CN108440401A - The preparation method of 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine - Google Patents
The preparation method of 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine Download PDFInfo
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- CN108440401A CN108440401A CN201810330040.0A CN201810330040A CN108440401A CN 108440401 A CN108440401 A CN 108440401A CN 201810330040 A CN201810330040 A CN 201810330040A CN 108440401 A CN108440401 A CN 108440401A
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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
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
Abstract
The invention discloses a kind of preparation methods of 5 [(4 ethyl piperazidine, 1 base) methyl] pyridine of Abemaciclib intermediates, 2 amine：The first step mixes 2 chlorine, 5 chloromethylpyridine and N ethyl piperazidines, is 60~90 DEG C of reactions 1~for 24 hours in temperature, cooling to obtain Formula II compound by post-processing；Second step mixes Formula II compound, catalyst, reaction reagent, the confined reaction in pressurized tank, is 130~140 DEG C of reactions 1~for 24 hours in temperature, cooling to obtain compound of formula I by post-processing.The method of the present invention has the advantages that raw material is more cheap, technique is more environmentally protective, industrialized production is more favorable using cheap pesticide imidacloprid and 2 chlorine of acetamiprid intermediate, 5 chloromethylpyridine as raw material.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical fields, specifically, being related to a kind of Abemaciclib intermediates 5- [(4- second
Base piperazine -1- bases) methyl] the new preparation method of pyridine -2- amine.
Background technology
On September 28th, 2017, FDA ratify the breast cancer new drug Abemaciclib listings of Li Lai companies, Abemaciclib
It is a kind of cell cycle protein dependent kinase CDK4 and 6 inhibitor of CDK.
The primary synthetic methods of Abemaciclib intermediates 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine are such as
Under：
First method, Li Lai companies with the bromo- 5- aldehyde radicals pyridine elder generations of 2- and n-ethylpiperazine by acetic acid sodium borohydride also
Then former amination does nitrogen source with LiHMDS under DBA palladiums and CyJohnPhos ligand catalysis and obtains intermediate 5- [(4- ethyl piperazines
Piperazine -1- bases) methyl] pyridine -2- amine；Later by improving, the first step uses Leuckart-Wallach reactions instead, with formic acid and original
Trimethyl orthoformate does reduction amination, and second step is reacted with Ullmann, and intermediate is obtained with ammonium hydroxide amination under red copper oxid catalysis
5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine, reaction equation are as follows：
Second method, patent CN106316935 disclose a kind of using 6- nitronicotinic acids as raw material, elder generation and n-ethylpiperazine
It is amide 6 by condensing agent PyBOP condensations, then palladium carbon hydrogenating reduction obtains compound 7, finally uses tetrahydrochysene lithium aluminium reducing amide
Abemaciclib intermediates 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine is obtained, reaction equation is as follows：
The third method, patent WO2009/141386 disclose one using 6- aminonicotinates as the new of starting material
Then method, the first upper Boc protections of 6- aminonicotinates are alcohol 10 with LAH reduction ethyl esters, are carried out with n-ethylpiperazine after upper Ms
N- is alkylated, and Boc is finally gone to protect to obtain Abemaciclib intermediates 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2-
Amine, reaction equation are as follows：
Three of the above method has the following defects：First method has been carried out industrialized production, raw material 2- by improvement
Bromo- 5- aldehyde radicals pyridine is more expensive；The raw material 6- nitronicotinic acids of second method are more expensive, and use expensive condensation again
Agent PyBOP, is finally restored with tetrahydrochysene lithium aluminium, is not suitable for industrialized production；The raw material 6- aminonicotinates of the third method,
Not only expensive starting materials, and preparation route is longer, is also not suitable for industrialized production.It is raw materials used just it is therefore desirable to explore one kind
Preferably, the new system of the simple Abemaciclib intermediates 5- of synthetic method [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine
Preparation Method.
Invention content
A kind of the object of the present invention is to provide raw materials cheap, simple Abemaciclib intermediates 5- [(4- of preparation method
Ethyl piperazidine -1- bases) methyl] pyridine -2- amine new preparation method.
To achieve the goals above, the technical solution adopted by the present invention is as follows：
One aspect of the present invention provides a kind of Abemaciclib intermediates 5- [(4- ethyl piperazidine -1- bases) methyl]
The preparation method of pyridine -2- amine, reaction equation are as follows：
The first step mixes 2-vhloro-5-chloromethylpyridine and n-ethylpiperazine, temperature be 60~90 DEG C of reactions 1~
For 24 hours, cooling to obtain Formula II compound by post-processing；
Second step mixes Formula II compound, catalyst, reaction reagent, and the confined reaction in pressurized tank is in temperature
130~140 DEG C of reactions 1~for 24 hours, it is cooling to obtain compound of formula I by post-processing.
The molar ratio of the 2-vhloro-5-chloromethylpyridine and n-ethylpiperazine is 1:(1~2).
Further include solvent in the first step, the addition of solvent is conventional amount used.
The solvent is tap water, acetonitrile, n,N-Dimethylformamide, acetone, at least one of tetrahydrofuran, preferably
For tap water.
Further include acid binding agent in the first step, the acid binding agent be potassium carbonate, saleratus, sodium carbonate, sodium bicarbonate,
At least one of triethylamine, n,N-diisopropylethylamine, n-ethylpiperazine, preferably n-ethylpiperazine.
The molar ratio of the acid binding agent and 2-vhloro-5-chloromethylpyridine is 1:1.
The second step compound of formula H, catalyst molar ratio be 1:(1.5~4).
Reaction reagent is liquefied ammonia, methanol, ethyl alcohol, isopropanol, n-butanol, isobutanol, ethylene glycol, concentration in the second step
For 25~28% ammonium hydroxide, preferably a concentration of 25~28% ammonium hydroxide.
Reaction reagent is also used as solvent in the second step, and the addition of solvent is conventional amount used.
Catalyst is at least one of copper powder, copper oxide, cuprous oxide in the second step.
Due to the adoption of the above technical scheme, the present invention has the following advantages and beneficial effect：
The preparation of Abemaciclib intermediates 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine provided by the invention
Method, using cheap pesticide imidacloprid and acetamiprid intermediate 2-vhloro-5-chloromethylpyridine as raw material, more cheap with raw material,
Technique is more environmentally protective, the more favorable advantage of industrialized production, and chemical reagent n-ethylpiperazine used in method of the invention is urged
Agent, acid binding agent and solvent etc. are cheap and easy to get, and reaction condition is mild, and post-processing is simple.
Specific implementation mode
In order to illustrate more clearly of the present invention, with reference to preferred embodiment, the present invention is described further.Ability
Field technique personnel should be appreciated that following specifically described content is illustrative and be not restrictive, this should not be limited with this
The protection domain of invention.
2-vhloro-5-chloromethylpyridine used in the embodiment of the present invention is purchased from Shanghai Yi Shi Chemical Co., Ltd.s, technical grade.
N-ethylpiperazine used in the embodiment of the present invention is purchased from Shanghai Yi Shi Chemical Co., Ltd.s, technical grade.
Other Conventional solvents and reagent used in the embodiment of the present invention are purchased from Sinopharm Chemical Reagent Co., Ltd., chemistry
It is pure.
Embodiment 1
The synthesis of 1- (the chloro- pyridin-3-yl methyl of 6-) -4- ethyl-piperazins (II)
By 2-vhloro-5-chloromethylpyridine (162g, 1.0mol), tap water 300mL and n-ethylpiperazine (171g, 1.5mol)
It is added in the reaction bulb of 1L, is warming up to 60~70 DEG C, stir 2h, be cooled to room temperature, potassium carbonate (138g, 1.0mol) is added and stirs
10 minutes, divides and go water phase, be dried to obtain 225g products, yield 94%.1H NMR (400MHz, D2O):R 0.81 (t, J=
7.2Hz, 3H), 1.8~2.7 (m, 10H), 3.34 (s, 2H), 7.24 (d, J=8Hz, 1H), 7.57 (dd, J=8,2Hz, 1H),
8.03 (d, J=2Hz, 1H).
Embodiment 2
The synthesis of 1- (the chloro- pyridin-3-yl methyl of 6-) -4- ethyl-piperazins (II)
By 2-vhloro-5-chloromethylpyridine (162g, 1.0mol), potassium carbonate (138g, 1.0mol), acetonitrile 800mL and N- second
Base piperazine (125g, 1.1mol) is added in the reaction bulb of 2L, is warming up to 60~70 DEG C, stirs 2h, is concentrated to dryness, and tap water is added
400mL is stirred 10 minutes, is divided and is gone water phase, is dried to obtain 222g products, yield 93%.
Embodiment 3
The synthesis of 1- (the chloro- pyridin-3-yl methyl of 6-) -4- ethyl-piperazins (II)
100mL is added in 2-vhloro-5-chloromethylpyridine (16.2g, 0.1mol) and n-ethylpiperazine (11.4g, 0.1mol)
Reaction bulb in, be warming up to 80~90 DEG C, stir 7h, be cooled to room temperature, be directly used in next step.
Embodiment 4
The synthesis of Abemaciclib intermediates 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine (I)
Into the reaction solution of embodiment 3 be added copper powder (12g, 0.19mol), a concentration of 25~28% ammonium hydroxide 150mL,
It is slowly ramped to 130~140 DEG C in 250mL seal-off pressure tanks, reacts 16~18h, is cooled to room temperature, filtrate is concentrated into after filtering
It is dry, it purifies to obtain product 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine (I) (7.5g, two step yields by column chromatography
34%).
Embodiment 5
The synthesis of Abemaciclib intermediates 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine (I)
By 1- (the chloro- pyridin-3-yl methyl of 6-) -4- ethyl-piperazins (24g, 0.1mol), copper powder (21g, 0.33mol), dense
Degree is added to for 25~28% ammonium hydroxide 126mL in 250mL pressurized tanks, confined reaction, is slowly ramped to 130~140 DEG C, reaction
16~18h is cooled to room temperature, and filtrate is concentrated to dryness after filtering, and product (11.5g, yield 52%) is obtained with recrystallized from acetonitrile.1H
NMR (400MHz, D2O):δ 0.96 (t, J=7.2Hz, 3H), 2.22 (dd, J=15,7.2Hz, 2H), 1.8~2.7 (m, 8H)
3.23 (s, 2H), 6.51 (d, J=8Hz, 1H), 7.35 (dd, J=8,2Hz, 1H), 7.69 (d, J=2Hz, 1H).
Embodiment 6
The synthesis of 1- (the chloro- pyridin-3-yl methyl of 6-) -4- ethyl-piperazins (II)
By 2-vhloro-5-chloromethylpyridine (162g, 1.0mol), tap water 300mL and n-ethylpiperazine (228g, 2.0mol)
It is added in the reaction bulb of 2L, is warming up to 60~70 DEG C, stir 2h, be cooled to room temperature, divide and go water phase, be dried to obtain 225g products,
Yield 94%.
The basic principles, main features and advantages of the present invention have been shown and described above.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this
The principle of invention, various changes and improvements may be made to the invention without departing from the spirit and scope of the present invention, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent defines.
Claims (10)
1. a kind of preparation method of 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine, it is characterised in that：Reaction equation
It is as follows：
The first step mixes 2-vhloro-5-chloromethylpyridine and n-ethylpiperazine, is 60~90 DEG C of reactions 1~for 24 hours in temperature, cold
But Formula II compound is obtained by post-processing；
Second step, by Formula II compound, catalyst, reaction reagent mix, the confined reaction in pressurized tank, temperature be 130~
140 DEG C of reactions 1~for 24 hours, it is cooling to obtain compound of formula I by post-processing.
2. the preparation method of 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine according to claim 1, feature
It is：The molar ratio of the 2-vhloro-5-chloromethylpyridine and n-ethylpiperazine is 1:(1~2).
3. the preparation method of 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine according to claim 1 or 2, special
Sign is：Further include solvent in the first step.
4. the preparation method of 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine according to claim 3, feature
It is：The solvent is tap water, acetonitrile, n,N-Dimethylformamide, acetone, at least one of tetrahydrofuran, preferably
Tap water.
5. the preparation method of 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine according to claim 1, feature
It is：Further include acid binding agent in the first step.
6. the preparation method of 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine according to claim 5, feature
It is：The acid binding agent is potassium carbonate, saleratus, sodium carbonate, sodium bicarbonate, triethylamine, N, N- diisopropylethylamine, N- second
At least one of base piperazine, preferably n-ethylpiperazine.
7. the preparation method of 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine according to claim 5, feature
It is：The molar ratio of the acid binding agent and 2-vhloro-5-chloromethylpyridine is 1:1.
8. the preparation method of 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine according to claim 1, feature
It is：The second step compound of formula H, catalyst molar ratio be 1:(1.5~4).
9. the preparation method of 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine according to claim 1, feature
It is：In the second step reaction reagent be liquefied ammonia, it is methanol, ethyl alcohol, isopropanol, n-butanol, isobutanol, ethylene glycol, a concentration of
25~28% ammonium hydroxide, preferably a concentration of 25~28% ammonium hydroxide.
10. the preparation method of 5- [(4- ethyl piperazidine -1- bases) methyl] pyridine -2- amine according to claim 1, feature
It is：Catalyst is at least one of copper powder, copper oxide, cuprous oxide in the second step.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1642938A (en) * | 2002-03-28 | 2005-07-20 | 阿斯特拉曾尼卡有限公司 | New compounds |
| CN101795567A (en) * | 2007-06-11 | 2010-08-04 | 高点制药有限责任公司 | New heteocyclic H3 antagonists |
| CN105622638A (en) * | 2014-10-29 | 2016-06-01 | 广州康盛贝特医药技术有限公司 | Pyrimido or pyridopyridone compound and its preparation method and use |
| CN105732615A (en) * | 2014-12-31 | 2016-07-06 | 山东轩竹医药科技有限公司 | CDK kinase inhibitor |
| WO2018045993A1 (en) * | 2016-09-09 | 2018-03-15 | 正大天晴药业集团股份有限公司 | Crystal form, salt type of substituted 2-hydro-pyrazole derivative and preparation method therefor |
-
2018
- 2018-04-13 CN CN201810330040.0A patent/CN108440401A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1642938A (en) * | 2002-03-28 | 2005-07-20 | 阿斯特拉曾尼卡有限公司 | New compounds |
| CN101795567A (en) * | 2007-06-11 | 2010-08-04 | 高点制药有限责任公司 | New heteocyclic H3 antagonists |
| CN105622638A (en) * | 2014-10-29 | 2016-06-01 | 广州康盛贝特医药技术有限公司 | Pyrimido or pyridopyridone compound and its preparation method and use |
| CN105732615A (en) * | 2014-12-31 | 2016-07-06 | 山东轩竹医药科技有限公司 | CDK kinase inhibitor |
| WO2018045993A1 (en) * | 2016-09-09 | 2018-03-15 | 正大天晴药业集团股份有限公司 | Crystal form, salt type of substituted 2-hydro-pyrazole derivative and preparation method therefor |
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