CN105418495A - Preparation method of thioether - Google Patents
Preparation method of thioether Download PDFInfo
- Publication number
- CN105418495A CN105418495A CN201510835079.4A CN201510835079A CN105418495A CN 105418495 A CN105418495 A CN 105418495A CN 201510835079 A CN201510835079 A CN 201510835079A CN 105418495 A CN105418495 A CN 105418495A
- Authority
- CN
- China
- Prior art keywords
- bromopyridine
- reaction
- hours
- methyl esters
- mercaptan
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention provides a preparation method of thioether and belongs to the technical field of pharmacy. The preparation method comprises the steps of making 3-bromopyridine-4-mercaptan and alkali reagent react for 5-40 hours in organic solvent at a first reaction temperature, and obtaining reaction mixed liquor; then getting the obtained reaction mixed liquor to make contact with methyl 2-bromoisobutyrate, and conducting a reaction for 0.5-30 hours at a second reaction temperature; obtaining a thioether compound through after-treatment. The preparation method is simple in operation, capable of effectively reducing generation of impurities and obtaining a high-purity product and suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of thioether, belong to pharmaceutical technology sectors.
Background technology
Compound shown in structural formula (I), chemistry 2-[[3-(4-cyano group naphthalene-1-base) pyridin-4-yl] sulfo-]-2 Methylpropionic acid by name,
Be a kind of urate anion transport body 1 inhibitor, may be used for treatment hyperuricemia and gout.
Sulfide based structural is there is in compound (I) structure, in its preparation process, can first be reacted by 3-bromopyridine-4-mercaptan and compound (01) and 2-isobutyl bromide methyl esters and compound (02), prepare thioether 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters and compound (03), reaction formula is shown below, and then 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters obtains compound (I) through series reaction:
In prior art, as disclosed the preparation method of the multiple similar compound of 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters in patent CN201180029484, but containing the unknown impuritie that a content is larger in the 2-obtained according to its method (3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl ester product, and be difficult to removing and disadvantageous effect can be brought to subsequent reactions.Therefore, need to study the preparation method of 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters, highly purified product can be obtained and easy handling is suitable for the method for suitability for industrialized production to obtain.
Summary of the invention
Summary of the invention
The invention provides the method that one prepares 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters, described method is first reacted according to certain reaction conditions with alkali reagent by 3-bromopyridine-4-mercaptan, and then react with 2-isobutyl bromide methyl esters, the lower highly purified 2-of foreign matter content (3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters can be obtained.
Detailed Description Of The Invention
The invention provides the method that one prepares 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters, according to described method, highly purified product can be obtained.Contriver finds, prepares 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters according to the method in patent CN201180029484, easily generates a kind of unknown impuritie, be called impurity A, and its content is comparatively large, reaches more than 15%, and is difficult to be removed by aftertreatment; And contriver finds by studying, if change reaction mass addition sequence and control the reaction times, then greatly can reduce the generation of this impurity A thus the purity of raising product.
One prepares the method for 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters, it comprises: shown in 3-bromopyridine-4-mercaptan and formula (01), compound and alkali reagent are in organic solvent after the first temperature of reaction reacts certain hour, obtain reaction mixture; Then shown in gained reaction mixture with 2-isobutyl bromide methyl esters and formula (02), compound contacts, in the second temperature of reaction reaction to reacting complete; Through aftertreatment, obtain 2-(3-bromopyridine-4-base the sulfenyl)-2 Methylpropionic acid methyl esters shown in formula (03),
Contriver finds, first 3-bromopyridine-4-mercaptan and alkali reagent are reacted in the first temperature of reaction in organic solvent, the generation of its reaction times to impurity A has material impact, and the reaction times is too short, then in product, Impurity A content is comparatively large, and is difficult to remove in aftertreatment.The reaction times that described 3-bromopyridine-4-mercaptan and alkali reagent react needs to control at 5 hours-40 hours.In some embodiments, the reaction times that described 3-bromopyridine-4-mercaptan and alkali reagent react needs to control at 5 hours-36 hours.In some embodiments, the reaction times that described 3-bromopyridine-4-mercaptan and alkali reagent react needs to control at 7 hours-36 hours.In some embodiments, the reaction times that described 3-bromopyridine-4-mercaptan and alkali reagent react needs to control at 7 hours-32 hours.In some embodiments, the reaction times that described 3-bromopyridine-4-mercaptan and alkali reagent react needs to control at 5 hours-30 hours.In some embodiments, the reaction times that described 3-bromopyridine-4-mercaptan and alkali reagent react needs to control at 7 hours-30 hours.In some embodiments, the reaction times that described 3-bromopyridine-4-mercaptan and alkali reagent react needs to control at 10 hours-30 hours.In some embodiments, the reaction times that described 3-bromopyridine-4-mercaptan and alkali reagent react needs to control at 10 hours-26 hours.In some embodiments, the reaction times that described 3-bromopyridine-4-mercaptan and alkali reagent react needs to control at 10 hours-24 hours.In some embodiments, the reaction times that described 3-bromopyridine-4-mercaptan and alkali reagent react needs to control at 12 hours-24 hours.In some embodiments, the reaction times that described 3-bromopyridine-4-mercaptan and alkali reagent react needs to control at 10 hours-16 hours.
Described first temperature of reaction is 20 DEG C-100 DEG C.In some embodiments, described first temperature of reaction is 40 DEG C-100 DEG C.In some embodiments, described first temperature of reaction is 50 DEG C-80 DEG C.
Described alkali reagent is salt of wormwood, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, or its hydrate, or its combination.In some embodiments, described alkali reagent is salt of wormwood, sodium carbonate, or cesium carbonate.In some embodiments, described alkali reagent is salt of wormwood.In some embodiments, described alkali reagent is cesium carbonate.
Described organic solvent is DMF, dimethyl sulfoxide (DMSO), THF, acetonitrile, alcohols or ketone or its combination.In some embodiments, described organic solvent is DMF, dimethyl sulfoxide (DMSO), or its combination.
Described second temperature of reaction is 0 DEG C-60 DEG C.In some embodiments, described second temperature of reaction is 40 DEG C-60 DEG C.In some embodiments, described second temperature of reaction is 0 DEG C-40 DEG C.In some embodiments, described second temperature of reaction is 10 DEG C-40 DEG C.In some embodiments, described second temperature of reaction is 20 DEG C-35 DEG C.In some embodiments, described second temperature of reaction is 20 DEG C-30 DEG C.
2-isobutyl bromide methyl esters shown in described reaction mixture with formula (02) contacts to comprise reaction mixture to join in 2-isobutyl bromide methyl esters or by 2-isobutyl bromide methyl esters and joins in reaction mixture.
2-isobutyl bromide methyl esters shown in described reaction mixture with formula (02) contacts, and reacts reaction in 0.5 hour-30 hours to reacting complete in the second temperature of reaction.In some embodiments, 1 hour-20 hours are reacted in the second temperature of reaction.In some embodiments, 1 hour-10 hours are reacted in the second temperature of reaction.In some embodiments, 1 hour-5 hours are reacted in the second temperature of reaction.Described reaction is complete refers to that high performance liquid chromatography (HPLC) detects, and raw material 3-bromopyridine-4-mercaptan residual content is less than 0.5%.
Described aftertreatment comprises: in reaction system, add water and extraction solvent, stir after 0.1-4 hour, separate aqueous layer and extraction solvent layer, gained removes desolventizing by after extraction solvent layer water and/or saturated common salt water washing, obtains 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters.In some embodiments, in reaction system, add water and extraction solvent, stir after 0.5-2 hour, separate aqueous layer and extraction solvent layer, except desolventizing after extraction solvent layer washes with water by gained, obtain 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters.
Described water layer can with extraction solvent extraction once, twice or more time.Described extraction solvent layer used water washs 1 time or twice or repeatedly, then uses saturated common salt water washing once or twice.Described removing after desolventizing comprises direct underpressure distillation or desiccant dryness is distilled except desolventizing.
Described extraction solvent is ethyl acetate, isopropyl acetate, methyl acetate, methylene dichloride, or its combination.
In some embodiments, described aftertreatment comprises: in reaction system, add water and ethyl acetate, stir 0.5 hour-2 hours, then stratification, aqueous layer with ethyl acetate extraction once, combined ethyl acetate layer, gained ethyl acetate washed with water washes twice, and then uses saturated common salt water washing once, the underpressure distillation of gained ethyl acetate layer, except desolventizing, obtain 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters.
The molar ratio of described alkali reagent and 3-bromopyridine-4-mercaptan is 1.05:1-3.0:1.In some embodiments, the molar ratio of described alkali reagent and 3-bromopyridine-4-mercaptan is 1.2:1-2.0:1.
In described reaction, each gram of 3-bromopyridine-4-mercaptan, described consumption of organic solvent is 2mL-25mL.In some embodiments, each gram of 3-bromopyridine-4-mercaptan, described consumption of organic solvent is 3mL-15mL.
The molar ratio of described 2-isobutyl bromide methyl esters and 3-bromopyridine-4-mercaptan is 1.01:1-3.0:1.In some embodiments, the molar ratio of described 2-isobutyl bromide methyl esters and 3-bromopyridine-4-mercaptan is 1.05:1-2.0:1.
In some embodiments, 3-bromopyridine-4-mercaptan and salt of wormwood after the first temperature of reaction reacts 3 hours-40 hours, obtain reaction mixture in dimethyl sulfoxide (DMSO); Then in gained reaction mixture, add 2-isobutyl bromide methyl esters, react 1 hour-30 hours in the second temperature of reaction; Through aftertreatment, obtain 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters.
In some embodiments, 3-bromopyridine-4-mercaptan and salt of wormwood after the first temperature of reaction reacts 3 hours-40 hours, obtain reaction mixture in dimethyl sulfoxide (DMSO); Then in gained reaction mixture, add 2-isobutyl bromide methyl esters, react 1 hour-30 hours in the second temperature of reaction; Then in reaction system, water and ethyl acetate is added, stir 0.5 hour-2 hours, then stratification, aqueous layer with ethyl acetate extracts once, combined ethyl acetate layer, and gained ethyl acetate washed with water washes twice, then saturated common salt water washing is used once, the underpressure distillation of gained ethyl acetate layer, except desolventizing, obtains 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters.
According to the method preparing 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters of the present invention, can obtain highly purified 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters, wherein Impurity A content can control below 2%.In some embodiments, according to the method preparing 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters of the present invention, in described 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters, Impurity A content can control below 1%.In some embodiments, according to the method preparing 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters of the present invention, in described 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters, Impurity A content can control below 0.5%.In some embodiments, according to the method preparing 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters of the present invention, in described 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters, Impurity A content can control below 0.1%.Method of the present invention is simple to operate, may be used for suitability for industrialized production.
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, g represents gram, and mL represents milliliter, and L represents liter, and mmol represents mmole, and mol represents mole, and min represents minute.
Embodiment 1
In reaction flask, add 3-bromopyridine-4-mercaptan (2.00g, 10.5mmol), salt of wormwood (2.90g, 21mmol), 2-isobutyl bromide methyl esters (2.10g, 11.6mmol) and DMF (10mL), 25 DEG C of stirring reactions 2 hours; It is complete that HPLC detects raw material 3-bromopyridine-4-thiol reactant, but Impurity A content is 16.6%.
Embodiment 2
In reaction flask, add 3-bromopyridine-4-mercaptan (13.06g, 55mmol), salt of wormwood (15.20g, 110mmol) and dimethyl sulfoxide (DMSO) (35mL), stir and be warming up to 70 DEG C of stirrings 3.5 hours.Then be cooled to 20 DEG C, drip 2-isobutyl bromide methyl esters (10.95g, 60.5mmol), dropwise, 20 DEG C are reacted 1 hour.In reaction system, drip water 100mL, then add ethyl acetate 100mL, finish, stir 1 hour.Then leave standstill separatory, separate organic layer, water layer extracts once with ethyl acetate 50mL again, merges organic layer; Organic layer washed with water secondary, uses water 100mL at every turn, then washs once with saturated aqueous common salt 100mL; The underpressure distillation of gained organic layer, except desolventizing, obtains the liquid 25.05g of 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters brownish black; HPLC detects, Impurity A content 4.2%, product purity: 92.2%.
Embodiment 3
In reaction flask, add 3-bromopyridine-4-mercaptan (13.06g, 55mmol), sodium carbonate (11.66g, 110mmol) and dimethyl sulfoxide (DMSO) (35mL), stir and be warming up to 70 DEG C of stirrings 5 hours.Then be cooled to 20 DEG C, drip 2-isobutyl bromide methyl esters (10.95g, 60.5mmol), dropwise, 20 DEG C-30 DEG C reactions 1 hour.In reaction system, drip water 100mL, then add ethyl acetate 100mL, finish, stir 1 hour.Then leave standstill separatory, separate organic layer, water layer extracts once with ethyl acetate 50mL again, merges organic layer; Organic layer washed with water secondary, uses water 100mL at every turn, then washs once with saturated aqueous common salt 100mL; The underpressure distillation of gained organic layer, except desolventizing, obtains the liquid 25.01g of 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters brownish black; HPLC detects, Impurity A content 1.9%, product purity: 96.9%.
Embodiment 4
In reaction flask, add 3-bromopyridine-4-mercaptan (13.06g, 55mmol), sodium carbonate (11.66g, 110mmol) and dimethyl sulfoxide (DMSO) (35mL), stir and be warming up to 70 DEG C of stirrings 5 hours.Then be cooled to 20 DEG C, drip 2-isobutyl bromide methyl esters (10.95g, 60.5mmol), dropwise, 20 DEG C-30 DEG C reactions 10 hours.In reaction system, drip water 100mL, then add ethyl acetate 100mL, finish, stir 1 hour.Then leave standstill separatory, separate organic layer, water layer extracts once with ethyl acetate 50mL again, merges organic layer; Organic layer washed with water secondary, uses water 100mL at every turn, then washs once with saturated aqueous common salt 100mL; The underpressure distillation of gained organic layer, except desolventizing, obtains the liquid 25.01g of 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters brownish black; HPLC detects, Impurity A content 0.4%, product purity: 97.9%.
Embodiment 5
In reaction flask, add 3-bromopyridine-4-mercaptan (13.06g, 55mmol), salt of wormwood (9.12g, 66mmol) and DMF (100mL), stir and be warming up to 50 DEG C of stirrings 7 hours.Then be cooled to 20 DEG C-25 DEG C, drip 2-isobutyl bromide methyl esters (10.95g, 60.5mmol), dropwise, 20 DEG C-25 DEG C reactions 1 hour.In reaction system, drip water 100mL, then add ethyl acetate 100mL, finish, stir 1 hour.Then leave standstill separatory, separate organic layer, water layer extracts once with ethyl acetate 50mL again, merges organic layer; Organic layer washed with water secondary, uses water 100mL at every turn, then washs once with saturated aqueous common salt 100mL; The underpressure distillation of gained organic layer, except desolventizing, obtains the liquid 25.13g of 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters brownish black; HPLC detects, Impurity A content 0.5%, product purity: 94.8%.
Embodiment 6
In reaction flask, add 3-bromopyridine-4-mercaptan (13.06g, 55mmol), salt of wormwood (22.8g, 165mmol) and dimethyl sulfoxide (DMSO) (50mL), stir and be warming up to 70 DEG C of stirrings 8 hours.Then be cooled to 20 DEG C-25 DEG C, drip 2-isobutyl bromide methyl esters (10.95g, 60.5mmol), dropwise, 25 DEG C-35 DEG C reactions 2 hours.In reaction system, drip water 100mL, then add ethyl acetate 100mL, finish, stir 1.5 hours.Then leave standstill separatory, separate organic layer, water layer extracts once with ethyl acetate 50mL again, merges organic layer; Organic layer washed with water secondary, uses water 100mL at every turn, then washs once with saturated aqueous common salt 100mL; The underpressure distillation of gained organic layer, except desolventizing, obtains the liquid 25.11g of 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters brownish black; HPLC detects, and Impurity A content is 0.1%, product purity: 98.1%.
Embodiment 7
In reaction flask, add 3-bromopyridine-4-mercaptan (13.06g, 55mmol), salt of wormwood (15.20g, 110mmol) and DMF (130mL), stir and be warming up to 70 DEG C of stirrings 10 hours.Then be cooled to 20 DEG C-25 DEG C, drip 2-isobutyl bromide methyl esters (10.95g, 60.5mmol), dropwise, 10 DEG C-20 DEG C reactions 10 hours.In reaction system, drip water 100mL, then add ethyl acetate 100mL, finish, stir 1 hour.Then leave standstill separatory, separate organic layer, water layer extracts once with ethyl acetate 50mL again, merges organic layer; Organic layer washed with water secondary, uses water 100mL at every turn, then washs once with saturated aqueous common salt 100mL; The underpressure distillation of gained organic layer, except desolventizing, obtains the liquid 25.21g of 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters brownish black; HPLC detects, and Impurity A content is 0.02%, product purity: 98.4%.
Embodiment 8
In reaction flask, add 3-bromopyridine-4-mercaptan (13.06g, 55mmol), salt of wormwood (15.20g, 110mmol) and dimethyl sulfoxide (DMSO) (150mL), stir and be warming up to 70 DEG C of stirrings 12 hours.Then be cooled to 15 DEG C-20 DEG C, drip 2-isobutyl bromide methyl esters (10.95g, 60.5mmol), dropwise, 10 DEG C-20 DEG C reactions 2 hours.In reaction system, drip water 100mL, then add ethyl acetate 100mL, finish, stir 1 hour.Then leave standstill separatory, separate organic layer, water layer extracts once with ethyl acetate 50mL again, merges organic layer; Organic layer washed with water secondary, uses water 100mL at every turn, then washs once with saturated aqueous common salt 100mL; The underpressure distillation of gained organic layer, except desolventizing, obtains the liquid 25.21g of 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters brownish black; HPLC detects, and Impurity A content is 0.02%, product purity: 98.1%.
Embodiment 9
In reaction flask, add 3-bromopyridine-4-mercaptan (68.40g, 0.36mol), salt of wormwood (99.36g, 0.72mol) and dimethyl sulfoxide (DMSO) 200mL, be warming up to 70 DEG C, stir after 24 hours, reaction solution is cooled to 20 DEG C, drip 2-bromo acid methyl esters (71.67g, 0.396mol), drip complete 20 DEG C and continue reactions 1 hour.Add 800mL water and 500mL ethyl acetate, stir after 1 hour, static separatory, separates organic layer, and water layer uses 200mL extraction into ethyl acetate once again, merges organic layer; Organic layer washed with water, twice each 400mL, then uses the water washing of 400mL saturated common salt once; Separate organic layer, the underpressure distillation of gained organic layer, except desolventizing, obtains brown liquid 109.7g; HPLC detects, and Impurity A content is 0.02%, and product purity is 98.6%.
Embodiment 10
In reaction flask, add 3-bromopyridine-4-mercaptan (68.40g, 0.36mol), salt of wormwood (100.00g, 0.72mol) and N, dinethylformamide 200mL, is warming up to 70 DEG C, stirs after 30 hours, reaction solution is cooled to 20 DEG C, drip 2-bromo acid methyl esters (71.67g, 0.396mol), drip and finish 20 DEG C of continuation reactions 1 hour.Add 800mL water and 500mL ethyl acetate, stir after 1 hour, static separatory, separates organic layer, and water layer uses 200mL extraction into ethyl acetate once again, merges organic layer; Organic layer washed with water, twice each 400mL, then uses the water washing of 400mL saturated common salt once; Separate organic layer, the underpressure distillation of gained organic layer, except desolventizing, obtains brown liquid 109.4g, and HPLC detects, and impurity A do not detected, product purity is 98.8%.
Embodiment 11:HPLC detection method
In the present invention, use the content of high performance liquid chromatography (HPLC) checked for impurities A, detection method is as follows:
Chromatographic column: AgilentEclipseplusC18 (4.6 × 100mm, 3.5um);
Column temperature: 30 DEG C;
Damping fluid: the 0.1mol/L sodium perchlorate aqueous solution, with phosphoric acid adjust pH to 2.5, shakes up, filters; Then above-mentioned solution mixes with 95:5 (volume ratio) with methyl alcohol;
Flow velocity: 1.0mL/min;
Determined wavelength: 270nm;
Gradient elution program:
| Time (min) | Damping fluid (%) | Acetonitrile (%) |
| 0 | 100 | 0 |
| 3 | 100 | 0 |
| 15 | 10 | 90 |
| 20 | 10 | 90 |
Rear operation: 3min;
In HPLC color atlas, retention time is the corresponding impurity A in peak of about 13.9min, and retention time is corresponding 2-(3-bromopyridine-4-base the sulfenyl)-2 Methylpropionic acid methyl esters in peak of about 12.3min.
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. prepare a method for 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters, comprising: 3-bromopyridine-4-mercaptan and alkali reagent, in organic solvent after the first temperature of reaction reacts 5 hours-40 hours, obtain reaction mixture; Then gained reaction mixture contacts with 2-isobutyl bromide methyl esters again, reacts 0.5 hour-30 hours in the second temperature of reaction; Through aftertreatment, obtain 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters.
2. method according to claim 1, described alkali reagent is salt of wormwood, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, or its hydrate, or its combination.
3. method according to claim 1, described organic solvent is DMF, dimethyl sulfoxide (DMSO), THF, acetonitrile, or its combination.
4. method according to claim 1, described first temperature of reaction is 20 DEG C-100 DEG C; Described second temperature of reaction is 0 DEG C-60 DEG C.
5. method according to claim 1, each gram of 3-bromopyridine-4-mercaptan, described consumption of organic solvent is 2mL-25mL.
6. method according to claim 1, wherein, reacts 7 hours-30 hours in the first temperature of reaction.
7. method according to claim 1, wherein, the molar ratio of 2-isobutyl bromide methyl esters and 3-bromopyridine-4-mercaptan is 1.01:1-3.0:1.
8. method according to claim 1, wherein, the molar ratio of alkali reagent and 3-bromopyridine-4-mercaptan is 1.05:1-3.0:1.
9. method according to claim 1, wherein, described aftertreatment comprises: in reaction system, add water and extraction solvent, stir after 0.1 hour-4 hours, separate aqueous layer and extraction solvent layer, water layer extraction solvent extracts once, merges extraction solvent layer, gained removes desolventizing by after extraction solvent layer water and/or saturated common salt water washing, obtains 2-(3-bromopyridine-4-base sulfenyl)-2 Methylpropionic acid methyl esters.
10. method according to claim 9, described extraction solvent is ethyl acetate, isopropyl acetate, methyl acetate, methylene dichloride, or its combination.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510835079.4A CN105418495B (en) | 2015-11-25 | 2015-11-25 | A kind of preparation method of thioether |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510835079.4A CN105418495B (en) | 2015-11-25 | 2015-11-25 | A kind of preparation method of thioether |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105418495A true CN105418495A (en) | 2016-03-23 |
| CN105418495B CN105418495B (en) | 2018-09-14 |
Family
ID=55497101
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510835079.4A Active CN105418495B (en) | 2015-11-25 | 2015-11-25 | A kind of preparation method of thioether |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105418495B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4983753A (en) * | 1981-05-21 | 1991-01-08 | Floyd Jr Middleton B | Precursors and synthesis of di-(methyl)-16,16-(dimethyl)-11-alpha,15-alpha beta-dihydroxy-9-oxo-2,13-trans,trans-prostadienoates |
| WO1999042438A1 (en) * | 1998-02-18 | 1999-08-26 | Zambon Group S.P.A. | Process for preparing 2-acetylthio-3-phenyl-propionic acid and the salts thereof |
| CN103068801A (en) * | 2010-06-16 | 2013-04-24 | 亚德生化公司 | Thioacetate compounds, compositions and methods of use |
-
2015
- 2015-11-25 CN CN201510835079.4A patent/CN105418495B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4983753A (en) * | 1981-05-21 | 1991-01-08 | Floyd Jr Middleton B | Precursors and synthesis of di-(methyl)-16,16-(dimethyl)-11-alpha,15-alpha beta-dihydroxy-9-oxo-2,13-trans,trans-prostadienoates |
| WO1999042438A1 (en) * | 1998-02-18 | 1999-08-26 | Zambon Group S.P.A. | Process for preparing 2-acetylthio-3-phenyl-propionic acid and the salts thereof |
| CN103068801A (en) * | 2010-06-16 | 2013-04-24 | 亚德生化公司 | Thioacetate compounds, compositions and methods of use |
| CN103864677A (en) * | 2010-06-16 | 2014-06-18 | 亚德生化公司 | Thioacetate compounds, compositions and methods of use |
Non-Patent Citations (1)
| Title |
|---|
| MASAHIKO SEKI，等: "Practical Synthesis of (R)-4-Mercaptopyrrolidine-2-thione from L-Aspartic Acid. Preparation of a Novel Orally Active 1-â-Methylcarbapenem, TA-949", 《J. ORG. CHEM.》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105418495B (en) | 2018-09-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3712130B1 (en) | Method for synthesis of roxadustat and intermediate compounds thereof | |
| CN109956901B (en) | Preparation method of isoquinolone compound | |
| CN109320489A (en) | A kind of color alkyl compound and preparation method thereof | |
| CN103788010B (en) | Febuxostat intermediate and preparation method thereof | |
| CN107118180A (en) | A kind of nitrogenous octatomic ring alkyne derivatives and preparation method thereof | |
| CN105418495A (en) | Preparation method of thioether | |
| CN102516133A (en) | Preparation method of methanesulfonic acid derivative | |
| CN106810546A (en) | A kind of umeclidinium compound | |
| CN113005169B (en) | Chiral resolution method of isobutyrate compound | |
| CN114605492A (en) | Preparation method of intermediate of palovaried | |
| CN104829588B (en) | A kind of Preparation Method And Their Intermediate of benzo [b] thiophene | |
| CN104945434B (en) | (2 ﹣ bis- substitution phosphines phenyl) -1- alkyl-indols Phosphine ligands and its synthetic method and application | |
| CN103351346A (en) | Preparation method of impurity HP1 in bendamustine hydrochloride | |
| CN107266304A (en) | Natural products Salvianolic Acid F novel synthesis | |
| CN103896889B (en) | Lapatinib intermediate and its preparation method and application | |
| CN108689893B (en) | Propargyl sulfone compound and preparation method and application thereof | |
| CN103601671B (en) | The preparation method of iodo trifluoro methyl pyridine | |
| CN107382742A (en) | A kind of new synthetic method of fluorine 4 (trifluoromethyl) anilinechloride of 5 chlorine of fragrance intermediate containing trifluoromethyl 2 | |
| CN101186620B (en) | Method for preparing phosphate of toluylene compounds containing phenol hydroxyl group | |
| CN106588786A (en) | Preparation method of high purity favipiravir impurity | |
| CN102329302A (en) | Method for preparing esomeprazole and salts thereof | |
| CN109467523A (en) | A kind of green synthesis method of the third sulfonic acid chloride of 3- chlorine | |
| CN104744337B (en) | The synthetic method of aryl sulfonic acid alkyl esters compound | |
| CN113072448B (en) | Aryl gemfibrozil derivative high-valence iodine compound and preparation method thereof | |
| CN111662233B (en) | Method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by one-step method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200616 Address after: 523808 Guangdong province Dongguan Songshan Lake Science and Technology Industrial Park Patentee after: SUNSHINE LAKE PHARMA Co.,Ltd. Address before: 512700 Guangdong city of Shaoguan province Ruyuan County town Jingjiang road dairy milk money service center on the first floor of No. 3 Patentee before: RUYUAN YAO AUTONOMOUS COUNTY DAZHONG DRUG TRADING Co.,Ltd. |
|
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 Songshan Lake Science and Technology Industrial Park, Dongguan City, Guangdong Province Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd. |