CN108530361A - A kind of synthesis technology of 5- [2- (3,5- Dimethoxyphenyls) ethyl] -1H- pyrazoles -3- amine - Google Patents
A kind of synthesis technology of 5- [2- (3,5- Dimethoxyphenyls) ethyl] -1H- pyrazoles -3- amine Download PDFInfo
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- CN108530361A CN108530361A CN201810474615.6A CN201810474615A CN108530361A CN 108530361 A CN108530361 A CN 108530361A CN 201810474615 A CN201810474615 A CN 201810474615A CN 108530361 A CN108530361 A CN 108530361A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/38—Nitrogen atoms
Abstract
The invention belongs to field of medicine and chemical technology, and in particular to a kind of new technique for synthesizing of 5 [2 (3,5 Dimethoxyphenyl) ethyl] 1H pyrazoles of AZD4547 key intermediates, 3 amine.It is with 2 (3,5 Dimethoxyphenyls) ethyl propionate be starting material, under basic catalyst, organic solvent existence condition with acetonitrile reaction, afterwards products therefrom under the conditions of the concentrated sulfuric acid with hydrazine hydrate cyclization, obtain 3 amine of target product 5 [2 (3,5 Dimethoxyphenyl) ethyl] 1H pyrazoles.The 5 [2 (3 of the offer of the present invention, 5 Dimethoxyphenyls) ethyl] 1H pyrazoles 3 amine synthetic method compared with prior art, substantially reduce the reaction time, product yield higher, and there is no the processes of purifying intermediate between two-step reaction, reaction time is shortened, and reduces discharge of wastewater, is suitable for industrialized production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of AZD4547 key intermediates 5- [2- (3,5- dimethoxies
Base phenyl) ethyl] -1H- pyrazoles -3- amine new technique for synthesizing.
Background technology
AZD4547 is researched and developed by Astrazeneca AB, for Treatment for Non-small Cell Lung such as gastric cancer, the cancer of the esophagus, breast cancer
Selective FGFR inhibitor, be still in the second stage of clinical research at present, structural formula is as follows：
Currently, about AZD4547 key intermediates 5- [2- (3,5- Dimethoxyphenyl) ethyl] -1H- pyrazoles -3- amine
It is less to synthesize document, Norman et al. is in Journal of Medicinal Chemistry, 55 (11), 5003-5012, and 2012
In report with 2- (3,5- Dimethoxyphenyl) ethyl propionate be raw material, sodium hydride effect under with acetonitrile reaction generate 5-
(3,5- Dimethoxyphenyl) -3- carbonyls-valeronitrile, then obtain target compound, two-step reaction yield difference with hydrazine hydrate cyclization
For 44% and 42%, and the first step needs column chromatography to obtain intermediate 5- (3,5- Dimethoxyphenyl) -3- carbonyls-valeronitrile, separately
There are reaction solution mutability agglutinations for outer the method, it is difficult to which emulsification is serious when stirring, and post-processing, and causes to isolate and purify difficult, receipts
The problems such as rate is relatively low.
Therefore there is an urgent need for high 5- [2- (3,5- Dimethoxyphenyls) second of a kind of easy to operate, high income of exploitation, product purity
Base] -1H- pyrazoles -3- amine new technique for synthesizing.
Invention content
In view of this, the purpose of the present invention is to provide a kind of 5- [2- (3,5- Dimethoxyphenyl) ethyl] -1H- pyrroles
The new technique for synthesizing of azoles -3- amine, reaction time consumption are short, easy to operate.
To achieve the above object, the technical scheme is that：
A kind of new technique for synthesizing of 5- [2- (3,5- Dimethoxyphenyl) ethyl] -1H- pyrazoles -3- amine comprising following
Step：
1) non-proton organic solvent is cooled to -50~-100 DEG C, basic catalyst, acetonitrile and 2- (3,5- bis- is added
Methoxyphenyl) ethyl propionate, it is rear to keep reacting 2~5 hours at -50~-100 DEG C；
2) non-proton organic solvent of the concentrated sulfuric acid, hydrazine hydrate is added into the solution of step 1), is warming up to 50-100 DEG C
Reaction 2~5 hours generates 5- [2- (3,5- Dimethoxyphenyl) ethyl] -1H- pyrazoles -3- amine.
Replace the sodium hydride used in the prior art in step 1) of the present invention using basic catalyst, the solvent used is not yet
Together, and reaction condition is explored, when temperature is -50~-100 DEG C, heat preservation can be completed to react for 2~5 hours, and will be anti-after reaction
Liquid is answered directly to carry out the reaction of step 2).The needs of background technology are heated at reflux, and the reaction time is 18 hours, and in step 1)
Column, purification of intermediates 5- (3,5- Dimethoxyphenyl) -3- carbonyls-valeronitrile were needed after reaction, the reaction time is long and operates
It is more complicated.
The step 2) of the present invention directly carries out on the basis of the reaction solution of step 1).Through overtesting, grope, has used dense sulphur
Acid carries out under strong acidic condition, improves reaction selectivity, the yield higher of target product.
The solvent that step 2) uses is non-protonic solvent, and reaction condition is 50-100 DEG C and reacts 2~5 hours, subsequently adopts
With chromatography column chromatography, product yield is up to 60% or more.And background technology solvent is ethyl alcohol, needs to be heated at reflux, and when reaction
Between 24 hours, reaction solution mutability agglutination, emulsification is serious when post-processing, and yield is only 42%.
Therefore, technique of the invention is by using the selection of the concentrated sulfuric acid, basic catalyst and solvent, excessively chromatographic column sequence
Adjustment, the synthesising reacting time that solves 5- [2- (3,5- Dimethoxyphenyl) ethyl] -1H- pyrazoles -3- amine is long, yield
Problem low, complicated for operation.In the technique of the present invention, the reaction time substantially shortens, yield improves, and two-step reaction is in same appearance
It is carried out in device, it is intermediate not to column, the purification process excessively of intermediate product, it is easy to operate.
As a preferred option, the step 1) basic catalyst be n-BuLi, it is tert-butyl lithium, potassium tert-butoxide, two different
Propylcarbamic lithium, potassium hydroxide it is one or more.
Further, preferably n-BuLi, tert-butyl lithium.
As a preferred option, the step 1) non-proton organic solvent be tetrahydrofuran, dioxane, n-hexane,
Hexamethylene it is one or more.
Further, preferably tetrahydrofuran.
As a preferred option, step 1) the insulation reaction time is 3-4 hours.
As a preferred option, the step 1) reaction temperature is -70~-80 DEG C.
As a preferred option, the step 1) basic catalyst, acetonitrile, 2- (3,5- Dimethoxyphenyl) ethyl propionate
The molar ratio to feed intake is 1.5-2.5:0.8-1.2:1.0.
Further, preferably 2.0:1.0:1.0.
As a preferred option, the step 2) reaction temperature is 75~90 DEG C.
As a preferred option, the step 2) concentrated sulfuric acid is the sulfuric acid solution that mass fraction is more than 75%.
Further, the sulfuric acid solution that preferably mass fraction is 98%.
As a preferred option, the step 2) concentrated sulfuric acid, hydrazine hydrate and the step 1) 2- (3,5- dimethoxy benzenes
Base) molar ratio that feeds intake of ethyl propionate is 0.9-1.1:1.3-1.8:1.0.
Further, preferably 1.0:1.4-1.6:1.
As a preferred option, the step 2) reaction time is 3-4 hours.
As a preferred option, step 2) includes last handling process afterwards, specially：The reaction solution of step 2) concentrates and through layer
Column chromatography is analysed, product 5- [2- (3,5- Dimethoxyphenyl) ethyl] -1H- pyrazoles -3- amine is obtained.
The second object of the present invention is to provide 5- [2- (3,5- Dimethoxyphenyls) prepared by a kind of technique of purpose one
Ethyl] -1H- pyrazoles -3- amine.
Technique using the present invention prepares 5- [2- (3,5- Dimethoxyphenyl) ethyl] -1H- pyrazoles -3- amine, when reaction
Between shorten, yield improves, and then the cost of product can be reduced.And the technological operation of the present invention is simple, is suitable for industrialization
Big production.It is significant for further preparing AZD4547.
The beneficial effects of the present invention are：
1) synthesising reacting time of 5- [2- (3,5- Dimethoxyphenyls) ethyl] -1H- pyrazoles -3- amine provided by the invention
Substantially shorten, operation is more simple, is suitable for industrialized large-scaled production.
2) in technique of the invention, two-step reaction carries out in same container, will cross column, purification process is positioned over reaction
Post-processing, solves the problems, such as to emulsify when original reaction solution mutability agglutination, post-processing serious, and simplifies operating process.
3) technique of the invention improves the yield of 5- [2- (3,5- Dimethoxyphenyls) ethyl] -1H- pyrazoles -3- amine extremely
60% or more, and product purity is high, reduces production cost.
Specific implementation mode
It detailed description of a preferred embodiment of the present invention will be given below.The reality of actual conditions is not specified in preferred embodiment
Proved recipe method, usually according to normal condition, illustrated embodiment are but not to be to preferably be illustrated to present disclosure
Present disclosure is only limitted to illustrated embodiment.So those skilled in the art according to foregoing invention content to embodiment party
Case carries out nonessential modifications and adaptations, still falls within protection scope of the present invention.
1 5- of embodiment [2- (3,5- Dimethoxyphenyls) ethyl] -1H- pyrazoles -3- amine synthetic schemes 1
1) 10mL anhydrous tetrahydro furans are cooled to -78 DEG C, 1.01mL (2.52mmol) n-BuLis (2.5mol/L is added
Hexane solution), be added dropwise 66.5 μ L acetonitriles.It is added dropwise, then 300mg2- (3,5- Dimethoxyphenyl) ethyl propionate is added dropwise
Tetrahydrofuran solution.Drop finishes, and reacts 3h at -78 DEG C.
2) concentrated sulfuric acid that 68.5 μ L mass fractions are 98% is added after the reaction was complete in TLC monitorings.115 μ L are slowly added dropwise again
The tetrahydrofuran solution of (1.89mmol) hydrazine hydrate, is added dropwise, and goes at 80 DEG C and reacts 3h.
3) yellow solid 156mg, yield 50.1% directly are obtained through chromatographing column chromatography after concentrating reaction solution.
2 5- of embodiment [2- (3,5- Dimethoxyphenyls) ethyl] -1H- pyrazoles -3- amine synthetic schemes 2
1) 10mL anhydrous dioxanes are cooled to -70 DEG C, 1.01mL (2.52mmol) n-BuLis (2.5mol/L is added
Hexane solution), be added dropwise 66.5 μ L acetonitriles.It is added dropwise, then 300mg2- (3,5- Dimethoxyphenyl) propionic acid second is added dropwise
Ester.Drop finishes, and reacts 3h at -60 DEG C.
2) concentrated sulfuric acid that 68.5 μ L mass fractions are 98% is added after the reaction was complete in TLC monitorings.115 μ L are slowly added dropwise again
The dioxane solution of (1.89mmol) hydrazine hydrate, is added dropwise, and goes at 60 DEG C and reacts 3h.
3) yellow solid 147mg, yield 48% directly are obtained through chromatographing column chromatography after concentrating reaction solution.
3 5- of embodiment [2- (3,5- Dimethoxyphenyls) ethyl] -1H- pyrazoles -3- amine synthetic schemes 3
1) 10mL anhydrous n-hexanes are cooled to -80 DEG C, addition 1.01mL (2.52mmol) n-BuLi be (2.5mol/L's
Hexane solution), 66.5 μ L acetonitriles are added dropwise.It is added dropwise, then 300mg 2- (3,5- Dimethoxyphenyl) ethyl propionate is added dropwise.
Drop finishes, and reacts 3h at -95 DEG C.
2) concentrated sulfuric acid that 68.5 μ L mass fractions are 98% is added after the reaction was complete in TLC monitorings.115 μ L are slowly added dropwise again
The hexane solution of (1.89mmol) hydrazine hydrate, is added dropwise, and goes at 90 DEG C and reacts 3h.
3) yellow solid 143.8mg, yield 46% directly are obtained through chromatographing column chromatography after concentrating reaction solution.
4 5- of embodiment [2- (3,5- Dimethoxyphenyls) ethyl] -1H- pyrazoles -3- amine synthetic schemes 4
1) 10mL tetrahydrofurans are cooled to -70 DEG C, 200mg (0.840mmol) 2- (3,5- Dimethoxyphenyl) is added
Ethyl propionate makes to be dissolved in tetrahydrofuran, and 188.35mg potassium tert-butoxides are added, add 44.3 μ L acetonitriles, -70 DEG C are stirred to react
3h。
2) concentrated sulfuric acid that 45.7 μ L mass fractions are 98% is added, 76.3 μ L (1.26mmol) hydrazine hydrates are slowly added dropwise
Tetrahydrofuran solution is added dropwise, and goes at 80 DEG C and reacts 3h.
3) white-yellowish solid 128mg, yield 61% directly are obtained through chromatographing column chromatography after concentrating reaction solution.
Hydrogen nuclear magnetic resonance spectrum analysis is carried out to product, it is as a result as follows：
M.p.110~112 DEG C.1H-NMR (DMSO-d6,400MHz), δ:6.62 (br s, 2H), 6.38 (d, J=
2.0Hz, 2H), 6.32 (t, J=2.0Hz, 1H), 5.45 (s, 1H), 3.78 (s, 6H), 2.86 (s, 4H).
The present invention develops one kind easy to operate, high income, product purity height as a result, and be suitable for industrialized large-scaled production
5- [2- (3,5- Dimethoxyphenyls) ethyl] -1H- pyrazoles -3- amine new technique for synthesizing.
Finally illustrate, the above examples are only used to illustrate the technical scheme of the present invention and are not limiting, although with reference to compared with
Good embodiment describes the invention in detail, it will be understood by those of ordinary skill in the art that, it can be to the skill of the present invention
Art scheme is modified or replaced equivalently, and without departing from the objective and range of technical solution of the present invention, should all be covered at this
In the right of invention.
Claims (10)
1. a kind of synthesis technology of 5- [2- (3,5- Dimethoxyphenyl) ethyl] -1H- pyrazoles -3- amine, which is characterized in that including
Following steps：
1) non-proton organic solvent is cooled to -50~-100 DEG C, basic catalyst, acetonitrile and 2- (3,5- dimethoxies is added
Base phenyl) ethyl propionate, it is rear to keep reacting 2~5 hours at -50~-100 DEG C；
2) concentrated sulfuric acid, the non-proton organic solvent dissolved with hydrazine hydrate are added into the reaction solution of step 1), is warming up to 50~100
DEG C reaction, 5- [2- (3,5- Dimethoxyphenyl) ethyl] -1H- pyrazoles -3- amine is generated in reaction solution.
2. technique according to claim 1, which is characterized in that the step 1) basic catalyst is n-BuLi, tertiary fourth
Base lithium, potassium tert-butoxide, lithium diisopropylamine, potassium hydroxide it is one or more.
3. technique according to claim 1, which is characterized in that step 1) and 2) non-proton organic solvent are tetrahydrochysene
Furans, dioxane, n-hexane, hexamethylene it is one or more.
4. technique according to claim 1, which is characterized in that the step 1) reaction temperature is -70~-80 DEG C.
5. technique according to claim 1, which is characterized in that the step 1) basic catalyst, acetonitrile, 2- (3,5- bis-
Methoxyphenyl) molar ratio that feeds intake of ethyl propionate is 1.5-2.5:0.8-1.2:1.0.
6. technique according to claim 1, which is characterized in that the step 2) reaction temperature is 75~90 DEG C.
7. technique according to claim 1, which is characterized in that the step 2) concentrated sulfuric acid is mass fraction more than 75%
Sulfuric acid solution.
8. technique according to claim 1, which is characterized in that the step 2) concentrated sulfuric acid, hydrazine hydrate and step 1) are described
The molar ratio that 2- (3,5- Dimethoxyphenyls) ethyl propionate feeds intake is 0.9-1.1:1.3-1.8:1.0.
9. technique according to claim 1, which is characterized in that reaction solution is concentrated and through chromatographing column chromatography, obtained step 2) afterwards
Product 5- [2- (3,5- Dimethoxyphenyls) ethyl] -1H- pyrazoles -3- amine.
10. 5- [2- (3,5- Dimethoxyphenyls) ethyl] -1H- pyrazoles -3- amine prepared by technique described in claim 1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111072638A (en) * | 2019-12-13 | 2020-04-28 | 上海工程技术大学 | Method for preparing AZD4547, intermediate and preparation method of intermediate |
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| CN107708690A (en) * | 2015-02-27 | 2018-02-16 | 南特生物科学公司 | Pyrimidine derivatives and their treatment use as kinase inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107708690A (en) * | 2015-02-27 | 2018-02-16 | 南特生物科学公司 | Pyrimidine derivatives and their treatment use as kinase inhibitor |
Non-Patent Citations (2)
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| BO RAM KIM ET AL: "Direct synthesis of pyrazoles from esters using tert-butoxide-assisted C-(C=O) coupling", 《CHEM.COMMUN.》 * |
| 张岩 等: "《炼钢生产知识》", 30 April 2015, 冶金工业出版社 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111072638A (en) * | 2019-12-13 | 2020-04-28 | 上海工程技术大学 | Method for preparing AZD4547, intermediate and preparation method of intermediate |
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