CN105622526A - Preparation method of 2-aminopyrazine derivatives - Google Patents

Preparation method of 2-aminopyrazine derivatives Download PDF

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Publication number
CN105622526A
CN105622526A CN201610101017.5A CN201610101017A CN105622526A CN 105622526 A CN105622526 A CN 105622526A CN 201610101017 A CN201610101017 A CN 201610101017A CN 105622526 A CN105622526 A CN 105622526A
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Prior art keywords
amino
bromo
pyrazine
preparation
aminopyrazine
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刘明星
姜卫东
王晚霞
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Hubei University of Technology
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Hubei University of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having 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
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The invention relates to a preparation method of 2-aminopyrazine derivatives, and belongs to the technical field of organic synthesis.With 2-cyanopyrazine as the raw material, by adding a sodium hypochlorite solution and alkali, 2-aminopyrazine is prepared through reaction, then 2-amino-3,5-dibromopyrazine is obtained through bromination reaction, and 2-amino-5-bromine-3-morpholinopyrazine, 2-amino-5-bromine-3-piperazinylpyrazine and 2-amino-5-bromine-3-pyrrolidylpyrazine are obtained after substitution reaction is conducted on 2-amino-3,5-dibromopyrazine as the raw material together with morpholine, piperazine and pyrrole respectively.With 2-cyanopyrazine as the raw material, different 2-aminopyrazine derivatives are prepared, the raw materials are low in price and easy to obtain, operation is easy, and target product yield is high.

Description

A kind of preparation method of 2-Aminopyrazine derivative
Technical field
The preparation method that the present invention relates to a kind of 2-Aminopyrazine derivative, belongs to technical field of organic synthesis.
Background technology
2-Aminopyrazine derivative is the key intermediate of many antitumor drug, such as Imidazopyrazine, morpholine Imidazopyrazine medicine; And it can as the synthetic intermediate of organic compound, as can be used as the substrate of imidazolidine hydride compounds.
At present, the synthesis of 2-Aminopyrazine derivative report is less, and has some shortcomings, such as route length, pollutes big, high in cost of production, the invention discloses a kind of simple to operate, mild condition, pollution is little, cost is low synthetic method, is conducive to large-scale production.
Summary of the invention
The method of the synthesis 2-Aminopyrazine derivative that the technical problem to be solved is in that to provide a kind of raw material to be easy to get, mild condition, technique are simple, easy to operate.
To achieve these goals, the present invention is raw material with 2 cyano pyrazine cheap and easy to get, through hydrolysis, reset, hydrolysis one kettle way obtains 2-Aminopyrazine (compound 1), carry out bromination reaction again and obtain 2-amino-3, 5-bis-bromo-pyrazine (compound 2), then with 2-amino-3, 5-bis-bromo-pyrazine be raw material respectively with morpholine, piperazine and pyrroles carry out substitution reaction and respectively obtain the bromo-morpholinyl pyrazine of 2-amino-5-(compound 3), the bromo-3-pyrrolidinyl pyrazine (compound 5) of 2-amino-5-bromo-3-piperazinyl pyrazines (compound 4) and 2-amino-5-. the structural formula of compound 1-5 is as follows:
Compound 1:R1=R2=H,
Compound 2:R1=R2=Br,
Compound 3:R1=morpholinyl, R2=Br,
Compound 4:R1=piperazinyl, R2=Br,
Compound 5:R1=pyrrolidinyl, R2=Br.
Its synthetic route is as follows:
Concrete technical scheme is:
It is raw material with 2 cyano pyrazine, add liquor natrii hypochloritis and alkali, it is obtained by reacting 2-Aminopyrazine, carry out bromination reaction again and obtain 2-amino-3,5-bis-bromo-pyrazine, then with 2-amino-3,5-bis-bromo-pyrazine is that raw material carries out substitution reaction with morpholine, piperazine and pyrroles respectively, respectively obtains the bromo-3-pyrrolidinyl pyrazine of 2-amino-5-bromo-morpholinyl pyrazine, 2-amino-5-bromo-3-piperazinyl pyrazines and 2-amino-5-.
In the preparation process of 2-Aminopyrazine, alkali used is: sodium hydroxide or potassium hydroxide, and paper mill wastewater is 20-30wt%, and reaction temperature is: 50 DEG C-60 DEG C.
In 2-amino-3, in the preparation process of 5-bis-bromo-pyrazine, bromating agent used is bromine, DBDMH or N-bromo-succinimide (NBS), and the molar ratio range of 2-Aminopyrazine and bromating agent is: 1:2-1:4.
In the preparation process of the bromo-3-pyrrole radicals pyrazine of 2-amino-5-bromo-morpholinyl pyrazine, 2-amino-5-bromo-3-piperazinyl pyrazines and 2-amino-5-, 2-amino-3, the molar ratio range of 5-bis-bromo-pyrazine and morpholine, piperazine and pyrroles is 1:1-1:1.3, reaction temperature is 70-100 DEG C, and the response time is 4-6h.
The invention have the advantages that the present invention utilizes 2 cyano pyrazine for raw material, prepare different 2-Aminopyrazine derivatives, raw material is cheap and easily-available, simple to operate, and target product yield is high.
Detailed description of the invention
Embodiment 1,2-Aminopyrazine preparation
In 500ml there-necked flask, add sodium hydroxide (30g) solution that concentration is 20% and liquor natrii hypochloritis (100ml), under room temperature, add 2 cyano pyrazine (21g, 0.2mol), stirring reaction 1h. Then reacting 4h at 50 DEG C��60 DEG C, extract with dichloromethane (4 �� 200ml), anhydrous sodium sulfate dries, and filters, concentrating under reduced pressure, obtains white solid 15.7g, yield 82.6%. Fusing point 118-121 DEG C;1H-NMR(CDCl3, 400MHz): �� 7.72 (S, 1H, CH), 7.89 (S, 1H, CH), 7.91 (S, 1H, CH), 4.2 (S, 2H, NH2).
Embodiment 2,2-amino-3,5-two bromo-pyrazine preparation
In 500ml there-necked flask, add 2-Aminopyrazine (19g, 0.2mol), the mixed solution of dichloromethane (200ml) and pyridine (50ml), room temperature is slowly added dropwise bromine (67.2g, dichloromethane (100ml) solution 0.42mol), 4h is stirred at room temperature, 100ml water is added in reaction system, stirring 2h, organic layer washed with water (100ml �� 3), organic facies is moved in the flask equipped with silica gel and activated carbon and be heated to reflux 1h, sucking filtration, decompression is distilled off solvent, gained solid adds in normal hexane (45ml), filtered while hot after backflow 2h, obtain yellow solid 39.4g after drying, yield is 77.8%. fusing point: 115-118 DEG C,1H-NMR(CDCl3, 400MHz): �� 7.91 (S, 1H, CH), 4.2 (S, 2H, NH2)��
The preparation of the bromo-morpholinyl pyrazine of embodiment 3,2-amino-5-
In 500ml there-necked flask, add morpholine (9.6g, 0.11mol) and 2-amino-3,5-bis-bromo-pyrazine (25.3g, 0.1mol) with in N-Methyl pyrrolidone (100ml), at 80 DEG C, reaction 6h, TLC follow the tracks of, after being cooled to room temperature, adding water 400ml, stirring, sucking filtration dries, obtaining yellow solid 22.5g, yield is 86.7%. Fusing point 134-137 DEG C;1H-NMR (DMSO, 400MHz): �� 7.70 (S, 1H), 6.28 (S, 2H), 3.85��3.62 (m, 4H).
The preparation of the bromo-3-piperazinyl pyrazines of embodiment 4,2-amino-5-
In 500ml there-necked flask, add piperazine (9.5g, 0.11mol), 2-amino-3,5-bis-bromo-pyrazine (25.3g, 0.1mol) with in N-Methyl pyrrolidone (100ml), at 90 DEG C, reaction 5h, TLC follow the tracks of, after being cooled to room temperature, adding water 400ml, stirring, sucking filtration dries, obtaining faint yellow solid 21.7g, yield is 83.6%. Fusing point: 393-396 DEG C;1H-NMR (DMSO, 400MHz): �� 2.0 (S, 1H, NH), 3.8 (S, 1H, CH), 2.9 (d, 2H, CH2), 2.0 (S, 2H, NH2), 3.67 (d, 2H, CH2).
The preparation of the bromo-3-pyrrolidinyl pyrazine of embodiment 5,2-amino-5-
In 500ml there-necked flask, add pyrroles (7.4g, 0.11mol), 2-amino-3,5-bis-bromo-pyrazine (25.3g, 0.1mol) with in N-Methyl pyrrolidone (100ml), at 100 DEG C, reaction 4h, TLC follow the tracks of, after being cooled to room temperature, adding water 400ml, stirring, sucking filtration dries, obtaining faint yellow solid 20.5g, yield is 84.3%.1H-NMR(CDCl3, 400MHz): �� 7..9 (S, 1H, CH), 4.0 (S, 2H, NH2), 6.95 (d, 1H, CH), 6.19 (d, 1H, CH).

Claims (4)

1. the preparation method of a 2-Aminopyrazine derivative, it is characterised in that:
It is raw material with 2 cyano pyrazine, add liquor natrii hypochloritis and alkali, it is obtained by reacting 2-Aminopyrazine, carry out bromination reaction again and obtain 2-amino-3,5-bis-bromo-pyrazine, then with 2-amino-3,5-bis-bromo-pyrazine is that raw material carries out substitution reaction with morpholine, piperazine and pyrroles respectively, respectively obtains the bromo-3-pyrrolidinyl pyrazine of 2-amino-5-bromo-morpholinyl pyrazine, 2-amino-5-bromo-3-piperazinyl pyrazines and 2-amino-5-.
2. preparation method according to claim 1, it is characterised in that in the preparation process of 2-Aminopyrazine, alkali used is: sodium hydroxide or potassium hydroxide, and paper mill wastewater is 20-30wt%, and reaction temperature is: 50 DEG C-60 DEG C.
3. preparation method according to claim 1, it is characterized in that, in 2-amino-3, in the preparation process of 5-bis-bromo-pyrazine, bromating agent used is bromine, DBDMH or N-bromo-succinimide, and the molar ratio range of 2-Aminopyrazine and bromating agent is: 1:2-1:4.
4. preparation method according to claim 1, it is characterized in that, in the preparation process of the bromo-3-pyrrole radicals pyrazine of 2-amino-5-bromo-morpholinyl pyrazine, 2-amino-5-bromo-3-piperazinyl pyrazines and 2-amino-5-, 2-amino-3, the molar ratio range of 5-bis-bromo-pyrazine and morpholine, piperazine and pyrroles is 1:1-1:1.3, reaction temperature is 70-100 DEG C, and the response time is 4-6h.
CN201610101017.5A 2016-02-24 2016-02-24 Preparation method of 2-aminopyrazine derivatives Pending CN105622526A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108570011A (en) * 2018-06-14 2018-09-25 枣庄九星生物科技有限公司 A kind of preparation method of 2- Aminopyrazine derivatives
CN110878056A (en) * 2019-11-12 2020-03-13 上海鑫响实业有限公司 Novel method for synthesizing 2-amino-3, 5-dibromopyrazine, product and application
WO2022129018A1 (en) 2020-12-17 2022-06-23 Merck Patent Gmbh Heteroaromatic isothiocyanates

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WO2012052745A1 (en) * 2010-10-21 2012-04-26 Centro Nacional De Investigaciones Oncológicas (Cnio) Combinations of pi3k inhibitors with a second anti -tumor agent

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108570011A (en) * 2018-06-14 2018-09-25 枣庄九星生物科技有限公司 A kind of preparation method of 2- Aminopyrazine derivatives
CN110878056A (en) * 2019-11-12 2020-03-13 上海鑫响实业有限公司 Novel method for synthesizing 2-amino-3, 5-dibromopyrazine, product and application
WO2022129018A1 (en) 2020-12-17 2022-06-23 Merck Patent Gmbh Heteroaromatic isothiocyanates

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Application publication date: 20160601