CN108484446A - Three nitrogen amidine amides compounds and preparation method thereof - Google Patents
Three nitrogen amidine amides compounds and preparation method thereof Download PDFInfo
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- CN108484446A CN108484446A CN201810411103.5A CN201810411103A CN108484446A CN 108484446 A CN108484446 A CN 108484446A CN 201810411103 A CN201810411103 A CN 201810411103A CN 108484446 A CN108484446 A CN 108484446A
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- nitrogen
- amidine
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- 0 CC(CC(N*)=N)=CC=C(*N=*c(cc1)ccc1C(**)=N)C=C Chemical compound CC(CC(N*)=N)=CC=C(*N=*c(cc1)ccc1C(**)=N)C=C 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
Abstract
The invention discloses a kind of three nitrogen amidine amides compounds and preparation method thereof, three nitrogen amidines first are added in reaction system by certain mol proportion with acyl chloride compound and are mixed, organic solvent is added, obtains three nitrogen amidine amides compound crude products in a heated condition, sterling is obtained after removing solvent.The advantage of the invention is that it reduces three nitrogen amidine toxic side effects, the slow release effect of three nitrogen amidines, easy to operate in preparation method, safety are improved, without using extremely toxic substance, organic solvent usage amount is few, dissolvent residual is reduced to minimum, has the advantages that environmental protection, high income, at low cost.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a kind of preparation method of three nitrogen amidine amides compound.
Background technology
Three nitrogen amidines also known as Benny's that, chemical name 4,4'- (diazoamino) bis- (benzenecarboximidamides) belong to fragrant double amidine classes, are one
The kind anti-Blood protozoan medicine of wide spectrum.It is the DNA synthesis by selective exclusion trypanosomiasis and replicates, and generates irreversibility with core
In conjunction with, to make the kinetoplast of trypanosome disappear, can not schizogamy approach to reach treatment the Yi Shi caused by trypanosome
The purpose of trypanosomiasis and horse covering disease disease, but the substance toxic side effect is big, and slow release effect is poor, and bioavailability is low, in order to optimize
With its drug effect of improvement and raising bioavailability.The exploitation of novel three nitrogen amidine derivatization drug is of great significance and makes with wide
Use foreground.
Invention content
The purpose of the present invention is big for three nitrogen amidine toxic side effects, and slow release effect is poor, and the low disadvantage of bioavailability provides one kind
Three nitrogen amidine amide compounds and preparation method thereof.
Three nitrogen amidine amide compounds, the compound structure general expression is such as shown in (I)：
(I) R in, n range are as follows：
N=1~3.
The preparation method of three nitrogen amidine amides compounds：Three nitrogen amidines, acyl chloride compound (chlorobenzoyl chloride, to methylbenzene first
Acyl chlorides, 4- nitrobenzoyl chlorides, 3- nitrobenzoyl chlorides, 2- nitrobenzoyl chlorides, 2,4- dinitrobenzoyl chlorides, 2- pyridine first
Acyl chlorides, chloroacetic chloride, acryloyl chloride, cinnamoyl chloride etc.), by certain mol proportion (1：1~3) it is added in reaction system and mixes, be added
One or more of organic solvent mixture (n-hexane, hexamethylene, benzene,toluene,xylene, petroleum ether, ether, methyl- tert
Butyl ether, ethyl acetate, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes etc.), in heating or counterflow condition
Lower reaction obtains three nitrogen amidine amides compound crude products, sterling is obtained after boiling off solvent.
The present invention remarkable result be：The compounds of this invention overcomes that three nitrogen amidine toxic side effects are big, and slow release effect is poor, biology
The low disadvantage of utilization rate, preparation method have it is easy to operate, rapid reaction is fast, isolate and purify conveniently, safe operation process, environmental protection
And the characteristics of high income.
Specific implementation mode
It, below will be to the preferred reality of the present invention in order to keep the purpose of the present invention, technical solution and advantageous effect clearer
Example is applied to be described in detail.
Embodiment 1：4,4'- (1- triazenes -1,3-) tryptase benzamido hydrochloride (compound 1)
1 preparation method of compound of the present embodiment is：Be added in 100 milliliters of round-bottomed flask three nitrogen amidines (10mmol,
2.81g), chlorobenzoyl chloride (10mmol, 1.40g), 40mL acetonitriles, 83 DEG C react 3 days, after reaction, filter, solids second
Acetoacetic ester is eluted, and three nitrogen amidine benzamide products 1 are obtained.1H NMR(400MHz,DMSO-d6)δ9.34(s,3H),9.03(s,
3H),8.18(s,1H),7.90(d,5H),7.68(s,3H),3.72–3.70(m,1H),3.347(s,3H).13C NMR
(101MHz,DMSO-d6)δ171.89,170.04,165.21,130.26,129.72,41.04,40.56,40.35,40.14,
39.93,39.73,39.52,39.31,22.76。
Embodiment 2：4,4'- (1- triazenes -1,3-) tryptase -4- toluyl amido hydrochlorides (compound 2)
2 preparation method of compound of the present embodiment is：Be added in 100 milliliters of round-bottomed flask three nitrogen amidines (10mmol,
2.81g), Butyltriphenylphosphonium chloride (10mmol, 1.18g), 40mL acetonitriles, 83 DEG C react 3 days, after reaction, filter, solids
It is eluted with ethyl acetate, obtains three nitrogen amidines to toluyl amine product 2.1H NMR(400MHz,DMSO-d6)δ9.348(s,
3H), 9.02 (s, 3H), 8.19 (s, 1H), 7.92 (d, J=8.3Hz, 3H), 7.706 (s, 3H), 3.719-3.704 (m, 1H),
3.348 (s, 4H), 1.84 (d, J=3.7Hz, 3H)13C NMR(101MHz,DMSO-d6)δ171.91,170.03,130.28,
41.04,40.56,40.36,40.15,39.94,39.73,39.52,39.31,22.76。
Embodiment 3：4,4'- (1- triazenes -1,3-) tryptase -2,4- dinitrobenzamide base hydrochloride (chemical combination
Object 3)
3 preparation method of compound of the present embodiment is：Be added in 100 milliliters of round-bottomed flask three nitrogen amidines (10mmol,
2.81g), 2,4- dinitrobenzoyl chlorides (10mmol, 1.94g), 40mL acetonitriles, 83 DEG C react 3 days, after reaction, filter,
Solids is eluted with ethyl acetate, obtains three nitrogen amidines 2,4- dinitrobenzamides product 3.1H NMR(400MHz,DMSO-
d6) δ 9.36 (s, 3H), 9.12 (s, 3H), 8.19 (s, 1H), 7.92 (d, J=8.3Hz, 3H), 7.69 (s, 3H), 3.82-3.58
(m, 1H), 3.34 (s, 3H), 1.84 (d, J=3.7Hz, 3H)13C NMR(101MHz,DMSO-d6)δ40.57,40.36,
40.16,39.95,39.74,39.53,39.32。
Embodiment 4：4,4'- (1- triazenes -1,3-) tryptase -4- chloro-benzoyl aminos hydrochloride (compound 4)
4 preparation method of compound of the present embodiment is：Be added in 100 milliliters of round-bottomed flask three nitrogen amidines (10mmol,
2.81g), chlorobenzoyl chloride (10mmol, 1.38g), 40mL acetonitriles, 83 DEG C react 3 days, after reaction, filter, solids second
Acetoacetic ester is eluted, and three nitrogen amidine 4- chlorobenzoyls amine products 4 are obtained.1H NMR(400MHz,DMSO-d6)δ9.35(s,3H),
9.02(s,3H),8.189(s,1H),7.92(d,3H),7.589(s,4),3.719–3.705(m,1H),3.353(s,3H),13C
NMR(101MHz,DMSO-d6)δ171.90,170.04,165.20,130.27,40.57,40.36,40.15,39.94,
39.73,39.52,39.31,22.77。
Claims (3)
1. three nitrogen amidine amides compounds are it is characterized in that, the compound structure general expression such as (I) is shown：
(I) R in, n range are as follows：
N=1~3.
2. the preparation method of three nitrogen amidine amides compound as claimed in claim 1, it is characterized in that by three nitrogen amidification of substrate
After conjunction object is mixed with the amide compound of 1~3 times of amount molar ratio, one kind or several in a certain amount of following organic solvent is added
Kind, it is reacted under heating or counterflow condition, reaction temperature obtains three nitrogen amidine amides compound crude products within the scope of 0~120 DEG C, removes
After removing solvent, three nitrogen amidine amide sterlings are obtained.
3. the preparation method of three nitrogen amidine amides compound as claimed in claim 2, characterized in that the organic solvent
For：N-hexane, hexamethylene, benzene,toluene,xylene, petroleum ether, ether, methyl tertiary butyl ether(MTBE), ethyl acetate, acetonitrile, dichloromethane
Alkane, chloroform, carbon tetrachloride, 1,2- dichloroethanes.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013127780A1 (en) * | 2012-03-01 | 2013-09-06 | Syngenta Participations Ag | Chemical compounds |
| CN104610096A (en) * | 2013-11-05 | 2015-05-13 | 河南领先科技药业有限公司 | Diminazene aceturate production method |
| CN107043337A (en) * | 2016-02-05 | 2017-08-15 | 王志训 | A kind of preparation method of amidine derivative |
| JP2018030792A (en) * | 2016-08-23 | 2018-03-01 | 東ソー株式会社 | Method for producing triazine compound using amidine |
-
2018
- 2018-05-02 CN CN201810411103.5A patent/CN108484446A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013127780A1 (en) * | 2012-03-01 | 2013-09-06 | Syngenta Participations Ag | Chemical compounds |
| CN104610096A (en) * | 2013-11-05 | 2015-05-13 | 河南领先科技药业有限公司 | Diminazene aceturate production method |
| CN107043337A (en) * | 2016-02-05 | 2017-08-15 | 王志训 | A kind of preparation method of amidine derivative |
| JP2018030792A (en) * | 2016-08-23 | 2018-03-01 | 東ソー株式会社 | Method for producing triazine compound using amidine |
Non-Patent Citations (2)
| Title |
|---|
| BRAITHWAITE, ANTONY W ETAL: "Existence of an extended series of antitumor compounds which bind to deoxyribonucleic acid by nonintercalative means", 《BIOCHEMISTRY》 * |
| 四川医学院主编: "《药物化学》", 31 December 1981 * |
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Application publication date: 20180904 |