CN103059040A - Synthesizing method of 5-chloro-7-methoxy thieno[3,2-b]pyridine - Google Patents
Synthesizing method of 5-chloro-7-methoxy thieno[3,2-b]pyridine Download PDFInfo
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- CN103059040A CN103059040A CN201310004200XA CN201310004200A CN103059040A CN 103059040 A CN103059040 A CN 103059040A CN 201310004200X A CN201310004200X A CN 201310004200XA CN 201310004200 A CN201310004200 A CN 201310004200A CN 103059040 A CN103059040 A CN 103059040A
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- pyridine
- thieno
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- methoxythiophene
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- 238000000034 method Methods 0.000 title abstract description 5
- FPKSLXUICLEJKO-UHFFFAOYSA-N 5-chloro-7-methoxythieno[3,2-b]pyridine Chemical compound COC1=CC(Cl)=NC2=C1SC=C2 FPKSLXUICLEJKO-UHFFFAOYSA-N 0.000 title abstract 3
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 14
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 claims abstract description 14
- VHXFEWNGLCHCOX-UHFFFAOYSA-N 7-hydroxy-4h-thieno[3,2-b]pyridin-5-one Chemical compound N1C(O)=CC(=O)C2=C1C=CS2 VHXFEWNGLCHCOX-UHFFFAOYSA-N 0.000 claims abstract description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000010992 reflux Methods 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 6
- 230000007062 hydrolysis Effects 0.000 claims abstract description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims abstract description 3
- 230000000694 effects Effects 0.000 claims abstract description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 62
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 31
- 238000010189 synthetic method Methods 0.000 claims description 18
- 125000004494 ethyl ester group Chemical group 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 13
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 9
- 239000011734 sodium Substances 0.000 claims description 9
- 229910052708 sodium Inorganic materials 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- -1 chloro- Chemical class 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 235000011167 hydrochloric acid Nutrition 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical class CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 3
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical class CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 235000019439 ethyl acetate Nutrition 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- 239000003643 water by type Substances 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 2
- 150000007942 carboxylates Chemical class 0.000 abstract 2
- 230000002378 acidificating effect Effects 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a synthesizing method of 5-chloro-7-methoxy thieno[3,2-b]pyridine. According to the invention, on a basis that 3-amino-2-methyl acetate-thiophene is adopted as a raw material, several times of tests are carried out, such that the process route of the invention is finally determined. According to the invention, 3-amino-2-methyl acetate-thiophene is adopted as an initial raw material, and is subjected to ring closure with diethyl malonate in ethanol in a strong alkali condition, such that 5,7-dihydroxy-6-ethyl carboxylate thieno[3,2-b]pyridine is obtained; the obtained 5,7-dihydroxy-6-ethyl carboxylate thieno[3,2-b]pyridine is subjected to hydrolysis decarboxylation under a strong acidic condition, such that 5,7-dihydroxy thieno[3,2-b]pyridine is obtained; the material is subjected to refluxing with phosphorus oxychloride under the effect of a catalyst, such that 5,7-dichloro-6-thieno[3,2-b]pyridine is obtained; 5,7-dichloro-6-thieno[3,2-b]pyridine is subjected to a room-temperature reaction in an N,N-dimethyl formamide solution with sodium methoxide as an alkali, such that the 5-chloro-7-methoxy thieno[3,2-b]pyridine is obtained.
Description
Technical field
The present invention relates to the also synthetic method of [3,2-b] pyridine of a kind of 5-chloro-7-methoxythiophene, belong to medicine, chemical technology field.
Background technology
5-chloro-7-methoxythiophene also [3,2-b] pyridine is a kind of white solid, is a kind of important medicinal intermediates.
5-chloro-7-methoxythiophene also [3,2-b] pyridine is occupied critical role in the medicine in future is synthetic, be the important intermediate of a lot of medicine, and a kind of to have the prices of raw and semifnished materials cheap so be necessary to develop, the synthetic method that synthesis technique is simple and productive rate is high.
Summary of the invention
The present invention take 3-amino-2-methyl acetate-thiophene under the prerequisite of raw material, grope through test of many times, finally determined the technique circuit of this patent.The present invention is as starting raw material take 3-amino-2-methyl acetate-thiophene, in ethanol with to close ring with diethyl malonate under the highly basic condition, obtain 5,7-dihydroxyl-6-carboxylic acid, ethyl ester thieno-[3,2-b] pyridine, then with resulting 5,7-dihydroxyl-6-carboxylic acid, ethyl ester thieno-[3,2-b] pyridine hydrolysis decarboxylation under strong acid condition obtains 5,7-dihydroxyl thieno-[3,2-b] pyridine, then reflux to such an extent that obtain 5,7-two chloro-, 6-thieno-[3 under the effect of catalyzer with phosphorus oxychloride, 2-b] pyridine, 5,7-two chloro-, 6-thieno-[3,2-b] pyridine is at N, do the alkali room temperature reaction with sodium methylate in the dinethylformamide solution and obtain also [3,2-b] pyridine of 5-chloro-7-methoxythiophene.
Above-mentioned 5-chloro-7-methoxythiophene is the synthetic method of [3,2-b] pyridine also, and it is characterized in that: starting raw material of the present invention refers to take 3-amino-2-methyl acetate-thiophene as starting raw material.
Above-mentioned 5-chloro-7-methoxythiophene is the synthetic method of [3,2-b] pyridine also, it is characterized in that: used highly basic refers to take sodium ethylate as alkali during synthetic 5,7-dihydroxyl-6-carboxylic acid, ethyl ester thieno-[3,2-b] pyridine.
Above-mentioned 5-chloro-7-methoxythiophene is the synthetic method of [3,2-b] pyridine also, it is characterized in that: the strong acid of 5,7-dihydroxyl-6-carboxylic acid, ethyl ester thieno-[3,2-b] pyridine hydrolysis decarboxylation indication is hydrochloric acid.
Above-mentioned 5-chloro-7-methoxythiophene is the synthetic method of [3,2-b] pyridine also, it is characterized in that: the catalyzer of synthetic 5,7-two chloro-, 6-thieno-[3,2-b] pyridine is DMF.
Above-mentioned 5-chloro-7-methoxythiophene also [3,2-b] synthetic method of pyridine, it is characterized in that: 5-chloro-7-methoxythiophene also [3,2-b] synthetic method of pyridine: in 500 milliliters there-necked flask, drop into 150 milliliters of ethanol, 5.4 gram sodium pieces are cut into small pieces, add in the there-necked flask in batches, rapid stirring, there are a large amount of hydrogen to emit and emit a large amount of heat, behind the sodium piece dissolve complete, with 10 gram 3-amino-2-methyl acetate-thiophene, 25 gram diethyl malonates add in the there-necked flask, reflux, reaction is spent the night, and reaction solution is down to room temperature naturally, filter, get white solid 13 grams of 5,7-dihydroxyl-6-carboxylic acid, ethyl ester thieno-[3,2-b] pyridine.In 250 milliliters single port bottle, add 13 gram 5,7-dihydroxyl-6-carboxylic acid, ethyl ester thieno-[3,2-b] pyridines, water is diluted to 120 milliliters with 20 milliliters of concentrated hydrochloric acids, and pours in the single port bottle reflux into, reaction is spent the night, naturally be down to room temperature, salt of wormwood acid adjustment degree has gray solid to separate out to about the PH=5, filter, dry to such an extent that gray solid 8.2 grams are 5,7-dihydroxyl thieno-[3,2-b] pyridine.Add 5 gram 5,7-dihydroxyl thieno-[3,2-b] pyridines in 100 milliliters single port bottle, phosphorus oxychloride drips 2 milliliters of DMFs, and reflux is put plate after four hours, react completely.Directly cross post, get also white solid 4.5 grams of [3,2-b] pyridine of 5,7-dichloro-thiophene.Drop into 4 gram 5,7-dihydroxyl thieno-[3,2-b] pyridines in 100 milliliters single port bottle, 40 milliliters of DMFs add 1.5 gram sodium methylates, and stirring at room is put plate after 6 hours, react completely.Reaction solution is poured in 100 ml waters, and 100 milliliters of ethyl acetates extract 3 times, and anhydrous sodium sulfate drying is spin-dried for, and chromatography column is purified, and get also [3,2-b] pyridine 2.3 grams of 5-chloro-7-methoxythiophene.
Above-mentioned take 3-amino-2-methyl acetate-thiophene as raw material synthetic 5-chloro-7-methoxythiophene also chemical reaction and the reaction formula of [3,2-b] pyridine is as follows:
(1) reaction equation of synthetic 5,7-dihydroxyl-6-carboxylic acid, ethyl ester thieno-[3,2-b] pyridine is:
(2) reaction is finished, and the reaction equation of hydrolysis decarboxylation is after processing:
(3) reaction is finished, and the change reaction equation of processing rear and phosphorus oxychloride is:
(4) after reaction is finished, with the reaction equation of sodium methylate be:
(5) react completely after, reaction solution is poured into water, ethyl acetate extraction, anhydrous sodium sulfate drying, chromatography column are purified and to be obtained also [3,2-b] pyridine of pure 5-chloro-7-methoxythiophene.
Embodiment
Embodiment:
Described 5-chloro-7-methoxythiophene also [3,2-b] synthetic method of pyridine makes: in 500 milliliters there-necked flask, drop into 150 milliliters of ethanol, 5.4 gram sodium pieces are cut into small pieces, add in the there-necked flask in batches, rapid stirring, there are a large amount of hydrogen to emit and emit a large amount of heat, behind the sodium piece dissolve complete, with 10 gram 3-amino-2-methyl acetate-thiophene, 25 gram diethyl malonates add in the there-necked flask, reflux, reaction is spent the night, and reaction solution is down to room temperature naturally, filter, get white solid 13 grams of 5,7-dihydroxyl-6-carboxylic acid, ethyl ester thieno-[3,2-b] pyridine.In 250 milliliters single port bottle, add 13 gram 5,7-dihydroxyl-6-carboxylic acid, ethyl ester thieno-[3,2-b] pyridines, water is diluted to 120 milliliters with 20 milliliters of concentrated hydrochloric acids, and pours in the single port bottle reflux into, reaction is spent the night, naturally be down to room temperature, salt of wormwood acid adjustment degree has gray solid to separate out to about the PH=5, filter, dry to such an extent that gray solid 8.2 grams are 5,7-dihydroxyl thieno-[3,2-b] pyridine.Add 5 gram 5,7-dihydroxyl thieno-[3,2-b] pyridines in 100 milliliters single port bottle, phosphorus oxychloride drips 2 milliliters of DMFs, and reflux is put plate after four hours, react completely.Directly cross post, get also white solid 4.5 grams of [3,2-b] pyridine of 5,7-dichloro-thiophene.Drop into 4 gram 5,7-dihydroxyl thieno-[3,2-b] pyridines in 100 milliliters single port bottle, 40 milliliters of DMFs add 1.5 gram sodium methylates, and stirring at room is put plate after 6 hours, react completely.Reaction solution is poured in 100 ml waters, and 100 milliliters of ethyl acetates extract 3 times, and anhydrous sodium sulfate drying is spin-dried for, and chromatography column is purified, and get also [3,2-b] pyridine 2.3 grams of 5-chloro-7-methoxythiophene.
Claims (6)
1.5-chloro-7-methoxythiophene also [3,2-b] synthetic method of pyridine is as starting raw material take 3-amino-2-methyl acetate-thiophene, in ethanol with to close ring with diethyl malonate under the highly basic condition, obtain 5,7-dihydroxyl-6-carboxylic acid, ethyl ester thieno-[3,2-b] pyridine, then with resulting 5,7-dihydroxyl-6-carboxylic acid, ethyl ester thieno-[3,2-b] pyridine hydrolysis decarboxylation under strong acid condition obtains 5,7-dihydroxyl thieno-[3,2-b] pyridine, then under the effect of catalyzer, reflux to such an extent that obtain 5 with phosphorus oxychloride, 7-two chloro-, 6-thieno-[3,2-b] pyridine, 5,7-two chloro-, 6-thieno-[3,2-b] pyridine does the alkali room temperature reaction with sodium methylate and obtains also [3,2-b] pyridine of 5-chloro-7-methoxythiophene in DMF solution.
2. the 5-chloro-7-methoxythiophene synthetic method of [3,2-b] pyridine also as claimed in claim, it is characterized in that: starting raw material of the present invention refers to take 3-amino-2-methyl acetate-thiophene as starting raw material.
3. the 5-chloro-7-methoxythiophene synthetic method of [3,2-b] pyridine also as claimed in claim is characterized in that: used highly basic refers to take sodium ethylate as alkali during synthetic 5,7-dihydroxyl-6-carboxylic acid, ethyl ester thieno-[3,2-b] pyridine.
4. the 5-chloro-7-methoxythiophene synthetic method of [3,2-b] pyridine also as claimed in claim, it is characterized in that: the strong acid of 5,7-dihydroxyl-6-carboxylic acid, ethyl ester thieno-[3,2-b] pyridine hydrolysis decarboxylation indication is hydrochloric acid.
5. the 5-chloro-7-methoxythiophene synthetic method of [3,2-b] pyridine also as claimed in claim, it is characterized in that: the catalyzer of synthetic 5,7-two chloro-, 6-thieno-[3,2-b] pyridine is DMF.
6. 5-chloro-7-methoxythiophene also [3 as claimed in claim, 2-b] synthetic method of pyridine, it is characterized in that: described 5-chloro-7-methoxythiophene also [3,2-b] synthetic method of pyridine makes: 5-chloro-7-methoxythiophene also [3,2-b] synthetic method of pyridine: in 500 milliliters there-necked flask, drop into 150 milliliters of ethanol, 5.4 gram sodium pieces are cut into small pieces, add in the there-necked flask in batches, rapid stirring, there are a large amount of hydrogen to emit and emit a large amount of heat, behind the sodium piece dissolve complete, with 10 gram 3-amino-2-methyl acetate-thiophene, 25 gram diethyl malonates add in the there-necked flask, reflux, reaction is spent the night, reaction solution is down to room temperature naturally, filter, get 5,7-dihydroxyl-6-carboxylic acid, ethyl ester thieno-[3,2-b] white solid 13 gram of pyridine, in 250 milliliters single port bottle, add 13 grams 5,7-dihydroxyl-6-carboxylic acid, ethyl ester thieno-[3,2-b] pyridine, water is diluted to 120 milliliters with 20 milliliters of concentrated hydrochloric acids, and pour in the single port bottle, reflux, reaction is spent the night, naturally be down to room temperature, salt of wormwood acid adjustment degree has gray solid to separate out to about the PH=5, filter, dry to such an extent that gray solid 8.2 grams are 5,7-dihydroxyl thieno-[3,2-b] pyridine, in 100 milliliters single port bottle, add 5 grams 5,7-dihydroxyl thieno-[3,2-b] pyridine, phosphorus oxychloride, drip 2 milliliters of N, dinethylformamide, reflux are put plate after four hours, react completely, directly cross post, get also white solid 4.5 grams of [3,2-b] pyridine of 5,7-dichloro-thiophene, in 100 milliliters single port bottle, drop into 4 grams 5,7-dihydroxyl thieno-[3,2-b] pyridine, 40 milliliters of N, dinethylformamide, add 1.5 gram sodium methylates, stirring at room is put plate after 6 hours, react completely, reaction solution is poured in 100 ml waters, and 100 milliliters of ethyl acetates extract anhydrous sodium sulfate drying 3 times, be spin-dried for, chromatography column is purified, and gets also [3,2-b] pyridine 2.3 grams of 5-chloro-7-methoxythiophene.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006342114A (en) * | 2005-06-10 | 2006-12-21 | Kyorin Pharmaceut Co Ltd | Fused bicyclic pyridine derivatives |
| WO2007136990A2 (en) * | 2006-05-16 | 2007-11-29 | Smithkline Beecham Corporation | Prolyl hydroxylase inhibitors |
| CN101189240A (en) * | 2005-03-24 | 2008-05-28 | 阿文尼尔药品公司 | Thienopyridinone derivatives as macrophage migration inhibitory factor inhibitors |
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- 2013-01-07 CN CN201310004200XA patent/CN103059040A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101189240A (en) * | 2005-03-24 | 2008-05-28 | 阿文尼尔药品公司 | Thienopyridinone derivatives as macrophage migration inhibitory factor inhibitors |
| JP2006342114A (en) * | 2005-06-10 | 2006-12-21 | Kyorin Pharmaceut Co Ltd | Fused bicyclic pyridine derivatives |
| WO2007136990A2 (en) * | 2006-05-16 | 2007-11-29 | Smithkline Beecham Corporation | Prolyl hydroxylase inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| JARVEST, RICHARD L，等: "Definition of the heterocyclic pharmacophore of bacterial methionyl tRNA synthetase inhibitors: potent antibacterially active non-quinolone analogues", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 14, no. 15, 2 August 2004 (2004-08-02), pages 3937 - 3941 * |
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