CN105418495B - A kind of preparation method of thioether - Google Patents
A kind of preparation method of thioether Download PDFInfo
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- CN105418495B CN105418495B CN201510835079.4A CN201510835079A CN105418495B CN 105418495 B CN105418495 B CN 105418495B CN 201510835079 A CN201510835079 A CN 201510835079A CN 105418495 B CN105418495 B CN 105418495B
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- bromopyridine
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- NIVLCGHVRAUFMT-UHFFFAOYSA-N C=[Br]c1cnccc1S Chemical compound C=[Br]c1cnccc1S NIVLCGHVRAUFMT-UHFFFAOYSA-N 0.000 description 1
- PQUSVJVVRXWKDG-UHFFFAOYSA-N CC(C)(C(OC)=O)Br Chemical compound CC(C)(C(OC)=O)Br PQUSVJVVRXWKDG-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
Abstract
The present invention provides a kind of preparation method of thioether, belongs to pharmaceutical technology field.The preparation method includes 3 bromopyridine, 4 mercaptan and base reagent in organic solvent after the first reaction temperature reacts 40 hours 5 hours, obtains reaction mixture；Then gained reaction mixture is contacted with 2 isobutyl bromide methyl esters again, is reacted 30 hours 0.5 hour in the second reaction temperature；By post-processing, the sulfide compound is obtained.The preparation method of the present invention is easy to operate, is capable of the generation of relatively low impurity, obtains the product of high-purity, is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation methods of thioether, belong to pharmaceutical technology field.
Background technology
Structure formula (I) compound represented, entitled 2- [[3- (4- cyano naphthalene -1- bases) pyridin-4-yl] the is thio] -2- of chemistry
Methylpropanoic acid,
It is a kind of 1 inhibitor of lithate anion transport body, can be used for treating hyperuricemia and gout.
There are sulfide based structural in compound (I) structure, in preparation process, 3- bromopyridine -4- mercaptan can be first passed through i.e.
Compound (01) and 2- isobutyl bromides methyl esters, that is, compound (02) reaction, are prepared thioether 2- (3- bromopyridine -4- bases sulfenyl) -
2 Methylpropionic acid methyl esters, that is, compound (03), reaction equation is shown below, then 2- (3- bromopyridine -4- bases sulfenyl) -2- methyl
Methyl propionate obtains compound (I) by series reaction：
In the prior art, as disclosed 2- (3- bromopyridine -4- bases sulfenyl) -2- methyl-props in patent CN201180029484
The preparation method of a variety of similar compounds of sour methyl esters, but 2- (3- bromopyridine -4- bases the sulfenyl) -2- first obtained according to its method
Containing the larger unknown impuritie of a content in base methyl propionate product, and it is difficult to remove and subsequent reactions can be brought unfavorable shadow
It rings.Therefore, it is necessary to study the preparation method of 2- (3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters, can be obtained with obtaining
The product of high-purity and the easily operated method suitable for industrialized production.
Invention content
Summary of the invention
The present invention provides a kind of method preparing 2- (3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters, the method
It is first reacted according to certain reaction condition with base reagent by 3- bromopyridine -4- mercaptan, is then reacted again with 2- isobutyl bromide methyl esters,
2- (3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters of the lower high-purity of impurity content can be obtained.
Detailed description of the invention
The present invention provides a kind of method preparing 2- (3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters, according to described
Method can obtain the product of high-purity.Inventor has found, 2- is prepared according to the method in patent CN201180029484
(3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters, easily generates a kind of unknown impuritie, referred to as impurity A, and its content is larger,
Reach 15% or more, and is difficult to remove by post-processing；And inventors discovered through research that, if changing reaction mass addition sequence
With the control reaction time, then the generation of this impurity A can be substantially reduced to improve the purity of product.
A method of preparing 2- (3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters comprising：3- bromopyridines -4-
Compound shown in mercaptan, that is, formula (01) is reacted after a certain period of time in the first reaction temperature in organic solvent with base reagent, is obtained anti-
Answer mixed liquor；Then gained reaction mixture is contacted with compound shown in 2- isobutyl bromides methyl esters, that is, formula (02), in the second reaction
Thermotonus to reaction finishes；By post-processing, 2- shown in formula (03) (3- bromopyridine -4- bases sulfenyl) -2- methyl-props are obtained
Sour methyl esters,
Inventor has found, first reacts 3- bromopyridine -4- mercaptan in the first reaction temperature in organic solvent with base reagent,
Its reaction time has a major impact the generation of impurity A, and the reaction time is too short, then Impurity A content is larger in product, and is difficult to
It is removed in post-processing.Reaction time that the 3- bromopyridines -4- mercaptan is reacted with base reagent needs to control 5 hours -40 small
When.In some embodiments, the 3- bromopyridines -4- mercaptan is reacted with base reagent reaction time need to control 5 hours -
36 hours.In some embodiments, the reaction time that the 3- bromopyridines -4- mercaptan is reacted with base reagent needs to control 7
- 36 hours hours.In some embodiments, the reaction time that the 3- bromopyridines -4- mercaptan is reacted with base reagent needs to control
System was at -32 hours 7 hours.In some embodiments, the reaction time that the 3- bromopyridines -4- mercaptan is reacted with base reagent needs
It controls at -30 hours 5 hours.In some embodiments, when the reaction that the 3- bromopyridines -4- mercaptan is reacted with base reagent
Between need control at -30 hours 7 hours.In some embodiments, the 3- bromopyridines -4- mercaptan reacts anti-with base reagent
Need control at -30 hours 10 hours between seasonable.In some embodiments, the 3- bromopyridines -4- mercaptan and base reagent are anti-
The reaction time answered needs to control at -26 hours 10 hours.In some embodiments, the 3- bromopyridines -4- mercaptan and alkali
The reaction time of reagent reaction needs to control at -24 hours 10 hours.In some embodiments, the 3- bromopyridines -4- sulphur
The reaction time that alcohol is reacted with base reagent needs to control at -24 hours 12 hours.In some embodiments, the 3- bromines pyrrole
The reaction time that pyridine -4- mercaptan is reacted with base reagent needs to control at -16 hours 10 hours.
First reaction temperature is 20 DEG C -100 DEG C.In some embodiments, first reaction temperature be 40 DEG C-
100℃.In some embodiments, first reaction temperature is 50 DEG C -80 DEG C.
The base reagent is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide or its hydrate or its group
It closes.In some embodiments, the base reagent is potassium carbonate, sodium carbonate or cesium carbonate.In some embodiments, described
Base reagent is potassium carbonate.In some embodiments, the base reagent is cesium carbonate.
The organic solvent is n,N-Dimethylformamide, dimethyl sulfoxide (DMSO), THF, acetonitrile, alcohols or ketone or its group
It closes.In some embodiments, the organic solvent be n,N-Dimethylformamide, dimethyl sulfoxide (DMSO), or combinations thereof.
Second reaction temperature is 0 DEG C -60 DEG C.In some embodiments, second reaction temperature is 40 DEG C -60
℃.In some embodiments, second reaction temperature is 0 DEG C -40 DEG C.In some embodiments, second reaction
Temperature is 10 DEG C -40 DEG C.In some embodiments, second reaction temperature is 20 DEG C -35 DEG C.In some embodiments
In, second reaction temperature is 20 DEG C -30 DEG C.
The reaction mixture is contacted with 2- isobutyl bromide methyl esters shown in formula (02) including reaction mixture to be added to
It is added in reaction mixture in 2- isobutyl bromide methyl esters or by 2- isobutyl bromide methyl esters.
The reaction mixture is contacted with 2- isobutyl bromide methyl esters shown in formula (02), reacts 0.5 in the second reaction temperature
- 30 hours hours reaction to reaction finishes.In some embodiments, it is reacted -20 hours 1 hour in the second reaction temperature.
In some embodiments, reacted -10 hours 1 hour in the second reaction temperature.In some embodiments, in the second reaction temperature
Reaction -5 hours 1 hour.It refers to high performance liquid chromatography (HPLC) detection that the reaction, which finishes, and raw material 3- bromopyridine -4- mercaptan is surplus
Surplus is less than 0.5%.
The post-processing includes：Water and extractant are added into reaction system, after stirring 0.1-4 hours, detaches water layer
With extractant layer, gained will remove solvent after extractant layer water and/or saturated common salt water washing, obtain 2- (3- bromine pyrroles
Pyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters.In some embodiments, water and extractant are added into reaction system, stirs
After mixing 0.5-2 hours, detaches water layer and extractant layer, gained remove solvent after extractant layer is washed with water, obtain 2-
(3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters.
The water layer can be extracted once, two or more times with extractant.The extractant layer can be washed with water 1 time
Or twice or repeatedly, it then washed once with saturated salt solution or twice.The removing solvent includes directly being evaporated under reduced pressure or doing
Solvent is distilled off after drying prescription drying.
The extractant is ethyl acetate, isopropyl acetate, methyl acetate, dichloromethane, or combinations thereof.
In some embodiments, described post-process includes：Water and ethyl acetate, stirring 0.5 are added into reaction system
- 2 hours hours were then allowed to stand layering, and aqueous layer with ethyl acetate extraction is primary, combined ethyl acetate layer, gained ethyl acetate layer
It is washed twice with water, then washed once with saturated salt solution, the vacuum distillation of gained ethyl acetate layer removes solvent, obtains 2-
(3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters.
The molar ratio of the base reagent and 3- bromopyridine -4- mercaptan is 1.05:1-3.0:1.In some embodiments
In, the molar ratio of the base reagent and 3- bromopyridine -4- mercaptan is 1.2:1-2.0:1.
In the reaction, each gram of 3- bromopyridine -4- mercaptan, the consumption of organic solvent is 2mL-25mL.In some realities
It applies in mode, each gram of 3- bromopyridine -4- mercaptan, the consumption of organic solvent is 3mL-15mL.
The molar ratio of the 2- isobutyl bromides methyl esters and 3- bromopyridine -4- mercaptan is 1.01:1-3.0:1.At some
In embodiment, the molar ratio of the 2- isobutyl bromides methyl esters and 3- bromopyridine -4- mercaptan is 1.05:1-2.0:1.
In some embodiments, 3- bromopyridines -4- mercaptan and potassium carbonate in dimethyl sulfoxide (DMSO) in the first reaction temperature
After reaction -40 hours 3 hours, reaction mixture is obtained；Then 2- isobutyl bromide methyl esters is added into gained reaction mixture,
Second reaction temperature is reacted -30 hours 1 hour；By post-processing, 2- (3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid is obtained
Methyl esters.
In some embodiments, 3- bromopyridines -4- mercaptan and potassium carbonate in dimethyl sulfoxide (DMSO) in the first reaction temperature
After reaction -40 hours 3 hours, reaction mixture is obtained；Then 2- isobutyl bromide methyl esters is added into gained reaction mixture,
Second reaction temperature is reacted -30 hours 1 hour；Then water and ethyl acetate are added into reaction system, stirring 0.5 hour -2 is small
When, it is then allowed to stand layering, aqueous layer with ethyl acetate extraction is primary, combined ethyl acetate layer, the washing of gained ethyl acetate washed with water
Twice, it then washed once with saturated salt solution, the vacuum distillation of gained ethyl acetate layer removes solvent, obtains 2- (3- bromine pyrroles
Pyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters.
The method according to the present invention for preparing 2- (3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters, can obtain
High-purity 2- (3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters, wherein Impurity A content can control 2% with
Under.In some embodiments, preparation 2- (3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters according to the present invention
Method, Impurity A content can control below 1% in 2- (3- bromopyridine -4- bases the sulfenyl) -2 Methylpropionic acid methyl esters.
In some embodiments, the side according to the present invention for preparing 2- (3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters
Method, Impurity A content can control below 0.5% in 2- (3- bromopyridine -4- bases the sulfenyl) -2 Methylpropionic acid methyl esters.
In some embodiments, the side according to the present invention for preparing 2- (3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters
Method, Impurity A content can control below 0.1% in 2- (3- bromopyridine -4- bases the sulfenyl) -2 Methylpropionic acid methyl esters.This
The invention method is easy to operate, can be used for industrialized production.
Specific implementation mode
In order to make those skilled in the art more fully understand technical scheme of the present invention, it is non-that some are disclosed further below
Limiting embodiment, the present invention is described in further detail.
Reagent used in the present invention can be bought or can described method system through the invention from the market
It is standby and obtain.
In the present invention, g expressions gram, mL indicates that milliliter, L indicate to rise, mmol expressions mM, mol expressions mole, min tables
Show minute.
Embodiment 1
In reaction bulb, addition 3- bromopyridine -4- mercaptan (2.00g, 10.5mmol), potassium carbonate (2.90g, 21mmol),
2- isobutyl bromides methyl esters (2.10g, 11.6mmol) and n,N-Dimethylformamide (10mL), 25 DEG C are stirred to react 2 hours；HPLC
Detection raw material 3- bromopyridine -4- thiol reactions finish, but Impurity A content is 16.6%.
Embodiment 2
In reaction bulb, 3- bromopyridine -4- mercaptan (13.06g, 55mmol), potassium carbonate (15.20g, 110mmol) is added
With dimethyl sulfoxide (DMSO) (35mL), stirring is warming up to 70 DEG C and stirs 3.5 hours.Then 20 DEG C are cooled to, 2- isobutyl bromide first is added dropwise
Ester (10.95g, 60.5mmol), is added dropwise, and 20 DEG C are reacted 1 hour.Water 100mL is added dropwise into reaction system, second is then added
Acetoacetic ester 100mL, finishes, and stirs 1 hour.It is then allowed to stand liquid separation, separates organic layer, water layer uses ethyl acetate 50mL extractions one again
It is secondary, merge organic layer；Organic layer be washed with water it is secondary, every time use water 100mL, then washed once with saturated salt solution 100mL；
The vacuum distillation of gained organic layer removes solvent, obtains the liquid of 2- (3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters brownish black
Body 25.05g；HPLC is detected, Impurity A content 4.2%, product purity：92.2%.
Embodiment 3
In reaction bulb, 3- bromopyridine -4- mercaptan (13.06g, 55mmol), sodium carbonate (11.66g, 110mmol) is added
With dimethyl sulfoxide (DMSO) (35mL), stirring is warming up to 70 DEG C and stirs 5 hours.Then 20 DEG C are cooled to, 2- isobutyl bromide methyl esters is added dropwise
(10.95g, 60.5mmol), is added dropwise, and is reacted 1 hour at 20 DEG C -30 DEG C.Water 100mL is added dropwise into reaction system, then
Ethyl acetate 100mL is added, finishes, stirs 1 hour.It is then allowed to stand liquid separation, separates organic layer, water layer uses ethyl acetate 50mL again
Extraction is primary, merges organic layer；Organic layer be washed with water it is secondary, every time use water 100mL, then washed with saturated salt solution 100mL
It washs primary；The vacuum distillation of gained organic layer removes solvent, obtains 2- (3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters palm fibre
The liquid 25.01g of black；HPLC is detected, Impurity A content 1.9%, product purity：96.9%.
Embodiment 4
In reaction bulb, 3- bromopyridine -4- mercaptan (13.06g, 55mmol), sodium carbonate (11.66g, 110mmol) is added
With dimethyl sulfoxide (DMSO) (35mL), stirring is warming up to 70 DEG C and stirs 5 hours.Then 20 DEG C are cooled to, 2- isobutyl bromide methyl esters is added dropwise
(10.95g, 60.5mmol), is added dropwise, and is reacted 10 hours at 20 DEG C -30 DEG C.Water 100mL is added dropwise into reaction system, then
Ethyl acetate 100mL is added, finishes, stirs 1 hour.It is then allowed to stand liquid separation, separates organic layer, water layer uses ethyl acetate 50mL again
Extraction is primary, merges organic layer；Organic layer be washed with water it is secondary, every time use water 100mL, then washed with saturated salt solution 100mL
It washs primary；The vacuum distillation of gained organic layer removes solvent, obtains 2- (3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters palm fibre
The liquid 25.01g of black；HPLC is detected, Impurity A content 0.4%, product purity：97.9%.
Embodiment 5
In reaction bulb, be added 3- bromopyridine -4- mercaptan (13.06g, 55mmol), potassium carbonate (9.12g, 66mmol) and
N,N-Dimethylformamide (100mL), stirring are warming up to 50 DEG C and stir 7 hours.Then 20 DEG C -25 DEG C are cooled to, 2- bromines are added dropwise
Methyl isobutyrate (10.95g, 60.5mmol), is added dropwise, and is reacted 1 hour at 20 DEG C -25 DEG C.Water is added dropwise into reaction system
Then 100mL is added ethyl acetate 100mL, finishes, stir 1 hour.It is then allowed to stand liquid separation, separates organic layer, water layer uses second again
Acetoacetic ester 50mL extractions are primary, merge organic layer；Organic layer be washed with water it is secondary, every time use water 100mL, then use saturated common salt
Water 100mL washed once；The vacuum distillation of gained organic layer removes solvent, obtains 2- (3- bromopyridine -4- bases sulfenyl) -2- methyl-props
The liquid 25.13g of sour methyl esters brownish black；HPLC is detected, Impurity A content 0.5%, product purity：94.8%.
Embodiment 6
In reaction bulb, be added 3- bromopyridine -4- mercaptan (13.06g, 55mmol), potassium carbonate (22.8g, 165mmol) and
Dimethyl sulfoxide (DMSO) (50mL), stirring are warming up to 70 DEG C and stir 8 hours.Then 20 DEG C -25 DEG C are cooled to, 2- isobutyl bromide first is added dropwise
Ester (10.95g, 60.5mmol), is added dropwise, and is reacted 2 hours at 25 DEG C -35 DEG C.Water 100mL is added dropwise into reaction system, so
Ethyl acetate 100mL is added afterwards, finishes, stirs 1.5 hours.It is then allowed to stand liquid separation, separates organic layer, water layer uses ethyl acetate again
50mL extractions are primary, merge organic layer；Organic layer be washed with water it is secondary, every time use water 100mL, then use saturated salt solution
100mL washed once；The vacuum distillation of gained organic layer removes solvent, obtains 2- (3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid
The liquid 25.11g of methyl esters brownish black；HPLC is detected, Impurity A content 0.1%, product purity：98.1%.
Embodiment 7
In reaction bulb, 3- bromopyridine -4- mercaptan (13.06g, 55mmol), potassium carbonate (15.20g, 110mmol) is added
With n,N-Dimethylformamide (130mL), stirring is warming up to 70 DEG C and stirs 10 hours.Then 20 DEG C -25 DEG C are cooled to, 2- is added dropwise
Isobutyl bromide methyl esters (10.95g, 60.5mmol), is added dropwise, and is reacted 10 hours at 10 DEG C -20 DEG C.It is added dropwise into reaction system
Then water 100mL is added ethyl acetate 100mL, finishes, stir 1 hour.It is then allowed to stand liquid separation, separates organic layer, water layer is used again
Ethyl acetate 50mL extractions are primary, merge organic layer；Secondary, each water 100mL is washed with water in organic layer, then with saturation food
Brine 100mL washed once；The vacuum distillation of gained organic layer removes solvent, obtains 2- (3- bromopyridine -4- bases sulfenyl) -2- methyl
The liquid 25.21g of methyl propionate brownish black；HPLC is detected, Impurity A content 0.02%, product purity：98.4%.
Embodiment 8
In reaction bulb, 3- bromopyridine -4- mercaptan (13.06g, 55mmol), potassium carbonate (15.20g, 110mmol) is added
With dimethyl sulfoxide (DMSO) (150mL), stirring is warming up to 70 DEG C and stirs 12 hours.Then 15 DEG C -20 DEG C are cooled to, 2- bromine isobutyls are added dropwise
Sour methyl esters (10.95g, 60.5mmol), is added dropwise, and is reacted 2 hours at 10 DEG C -20 DEG C.Water is added dropwise into reaction system
Then 100mL is added ethyl acetate 100mL, finishes, stir 1 hour.It is then allowed to stand liquid separation, separates organic layer, water layer uses second again
Acetoacetic ester 50mL extractions are primary, merge organic layer；Organic layer be washed with water it is secondary, every time use water 100mL, then use saturated common salt
Water 100mL washed once；The vacuum distillation of gained organic layer removes solvent, obtains 2- (3- bromopyridine -4- bases sulfenyl) -2- methyl-props
The liquid 25.21g of sour methyl esters brownish black；HPLC is detected, Impurity A content 0.02%, product purity：98.1%.
Embodiment 9
In reaction bulb, 3- bromopyridine -4- mercaptan (68.40g, 0.36mol), potassium carbonate (99.36g, 0.72mol) is added
With dimethyl sulfoxide (DMSO) 200mL, 70 DEG C are warming up to, after stirring 24 hours, reaction solution is cooled to 20 DEG C, 2- bromo acids are added dropwise
Methyl esters (71.67g, 0.396mol), drop finishes 20 DEG C, and the reaction was continued 1 hour.800mL water and 500mL ethyl acetate, stirring 1 is added
After hour, static liquid separation separates organic layer, and water layer uses the extraction of 200mL ethyl acetate primary, merges organic layer again；Organic layer is used
Water washing, each 400mL, then washed once with 400mL saturated salt solutions twice；Separate organic layer, the decompression of gained organic layer
Solvent is distilled off, obtains brown liquid 109.7g；HPLC is detected, Impurity A content 0.02%, product purity 98.6%.
Embodiment 10
In reaction bulb, addition 3- bromopyridine -4- mercaptan (68.40g, 0.36mol), potassium carbonate (100.00g,
0.72mol) with n,N-Dimethylformamide 200mL, 70 DEG C are warming up to, after stirring 30 hours, reaction solution is cooled to 20 DEG C, drop
Add 2- bromo acids methyl esters (71.67g, 0.396mol), drop finishes 20 DEG C, and the reaction was continued 1 hour.800mL water and 500mL is added
Ethyl acetate, after stirring 1 hour, static liquid separation separates organic layer, and water layer is used the extraction of 200mL ethyl acetate primary, is associated with again
Machine layer；Organic layer is washed with water, twice each 400mL, then washed once with 400mL saturated salt solutions；Organic layer is separated, institute
It obtains organic layer vacuum distillation and removes solvent, obtain brown liquid 109.4g, HPLC detection, impurity A is not detected, product purity is
98.8%.
Embodiment 11：HPLC detection methods
In the present invention, using the content of high performance liquid chromatography (HPLC) checked for impurities A, detection method is as follows：
Chromatographic column：Agilent Eclipse plus C18 (4.6 × 100mm, 3.5um)；
Column temperature：30℃；
Buffer solution：0.1mol/L sodium perchlorate aqueous solutions are shaken up with phosphoric acid tune pH value to 2.5, filtering；Then above-mentioned molten
Liquid is with methanol with 95:5 (volume ratios) mix；
Flow velocity：1.0mL/min；
Detection wavelength：270nm；
Gradient elution program：
| Time (min) | Buffer solution (%) | Acetonitrile (%) |
| 0 | 100 | 0 |
| 3 | 100 | 0 |
| 15 | 10 | 90 |
| 20 | 10 | 90 |
After run：3min；
In HPLC chromatogram, the peak that retention time is about 13.9min corresponds to impurity A, and retention time is the peak of about 12.3min
Corresponding 2- (3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters.
The method of the present invention is described by preferred embodiment, related personnel can obviously hold within the present invention,
Method described herein and application are modified or are suitably changed and combined in spirit and scope, to realize and apply the present invention
Technology.Those skilled in the art can use for reference present disclosure, be suitably modified technological parameter realization.In particular, it should be pointed out that institute
There are similar replacement and change apparent to those skilled in the art, they are considered as being included in the present invention
It is interior.
Claims (6)
1. a kind of method preparing 2- (3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters, including：3- bromopyridine -4- mercaptan
With base reagent in organic solvent after the first reaction temperature reacts -30 hours 7 hours, reaction mixture is obtained；Then gained
Reaction mixture is contacted with 2- isobutyl bromide methyl esters again, is reacted -5 hours 1 hour in the second reaction temperature；By post-processing, obtain
To 2- (3- bromopyridine -4- bases sulfenyl) -2 Methylpropionic acid methyl esters；Wherein, first reaction temperature is 20 DEG C -100 DEG C；It is described
Second reaction temperature is 10 DEG C -40 DEG C；The molar ratio of 2- isobutyl bromides methyl esters and 3- bromopyridine -4- mercaptan is 1.01:1-
3.0:1；The molar ratio of base reagent and 3- bromopyridine -4- mercaptan is 1.05:1-3.0:1.
2. according to the method described in claim 1, the base reagent be potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, hydrogen-oxygen
Change lithium or its hydrate, or combinations thereof.
3. according to the method described in claim 1, the organic solvent be n,N-Dimethylformamide, dimethyl sulfoxide (DMSO), THF,
Acetonitrile, or combinations thereof.
4. according to the method described in claim 1, each gram of 3- bromopyridine -4- mercaptan, the consumption of organic solvent is 2mL-
25mL。
5. according to the method described in claim 1, wherein, the post-processing includes：Water is added into reaction system and extracts molten
Agent after stirring -4 hours 0.1 hour, detaches water layer and extractant layer, and water layer extractant extracts once, and merging extracts molten
Oxidant layer, gained will remove solvent after extractant layer water and/or saturated common salt water washing, obtain 2- (3- bromopyridine -4- base sulphur
Base) -2 Methylpropionic acid methyl esters.
6. according to the method described in claim 5, the extractant is ethyl acetate, isopropyl acetate, methyl acetate, dichloro
Methane, or combinations thereof.
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| CN201510835079.4A CN105418495B (en) | 2015-11-25 | 2015-11-25 | A kind of preparation method of thioether |
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