CN104610110A - Method for preparing 4-substituted thiobenzamide derivative - Google Patents
Method for preparing 4-substituted thiobenzamide derivative Download PDFInfo
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- CN104610110A CN104610110A CN201410856141.3A CN201410856141A CN104610110A CN 104610110 A CN104610110 A CN 104610110A CN 201410856141 A CN201410856141 A CN 201410856141A CN 104610110 A CN104610110 A CN 104610110A
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Abstract
The invention relates to a method for preparing a 4-substituted thiobenzamide derivative as shown in a formula (I). The method comprises the following step: using water as a solvent and after sodium hydroxide and 4-alkoxy benzonitrile react with each other, sequentially adding sodium hydrosulfide and ammonium salt for reaction, wherein the formula (I) and a structural formula (II) of the 4-alkoxy benzonitrile are shown in the description, in the formula (I) and formula (II), R represents an aliphatic hydrocarbon group with 1 to 6 hydrogen atoms or carbon atoms. The method uses the water as the solvent, is low in cost and is environmental-friendly.
Description
Technical field
The present invention relates to preparation and can be used as the intermediate of 2-(3-cyano-phenyl) thiazole derivative of medicine and the preparation method of 4-replacement thiobenzoyl sulfonamide derivatives.
Background technology
4-replaces thiobenzoyl sulfonamide derivatives, and its structure is such as formula shown in (I), and what can be used as 2-(3-cyano-phenyl) thiazole derivative of the xanthine oxidase inhibitor of gout or hyperuricemia curative etc. prepares intermediate,
Robbins etc. are reported in the preparation method shown in following equation at US 2005/75503, and productive rate is up to 97.57%; But the method needs to adopt H
2s, H
2s has irritating stink, not environmentally; And need pressurization, it is high to equipment requirements,
Zheng Fan etc. in the synthesis [J] of Febuxostat. Chinese Journal of Pharmaceuticals, 2009,40 (10): 726. disclose the method being prepared thiobenzoyl amine compound by benzonitrile compound, use thioacetamide and Tripyrophosphoric acid, yield 90.7%.Polyphosphoric acid is at room temperature semi-solid state, very thickness, stirs difficulty,
Zhao Liyun, at synthesis technique and the quality standard research [D] of Febustat, University Of Hebei, 2010; This method productive rate only about 66%,
Spychala, Jaroslaw; Synthetic Communications [J] .2000,30 (6): 1083, yield 83%, the method adopts pyridine as solvent, and pyridine smell is more unpleasant, and cost is higher,
The synthesis [J] of the antigout drug Febuxostat of Zhang Yinguang etc. Chinese pharmaceutical chemistry impurity, during 2010,20 (4): 282. use magnesium chloride, reaction system easily becomes colloidal, and the amount of solvent requires more,
Summary of the invention
The object of the present invention is to provide be suitable for safe, cheap, easy and high yield prepare the method that 4-replaces thiobenzoyl sulfonamide derivatives.
The present inventor has carried out in depth studying to reach above-mentioned purpose, found that compared with method in the past, safe, cheap, easy and high yield prepare the method that 4-replaces thiobenzoyl sulfonamide derivatives.
Summary of the invention
First aspect present invention provides the 4-shown in formula (I) to replace the preparation method of thiobenzoyl sulfonamide derivatives, it comprises: in aprotic polar solvent, under ammonium sulfate exists, 4-substituted benzene formonitrile HCN (II) and Sodium sulfhydrate react, 4-shown in preparation formula (I) replaces thiobenzoyl sulfonamide derivatives
Wherein, R represents that hydrogen atom or carbonatoms are the aliphatic hydrocarbyl of 1-6.
Second aspect present invention provides the 4-shown in another kind of preparation formula (I) to replace the method for thiobenzoyl sulfonamide derivatives, and it comprises: take water as solvent, after sodium hydroxide and 4-alkoxy benzene formonitrile HCN react, then adds Sodium sulfhydrate and ammonium salt reaction successively,
Wherein, R represents that hydrogen atom or carbonatoms are the aliphatic hydrocarbyl of 1-6.
Detailed Description Of The Invention
First aspect present invention provides the 4-shown in formula (I) to replace the preparation method of thiobenzoyl sulfonamide derivatives, it comprises: in aprotic polar solvent, under ammonium sulfate exists, 4-substituted benzene formonitrile HCN (II) and Sodium sulfhydrate react, 4-shown in preparation formula (I) replaces thiobenzoyl sulfonamide derivatives
In formula, R represents that hydrogen atom or carbonatoms are the aliphatic hydrocarbyl of 1-6.
In certain embodiments, described carbonatoms is that the aliphatic hydrocarbyl of 1-6 refers to that carbonatoms is the saturated of the straight or branched of 1-6 or undersaturated aliphatic hydrocarbyl.Such as can enumerate the alkyl of the carbonatoms 1-6 such as methyl, ethyl, n-propyl, normal-butyl, n-pentyl, just base, sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, isopentyl, neo-pentyl, tert-pentyl, isohexyl, 2-methyl amyl and 1-ethyl-butyl, with 2-propenyl, crotyl, 3-butenyl, pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl 2-propenyl, 2-methyl-2-propenyl, 1, 1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1, 1-dimethyl-crotyl, 1-ethyl-crotyl, 2-ethyl-crotyl, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, 1-methyl-3-pentenyl, the thiazolinyl of the carbonatoms 3-6 such as 2-methyl-3-pentenyl and 3-methyl-3-pentenyl.In certain embodiments, R is hydrogen atom, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, pentenyl and 2-methyl-2-propenyl, and in further embodiments, R is hydrogen atom or isobutyl-.
In certain embodiments, described aprotic polar solvent can be used alone or as a mixture any one in the aprotic polar solvent of DMF, N-Methyl pyrrolidone, DMSO or tetramethylene sulfone etc., also can add water to use in these reaction solvents.In certain embodiments, described aprotic polar solvent is DMF, DMSO or tetramethylene sulfone, is DMF in certain embodiments.The consumption of this aprotic polar solvent by volume of 1 ~ 50 times, is 3 ~ 10 times relative to 4-hydroxy-phenylformonitrile in certain embodiments.The volume ratio of the scope and this aprotic polar solvent that add water is the scope of 1:0 ~ 1:1.5.
In certain embodiments, temperature of reaction is 0 ~ 150 DEG C, and in further embodiments, temperature of reaction is 10 ~ 60 DEG C.
In certain embodiments, reaction pressure is that 0 ~ 2 barometric pressure range is carried out, and in further embodiments, reaction pressure is that 1 ~ 1.5 barometric pressure range is carried out.
In certain embodiments, the reaction times can according to 4-hydroxy-phenylformonitrile, ammonium sulfate or ammonium chloride and the amount of Sodium sulfhydrate, the difference of the condition such as temperature of reaction and pressure and different, terminates within the scope of 5min ~ 15 day.
In certain embodiments, described Sodium sulfhydrate can be anhydride or hydrate, in certain embodiments, uses hydrate; Its usage quantity is 0.5 ~ 50 mole of times of equivalent of 4-hydroxy-phenylformonitrile, and in certain embodiments, its usage quantity is 1 ~ 10 mole of times of equivalent.
In certain embodiments, the usage quantity of described ammonium sulfate is 0.1-10 times of molar equivalent of 4-hydroxy-phenylformonitrile, preferred 0.5-3 times molar equivalent.
In certain embodiments, the aftertreatment of reaction uses dilute hydrochloric acid to regulate the pH value of reaction mixture, then filters the solid of precipitation; In certain embodiments the pH of reaction mixture is transferred to 5.5-7.0.
The method prepared 4-and replace thiobenzoyl sulfonamide derivatives of the present invention, safety, cheap and high yield.
Second aspect present invention provides the 4-shown in another kind of preparation formula (I) to replace the method for thiobenzoyl sulfonamide derivatives, it comprises: in water, add sodium hydroxide and 4-alkoxy benzene formonitrile HCN, after stirring clarification, then add Sodium sulfhydrate successively and ammonium salt reacts
In formula, R represents the aliphatic hydrocarbyl of hydrogen atom or carbonatoms 1-6.
In each method of system of the present invention, the R in above-mentioned formula (I) and above-mentioned formula (II) represents the aliphatic hydrocarbyl of hydrogen atom or carbonatoms 1-6.The aliphatic hydrocarbyl of described carbonatoms 1-6 refers to the saturated of the straight or branched of carbonatoms 1-6 or undersaturated aliphatic hydrocarbyl.Such as can enumerate the alkyl of the carbonatoms 1-6 such as methyl, ethyl, n-propyl, normal-butyl, n-pentyl, just base, sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, isopentyl, neo-pentyl, tert-pentyl, isohexyl, 2-methyl amyl and 1-ethyl-butyl, with 2-propenyl, crotyl, 3-butenyl, pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl 2-propenyl, 2-methyl-2-propenyl, 1, 1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1, 1-dimethyl-crotyl, 1-ethyl-crotyl, 2-ethyl-crotyl, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, 1-methyl-3-pentenyl, the thiazolinyl of the carbonatoms 3-6 such as 2-methyl-3-pentenyl and 3-methyl-3-pentenyl.R is hydrogen atom, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, pentenyl and 2-methyl-2-propenyl in certain embodiments, and in further embodiments, R is hydrogen atom or isobutyl-.
In certain embodiments, described ammonium salt is ammonium sulfate, ammonium chloride, brometo de amonio or its combination.
In certain embodiments, described solvent is water, and consumption by volume of 2 ~ 50 times, is 5 ~ 20 times relative to 4-hydroxy-phenylformonitrile in certain embodiments.
In certain embodiments, described temperature of reaction is 0 ~ 150 DEG C, is 10 ~ 60 DEG C in one embodiment, preferably 50 DEG C.
In certain embodiments, described reaction is that 0 ~ 2 barometric pressure range is carried out at pressure, carries out in certain embodiments 1 ~ 1.5 barometric pressure range.
In certain embodiments, the reaction times can according to 4-hydroxy-phenylformonitrile, ammonium sulfate or ammonium chloride and the amount of Sodium sulfhydrate, the difference of the condition such as temperature of reaction and pressure and different, terminates within the scope of 5min ~ 15 day.
In certain embodiments, described Sodium sulfhydrate can be anhydride or hydrate, uses hydrate in certain embodiments; Its usage quantity is 0.5 ~ 50 mole of times of equivalent of 4-hydroxy-phenylformonitrile, and in certain embodiments, its usage quantity is 1 ~ 10 mole of times of equivalent.
In certain embodiments, described ammonium sulfate or the usage quantity of ammonium chloride are 0.1 ~ 10 times of molar equivalent of 4-hydroxy-phenylformonitrile, in certain embodiments, are 0.5 ~ 3 times of molar equivalent.
In certain embodiments, the usage quantity of described sodium hydroxide is 0.5 ~ 10 times of molar equivalent of 4-hydroxy-phenylformonitrile, is 0.9 ~ 1.5 times of molar equivalent in certain embodiments;
In certain embodiments, the aftertreatment of described reaction uses dilute hydrochloric acid to regulate the pH of reaction mixture, then filters the solid of precipitation; In certain embodiments pH is transferred to 5.5 ~ 7.0.
The method prepared 4-and replace thiobenzoyl sulfonamide derivatives of the present invention, productive rate, more than 95%, adopts water as solvent, the low and environmental friendliness of cost.
Embodiment
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
In the present invention, M represents mole often liter, and h represents hour, and min represents minute, and g represents gram, and ml represents milliliter.
The preparation of embodiment 14-hydroxythiobenzamide
Sodium sulfhydrate hydrate (8.4g) joins in DMF (10ml), open and stir, add 4-hydroxy-phenylformonitrile (5.0g) and ammonium sulfate (2.77g), stir 16h at 40 DEG C after, with 2M salt acid for adjusting pH to 5.5 ~ 7.0, then cool to 0 ~ 5 DEG C, filter, dry 4-hydroxythiobenzamide (6.12g, yield: 95.2%).
The preparation of embodiment 24-isobutoxy thiobenzamide
Sodium sulfhydrate hydrate (8.4g) joins in DMF (10ml) and water (2ml), open and stir, add 4-hydroxy-phenylformonitrile (5.0g) and ammonium sulfate (2.77g), stir 24h at 40 DEG C after, with 2M salt acid for adjusting pH to 5.5 ~ 7.0, then cool to 0 ~ 5 DEG C, filter, dry 4-hydroxythiobenzamide (6.15g, yield: 95.5%).
The preparation of embodiment 34-hydroxythiobenzamide
Sodium hydroxide (1.68g), 4-hydroxy-phenylformonitrile (5g) add in water (50ml), unlatching stirs to clarify, add ammonium sulfate (2.77g) and Sodium sulfhydrate hydrate (8.4g) successively, 24h is reacted at 50 DEG C, cooling, with 2M salt acid for adjusting pH to 5.5, separate out solid, filtration, dry 4-hydroxythiobenzamide (6.25g, yield 97.2%).
The preparation of embodiment 44-isobutoxy thiobenzamide
Sodium hydroxide (1.68g), 4-hydroxy-phenylformonitrile (5g) add in water (50ml), unlatching stirs to clarify, add ammonium chloride (2.25g) and Sodium sulfhydrate hydrate (8.4g) successively, 24h is reacted at 50 DEG C, cooling, with 2M salt acid for adjusting pH to 7.0, separates out solid, filtration, dry 4-hydroxythiobenzamide (6.33g, yield 98.44%).
The preparation of comparative example 14-isobutoxy thiobenzamide
While stir Sodium sulfhydrate 2.35g, water 10ml, add 4-hydroxy benzonitrile 1.0g and ammonium chloride 2.25g.Stir after 22 hours at 40 DEG C, add 2M hydrochloric acid 9.5ml, then add water 2.0ml.Stir under ice-cooling, the solid that leaching obtains, dry, obtain 4-hydroxythiobenzamide 0.65g, yield 50%.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.
Claims (10)
1. the 4-shown in a preparation formula (I) replaces the method for thiobenzoyl sulfonamide derivatives, it comprises: in water, adds the 4-alkoxy benzene formonitrile HCN shown in sodium hydroxide and formula (II), after stirring clarification, add Sodium sulfhydrate successively again and ammonium salt reacts
In formula, described R is hydrogen atom or isobutyl-.
2. method according to claim 1, described ammonium salt is ammonium sulfate, ammonium chloride, brometo de amonio or its combination.
3. method according to claim 1, the temperature of described reaction is 10 ~ 60 DEG C or 50 DEG C.
4. method according to claim 1, described reaction is that 1 ~ 1.5 barometric pressure range is carried out at pressure.
5. method according to claim 1, described Sodium sulfhydrate is anhydride or hydrate, and its usage quantity is 1 ~ 10 times of molar equivalent of 4-hydroxy-phenylformonitrile.
6. method according to claim 1, the usage quantity of described ammonium salt is 0.5 ~ 3 times of molar equivalent.
7. method according to claim 1, the usage quantity of described sodium hydroxide is 0.9 ~ 1.5 times of molar equivalent of 4-hydroxy-phenylformonitrile.
8. method according to claim 1, the aftertreatment of described reaction uses dilute hydrochloric acid to regulate the pH of reaction mixture to be 5.5 ~ 7.0.
9. method according to claim 1, it comprises: sodium hydroxide (1.68g), 4-hydroxy-phenylformonitrile (5g) add in water (50ml), unlatching stirs to clarify, add ammonium chloride (2.25g) and Sodium sulfhydrate hydrate (8.4g) successively, react 24h at 50 DEG C, cooling, with 2M salt acid for adjusting pH to 7.0, separate out solid, filtration, dry 4-hydroxythiobenzamide.
10. method according to claim 1, it comprises: sodium hydroxide (1.68g), 4-hydroxy-phenylformonitrile (5g) add in water (50ml), unlatching stirs to clarify, add ammonium sulfate (2.77g) and Sodium sulfhydrate hydrate (8.4g) successively, 24h is reacted at 50 DEG C, cooling, with 2M salt acid for adjusting pH to 5.5, separates out solid, filtration, dry 4-hydroxythiobenzamide.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106928108A (en) * | 2016-11-29 | 2017-07-07 | 苏州弘森药业股份有限公司 | A kind of process for synthesizing thioamides |
| CN109206348A (en) * | 2018-09-13 | 2019-01-15 | 内蒙古工业大学 | It is a kind of to utilize CO2Regulation replaces the method for cyanophenyl synthesis thiobenzamide analog derivative |
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|---|---|---|---|---|
| US6541667B1 (en) * | 2001-12-17 | 2003-04-01 | Bayer Corporation | Methods for preparation of thioamides |
| WO2005012273A2 (en) * | 2003-07-30 | 2005-02-10 | Abbott Laboratories | Process for the preparation of substituted thiazoles |
| CN102239151A (en) * | 2008-10-21 | 2011-11-09 | 梅里亚有限公司 | Thioamide compounds, method of making and method of using thereof |
| CN102459164A (en) * | 2009-06-09 | 2012-05-16 | 帝人制药株式会社 | Method for producing 4-substituted benzothioamide derivative |
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2014
- 2014-12-31 CN CN201410856141.3A patent/CN104610110A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6541667B1 (en) * | 2001-12-17 | 2003-04-01 | Bayer Corporation | Methods for preparation of thioamides |
| WO2005012273A2 (en) * | 2003-07-30 | 2005-02-10 | Abbott Laboratories | Process for the preparation of substituted thiazoles |
| CN102239151A (en) * | 2008-10-21 | 2011-11-09 | 梅里亚有限公司 | Thioamide compounds, method of making and method of using thereof |
| CN102459164A (en) * | 2009-06-09 | 2012-05-16 | 帝人制药株式会社 | Method for producing 4-substituted benzothioamide derivative |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106928108A (en) * | 2016-11-29 | 2017-07-07 | 苏州弘森药业股份有限公司 | A kind of process for synthesizing thioamides |
| CN109206348A (en) * | 2018-09-13 | 2019-01-15 | 内蒙古工业大学 | It is a kind of to utilize CO2Regulation replaces the method for cyanophenyl synthesis thiobenzamide analog derivative |
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Application publication date: 20150513 |