CN110015980A - A kind of method of synthesizing tertiary butyl sulfenamide - Google Patents
A kind of method of synthesizing tertiary butyl sulfenamide Download PDFInfo
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- CN110015980A CN110015980A CN201910396739.1A CN201910396739A CN110015980A CN 110015980 A CN110015980 A CN 110015980A CN 201910396739 A CN201910396739 A CN 201910396739A CN 110015980 A CN110015980 A CN 110015980A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C313/02—Sulfinic acids; Derivatives thereof
- C07C313/04—Sulfinic acids; Esters thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C313/02—Sulfinic acids; Derivatives thereof
- C07C313/06—Sulfinamides
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Abstract
The invention belongs to chemosynthesis technical fields, and in particular to the synthetic method of t-butyl sulfonamide.Present invention aim to address document reaction route is long, reaction speed is slow, and wastewater flow rate is big, and toxic articles chlorine uses problem.A method of preparing t-butyl sulfonamide, the first step is using two sulphur of tert-butyl as starting material, pass through 2 catalyst of VO (acac) and the hydrogen peroxide oxidation synthesizing tertiary butyl sulfoxide tert-butyl ester, the second step tert-butyl sulfoxide tert-butyl ester obtains t-butyl sulfonamide through bromine on bromine and ammonium hydroxide amination in a solvent.Raw material of the present invention is easy to get, easy to operate, and safety and environmental protection, cost is relatively low, and yield is higher, is the proper method for preparing t-butyl sulfonamide.
Description
Technical field:
The invention belongs to chemosynthesis technical fields, and in particular to the synthetic method of t-butyl sulfonamide.
Background technique:
A kind of efficient synthesis of the t-butyl sulfonamide as Chiral Amine, is widely applied in pharmaceutical synthesis.
Synthesis in document about raceme is few, and there are two types of main methods, first is that using two sulphur of tert-butyl and acetic acid and dioxygen water oxygen
It is melted into the thio tert-butyl ester of tert-butyl sulfinic acid, is then reacted again with chlorine and ammonium hydroxide and generates raceme t-butyl sulfonamide.Two
It is to react to be oxidized to the thio tert-butyl ester of tert-butyl sulfinic acid with chlorination sulfone using two sulphur of tert-butyl, is then generated again with chlorine reaction
Generate raceme t-butyl sulfonamide.Bubble is too many in this method reaction process, and many acid gas corrosions of output are big.
Racemization t-butyl sulfonamide fusing point is low, compared with chirality, just readily becomes liquid condition containing a small amount of impurity,
It is not easy to be precipitated.
Document (Chengdu Organic Chemistry Inst., Chinese Academy of Sciences the Ph.D. Dissertation, " system of chiral t-butyl sulfonamide
The research of standby and its diimine organometallic reagent asymmetric reduction reaction ", author: Sun Xiaoxia, page 26, page 93 and
Page 25.) first step is disclosed to aoxidize the generation thio tert-butyl ester of tert-butyl sulfinic acid from two sulphur of tert-butyl, this reacts original adoption
Document V2O5 and VO (acac) 2 reacts in ethanol, and reaction speed is slow, and reaction is not thorough, and describes with document not consistent；Replacement
To do solvent reaction in acetic acid, speed is improved, but wastewater flow rate is big when purification of acetic acid.
Summary of the invention:
Present invention aim to address document reaction route is long, reaction speed is slow, and wastewater flow rate is big, and toxic articles chlorine use is asked
Topic, provides a kind of method for preparing two sulphur of tert-butyl, using two sulphur of tert-butyl as starting material, product is made through two-step reaction, former
Material is easy to get, is easy to operate, safety and environmental protection, cost is relatively low, and yield is higher.
The present invention in order to solve the above problem used by technical solution be: a method of prepare two sulphur of tert-butyl, first
Step is using two sulphur of tert-butyl as starting material, by 2 catalyst of VO (acac) and the hydrogen peroxide oxidation synthesizing tertiary butyl sulfoxide tert-butyl ester,
The second step tert-butyl sulfoxide tert-butyl ester obtains t-butyl sulfonamide through bromine on bromine and ammonium hydroxide amination in a solvent.
A kind of method preparing two sulphur of tert-butyl, specifically comprises the processes of:
1, specifically comprises the processes of: step 1: middle two sulphur of addition raw material tert-butyl, the tert-butyl alcohol and VO (acac) 2,20 in reactor
~25 DEG C start to be continuously added to hydrogen peroxide, and material temperature in kettle controls at 20~25 DEG C, is all added and finishes, and keeps the temperature 25~30 DEG C
Reaction 5~8 hours, sampling HPLC detection；It is concentrated under reduced pressure after reaction, steams the tert-butyl alcohol, common salt aqueous solution is added and is washed
It washs, is concentrated under reduced pressure, normal heptane replacement continues to be concentrated into not flow liquid, the thio tert-butyl ester of gained tert-butyl sulfinic acid；
Step 2: the thio tert-butyl ester of tert-butyl sulfinic acid and solvent made from the first step are added into reactor, then continuously
Bromine solution after solvent dilution is added, controls temperature -5-0 degree in bottle, is slowly added to, and all it is small to terminate insulation reaction 2 for addition
When, HPLC detection and GC detection after sampling methanol is derivative；It is added in 5-10eq concentrated ammonia solution after the reaction was completed, controls temperature
0-5 degree after being all added, is concentrated under reduced pressure, and low polar solvent extraction, TLC is detected without small polar impurity；Ethyl acetate is added
It is extracted, is dried, filtered, be concentrated into 2 times of weight of product, filter micro insoluble matter, filtrate continues to be concentrated to dryness, and is added just
Heptane replacement adds normal heptane mashing, obtains white products.
Two sulphur of raw material tert-butyl, VO (acac) 2, hydrogen peroxide molar ratio are 1:0.005-0.01:1.2- in the first step
1.3。
Bromine additional amount is the 0.95-1.05 equivalent of the tert-butyl sulfoxide tert-butyl ester in the second step.In the second step
Solvent selects methylene chloride or dichloroethanes.
It is described to be continuously added to using dropwise addition mode；The hydrogen peroxide addition time is 5 hours；Ammonium hydroxide additional amount is to guarantee reacting ammonia
Water is enough.
The low polar solvent is normal heptane or normal heptane and methylene chloride mixed solvent.
It is of the invention that the reaction mechanism is as follows:
The novelty of the present invention is reaction process clear route, the first step uses the tert-butyl alcohol for raw material, and reaction system is former
Material and catalyst reasonable compatibility, accelerate reaction speed, it is big to avoid document acetic acid solvent method post-processing wastewater flow rate, and generate not
Tractable waste, chlorine belongs to severe poisonous chemicals in second step, by control --- and the present invention use bromine and ammonium hydroxide for
Raw material avoids bis- (tert-butyl sulfenyl) amine, reaction small using raw material risk by the way that intermediate to be added in ammonium hydroxide
Mild condition, yield are higher.And reaction condition of the present invention is mild, and it is easily controllable, it is environmental-friendly.
Specific embodiment:
Invention is further described in detail combined with specific embodiments below, but the invention is not limited to specific implementations
Example.
Embodiment 1
Into reaction flask, middle two sulphur of addition 200g tert-butyl, the 400g tert-butyl alcohol and 2,20~25 DEG C of 1.5g VO (acac) are opened
Begin that content 25-30% 1.10~1.15eq of hydrogen peroxide is added dropwise, be added dropwise 5 hours, material temperature in kettle is controlled at 20~25 DEG C.It is added dropwise
After, it keeps the temperature 25~30 DEG C and reacts 5~8 hours, sampling HPLC detection.It is concentrated under reduced pressure after reaction, steams the tert-butyl alcohol, add
Enter common salt aqueous solution to be washed, be concentrated under reduced pressure, normal heptane replacement continues to be concentrated into not flow liquid, and gained tert-butyl sulfinic acid is thio
The tert-butyl ester, HPLC purity is 89%.Yield is 82%.
The thio tert-butyl ester of 198 grams of tert-butyl sulfinic acid and 562 grams of methylene chloride are added into reaction flask, methylene chloride is added dropwise
1.01Eq bromine solution after dilution controls temperature -5-0 degree in bottle, is added dropwise slowly, completion of dropwise addition insulation reaction 2 hours, sampling
HPLC detection after methanol is derivative (impurity is tert-butyl bromide and tert-butyl trithio).It is added drop-wise to 10eq concentrated ammonia solution after the reaction was completed
In, temperature 0-5 degree is controlled, after completion of dropwise addition, is concentrated under reduced pressure, methylene chloride/normal heptane=1:10 is added) it is extracted, then use
Normal heptane extraction, TLC detection eliminate small polar impurity.Ethyl acetate is added to be extracted, dries, filters, is concentrated into product
2 times of weight, filter micro insoluble matter, filtrate continues to be concentrated to dryness, be added normal heptane replacement twice, add a small amount of normal heptane
Mashing, obtains white products, yield 77%.
Embodiment 2
Into reaction flask, middle two sulphur of addition 200g tert-butyl, the 400g tert-butyl alcohol and 2,20~25 DEG C of 1.6g VO (acac) are opened
Begin that content 25-30% 1.10~1.15eq of hydrogen peroxide is added dropwise, be added dropwise 5 hours, material temperature in kettle is controlled at 20~25 DEG C.It is added dropwise
After, it keeps the temperature 25~30 DEG C and reacts 5~8 hours, sampling HPLC detection.It is concentrated under reduced pressure after reaction, steams the tert-butyl alcohol, add
Enter common salt aqueous solution to be washed, be concentrated under reduced pressure, normal heptane replacement continues to be concentrated into not flow liquid, and gained tert-butyl sulfinic acid is thio
The tert-butyl ester, HPLC purity is 90%.Yield is 81%.
The thio tert-butyl ester of 198 grams of tert-butyl sulfinic acid and 562 grams of dichloroethanes are added into reaction flask, methylene chloride is added dropwise
0.95Eq bromine solution after dilution controls temperature -5-0 degree in bottle, is added dropwise slowly, completion of dropwise addition insulation reaction 2 hours, sampling
HPLC detection and GC detection after methanol is derivative (impurity is tert-butyl bromide and tert-butyl trithio).It is dense that it is added drop-wise to 8eq after the reaction was completed
In ammonia spirit, temperature 0-5 degree is controlled, after completion of dropwise addition, is concentrated under reduced pressure, methylene chloride/normal heptane=1:10 is added) extracted
It takes, then is extracted with normal heptane, TLC detection eliminates small polar impurity.Ethyl acetate is added to be extracted, dries, filters, is concentrated
To 2 times of weight of product, micro insoluble matter is filtered, filtrate continues to be concentrated to dryness, and normal heptane replacement is added twice, adds a small amount of
Normal heptane mashing, obtains white products, yield 71%.
Embodiment 3
Into reaction flask, middle two sulphur of addition 200g tert-butyl, the 400g tert-butyl alcohol and 2,20~25 DEG C of 1.6g VO (acac) are opened
Begin that content 25-30% 1.10~1.15eq of hydrogen peroxide is added dropwise, be added dropwise 5 hours, material temperature in kettle is controlled at 20~25 DEG C.It is added dropwise
After, it keeps the temperature 25~30 DEG C and reacts 5~8 hours, sampling HPLC detection.It is concentrated under reduced pressure after reaction, steams the tert-butyl alcohol, add
Enter common salt aqueous solution to be washed, be concentrated under reduced pressure, normal heptane replacement continues to be concentrated into not flow liquid, and gained tert-butyl sulfinic acid is thio
The tert-butyl ester, HPLC purity is 90%.Yield is 81%.
The thio tert-butyl ester of 98 grams of tert-butyl sulfinic acid and 362 grams of methylene chloride are added into reaction flask, methylene chloride is added dropwise
1.05Eq bromine solution after dilution controls temperature -5-0 degree in bottle, is added dropwise slowly, completion of dropwise addition insulation reaction 2 hours, sampling
HPLC detection and GC detection after methanol is derivative (impurity is tert-butyl bromide and tert-butyl trithio).It is dense that it is added drop-wise to 5eq after the reaction was completed
In ammonia spirit, temperature 0-5 degree is controlled, after completion of dropwise addition, is concentrated under reduced pressure, methylene chloride/normal heptane=1:10 is added) extracted
It takes, then is extracted with normal heptane, TLC is detected without small polar impurity.Ethyl acetate is added to be extracted, dries, filters, is concentrated into production
2 times of weight of product, filter micro insoluble matter, and filtrate continues to be concentrated to dryness, and normal heptane replacement is added twice, add a small amount of positive heptan
Alkane mashing, obtains white products, yield 66%.
Claims (7)
1. a kind of method for preparing t-butyl sulfonamide, it is characterized in that: the first step passes through using two sulphur of tert-butyl as starting material
2 catalyst of VO (acac) and the hydrogen peroxide oxidation synthesizing tertiary butyl sulfoxide tert-butyl ester, the second step tert-butyl sulfoxide tert-butyl ester is in solvent
It is middle to obtain t-butyl sulfonamide through bromine on bromine and ammonium hydroxide amination.
2. a kind of method for preparing two sulphur of tert-butyl according to claim 1, it is characterized in that: specifically comprises the processes of: step 1:
Middle two sulphur of addition raw material tert-butyl, the tert-butyl alcohol and VO(acac in reactor) 2,20 ~ 25 DEG C start to be continuously added to hydrogen peroxide, in kettle
Temperature of charge is controlled at 20 ~ 25 DEG C, is all added and is finished, and is kept the temperature 25 ~ 30 DEG C and is reacted 5 ~ 8 hours, sampling HPLC detection；Reaction knot
It is concentrated under reduced pressure after beam, steams the tert-butyl alcohol, common salt aqueous solution is added and is washed, is concentrated under reduced pressure, normal heptane replacement continues to be concentrated into
Not flow liquid, the thio tert-butyl ester of gained tert-butyl sulfinic acid；
Step 2: the thio tert-butyl ester of tert-butyl sulfinic acid and solvent made from the first step are added into reactor, then it is continuously added to
Bromine solution after solvent dilution, controls temperature -5-0 degree in bottle, is slowly added to, and being all added terminates insulation reaction 2 hours, takes
HPLC detection and GC detection after sample methanol is derivative；It is added in 5-10eq concentrated ammonia solution after the reaction was completed, controls temperature 0-5
Degree after being all added, is concentrated under reduced pressure, and low polar solvent extraction, TLC is detected without small polar impurity；Be added ethyl acetate into
Row extraction, dries, filters, is concentrated into 2 times of weight of product, filters micro insoluble matter, filtrate continues to be concentrated to dryness, and positive heptan is added
Alkane replacement adds normal heptane mashing, obtains white products.
3. a kind of method for preparing t-butyl sulfonamide according to claim 1 or 2, it is characterized in that: the first step
Middle two sulphur of raw material tert-butyl, VO (acac) 2, hydrogen peroxide molar ratio are 1:0.005-0.01:1.2-1.3.
4. according to right want 1 or 2 described in a kind of method for preparing t-butyl sulfonamide, it is characterized in that: in the second step
Bromine additional amount is the 0.95-1.05 equivalent of the tert-butyl sulfoxide tert-butyl ester.
5. a kind of method for preparing t-butyl sulfonamide according to claim 1 or 2, it is characterized in that: the second step
Middle solvent selects methylene chloride or dichloroethanes.
6. a kind of method for preparing t-butyl sulfonamide according to claim 1 or 2, it is characterized in that: described continuously add
Enter to use dropwise addition mode；The hydrogen peroxide addition time is 5 hours；Ammonium hydroxide additional amount is to guarantee that reaction ammonium hydroxide is enough.
7. a kind of method for preparing t-butyl sulfonamide according to claim 2, it is characterized in that: the low polar solvent
For normal heptane or normal heptane and methylene chloride mixed solvent.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112279791A (en) * | 2020-12-30 | 2021-01-29 | 和鼎（南京）医药技术有限公司 | Method for preparing chiral tert-butyl sulfinamide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104114553A (en) * | 2011-12-12 | 2014-10-22 | 雷迪博士实验室有限公司 | Substituted pyrazolo[1,5-a] pyridine as tropomyosin receptor kinase (Trk) inhibitors |
| CN108467353A (en) * | 2018-05-11 | 2018-08-31 | 上海晋鲁医药科技有限公司 | A kind of preparation method of the pure t-butyl sulfonamide of mapping |
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2019
- 2019-05-14 CN CN201910396739.1A patent/CN110015980A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104114553A (en) * | 2011-12-12 | 2014-10-22 | 雷迪博士实验室有限公司 | Substituted pyrazolo[1,5-a] pyridine as tropomyosin receptor kinase (Trk) inhibitors |
| CN108467353A (en) * | 2018-05-11 | 2018-08-31 | 上海晋鲁医药科技有限公司 | A kind of preparation method of the pure t-butyl sulfonamide of mapping |
Non-Patent Citations (1)
| Title |
|---|
| MASAKAZU WAKAYAMA ET AL.: "Recycling the tert-Butanesulfinyl Group in the Synthesis of Amines Using tert-Butanesulfinamide", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112279791A (en) * | 2020-12-30 | 2021-01-29 | 和鼎（南京）医药技术有限公司 | Method for preparing chiral tert-butyl sulfinamide |
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Application publication date: 20190716 |