the complex reaction system that combination selection catalyzer, part, alkali and promotor and organic solvent form, thus high yield can obtain object product, have a good application prospect and industrial production potential widely in medicine intermediate synthesis technical field.
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
Under room temperature, (be 1 of volume ratio 1:3 to appropriate organic solvent, 4-dioxane and DMF (N, dinethylformamide) mixture) in, add 100mmol above formula (I) compound, 50mmol above formula (II) compound, 8mmol catalyzer dppePdCl
2, 10mmol ligand L 1,100mmol alkali DMEA and 10mmol accelerant C u (OTf), be then warming up to 80 DEG C, and stirring reaction 9 hours at such a temperature;
After reaction terminates, filter, be neutral by filtrate hydrochloric acid soln adjust ph, then fully vibrate with saturated sodium bicarbonate aqueous solution, then add extraction into ethyl acetate 2-3 time, isolate organic phase and merge organic phase, concentrating under reduced pressure, residue crosses silica gel column chromatography, carries out wash-out with the equal-volume mixture of acetone and sherwood oil, thus obtaining above formula (III) compound, productive rate is 93.9%.
1HNMR(CDCl
3,300MHz)δ8.09(d,J＝8.2Hz,1H),8.01(d,J＝8.6Hz,2H),7.94(d,J＝7.9Hz,1H),7.52-7.47(m,3H),7.42(t,J＝7.1Hz,1H)。
Embodiment 2
Reaction formula is with embodiment 1, and concrete reaction process is as follows:
Under room temperature, (be 1 of volume ratio 1:3 to appropriate organic solvent, 4-dioxane and DMF (N, dinethylformamide) mixture) in, add 100mmol above formula (I) compound, 75mmol above formula (II) compound, 10mmol catalyzer dppePdCl
2, 15mmol ligand L 1,130mmol alkali DMEA and 12mmol accelerant C u (OTf), be then warming up to 90 DEG C, and stirring reaction 8 hours at such a temperature;
After reaction terminates, filter, be neutral by filtrate hydrochloric acid soln adjust ph, then fully vibrate with saturated sodium bicarbonate aqueous solution, then add extraction into ethyl acetate 2-3 time, isolate organic phase and merge organic phase, concentrating under reduced pressure, residue crosses silica gel column chromatography, carries out wash-out with the equal-volume mixture of acetone and sherwood oil, thus obtaining above formula (III) compound, productive rate is 94.3%.
Nuclear-magnetism characterization data is with embodiment 1.
Embodiment 3
Reaction formula is with embodiment 1, and concrete reaction process is as follows:
Under room temperature, (be 1 of volume ratio 1:3 to appropriate organic solvent, 4-dioxane and DMF (N, dinethylformamide) mixture) in, add 100mmol above formula (I) compound, 100mmol above formula (II) compound, 12mmol catalyzer dppePdCl
2, 20mmol ligand L 1,160mmol alkali DMEA and 15mmol accelerant C u (OTf), be then warming up to 100 DEG C, and stirring reaction 6 hours at such a temperature;
After reaction terminates, filter, be neutral by filtrate hydrochloric acid soln adjust ph, then fully vibrate with saturated sodium bicarbonate aqueous solution, then add extraction into ethyl acetate 2-3 time, isolate organic phase and merge organic phase, concentrating under reduced pressure, residue crosses silica gel column chromatography, carries out wash-out with the equal-volume mixture of acetone and sherwood oil, thus obtaining above formula (III) compound, productive rate is 94.2%.
Nuclear-magnetism characterization data is with embodiment 1.
Embodiment 4
Reaction formula is with embodiment 1, and concrete reaction process is as follows:
Under room temperature, (be 1 of volume ratio 1:3 to appropriate organic solvent, 4-dioxane and DMF (N, dinethylformamide) mixture) in, add 100mmol above formula (I) compound, 80mmol above formula (II) compound, 8mmol catalyzer dppePdCl
2, 12mmol ligand L 1,150mmol alkali DMEA and 14mmol accelerant C u (OTf), be then warming up to 85 DEG C, and stirring reaction 7 hours at such a temperature;
After reaction terminates, filter, be neutral by filtrate hydrochloric acid soln adjust ph, then fully vibrate with saturated sodium bicarbonate aqueous solution, then add extraction into ethyl acetate 2-3 time, isolate organic phase and merge organic phase, concentrating under reduced pressure, residue crosses silica gel column chromatography, carries out wash-out with the equal-volume mixture of acetone and sherwood oil, thus obtaining above formula (III) compound, productive rate is 94.6%.
Nuclear-magnetism characterization data is with embodiment 1.
From above-described embodiment 1-4, the described reaction method of the application of the invention, high yield can obtain object product, thus overcome the too low defect of productive rate in prior art, industrially have a good application prospect and production potential.
Embodiment 5-20
Embodiment 5-8: except catalyzer is replaced with Pd (PPh
3)
2cl
2outward, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 5-8 in turn.
Embodiment 9-12: except catalyzer is replaced with Pd (dpbpf) Cl
2outward, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 9-12 in turn.
Embodiment 13-16: except catalyzer is replaced with PdCl
2(CH
3cN)
2outward, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 13-16 in turn.
Embodiment 17-20: except catalyzer is replaced with Pd (PhCN)
2cl
2outward, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 17-20 in turn.
The results are shown in following table 1.
Table 1
As can be seen here, in all catalyzer, dppePdCl
2have best catalytic effect, other catalyzer all causes productive rate to have significant reduction, but still is significantly higher than 80%, and this is still higher than productive rate of the prior art.
Embodiment 21-28
Embodiment 21-24: replace with except L2 except by part, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 21-24 in turn.
Embodiment 25-28: except being omitted by part, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 25-28 in turn.
The results are shown in following table 2.
Table 2
As can be seen here, in ligand L 1 and L2, L1 can obtain the productive rate up to about 94%, and the productive rate of L2 then has significant reduction.It can also be seen that, when not using any part, its products collection efficiency and L2 are more or less the same, and this proves that L2 does not play any front and promotes and improve effect.
Embodiment 29-44
Embodiment 29-32: replace with except TMEDA except by alkali, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 29-32 in turn.
Embodiment 33-36: replace with except DMEDA except by alkali, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 33-36 in turn.
Embodiment 37-40: replace with except DIPEA except by alkali, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 37-40 in turn.
Embodiment 41-44: replace with except triethylamine except by alkali, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 41-44 in turn.
The results are shown in following table 3.
Table 3
As can be seen here, in all alkali, DMEA has best effect, and other alkali all causes productive rate to have significant reduction, especially DMEDA and triethylamine, and productive rate has been reduced to lower than 80%.
Embodiment 45-48
Except being omitted by promotor copper trifluoromethanesulfcomposite, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 45-48 in turn.Found that, its products collection efficiency is 88.5-89.3%, reduces about 5-6 percentage point than embodiment 1-4, demonstrates the existence of copper trifluoromethanesulfcomposite thus, can improve productive rate further, and this is beyond thought.
Embodiment 49-56
Embodiment 49-52: except organic solvent is replaced with single solvent 1 by the mixture of Isosorbide-5-Nitrae-dioxane and DMF (DMF), outside 4-dioxane, other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 49-52 in turn.
Embodiment 53-56: except replacing with except single solvent DMF by organic solvent by the mixture of Isosorbide-5-Nitrae-dioxane and DMF (DMF), other operation is all constant, thus repeats to implement embodiment 1-4, obtains embodiment 53-56 in turn.
The results are shown in following table 4.
Table 4
As can be seen here, when being used alone Isosorbide-5-Nitrae-dioxane or DMF, the equal decrease to some degree of productive rate, reduces more obvious, when this proves the mixture when both uses, can obtain best solvent effect when being especially used alone DMF.
In sum, the invention provides a kind of synthetic method that can be used as the condensed ring thiazole compound of medicine intermediate, described method is by the use of suitable substrates, and the complex reaction system that combination selection catalyzer, part, alkali and promotor and organic solvent form, thus high yield can obtain object product, have a good application prospect and industrial production potential widely in medicine intermediate synthesis technical field.
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 (10)
1. the synthetic method of condensed ring thiazole compound shown in a following formula (III), described method comprises: in organic solvent, following formula (I) compound and following formula (II) compound react under catalyzer, part, alkali and promotor effect, thus obtain described formula (III) compound
Wherein, R
1-R
3be selected from H, C independently of one another
1-C
6alkyl, C
1-C
6alkoxy or halogen;
X is halogen;
M is alkali metal atom.
2. synthetic method as claimed in claim 1, is characterized in that described catalyzer is Pd (PPh
3)
2cl
2(two (triphenylphosphine) palladium chloride), Pd (dpbpf) Cl
2(1,1 '-bis-(two-tertiary butyl phosphine) ferrocene dichloro closes palladium), PdCl
2(CH
3cN)
2(two (cyanogen methyl) palladium chloride), dppePdCl
2(the two diphenyl phosphine oxide Palladous chloride of 1,2-) or Pd (PhCN)
2cl
2any one in (two (cyano group benzene) palladium chloride), most preferably is dppePdCl
2(the two diphenyl phosphine oxide Palladous chloride of 1,2-).
3. synthetic method as claimed in claim 2, is characterized in that: described part is following formula L1 or L2,
Described part most preferably is L1.
4. the synthetic method as described in any one of claim 2-3, it is characterized in that described alkali is Tetramethyl Ethylene Diamine (TMEDA), N, N '-dimethyl-ethylenediamine (DMEDA), N, N-diisopropylethylamine (DIPEA), N, any one in N-dimethylethanolamine (DMEA) or triethylamine, most preferably be N, N-dimethylethanolamine (DMEA).
5. the synthetic method as described in any one of claim 1-4, is characterized in that: described promotor is copper trifluoromethanesulfcomposite (Cu (OTf)
2).
6. the synthetic method as described in any one of claim 1-5, is characterized in that: the mol ratio of described formula (I) compound and formula (II) compound is for being 1:0.5-1.
7. the synthetic method as described in any one of claim 1-6, is characterized in that: the mol ratio of described formula (I) compound and catalyzer is 1:0.08-0.12.
8. the synthetic method as described in any one of claim 1-7, is characterized in that: the mol ratio of described formula (I) compound and part is 1:0.1-0.2.
9. the synthetic method as described in any one of claim 1-8, is characterized in that: the mol ratio of described formula (I) compound and alkali is 1:1-1.6.
10. the synthetic method as described in any one of claim 1-9, is characterized in that: the mol ratio of described formula (I) compound and promotor is 1:0.1-0.15.
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|---|---|---|---|---|
| CN102753545A (en) * | 2009-12-15 | 2012-10-24 | 盐野义制药株式会社 | Oxadiazole derivative having endothelial lipase inhibitory activity |
| CN104193628A (en) * | 2014-08-12 | 2014-12-10 | 庄伟萍 | Amino arone compound used as medical intermediate and synthesis method of amino arone compound |
| CN105037073A (en) * | 2015-07-13 | 2015-11-11 | 剪士卫 | Synthetic method for biaryl compounds |
| CN105198867A (en) * | 2015-08-26 | 2015-12-30 | 尹强 | Catalyzed synthesis method for benzothiazole derivatives |
-
2016
- 2016-02-15 CN CN201610085894.8A patent/CN105503771A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102753545A (en) * | 2009-12-15 | 2012-10-24 | 盐野义制药株式会社 | Oxadiazole derivative having endothelial lipase inhibitory activity |
| CN104193628A (en) * | 2014-08-12 | 2014-12-10 | 庄伟萍 | Amino arone compound used as medical intermediate and synthesis method of amino arone compound |
| CN105037073A (en) * | 2015-07-13 | 2015-11-11 | 剪士卫 | Synthetic method for biaryl compounds |
| CN105198867A (en) * | 2015-08-26 | 2015-12-30 | 尹强 | Catalyzed synthesis method for benzothiazole derivatives |
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