CN106699608A - Benzene guanidine containing strong electron withdrawing group and preparation method of salt thereof - Google Patents
Benzene guanidine containing strong electron withdrawing group and preparation method of salt thereof Download PDFInfo
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- CN106699608A CN106699608A CN201611218264.XA CN201611218264A CN106699608A CN 106699608 A CN106699608 A CN 106699608A CN 201611218264 A CN201611218264 A CN 201611218264A CN 106699608 A CN106699608 A CN 106699608A
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- benzene guanidine
- benzene
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- guanidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/02—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of guanidine from cyanamide, calcium cyanamide or dicyandiamides
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/12—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing organo-metallic compounds or metal hydrides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
- B01J2231/34—Other additions, e.g. Monsanto-type carbonylations, addition to 1,2-C=X or 1,2-C-X triplebonds, additions to 1,4-C=C-C=X or 1,4-C=-C-X triple bonds with X, e.g. O, S, NH/N
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a benzene guanidine containing strong electron withdrawing group and preparation method of salt thereof. The benzene guanidine and the salt compound of the benzene guanidine can be applied as the accelerator of rubber, medicine intermediate and the antiseptic agent of medical insecticide and pesticide. The benzene guanidine is mostly prepared in an acid reaction reaction of aromatic amines compounds and cyanamide. But if the aromatic amines contain strong electron withdrawing groups, the reaction does not happen, and the benzene guanidine cannot be prepared. According to the benzene guanidine and the preparation method, some catalysts are added to boost the reaction of the aromatic amines containing strong electron withdrawing groups which are not prone to the guanidine reaction, make the reaction smoothly carried out, and prepare the benzene guanidine salt with a high yield rate. The preparation method comprises the steps of S1, adding the benzene guanidine containing strong electron withdrawing droups, acetonitrile and anhydrous mono cyanide into a reaction kettle containing a blender to cool down to 0 DEG C, S2, slowly adding the catalysts into the reaction kettle, after adding the catalysts, taking away a cryostat, and making the solution react for certain time, S3, filtering out the product prepared in S2, using acetonitrile, water or ethanol for recrystallization to prepare the benzene guanidine salt, S4, dissolving the benzene guanidine salt prepared in S3 in acetonitrile water, using 15% sodium hydrate solution to adjust the pH value to 9.5, and obtain the benzene guanidine.
Description
Technical field
The invention belongs to pharmaceutical intermediate synthesis technical field, more particularly to a kind of benzene guanidine containing strong electron-withdrawing group group and
The preparation method of its salt.
Background technology
Benzene guanidine and its salt containing strong electron-withdrawing group group can serve as sterilized and insecticide in itself, it is also possible to be used as intermediate
In making medicine, such as document Identification of pyrimidine derivatives as hSMG-
1inhibitorsBy:Gopalsamy,Ariamala；Bennett,Eric M.；Shi,Mengxiao；Zhang,Wei-Guo；
Bard,Joel；Yu, Ker, Bioorganic＆Medicinal Chemistry Letters, 22 (21), 6636-6641；2012
Benzsulfamide guanidine prepares new targeting anticarcinogen and treats lung cancer for smelting between the use of middle report.Document Preparation of
isoquinolinone derivatives useful in the treatment of cancer By:Kaloun,El
Bachir；Schmitt,Philippe；Kruczynski, Anna, PCT Int.Appl., 2016034642,10Mar 2016 report
Medicine obtained in nitroguanidine can the smelting various cancers for the treatment of between road is used.
The preparation method above-mentioned reported in the literature of benzene guanidine and its salt containing strong electron-withdrawing group group, the reaction time is long, produces
Thing will pass through complicated processing procedure, and yield is very low.
The content of the invention
Problem, the present invention present in synthetic technology for the existing benzene guanidine containing strong electron-withdrawing group group of solution and its salt
There is provided a kind of benzene guanidine containing strong electron-withdrawing group group and its effective efficient preparation method of salt.
Benzene guanidine and its salt compounds can be used as the bactericide in medicine intermediate and medical insecticide and agricultural chemicals.It is mostly
It is obtained under the conditions of acid reaction using aromatic amine compounds and cyanamide.But if containing strong electron-withdrawing group group on arylamine, this
The reaction of sample is just not susceptible to, and is also made phenyl guanidine compound with regard to difficulty.The present invention is to containing strong electron-withdrawing group group on arylamine
More so be not susceptible to guanidineization reaction reaction, add some catalyst, be smoothed out reaction, and in high yield be obtained
Guanidines and its salt.
The present invention is adopted the following technical scheme that and realizes its goal of the invention：
(1) aniline rolled into a ball containing strong electron-withdrawing group, acetonitrile and anhydrous mononitrile amine are added in the reactor with stirring
It is as cold as 0 DEG C；
(2) catalyst is slowly added dropwise in reactor, catalyst has below formula：
M in catalyst can be that metal can also be unusual metal, such as can be SiOr Sn,
R1R2R3It is the identical or different alkyl of C1~C6, R1R2R3In one or two groups can also be H atom,
X is that halogen atom can be Cl or Br.
(3) cryostat is removed after catalyst is dripped in room temperature or 30 DEG C of reaction certain hours；Generation white product is separated out.
(4) recrystallized with acetonitrile, water or ethanol after whiteness obtained above is filtered out, 80 DEG C of drying systems
Obtain phenyl guanidinesalt.
(5) by phenyl guanidinesalt obtained by (4) by weight 1:1 is dissolved in acetonitrile water, is slowly added into 15% NaOH
Solution is as cold as 0 DEG C of filtering product, washing drying and guanidines is obtained to pH value to 9.5.
(6) the benzene guanidine containing strong electron-withdrawing group group of the invention and its simple high income of salt preparation method, product purity are high, it is easy to
Industrialized production.
The synthetic route of benzene guanidine of the present invention and its salt is as follows：
Specific embodiment
With reference to embodiment, the invention will be further described.
Embodiment 1：
Cyano-aniline, mononitrile amine 8.4g (0.2mol) and acetonitrile 120g between 11.8g (0.1mol) are added in four-hole bottle, is opened and is stirred
Mixing makes it all dissolve, and is as cold as 0 DEG C；Trim,ethylchlorosilane 12g is slowly added dropwise to, the cool bath room temperature reaction of ice is removed after completion of dropping
10 hours, filtering, acetonitrile wash, dry it is prepared between cyano group benzene guanidinesalt 18.6g.HPLC purity 98.5%, yield 94.4%.
Embodiment 2：
Amido benzsulfamide, mononitrile amine 12.6g (0.3mol) and acetonitrile between 17.2g (0.1mol) are added in four-hole bottle
120g, opening stirring makes it all dissolve, and is as cold as 0 DEG C；Tributyltin chloride 18g is slowly added dropwise to, ice is removed after completion of dropping cool
Bath room temperature reaction 16 hours, filtering, acetonitrile wash, dry it is prepared between benzene sulfonamido benzene guanidinesalt 24.1g.HPLC purity 98%, receives
Rate 96%.
Embodiment 3：
13.8g (0.1mol) meta nitro aniline, mononitrile amine 8.4g (0.2mol) and acetonitrile 120g are added in four-hole bottle, is opened and is stirred
Mixing makes it all dissolve, and is as cold as 0 DEG C；Tributyltin chloride 18g is slowly added dropwise to, the cool bath room temperature reaction of ice is removed after completion of dropping
12 hours, filtering, acetonitrile were washed, dry prepared m-nitro guanidinesalt 20.75g.HPLC purity 97.8%, yield 95.6%.
Embodiment 4：
Amido benzsulfamide, mononitrile amine 12.6g (0.3mol) and acetonitrile between 17.2g (0.1mol) are added in four-hole bottle
120g, opening stirring makes it all dissolve, and is as cold as 0 DEG C；Tributyltin chloride 12g is slowly added dropwise to, ice is removed after completion of dropping cool
Bath room temperature reaction 12 hours, filtering, acetonitrile wash, dry it is prepared between benzene sulfonamido benzene guanidinesalt 25.1g.
Benzene sulfonamido benzene guanidinesalt 25.1g is dissolved in 1 between being added in 500ml beakers：In 1 250g acetonitrile water, slowly drip
Add
15% sodium hydroxide solution, stirs in drop until pH value is 9.5, is as cold as 0 DEG C and stands 4 hours, filtering, water
Wash, dry be obtained between benzene sulfonamido benzene guanidine 19.2g.HPLC purity 98.5%, yield 92.3%.
Claims (6)
1. it is a kind of containing strong electron-withdrawing group group benzene guanidine and its salt preparation method.It is characterized in that this benzene guanidine is with the benzene of raw material
Contain strong electron-withdrawing group on amine, described electron-withdrawing group is located at ortho position, meta and the contraposition of amido, and described electron-withdrawing group is nitre
Base, cyano group, sulfoamido.
2. benzene guanidine according to claim 1 and its salt are have below formula：
3. the catalyst of the preparation of benzene guanidine according to claim 1 and its salt is have below formula：
4. M according to claim 2 in catalyst can be with it is characterized in that can be that metal can also be unusual metal, such as
It is SiOr Sn,R1R2R3It is the alkyl of C1~C6, can be the same or different, R1R2R3In one or two groups can also
It is H atom, X is that halogen atom can be Cl or Br.
5. catalyst according to claim 3 can be used alone, it is also possible to compounding use.
6. it is a kind of containing strong electron-withdrawing group group benzene guanidine and its salt preparation method.Characterized in that, inhaling electricity containing strong on aniline
Subbase, cyanamide is anhydrous, and its ratio is (mole %)；Aniline：Cyanamide is 1：1~3.
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| CN201611218264.XA CN106699608A (en) | 2016-12-26 | 2016-12-26 | Benzene guanidine containing strong electron withdrawing group and preparation method of salt thereof |
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Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0558985A (en) * | 1991-08-29 | 1993-03-09 | Kanebo Ltd | Production of cyanoguanidine derivative |
| CN1385423A (en) * | 2001-05-15 | 2002-12-18 | 马韵升 | N-(4,6-disubstituted 6 pyrimidine-2-)aniline and intermediate products preparation pocess thereof |
| WO2003051886A1 (en) * | 2001-12-17 | 2003-06-26 | Smithkline Beecham Corporation | Pyrazolopyridazine derivatives |
| WO2004099187A1 (en) * | 2003-05-06 | 2004-11-18 | Il Yang Pharm. Co. Ltd. | N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof |
| WO2005016914A1 (en) * | 2003-08-14 | 2005-02-24 | Smithkline Beecham Corporation | Chemical compounds |
| CN1631882A (en) * | 2004-12-02 | 2005-06-29 | 江苏耕耘化学有限公司 | Preparation method of agricultural fungicide N-(4,6-dimethyl pyrimidine-2-yl) aniline |
| CN1946657A (en) * | 2004-02-20 | 2007-04-11 | 切夫里昂菲利普化学有限责任公司 | Methods of preparation of an olefin oligomerization catalyst |
| US20130096148A1 (en) * | 2010-06-28 | 2013-04-18 | Hetero Research Foundation | Process for etravirine intermediate and polymorphs of etravirine |
| CN103373994A (en) * | 2012-04-19 | 2013-10-30 | 癌症研究技术有限公司 | Therapeutic compounds |
| CN103524442A (en) * | 2009-03-26 | 2014-01-22 | 常州英诺升康生物医药科技有限公司 | Pyrimidine compound, triazine compound and application thereof as medicine |
| WO2016034642A1 (en) * | 2014-09-02 | 2016-03-10 | Pierre Fabre Medicament | Isoquinolinone derivatives useful in the treatment of cancer |
-
2016
- 2016-12-26 CN CN201611218264.XA patent/CN106699608A/en active Pending
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0558985A (en) * | 1991-08-29 | 1993-03-09 | Kanebo Ltd | Production of cyanoguanidine derivative |
| CN1385423A (en) * | 2001-05-15 | 2002-12-18 | 马韵升 | N-(4,6-disubstituted 6 pyrimidine-2-)aniline and intermediate products preparation pocess thereof |
| WO2003051886A1 (en) * | 2001-12-17 | 2003-06-26 | Smithkline Beecham Corporation | Pyrazolopyridazine derivatives |
| WO2004099187A1 (en) * | 2003-05-06 | 2004-11-18 | Il Yang Pharm. Co. Ltd. | N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof |
| WO2004099186A1 (en) * | 2003-05-06 | 2004-11-18 | Il Yang Pharm Co., Ltd. | N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof |
| WO2005016914A1 (en) * | 2003-08-14 | 2005-02-24 | Smithkline Beecham Corporation | Chemical compounds |
| CN1946657A (en) * | 2004-02-20 | 2007-04-11 | 切夫里昂菲利普化学有限责任公司 | Methods of preparation of an olefin oligomerization catalyst |
| CN1631882A (en) * | 2004-12-02 | 2005-06-29 | 江苏耕耘化学有限公司 | Preparation method of agricultural fungicide N-(4,6-dimethyl pyrimidine-2-yl) aniline |
| CN103524442A (en) * | 2009-03-26 | 2014-01-22 | 常州英诺升康生物医药科技有限公司 | Pyrimidine compound, triazine compound and application thereof as medicine |
| US20130096148A1 (en) * | 2010-06-28 | 2013-04-18 | Hetero Research Foundation | Process for etravirine intermediate and polymorphs of etravirine |
| CN103373994A (en) * | 2012-04-19 | 2013-10-30 | 癌症研究技术有限公司 | Therapeutic compounds |
| WO2016034642A1 (en) * | 2014-09-02 | 2016-03-10 | Pierre Fabre Medicament | Isoquinolinone derivatives useful in the treatment of cancer |
Non-Patent Citations (3)
| Title |
|---|
| ARIAMALA GOPALSAMY等: "Identification of pyrimidine derivatives as hSMG-1 inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| RYAN E. LOOPER等: "Chlorotrimethyls ilane Activation of Acylcyanamides for the Synthesis of Mono- N -acylguanidines", 《J. ORG. CHEM.》 * |
| 刘小余等: "芳基胍的合成及表征", 《精细化工中间体》 * |
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