CN102746319B - A kind of preparation method of thienopyridine ketone compounds - Google Patents
A kind of preparation method of thienopyridine ketone compounds Download PDFInfo
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- 0 CC(c1c(*)[s]c(*)c1C)=O Chemical compound CC(c1c(*)[s]c(*)c1C)=O 0.000 description 2
- VBBWSQPPBMCSDC-SYZQJQIISA-N C/C=N/c1c(C(C)=O)c(C)c(-c(cc[s]2)c2Cl)[s]1 Chemical compound C/C=N/c1c(C(C)=O)c(C)c(-c(cc[s]2)c2Cl)[s]1 VBBWSQPPBMCSDC-SYZQJQIISA-N 0.000 description 1
- ZDTMZRQGBCLXDY-UHFFFAOYSA-N CCN(C=C1)c([s]c(-c(cc[s]2)c2Cl)c2C)c2C1=O Chemical compound CCN(C=C1)c([s]c(-c(cc[s]2)c2Cl)c2C)c2C1=O ZDTMZRQGBCLXDY-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a kind of preparation method of thienopyridine ketone compounds; the method is the thienopyridine ketone compounds that raw material carries out the formula that is obtained by reacting (II) structure with the 2-amido-3-acetyl thiophene compounds of formula (I) structure and DMF dimethylacetal.Compared with prior art thiophenes annulation, the present invention utilizes N, dinethylformamide dimethylacetal first with the ethanoyl generation condensation reaction of 3-position in 2-amido-3-acetyl thiophene compounds, further with the amido generation Intramolecular substitution reaction Cheng Huan of 2-position, one-step synthesis thienopyridine ketone compounds, synthetic method is simple, mild condition; Further, R
1and R
2can be multiple different substituted radical, the scope of application is wider.
Description
Technical field
The invention belongs to organic synthesis field, particularly relate to a kind of preparation method of thienopyridine ketone compounds.
Background technology
Thienopyridines is one of heterogeneous ring compound the most popular of research both at home and abroad, this compounds is widely used in dye industry, and in sterilization, antitumor and cancer etc., also there is good curative effect, the medicine of tranquillizer and treatment hypertension, asthma, diabetes, Peptic Ulcers and nervous system disease can be used as.
Wherein, thienopyridine ketone compounds is a kind of organic compound be extensively present among natural product, major part has important biology, pharmaceutical activity, as: thieno-[2,3-b] pyridine-6 (7H)-one analog derivative can be used as kinase inhibitor, and Thienopyridinone methane amide can be used for treating disease that malignant tumour, autoimmunity or pathological inflammatory cause and commercial oral anti-diabetic agent prasugrel is also thienopyridine ketones derivant.Simultaneously, thienopyridine ketone compounds also can be used as the intermediate of a class polyfunctional organic compound, be widely used in the field such as Synthetic Organic Chemistry, pharmaceutical synthesis chemistry, as: pharmaceutical active compounds non-peptide class human interstital-cell-stimulating hormone releasing hormone (LHRH) receptor antagonist, vip receptor inhibitor etc., its basic mother nucleus structure is Thienopyridinone.
At present, the synthetic method of thienopyridine ketone compounds is mainly divided three classes: carry out chemically modified to Thienopyridinone mother nucleus structure; Pyrithione compounds Cheng Huan; Thiophenes Cheng Huan.Existing Thienopyridinone is adopted to be that raw material carries out chemically modified to its female ring structure, existing mother nucleus structure can only be modified, can not synthesize new Thienopyridinone structure, and be only applicable to the Thienopyridinone with active substituent group in female ring, its range of application is subject to a definite limitation.Build thiophthene cyclization by pyrithione compounds through annulation and become thienopyridine ketone compounds, comprise itrile group pyrithione, aldehyde radical pyrithione compounds and α-halogenatedcarbonylcompounds to react, produce hydrogen halide in this type of synthetic reaction process, need to add alkali as acid binding agent.Thiophenes is built and pyridone structure by annulation, need through the condensation reaction of ketone and methylcarbonate, 1,3-dicarbonyl compound and the condensation reaction of acid anhydrides, the substitution reaction of enol and azepine annulation etc. comparatively multi-step realize; And this synthetic method is only applicable to the thiophenes with halogen group on 2-position, synthesis obtains the thienopyridine ketone compounds that 5-bit strip has carbonyl substituted, and its range of application is subject to a definite limitation.
The patent No. is WO2005018567 and document " Design; syhtnesis; and structure-activityrelations of thieno [2; 3-b] pyridin-4-one derivatives as a novel class of potent; orallyactive; non-peptide luteinizing hormone-releasing hormone receptor antagonists " (J.Med.Chem.2006,49,3809) the multiple thienopyridine ketone compounds that can be used as medicinal intermediates or itself there is bio-pharmaceutical activity is disclosed.This kind of thienopyridine ketone compound all becomes cyclization to become by thiophene compound, and synthesis step is more, and needs to select different synthetic methods according to different substituted radicals, and range of application is restricted.The present invention is directed to this kind of thienopyridine ketone compound and propose a kind of new synthetic method.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is the preparation method providing a kind of thienopyridine ketone compounds, and the method step is simple and the scope of application is wider.
The invention provides a kind of preparation method of thienopyridine ketone compounds, comprise the following steps:
2-amido-3-acetyl thiophene the compounds of formula (I) structure and DMF dimethylacetal are reacted, obtains the thienopyridine ketone compounds of formula (II) structure;
Wherein, R
1for-H ,-A ,-COA ,-CONA
2,-COAr ,-SO
2a ,-SO
2ar ,-Ar or-Het;
R
2for-COA ,-COAr ,-COOA ,-Ar or-Het;
Described A is C1 ~ C30 chain-like alkyl, C1 ~ C30 replaces chain-like alkyl or C3 ~ C7 cycloalkyl;
Described Het is for containing 1 ~ 4 heteroatomic monocycle unsaturated heterocycle, containing 1 ~ 4 heteroatomic dicyclo unsaturated heterocycle, containing 1 ~ 4 heteroatomic replacement monocycle unsaturated heterocycle or containing 1 ~ 4 heteroatomic substituted bicyclic unsaturated heterocycle, and described heteroatoms is one or more in N, O and S atom.
Preferably, it be the chain-like alkyl containing 1 ~ 20 substituted radical that described C1 ~ C30 replaces chain-like alkyl, and described substituted radical is one or more in OH, F, Cl, Br, Ar and Het.
Preferably, described replacement monocycle unsaturated heterocycle and substituted bicyclic unsaturated heterocycle are separately independently containing 1 ~ 3 substituted radical;
The substituted radical of described replacement monocycle unsaturated heterocycle and substituted bicyclic unsaturated heterocycle is independently F, Cl, Br, I, A, OH, CHO, COA, COOH, COOA, CN, NO separately
2, NH
2, NHA, NA
2, CONHA and CONA
2in one or more.
Preferably, the 2-amido-3-acetyl thiophene compounds of described formula (I) structure and the mol ratio of DMF dimethylacetal are 1:1 ~ 10.
Preferably, the temperature of reaction of described reaction is 80 DEG C ~ 140 DEG C, and the reaction times is 1h ~ 10h.
Preferably, described Ar is phenyl, substituted-phenyl, xenyl, substituted biphenyl base, naphthyl or substituted naphthyl.
Preferably, described substituted-phenyl, substituted biphenyl base and substituted naphthyl are separately independently containing 1 ~ 5 substituted radical;
The substituted radical of described substituted-phenyl, substituted biphenyl base and substituted naphthyl is independently A, F, Cl, Br, I, OA, OH, CHO, COA, NH separately
2, NHA, NA
2, NO
2, COOA, COOH, CONH
2, CONH
2, CONHA, CONA
2, SO
2one or more in A, CN and Het.
Preferably, the 2-amido-3-acetyl thiophene compounds of described formula (I) structure is prepared as follows:
The lsothiocyanates of methyl ethyl diketone, formula (III) structure and the Beta-bromo compound of formula (IV) structure are reacted, obtains the 2-amido-3-acetyl thiophene compounds of formula (I) structure;
R
1-N=C=S（III）
Br-CH
2-R
2（IV）。
Preferably, the mol ratio of the lsothiocyanates of described methyl ethyl diketone, formula (III) structure and the Beta-bromo compound of formula (IV) structure is 0.8 ~ 1.2:0.8 ~ 1.2:0.8 ~ 1.2.
The invention provides a kind of preparation method of thienopyridine ketone compounds; the method is the thienopyridine ketone compounds that raw material carries out the formula that is obtained by reacting (II) structure with the 2-amido-3-acetyl thiophene compounds of formula (I) structure and DMF dimethylacetal.Compared with prior art thiophenes annulation, the present invention utilizes N, dinethylformamide dimethylacetal first with the ethanoyl generation condensation reaction of 3-position in 2-amido-3-acetyl thiophene compounds, further with the amido generation Intramolecular substitution reaction Cheng Huan of 2-position, one-step synthesis thienopyridine ketone compounds, synthetic method is simple, mild condition; Further, R
1and R
2can be multiple different substituted radical, the scope of application is wider.
Experimental result shows, preparation method of the present invention obtains thienopyridine ketone compounds productive rate and reaches as high as 90%.
Embodiment
The invention provides a kind of preparation method of thienopyridine ketone compounds; comprise the following steps: by the 2-amido-3-acetyl thiophene compounds of formula (I) structure and N; dinethylformamide dimethylacetal reacts, and obtains the thienopyridine ketone compounds of formula (II) structure.
Wherein, R
1for-H ,-A ,-COA ,-CONA
2,-COAr ,-SO
2a ,-SO
2ar ,-Ar or-Het; R
2for-COA ,-COAr ,-COOA ,-Ar or-Het; Described A is C1 ~ C30 chain-like alkyl, C1 ~ C30 replaces chain-like alkyl or C3 ~ C7 cycloalkyl; Described Het is for containing 1 ~ 4 heteroatomic monocycle unsaturated heterocycle, containing 1 ~ 4 heteroatomic dicyclo unsaturated heterocycle, containing 1 ~ 4 heteroatomic replacement monocycle unsaturated heterocycle or containing 1 ~ 4 heteroatomic substituted bicyclic unsaturated heterocycle, and described heteroatoms is one or more in N, O and S atom.When Het be dicyclo unsaturated heterocycle or substituted bicyclic unsaturated heterocycle time, heteroatoms can be positioned on one of them ring simultaneously, also can lay respectively on different rings.
According to the present invention, the mol ratio of described 2-amido-3-acetyl thiophene compounds and DMF dimethylacetal (DMFDMA) is 1: 1 ~ 10, is preferably 1:1.5 ~ 5.0, is more preferably 1: 1.5 ~ 3, most preferably is 1: 1.8 ~ 2.2.The present invention is preferably react in DMF (DMF) at solvent, DMFDMA and DMF similar, the therefore higher interference can avoiding DMF of DMFDMA concentration, is conducive to the carrying out reacted.
DMFDMA first with the ethanoyl generation condensation reaction of 3-position in 2-amido-3-acetyl thiophene compounds; further with the amido generation Intramolecular substitution reaction of 2-position; thus formation pyridine ring, realize the synthesis of thienopyridine ketone compounds, synthetic method is simple.
Reaction conditions of the present invention is gentle, requires not harsh, all can carry out being obtained by reacting thienopyridine ketone compounds at 80 DEG C ~ 140 DEG C to temperature condition, is preferably 90 DEG C ~ 130 DEG C, is more preferably 100 DEG C ~ 120 DEG C, most preferably is 110 ~ 120 DEG C.
The reaction times of described reaction is 1h ~ 10h, is preferably 1h ~ 5h, is more preferably 1h ~ 3h, most preferably is 1.5 ~ 2h.
According to the present invention, it is the chain-like alkyl containing 1 ~ 20 substituted radical that described C1 ~ C30 replaces chain-like alkyl, is preferably containing 1 ~ 10 substituted radical, replaces in chain-like alkyl and have at most 20 H atom to be substituted.When substituted radical number is 1, substituted radical is OH, F, Cl, Br, Ar or Het; When substituted radical number is 2 ~ 20, substituted radical is one or more in OH, F, Cl, Br, Ar and Het.Described replacement chain-like alkyl is preferably C1 ~ C10 and replaces chain-like alkyl, and now the number of substituted radical is preferably 1 ~ 7, is more preferably 1 ~ 5, most preferably is 1 ~ 3.
Described replacement monocycle unsaturated heterocycle is the monocycle unsaturated heterocycle containing 1 ~ 3 substituted radical, is preferably containing 1 ~ 2 substituted radical, the H atom that substituted radical substituted heterocycle is connected with C atom.When the number of substituted radical is 1, substituted radical is F, Cl, Br, I, A, OH, CHO, COA, COOH, COOA, CN, NO
2, NH
2, NHA, NA
2, CONHA or CONA
2; When the number of substituted radical is 2 ~ 3, substituted radical is F, Cl, Br, I, A, OH, CHO, COA, COOH, COOA, CN, NO
2, NH
2, NHA, NA
2, CONHA and CONA
2in one or more.
Described substituted bicyclic unsaturated heterocycle is the dicyclo unsaturated heterocycle containing 1 ~ 3 substituted radical, is preferably containing 1 ~ 2 substituted radical, the H atom that substituted radical substituted heterocycle is connected with C atom.When the number of substituted radical is 1, substituted radical is F, Cl, Br, I, A, OH, CHO, COA, COOH, COOA, CN, NO
2, NH
2, NHA, NA
2, CONHA or CONA
2; When the number of substituted radical is 2 ~ 3, substituted radical is F, Cl, Br, I, A, OH, CHO, COA, COOH, COOA, CN, NO
2, NH
2, NHA, NA
2, CONHA and CONA
2in one or more.
According to the present invention, described Ar is phenyl, substituted-phenyl, xenyl, substituted biphenyl base, naphthyl or substituted naphthyl.
Described substituted-phenyl contains 1 ~ 5 substituted radical, is preferably containing 1 ~ 3 substituted radical.
H atom on the substituted radical substituted benzene ring of described substituted-phenyl.When substituted radical number is 1, substituted radical is A, F, Cl, Br, I, OA, OH, CHO, COA, NH
2, NHA, NA
2, NO
2, COOA, COOH, CONH
2, CONH
2, CONHA, CONA
2, SO
2a, CN or Het; When substituted radical number is 2 ~ 5, substituted radical is A, F, Cl, Br, I, OA, OH, CHO, COA, NH
2, NHA, NA
2, NO
2, COOA, COOH, CONH
2, CONH
2, CONHA, CONA
2, SO
2one or more in A, CN and Het.
Described substituted biphenyl base contains 1 ~ 5 substituted radical, is preferably containing 1 ~ 3 substituted radical.
H atom on the substituted radical substituted benzene ring of described substituted biphenyl base.When substituted radical number is 1, substituted radical is A, F, Cl, Br, I, OA, OH, CHO, COA, NH
2, NHA, NA
2, NO
2, COOA, COOH, CONH
2, CONH
2, CONHA, CONA
2, SO
2a, CN or Het; When substituted radical number is 2 ~ 5, substituted radical is A, F, Cl, Br, I, OA, OH, CHO, COA, NH
2, NHA, NA
2, NO
2, COOA, COOH, CONH
2, CONH
2, CONHA, CONA
2, SO
2one or more in A, CN and Het.
Described substituted naphthyl contains 1 ~ 5 substituted radical, is preferably containing 1 ~ 3 substituted radical.
H atom on the substituted radical substituted benzene ring of described naphthyl.When substituted radical number is 1, substituted radical is A, F, Cl, Br, I, OA, OH, CHO, COA, NH
2, NHA, NA
2, NO
2, COOA, COOH, CONH
2, CONH
2, CONHA, CONA
2, SO
2a, CN or Het; When substituted radical number is 2 ~ 5, substituted radical is A, F, Cl, Br, I, OA, OH, CHO, COA, NH
2, NHA, NA
2, NO
2, COOH, CONH
2, CONH
2, CONHACONH
2, SO
2one or more in A, CN and Het.
R in the present invention as can be seen from the above
1and R
2can be multiple different substituted radical, synthetic method step is simple and the scope of application is wider.
According to the present invention; 2-amido-3-acetyl thiophene the compounds of described formula (I) structure is preferably prepared as follows: the lsothiocyanates of methyl ethyl diketone, formula (III) structure and the Beta-bromo compound of formula (IV) structure are reacted, and obtains the 2-amido-3-acetyl thiophene compounds of formula (I) structure.
R
1-N=C=S（III）
Br-CH
2-R
2（IV）
Wherein, the mol ratio of the lsothiocyanates of described methyl ethyl diketone, formula (III) structure and the Beta-bromo compound of formula (IV) structure is 0.8 ~ 1.2:0.8 ~ 1.2:0.8 ~ 1.2.R in formula (III) structure
1, R in formula (IV) structure
2with the R in the 2-amido-3-acetyl thiophene compounds of formula (I) structure
1and R
2identical.
Synthesizing thiofuran the raw material 2-amido-3-acetyl thiophene compounds reaction conditions of pyridine compounds is gentle as can be seen from the above, obtains than being easier to.
In order to further illustrate the present invention, below in conjunction with embodiment, the preparation method to a kind of thienopyridine ketone compounds provided by the invention is described in detail.
In following examples, agents useful for same is commercially available.
Embodiment 1
At room temperature; by 10mmol methyl ethyl diketone, 20mmol Anhydrous potassium carbonate and 30ml N; dinethylformamide (DMF) mix and blend; slowly add 10mmol PhNCS; reaction 2h; add 10mmol Beta-bromo methyl phenyl ketone; after continuing reaction 2h, reaction solution is poured in saturated aqueous common salt, 20ml dichloromethane extraction three times; merge organic phase; after 20ml water washes three times, add 5g anhydrous sodium sulfate drying, filter; removing organic solvent, is separated through silica gel column chromatography and obtains 2-anilino-3-ethanoyl-4-methyl-5-benzoyl thiophene.
The preparation method of 2-amido-3-acetyl thiophene compound used in following examples is same as above, and difference is that the lsothiocyanates of starting materials of formulae (III) structure is different with the selection of the Beta-bromo compound of formula (IV) structure.
2-(4-anisole amido)-3-ethanoyl-4-methyl-5-(4-nitrophenyl) thiophene: raw material is 4-anisole lsothiocyanates, P-nitrobenzyl bromide.
2-(2-chloroanilino)-3-ethanoyl-4-methyl-5-(4-nitrophenyl) thiophene: raw material is 2-chlorobenzene lsothiocyanates, P-nitrobenzyl bromide.
2-anilino-3-ethanoyl-4-methyl-5-ethoxycarbonyl thiophene: raw material is PhNCS, bromoethyl acetate.
2-(2-methoxyl group-5-chloroanilino)-3-ethanoyl-4-methyl-5-benzoyl thiophene: raw material is 2-methoxyl group-5-chlorobenzene lsothiocyanates, bromoacetophenone.
2-benzyl amino-3-ethanoyl-4-methyl-5-(4-nitrophenyl) thiophene: raw material is BITC, P-nitrobenzyl bromide.
2-(4-anisole amido)-3-ethanoyl-4-methyl-5-ethoxycarbonyl thiophene: raw material is 4-anisole lsothiocyanates, bromoethyl acetate.
2-(4-anisole amido)-3-ethanoyl-4-methyl-5-benzoyl thiophene: raw material is 4-anisole lsothiocyanates, bromoacetophenone.
2-ethylamino--3-ethanoyl-4-methyl-5-(2-chlorothiophene base) thiophene: raw material is ethyl isothiocyanate, the chloro-3-bromomethyl thiophene of 2-.
2-amido-3-ethanoyl-4-methyl-5-benzoyl thiophene: raw material is isothiocyanic acid potassium, bromoacetophenone.
2-benzidion-3-ethanoyl-4-methyl-5-ethoxycarbonyl thiophene: raw material is xenyl lsothiocyanates, bromoethyl acetate.
2-sulfonyloxy methyl amido-3-ethanoyl-4-methyl-5-(4-aminomethyl phenyl) thiophene: raw material is 2-methyl sulphonyl lsothiocyanates, to methyl-benzyl bromine.
2-(4-itrile group anilino)-3-ethanoyl-4-methyl-5-benzoyl thiophene: raw material is 4-itrile group PhNCS, bromoacetophenone.
Embodiment 2
By the 2-anilino-3-ethanoyl-4-methyl-5-benzoyl thiophene obtained in 2mmol embodiment 1, 4mmol DMFDMA and 20ml DMF adds to and is equipped with in the 50ml round-bottomed flask of reflux condensing tube and agitator, under the condition stirred, be heated to 120 DEG C, after reaction 2h, reaction solution is poured in 100ml saturated aqueous common salt, 30ml dichloromethane extraction twice, merge organic phase, 30ml water washing twice, add 5g anhydrous sodium sulfate drying, filter, removing organic solvent, be separated through silica gel column chromatography and obtain 2-benzoyl-3-methyl-7-tolylthiophene also [2, 3-b] pyridine-4 [7H] ketone, productive rate is 90%.Reaction formula is as follows:
Utilize nucleus magnetic resonance to the 2-benzoyl-3-methyl-7-tolylthiophene obtained in embodiment 2 also [2,3-b] pyridine-4 [7H] ketone analyze, obtain its hydrogen spectrum and carbon compose, result is as follows:
1H NMR(300MHz,CDCl
3):δ2.66(s,3H),6.39(d,J=7.8Hz,1H),7.44–7.60(m,9H),7.74(d,J=6.9Hz,2H)。
13C NMR(150MHz,CDCl
3):δ17.32,115.86,125.33,127.83,128.61,130.17,130.51,132.49,139.10139.51,141.77,144.03,155.16,177.01,190.27。
Utilize ultimate analysis to the 2-benzoyl-3-methyl-7-tolylthiophene obtained in embodiment 2 also [2,3-b] pyridine-4 [7H] ketone analyze, obtain its each atom content.
Anal.Calc.For C
21H
15NO
2S（%）:C,73.02;H,4.38;N,4.06.Found:C,73.52;H,4.41;N,4.09.
Embodiment 3
By 2-(4-anisole amido)-3-ethanoyl-4-methyl-5-(4-nitrophenyl) thiophene obtained in 2mmol embodiment 1, 2mmol DMFDMA and 30ml DMF adds to and is equipped with in the 50ml round-bottomed flask of reflux condensing tube and agitator, under the condition stirred, be heated to 130 DEG C, after reaction 5h, reaction solution is poured in 100ml saturated aqueous common salt, 30ml dichloromethane extraction twice, merge organic phase, 30ml water washing twice, add 5g anhydrous sodium sulfate drying, filter, removing organic solvent, be separated through silica gel column chromatography and obtain 2-(4-nitrophenyl)-3-methyl-7-(4-p-methoxy-phenyl) thieno-[2, 3-b] pyridine-4 (7H) ketone, productive rate is 50%.Reaction formula is as follows:
Utilize nucleus magnetic resonance to analyze the 2-obtained in embodiment 3 (4-nitrophenyl)-3-methyl-7-(4-p-methoxy-phenyl) thieno-[2,3-b] pyridine-4 (7H) ketone, obtain its hydrogen spectrum and carbon spectrum, result is as follows:
1H NMR(400MHz,DMSO):δ2.68(s,3H),3.85(s,3H),6.19(d,J=7.2Hz,1H),7.17(d,J=8.8Hz,2H),7.63(d,J=8.8Hz,2H),7.73(d,J=8.8Hz,2H),7.83(d,J=7.6Hz,1H),8.27(d,J=8.8Hz,2H)。
13C NMR(100MHz,DMSO):δ15.01,55.65,114.53,115.34,123.98,125.32,127.14,127.94,130.02,130.18,133.56,134.72,139.44,140.58,146.30,152.82,160.04,175.20。
Utilize ultimate analysis to analyze the 2-obtained in embodiment 3 (4-nitrophenyl)-3-methyl-7-(4-p-methoxy-phenyl) thieno-[2,3-b] pyridine-4 (7H) ketone, obtain its each atom content.
Anal.Calc.For C
21H
16N
2O
4S（%）:C,64.27;H,4.11;N,7.14.Found:C,64.55;H,4.13;N,7.20.
Embodiment 4
By 2-(2-chloroanilino)-3-ethanoyl-4-methyl-5-(4-nitrophenyl) thiophene obtained in 2mmol embodiment 1, 6mmol DMFDMA and 30ml DMF adds to and is equipped with in the 50ml round-bottomed flask of reflux condensing tube and agitator, under the condition stirred, be heated to 140 DEG C, after reaction 1h, reaction solution is poured in 100ml saturated aqueous common salt, 30ml dichloromethane extraction twice, merge organic phase, 30ml water washing twice, add 5g anhydrous sodium sulfate drying, filter, removing organic solvent, be separated through silica gel column chromatography and obtain 2-(4-nitrophenyl)-3-methyl-7-(2-chloro-phenyl-) thieno-[2, 3-b] pyridine-4 (7H) ketone, productive rate is 75%.Reaction formula is as follows:
Embodiment 5
By the 2-anilino-3-ethanoyl-4-methyl-5-ethoxycarbonyl thiophene obtained in 2mmol embodiment 1, 3mmol DMFDMA and 15ml DMF adds to and is equipped with in the 50ml round-bottomed flask of reflux condensing tube and agitator, under the condition stirred, be heated to 120 DEG C, after reaction 3h, reaction solution is poured in 100ml saturated aqueous common salt, 30ml dichloromethane extraction twice, merge organic phase, 30ml water washing twice, add 5g anhydrous sodium sulfate drying, filter, removing organic solvent, be separated through silica gel column chromatography and obtain 2-ethoxycarbonyl-3-methyl-7-tolylthiophene also [2, 3-b] pyridine-4 (7H) ketone, productive rate is 72%.Reaction formula is as follows:
Embodiment 6
By 2-(2-methoxyl group-5-the chloroanilino)-3-ethanoyl-4-methyl-5-benzoyl thiophene obtained in 2mmol embodiment 1, 20mmol DMFDMA and 25ml DMF adds to and is equipped with in the 50ml round-bottomed flask of reflux condensing tube and agitator, under the condition stirred, be heated to 80 DEG C, after reaction 10h, reaction solution is poured in 100ml saturated aqueous common salt, 30ml dichloromethane extraction twice, merge organic phase, 30ml water washing twice, add 5g anhydrous sodium sulfate drying, filter, removing organic solvent, be separated through silica gel column chromatography and obtain 2-benzoyl-3-methyl-7-(2-methoxyl group-5-chloro-phenyl-) thieno-[2, 3-b] pyridine-4 (7H) ketone, productive rate is 61%.Reaction formula is as follows:
Embodiment 7
By 2-benzyl amino-3-ethanoyl-4-methyl-5-(4-nitrophenyl) thiophene obtained in 2mmol embodiment 1, 8mmol DMFDMA and 25ml DMF adds to and is equipped with in the 50ml round-bottomed flask of reflux condensing tube and agitator, under the condition stirred, be heated to 115 DEG C, after reaction 2.5h, reaction solution is poured in 100ml saturated aqueous common salt, 30ml dichloromethane extraction twice, merge organic phase, 30ml water washing twice, add 5g anhydrous sodium sulfate drying, filter, removing organic solvent, be separated through silica gel column chromatography and obtain 2-(4-nitrophenyl)-3-methyl-7-benzyl thieno-[2, 3-b] pyridine-4 (7H) ketone, productive rate is 81%.Reaction formula is as follows:
Embodiment 8
By 2-(4-anisole the amido)-3-ethanoyl-4-methyl-5-ethoxycarbonyl thiophene obtained in 2mmol embodiment 1, 10mmol DMFDMA and 20ml DMF adds to and is equipped with in the 50ml round-bottomed flask of reflux condensing tube and agitator, under the condition stirred, be heated to 110 DEG C, after reaction 5h, reaction solution is poured in 100ml saturated aqueous common salt, 30ml dichloromethane extraction twice, merge organic phase, 30ml water washing twice, add 5g anhydrous sodium sulfate drying, filter, removing organic solvent, be separated through silica gel column chromatography and obtain 2-ethoxycarbonyl-3-methyl-7-(4-p-methoxy-phenyl) thieno-[2, 3-b] pyridine-4 (7H) ketone, productive rate is 80%.Reaction formula is as follows:
Embodiment 9
By 2-(4-anisole the amido)-3-ethanoyl-4-methyl-5-benzoyl thiophene obtained in 2mmol embodiment 1, 10mmol DMFDMA and 30ml DMF adds to and is equipped with in the 50ml round-bottomed flask of reflux condensing tube and agitator, under the condition stirred, be heated to 90 DEG C, after reaction 8h, reaction solution is poured in 100ml saturated aqueous common salt, 30ml dichloromethane extraction twice, merge organic phase, 30ml water washing twice, add 5g anhydrous sodium sulfate drying, filter, removing organic solvent, be separated through silica gel column chromatography and obtain 2-benzoyl-3-methyl-7-(4-p-methoxy-phenyl)-thieno-[2, 3-b] pyridine-4 (7H) ketone, productive rate is 72%.Reaction formula is as follows:
Embodiment 10
By 2-ethylamino--3-ethanoyl-4-methyl-5-(the 2-chlorothiophene base) thiophene obtained in 2mmol embodiment 1, 9mmol DMFDMA and 30ml DMF adds to and is equipped with in the 50ml round-bottomed flask of reflux condensing tube and agitator, under the condition stirred, be heated to 100 DEG C, after reaction 5h, reaction solution is poured in 100ml saturated aqueous common salt, 30ml dichloromethane extraction twice, merge organic phase, 30ml water washing twice, add 5g anhydrous sodium sulfate drying, filter, removing organic solvent, be separated through silica gel column chromatography and obtain 2-(2-chlorothiophene base)-3-methyl-7-ethylthiophene also [2, 3-b] pyridine-4 (7H) ketone, productive rate is 66%.Reaction formula is as follows:
Embodiment 11
By the 2-amido-3-ethanoyl-4-methyl-5-benzoyl thiophene obtained in 2mmol embodiment 1, 5mmol DMFDMA and 30ml DMF adds to and is equipped with in the 50ml round-bottomed flask of reflux condensing tube and agitator, under the condition stirred, be heated to 95 DEG C, after reaction 4.5h, reaction solution is poured in 100ml saturated aqueous common salt, 30ml dichloromethane extraction twice, merge organic phase, 30ml water washing twice, add 5g anhydrous sodium sulfate drying, filter, removing organic solvent, be separated through silica gel column chromatography and obtain 2-benzoyl-3 methyl thiophene also [2, 3-b] pyridine-4 (7H) ketone, productive rate is 63%.Reaction formula is as follows:
Embodiment 12
By the 2-benzidion-3-ethanoyl-4-methyl-5-ethoxycarbonyl thiophene obtained in 2mmol embodiment 1, 10mmol DMFDMA and 30ml DMF adds to and is equipped with in the 50ml round-bottomed flask of reflux condensing tube and agitator, under the condition stirred, be heated to 120 DEG C, after reaction 3h, reaction solution is poured in 100ml saturated aqueous common salt, 30ml dichloromethane extraction twice, merge organic phase, 30ml water washing twice, add 5g anhydrous sodium sulfate drying, filter, removing organic solvent, be separated through silica gel column chromatography and obtain 2-ethoxycarbonyl-3-methyl-7-xenyl thieno-[2, 3-b] pyridine-4 (7H) ketone, productive rate is 76%.Reaction formula is as follows:
Embodiment 13
By 2-sulfonyloxy methyl amido-3-ethanoyl-4-methyl-5-(4-aminomethyl phenyl) thiophene obtained in 2mmol embodiment 1, 7mmol DMFDMA and 30ml DMF adds to and is equipped with in the 50ml round-bottomed flask of reflux condensing tube and agitator, under the condition stirred, be heated to 100 DEG C, after reaction 1.5h, reaction solution is poured in 100ml saturated aqueous common salt, 30ml dichloromethane extraction twice, merge organic phase, 30ml water washing twice, add 5g anhydrous sodium sulfate drying, filter, removing organic solvent, be separated through silica gel column chromatography and obtain 2-(4-aminomethyl phenyl)-3-methyl-7-methyl sulphonyl thieno-[2, 3-b] pyridine-4 (7H) ketone, productive rate is 77%.Reaction formula is as follows:
Embodiment 14
By 2-(4-itrile group the anilino)-3-ethanoyl-4-methyl-5-benzoyl thiophene obtained in 2mmol embodiment 1, 4mmol DMFDMA and 25ml DMF adds to and is equipped with in the 50ml round-bottomed flask of reflux condensing tube and agitator, under the condition stirred, be heated to 125 DEG C, after reaction 3h, reaction solution is poured in 100ml saturated aqueous common salt, 30ml dichloromethane extraction twice, merge organic phase, 30ml water washing twice, add 5g anhydrous sodium sulfate drying, filter, removing organic solvent, be separated through silica gel column chromatography and obtain 2-benzoyl-3-methyl-7-(4-cyanophenyl) thieno-[2, 3-b] pyridine-4 (7H) ketone, productive rate is 86%.Reaction formula is as follows:
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (5)
1. a preparation method for thienopyridine ketone compounds, is characterized in that, comprises the following steps:
2-amido-3-acetyl thiophene the compounds of formula (I) structure and DMF dimethylacetal are reacted, obtains the thienopyridine ketone compounds of formula (II) structure;
Wherein, R
1for-H ,-A ,-COA ,-CONA
2,-COAr ,-SO
2a ,-SO
2ar ,-Ar or-Het;
R
2for-COA ,-COAr ,-COOA ,-Ar or-Het;
Described A is C1 ~ C30 chain-like alkyl, C1 ~ C30 replaces chain-like alkyl or C3 ~ C7 cycloalkyl;
Described Het is for containing 1 ~ 4 heteroatomic monocycle unsaturated heterocycle, containing 1 ~ 4 heteroatomic dicyclo unsaturated heterocycle, containing 1 ~ 4 heteroatomic replacement monocycle unsaturated heterocycle or containing 1 ~ 4 heteroatomic substituted bicyclic unsaturated heterocycle, and described heteroatoms is one or more in N, O and S atom;
Described Ar is phenyl, substituted-phenyl, xenyl, substituted biphenyl base, naphthyl or substituted naphthyl;
It is chain-like alkyl containing 1 ~ 20 substituted radical that described C1 ~ C30 replaces chain-like alkyl, and described substituted radical is one or more in OH, F, Cl, Br, Ar and Het;
Described replacement monocycle unsaturated heterocycle and substituted bicyclic unsaturated heterocycle are separately independently containing 1 ~ 3 substituted radical;
The substituted radical of described replacement monocycle unsaturated heterocycle and substituted bicyclic unsaturated heterocycle is independently F, Cl, Br, I, A, OH, CHO, COA, COOH, COOA, CN, NO separately
2, NH
2, NHA, NA
2, CONHA and CONA
2in one or more;
Described substituted-phenyl, substituted biphenyl base and substituted naphthyl are separately independently containing 1 ~ 5 substituted radical;
The substituted radical of described substituted-phenyl, substituted biphenyl base and substituted naphthyl is independently A, F, Cl, Br, I, OA, OH, CHO, COA, NH separately
2, NHA, NA
2, NO
2, COOA, COOH, CONH
2, CONH
2, CONHA, CONA
2, SO
2one or more in A, CN and Het;
And R
1for C3 ~ C7 cycloalkyl ,-COA ,-CONA
2,-SO
2ar or-SO
2during A, or R
2during for-COA or-COOA, A is not C3 ~ C7 cycloalkyl.
2. preparation method according to claim 1, is characterized in that, the 2-amido-3-acetyl thiophene compounds of described formula (I) structure and the mol ratio of DMF dimethylacetal are 1:1 ~ 10.
3. preparation method according to claim 1, is characterized in that, the temperature of reaction of described reaction is 80 DEG C ~ 140 DEG C, and the reaction times is 1h ~ 10h.
4. preparation method according to claim 1, is characterized in that, the 2-amido-3-acetyl thiophene compounds of described formula (I) structure is prepared as follows:
The lsothiocyanates of methyl ethyl diketone, formula (III) structure and the Beta-bromo compound of formula (IV) structure are reacted, obtains the 2-amido-3-acetyl thiophene compounds of formula (I) structure;
R
1-N＝C＝S (III)
Br-CH
2-R
2(IV)。
5. preparation method according to claim 4, it is characterized in that, the mol ratio of the lsothiocyanates of described methyl ethyl diketone, formula (III) structure and the Beta-bromo compound of formula (IV) structure is 0.8 ~ 1.2:0.8 ~ 1.2:0.8 ~ 1.2.
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Citations (2)
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|---|---|---|---|---|
| CN1146206A (en) * | 1994-04-19 | 1997-03-26 | 武田药品工业株式会社 | Bicyclic thiophene derivatives and use as gonadotropin releasing hormone antagonists |
| WO2005018567A2 (en) * | 2003-08-22 | 2005-03-03 | Bayer Pharmaceuticals Corporation | Compounds and compositions for the treatment of diabetes and diabetes-related disorders |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1146206A (en) * | 1994-04-19 | 1997-03-26 | 武田药品工业株式会社 | Bicyclic thiophene derivatives and use as gonadotropin releasing hormone antagonists |
| WO2005018567A2 (en) * | 2003-08-22 | 2005-03-03 | Bayer Pharmaceuticals Corporation | Compounds and compositions for the treatment of diabetes and diabetes-related disorders |
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| An improved method for the synthesis of aminothiophenes precursors of thieno[2,3-b]pyrrole;Geoffroy Sommen，等;《Tetrahedron Letters》;20020131;第43卷(第2期);第257-259页 * |
| New Synthetic Approaches to 4(lH)-Pyridinone Derivatives. 3. 2-Bromoacetylated Enamines as Pyridine Ring Synthons;Riaz F. Abdulla，等;《J. Org. Chem.》;19790430;第44卷(第8期);第1349-1351页 * |
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