CN110156791A - The preparation of (5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base) t-butyl carbamate - Google Patents
The preparation of (5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base) t-butyl carbamate Download PDFInfo
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- CN110156791A CN110156791A CN201910498955.7A CN201910498955A CN110156791A CN 110156791 A CN110156791 A CN 110156791A CN 201910498955 A CN201910498955 A CN 201910498955A CN 110156791 A CN110156791 A CN 110156791A
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The present invention relates to a kind of (5- tosyl -5H- pyrrolo-es [2; 3-b] pyrazine -2- base) t-butyl carbamate preparation method; the preparation method is with pyrazine -2; 5- diamines is starting material; (5- tosyl -5H- pyrrolo- [2 is made by series reaction; 3-b] pyrazine -2- base) t-butyl carbamate; optimize synthetic route; reaction condition is mildly controllable; it operates and post-processes and is simple and convenient; and product yield improves, and can save production cost and time, is suitble to large-scale industrial production.
Description
Technical field
The present invention relates to chemical technology fields, more particularly to a kind of (5- tosyl -5H- pyrrolo- [2,3-b] pyrrole
Piperazine -2- base) t-butyl carbamate preparation method.
Background technique
(5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base) t-butyl carbamate is a kind of important fine
Industrial chemicals and medicine intermediate, molecular formula C18H20N4O4S, molecular structure are as follows:
The preparation process of existing (5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base) t-butyl carbamate is multiple
Miscellaneous, yield is low, and the production time is long, for this purpose, the present invention proposes one kind (5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2-
Base) t-butyl carbamate preparation method.
Summary of the invention
Therefore, for the above content, the present invention provides one kind (5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2-
Base) t-butyl carbamate preparation method, solve prior art preparation complex process, yield is low, production time long problem.
In order to achieve the above objectives, the present invention is achieved by the following technical solutions:
A kind of preparation method of (5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base) t-butyl carbamate, including
Following steps:
(1) it is dissolved in n,N-Dimethylformamide with pyrazine -2,5- diamines and ethyl alcohol for raw material, under nitrogen protection, in 50~
60 DEG C of 3~5h of reaction, reaction obtain compound 1；
(2) compound 1 for obtaining step (1) reacts 2~4h under the catalysis of the concentrated sulfuric acid at a temperature of 90~120 DEG C, takes off
Water obtains compound 2；
(3) compound 2 that step (2) obtains is dissolved in toluene, and a certain amount of catalyst and acid binding agent is added, then slowly
Paratoluensulfonyl chloride is added, the 90~120min that added after paratoluensulfonyl chloride that the reaction was continued uses sodium carbonate after reaction
Solution washing extraction 2~3 times, with the dry 15~18h of sodium sulphate, filtering is concentrated under reduced pressure, and obtains compound 3；
(4) compound 3 that step (3) obtains is under the conditions of the sulfuric acid solution of sodium nitrite and mass fraction 50%, at 80~90 DEG C
Compound 4 is generated after reacting 1.5~2.5h；
(5) compound 4 that step (4) obtains and hydrogen halides generation halogenation generation compound 5, compound 4 and hydrogen halides
Molar ratio is 1:1.6~2；
(6) compound 5 that step (5) obtains is dissolved in pyridine, is then slowly added into t-butyl carbamate, in 50~70 DEG C
1~2h of lower reaction dries 15~18h with sodium sulphate after reaction with aqueous sodium carbonate washing extraction 2~3 times, filter,
It is concentrated under reduced pressure, obtains (5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base) t-butyl carbamate.
A further improvement is that: the molar ratio of pyrazine -2,5- diamines and ethyl alcohol is 1:1.5~1.8 in the step (1).
A further improvement is that: the molar ratio of step (3) compound 2 and paratoluensulfonyl chloride is 1:1.3~1.6.
A further improvement is that: the catalyst in the step (3) is 4-dimethylaminopyridine.
A further improvement is that: the quality of catalyst is the 2~4% of compound 2 in the step (3).
A further improvement is that: the acid binding agent in the step (3) is triethylamine, pyridine, N, N- diisopropylethylamine, four
Any one in butylammonium bromide.
A further improvement is that: the quality of the acid binding agent in the step (3) is the 3~6% of compound 2.
A further improvement is that: the quality of sulfuric acid solution is 4~6 times of compound 3, sodium nitrite in the step (4)
Quality be compound 3 10~30%.
A further improvement is that: step (5) hydrogen halides is hydrogen bromide.
Synthetic route of the invention is as follows:
By using preceding solution, the beneficial effects of the present invention are:
With pyrazine -2,5- diamines, for starting material, (5- tosyl -5H- pyrrolo- is made by series reaction in the present invention
[2,3-b] pyrazine -2- base) t-butyl carbamate, synthetic route is optimized, reaction condition is mildly controllable, operation and post-processing
It is simple and convenient, and product yield improves, and can save production cost and time, is suitble to large-scale industrial production.
Specific embodiment
Carry out the embodiment that the present invention will be described in detail below with reference to specific embodiment, how skill is applied to the present invention whereby
Art means solve technical problem, and the realization process for reaching technical effect can fully understand and implement.
Unless otherwise specified, the conventional hand that technological means employed in embodiment is well known to those skilled in the art
Section, used reagent and product are also available commercial.The source of agents useful for same, trade name and it is necessary to list it
Constituent person is indicated on the first occurrence.
Embodiment one
A kind of preparation method of (5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base) t-butyl carbamate, it is special
Sign is: the following steps are included:
(1) with pyrazine -2,5- diamines and ethyl alcohol for raw material, the molar ratio of pyrazine -2,5- diamines and ethyl alcohol is 1:1.5, is dissolved in N,
In dinethylformamide, under nitrogen protection, 5h is reacted at 50 °C, reaction obtains compound 1；
(2) compound 1 for obtaining step (1) reacts 4h, dehydrationization at a temperature of 90 DEG C under the catalysis of the concentrated sulfuric acid
Close object 2；
(3) compound 2 that step (2) obtains is dissolved in toluene, and 4-dimethylaminopyridine and triethylamine is added, wherein 4- bis-
Methylamino pyridine quality is the 2% of compound 2, and the quality of triethylamine is the 3% of compound 2, is then slowly added into tolysulfonyl
The molar ratio of chlorine, compound 2 and paratoluensulfonyl chloride is 1:1.3, the 90min that added after paratoluensulfonyl chloride that the reaction was continued, instead
With aqueous sodium carbonate washing extraction 2 times after answering, with the dry 15h of sodium sulphate, filtering is concentrated under reduced pressure, and obtains compound 3；
(4) compound 3 generates compound after reacting 2.5h at 80 DEG C under the conditions of the sulfuric acid of sodium nitrite and mass fraction 50%
4, the quality of sulfuric acid solution is 4 times of compound 3, and the quality of sodium nitrite is the 10% of compound 3；
(5) molar ratio of compound 4 and hydrogen bromide generation halogenation generation compound 5, compound 4 and hydrogen bromide is 1:1.6；
(6) compound 5 is dissolved in pyridine, is then slowly added into t-butyl carbamate, 2h is reacted at 50 DEG C, reaction terminates
Afterwards with aqueous sodium carbonate washing extraction 2 times, with the dry 15h of sodium sulphate, filtering is concentrated under reduced pressure, and obtains (5- tosyl-
5H- pyrrolo- [2,3-b] pyrazine -2- base) t-butyl carbamate.
Embodiment two
A kind of preparation method of (5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base) t-butyl carbamate, it is special
Sign is: the following steps are included:
(1) with pyrazine -2,5- diamines and ethyl alcohol for raw material, the molar ratio of pyrazine -2,5- diamines and ethyl alcohol is 1:1.6, is dissolved in N,
In dinethylformamide, under nitrogen protection, in 55 DEG C of reaction 4h, reaction obtains compound 1；
(2) compound 1 for obtaining step (1) reacts 3h, dehydrationization at a temperature of 105 DEG C under the catalysis of the concentrated sulfuric acid
Close object 2；
(3) compound 2 that step (2) obtains is dissolved in toluene, and 4-dimethylaminopyridine and N is added, N- diisopropyl second
Amine, wherein the quality of 4-dimethylaminopyridine is the 3% of compound 2, and the quality of n,N-diisopropylethylamine is compound 2
4.5%, it is then slowly added into paratoluensulfonyl chloride, the molar ratio of compound 2 and paratoluensulfonyl chloride is 1:1.5, has been added to first
The reaction was continued after benzene sulfonyl chloride 100min, after reaction with aqueous sodium carbonate washing extraction 2 times, with the dry 16h of sodium sulphate,
Filtering is concentrated under reduced pressure, and obtains compound 3；
(4) compound 3 generates compound 4 after reacting 2h under the conditions of the sulfuric acid of sodium nitrite and mass fraction 50%, at 85 DEG C,
The quality of sulfuric acid solution is 5 times of compound 3, and the quality of sodium nitrite is the 20% of compound 3；
(5) molar ratio of compound 4 and hydrogen bromide generation halogenation generation compound 5, compound 4 and hydrogen bromide is 1:1.8；
(6) compound 5 is dissolved in pyridine, is then slowly added into t-butyl carbamate, 1.5h, reaction knot are reacted at 60 DEG C
The washing of Shu Houyong aqueous sodium carbonate extraction 2 times, with the dry 16h of sodium sulphate, filtering is concentrated under reduced pressure, and obtains (5- tosyl
Base -5H- pyrrolo- [2,3-b] pyrazine -2- base) t-butyl carbamate.
Embodiment three
A kind of preparation method of (5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base) t-butyl carbamate, it is special
Sign is: the following steps are included:
(1) with pyrazine -2,5- diamines and ethyl alcohol for raw material, the molar ratio of pyrazine -2,5- diamines and ethyl alcohol is 1:1.8, is dissolved in N,
In dinethylformamide, under nitrogen protection, in 60 DEG C of reaction 3h, reaction obtains compound 1；
(2) compound 1 for obtaining step (1) reacts 2h, dehydrationization at a temperature of 120 DEG C under the catalysis of the concentrated sulfuric acid
Close object 2；
(3) compound 2 that step (2) obtains is dissolved in toluene, and 4-dimethylaminopyridine and tetrabutylammonium bromide is added,
The quality of middle 4-dimethylaminopyridine is the 4% of compound 2, and the quality of tetrabutylammonium bromide is the 6% of compound 2, then slowly
The molar ratio of addition paratoluensulfonyl chloride, compound 2 and paratoluensulfonyl chloride is 1:1.6, and it is subsequent to have added paratoluensulfonyl chloride
Continuous reaction 120min, after reaction with aqueous sodium carbonate washing extraction 3 times, with the dry 18h of sodium sulphate, filter, depressurize it is dense
Contracting, obtains compound 3；
(4) compound 3 generates compound after reacting 1.5h at 90 DEG C under the conditions of the sulfuric acid of sodium nitrite and mass fraction 50%
4, the quality of sulfuric acid solution is 6 times of compound 3, and the quality of sodium nitrite is the 30% of compound 3；
(5) molar ratio of compound 4 and hydrogen bromide generation halogenation generation compound 5, compound 4 and hydrogen bromide is 1:2；
(6) compound 5 is dissolved in pyridine, is then slowly added into t-butyl carbamate, 1h is reacted at 70 DEG C, reaction terminates
Afterwards with aqueous sodium carbonate washing extraction 3 times, with the dry 18h of sodium sulphate, filtering is concentrated under reduced pressure, and obtains (5- tosyl-
5H- pyrrolo- [2,3-b] pyrazine -2- base) t-butyl carbamate.
The foregoing descriptions are merely the embodiment using this origination techniques content, any those skilled in the art use this wound
Make done modifications and changes, all belong to the scope of the patents of this creation opinion, and is not limited to those disclosed embodiments.
Claims (9)
1. a kind of preparation method of (5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base) t-butyl carbamate,
It is characterized in that: the following steps are included:
(1) it is dissolved in n,N-Dimethylformamide with pyrazine -2,5- diamines and ethyl alcohol for raw material, under nitrogen protection, in 50~
60 DEG C of 3~5h of reaction, reaction obtain compound 1；
(2) compound 1 for obtaining step (1) reacts 2~4h under the catalysis of the concentrated sulfuric acid at a temperature of 90~120 DEG C, takes off
Water obtains compound 2；
(3) compound 2 that step (2) obtains is dissolved in toluene, and a certain amount of catalyst and acid binding agent is added, then slowly
Paratoluensulfonyl chloride is added, the 90~120min that added after paratoluensulfonyl chloride that the reaction was continued uses sodium carbonate after reaction
Solution washing extraction 2~3 times, with the dry 15~18h of sodium sulphate, filtering is concentrated under reduced pressure, and obtains compound 3；
(4) compound 3 that step (3) obtains is under the conditions of the sulfuric acid solution of sodium nitrite and mass fraction 50%, at 80~90 DEG C
Compound 4 is generated after reacting 1.5~2.5h；
(5) compound 4 that step (4) obtains and hydrogen halides generation halogenation generation compound 5, compound 4 and hydrogen halides
Molar ratio is 1:1.6~2；
(6) step (5) is obtained compound 5 to be dissolved in pyridine, is then slowly added into t-butyl carbamate, at 50~70 DEG C
1~2h is reacted, after reaction with aqueous sodium carbonate washing extraction 2~3 times, with the dry 15~18h of sodium sulphate, filters, subtract
Pressure concentration, obtains (5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base) t-butyl carbamate.
2. a kind of 5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base according to claim 1) carbamic acid
The preparation method of the tert-butyl ester, it is characterised in that: in the step (1) molar ratio of pyrazine -2,5- diamines and ethyl alcohol be 1:1.5~
1.8。
3. a kind of 5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base according to claim 1) carbamic acid
The preparation method of the tert-butyl ester, it is characterised in that: the molar ratio of compound 2 and paratoluensulfonyl chloride is 1:1.3 in the step (3)
~1.6.
4. a kind of 5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base according to claim 1) carbamic acid
The preparation method of the tert-butyl ester, it is characterised in that: the catalyst in the step (3) is 4-dimethylaminopyridine.
5. a kind of 5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base according to claim 1) carbamic acid
The preparation method of the tert-butyl ester, it is characterised in that: the quality of catalyst is the 2~4% of compound 2 in the step (3).
6. a kind of 5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base according to claim 1) carbamic acid
The preparation method of the tert-butyl ester, it is characterised in that: the acid binding agent in the step (3) is triethylamine, pyridine, N, N- diisopropyl second
Any one in amine, tetrabutylammonium bromide.
7. a kind of 5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base according to claim 1) carbamic acid
The preparation method of the tert-butyl ester, it is characterised in that: the quality of the acid binding agent in the step (3) is the 3~6% of compound 2.
8. a kind of 5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base according to claim 1) carbamic acid
The preparation method of the tert-butyl ester, it is characterised in that: the quality of sulfuric acid solution is 4~6 times of compound 3, nitrous in the step (4)
The quality of sour sodium is the 10~30% of compound 3.
9. a kind of 5- tosyl -5H- pyrrolo- [2,3-b] pyrazine -2- base according to claim 1) carbamic acid
The preparation method of the tert-butyl ester, it is characterised in that: hydrogen halides is hydrogen bromide in the step (5).
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012165914A2 (en) * | 2011-06-01 | 2012-12-06 | Green Cross Corporation | Novel diphenylmethane derivatives as sglt2 inhibitors |
| CN108864057A (en) * | 2017-05-16 | 2018-11-23 | 山东大学 | Bis- target spot inhibitor of JAK and HDAC containing 4- amino-pyrazol structure and its preparation method and application |
| CN109369659A (en) * | 2018-12-06 | 2019-02-22 | 浙江师范大学 | A kind of synthetic method of JAK inhibitor |
-
2019
- 2019-06-11 CN CN201910498955.7A patent/CN110156791A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012165914A2 (en) * | 2011-06-01 | 2012-12-06 | Green Cross Corporation | Novel diphenylmethane derivatives as sglt2 inhibitors |
| CN108864057A (en) * | 2017-05-16 | 2018-11-23 | 山东大学 | Bis- target spot inhibitor of JAK and HDAC containing 4- amino-pyrazol structure and its preparation method and application |
| CN109369659A (en) * | 2018-12-06 | 2019-02-22 | 浙江师范大学 | A kind of synthetic method of JAK inhibitor |
Non-Patent Citations (4)
| Title |
|---|
| ETHEL GARNIER，等: "Highly Diastereoselective Synthesis of C(6)-Functionalized Dihydroimidazotriazines", 《ORGANIC LETTERS》 * |
| JEAN-MICHEL CHEZAL，等: "Evaluation of Radiolabeled (Hetero)Aromatic Analogues of N-(2-diethylaminoethyl)-4-iodobenzamide for Imaging and Targeted Radionuclide Therapy of Melanoma", 《J. MED. CHEM.》 * |
| MINZAN ZUO，等: "Design and synthesis of indoline thiohydantoin derivatives based on enzalutamide as antiproliferative agents against prostate cancer", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| PETER W. FEIT，等: "Aminobenzoic Acid Diuretics. 8.2 3,4-Disubstituted 5-Methylsulfonylbenzoic Acids and Related Compounds", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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