CN105622526A - Preparation method of 2-aminopyrazine derivatives - Google Patents
Preparation method of 2-aminopyrazine derivatives Download PDFInfo
- 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
- Authority
- CN
- China
- Prior art keywords
- amino
- bromo
- pyrazine
- preparation
- aminopyrazine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- AFAZKQSUUMIGID-UHFFFAOYSA-N C=CCC(NC(CBr)C(N)N)Br Chemical compound C=CCC(NC(CBr)C(N)N)Br AFAZKQSUUMIGID-UHFFFAOYSA-N 0.000 description 1
- PMSVVUSIPKHUMT-UHFFFAOYSA-N N#Cc1nccnc1 Chemical compound N#Cc1nccnc1 PMSVVUSIPKHUMT-UHFFFAOYSA-N 0.000 description 1
- ZFNVUICERIHJNK-UHFFFAOYSA-N NC(C(N1CCOCC1)=N1)NC=C1Br Chemical compound NC(C(N1CCOCC1)=N1)NC=C1Br ZFNVUICERIHJNK-UHFFFAOYSA-N 0.000 description 1
- XFTQRUTUGRCSGO-UHFFFAOYSA-N Nc1nccnc1 Chemical compound Nc1nccnc1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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
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.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610101017.5A CN105622526A (en) | 2016-02-24 | 2016-02-24 | Preparation method of 2-aminopyrazine derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610101017.5A CN105622526A (en) | 2016-02-24 | 2016-02-24 | Preparation method of 2-aminopyrazine derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
CN105622526A true CN105622526A (en) | 2016-06-01 |
Family
ID=56037910
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610101017.5A Pending CN105622526A (en) | 2016-02-24 | 2016-02-24 | Preparation method of 2-aminopyrazine derivatives |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN105622526A (en) |
Cited By (3)
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 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102428087A (en) * | 2009-04-16 | 2012-04-25 | 西班牙国家癌症研究中心 | Imidazopyrazines for use as kinase inhibitors |
WO2012052745A1 (en) * | 2010-10-21 | 2012-04-26 | Centro Nacional De Investigaciones Oncológicas (Cnio) | Combinations of pi3k inhibitors with a second anti -tumor agent |
-
2016
- 2016-02-24 CN CN201610101017.5A patent/CN105622526A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102428087A (en) * | 2009-04-16 | 2012-04-25 | 西班牙国家癌症研究中心 | Imidazopyrazines for use as kinase inhibitors |
WO2012052745A1 (en) * | 2010-10-21 | 2012-04-26 | Centro Nacional De Investigaciones Oncológicas (Cnio) | Combinations of pi3k inhibitors with a second anti -tumor agent |
Non-Patent Citations (6)
Title |
---|
SONIA MARTÍNEZ GONZÁLEZ ET AL.: "Imidazo[1,2-a]pyrazines as novel PI3K inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
STACY VAN EPPS ET AL.: "Design and synthesis of tricyclic cores for kinase inhibition", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
姜卫东: "2-氨基吡嗪衍生物的合成研究", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 * |
姜卫东等: "3,5-二溴-2-氨基吡嗪的合成研究", 《广州化工》 * |
郑国祥等: "3,5-二溴-2-氨基吡嗪的合成", 《浙江化工》 * |
陈晨等: "2-氨基-5-溴-3-吗啉-4-基吡嗪的合成", 《精细化工》 * |
Cited By (3)
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 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103242197B (en) | Preparation method of ultraviolet absorbent intermediate etocrilene (ETO) | |
CN109053625B (en) | Preparation method of substituted benzothiazole C2 alkylated derivative | |
CN105622526A (en) | Preparation method of 2-aminopyrazine derivatives | |
EP3215481A1 (en) | Method for producing biphenylamines from azobenzoles by ruthenium catalysis | |
Tang et al. | Synthesis of 1, 5-disubstituted tetrazoles via Suzuki–Miyaura cross-coupling of 5-chloro-1-phenyltetrazole | |
CN110642798B (en) | Green synthesis method of N-substituted-1, 4-dihydro-2, 3-quinoxalinedione compound | |
CN108774129A (en) | The method that visible light catalytic organic boronic prepares esters of alpha, beta, unsaturated carboxylic acids derivative | |
DE112012005176T5 (en) | Process for synthesizing 1- (2-fluorobenzyI) -1H-pyrazolo [3,4-b] pyridine-3-formamidine hydrochloride | |
Xiao et al. | Novel two-step, one-pot synthesis of primary acylureas | |
Chen et al. | Domino reaction of anilines with 3, 4-dihydro-2H-pyran catalyzed by cation-exchange resin in water: an efficient synthesis of 1, 2, 3, 4-tetrahydroquinoline derivatives | |
Sahnoun et al. | Cs2CO3 in pyrrolidinone promoted hydration of functionalized (hetero) aryl nitriles under metal-free conditions | |
CN103739417B (en) | A kind of method synthesizing aromatic primary amine in recirculated water phase system | |
CN108358835B (en) | Preparation method of 2,3, 5-trichloropyridine | |
CN103272638B (en) | Chiral guanidine catalysts based on tartaric acid skeleton, preparation method and application thereof | |
CN107353245A (en) | A kind of synthetic method of quinolines | |
CN107915694A (en) | 1 [2 (2,4 3,5-dimethylphenyl sulfydryl) phenyl] piperazine hydrochloride and preparation method thereof | |
CN105732375B (en) | A kind of method that gallic acid synthesizes 3,4,5-tri-methoxybenzoate | |
CN106854177A (en) | A kind of preparation method of the formaldehyde of 6 chlorine, 4 pyridone 3 | |
CN102718694B (en) | 3-cyan substituted indole compound and synthetic method thereof | |
CN102010279A (en) | Method for preparing vinylaromatic derivatives | |
Yang | A facile synthesis of 1, 3, 4-trisubstituted isoquinolines | |
CN109956940A (en) | A kind of method that the rich former times cloth intermediate cyano reaction of pa prepares heteroaryl cyanide | |
Zhang et al. | Imidazolium chloride as an additive for synthesis of perimidines using 1, 8-diaminonaphthalene and DMF derivatives | |
CN108911972A (en) | A kind of racemization recovery method for splitting by-product in mother liquor of sitafloxacin intermediate | |
Wang et al. | A new and convenient synthesis of germatranes using molecular sieves (3 Å) as dehydrating agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20160601 |