CN104478808A - Pharmaceutically acceptable salt of imidazole insectifuge as well as preparation method and application of salt - Google Patents
Pharmaceutically acceptable salt of imidazole insectifuge as well as preparation method and application of salt Download PDFInfo
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- CN104478808A CN104478808A CN201410737508.XA CN201410737508A CN104478808A CN 104478808 A CN104478808 A CN 104478808A CN 201410737508 A CN201410737508 A CN 201410737508A CN 104478808 A CN104478808 A CN 104478808A
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Abstract
The invention discloses a pharmaceutically acceptable salt of an imidazole insectifuge as well as a preparation method and application of the salt. The invention provides a novel compound (I) shown in the specification, wherein the compound (I) is an addition salt of a compound (II) and obtained by reacting the compound (II) with a pharmaceutically acceptable acid X in an organic solvent or a mixture of the organic solvent and water in the presence of a catalyst, and the compound (I) can be optically transformed into a hydrate. The compound (I) is simple in preparation process, high in yield and high in dissolution rate in water ethanol, so the effective compound is relatively good in bioavailability.
Description
Technical field
The invention belongs to medicinal chemistry art, particularly a kind of Anthelmintic imidazoles pharmaceutically acceptable salt and preparation method thereof and application.
Background technology
Early stage from the sixties in 20th century, since U.S.'s synthesis Thiabendazole, synthesize hundreds of Anthelmintic imidazoles.Thiabendazole was once widely used in all over the world, in order to drive away various animal (as ox, sheep, goat, pig, horse, fowl etc.) gastrointestinal parasite.At present, be other Anthelmintic imidazoles gradually---as albendazole, oxfendazole, fenbendazole, mebendazole, flubendazole etc. are replaced.The feature of this class medicine is that expelling parasite spectrum is wide, and anthelminthic effect is good, even also has certain to kill larva and worm's ovum effect.
Anthelmintic imidazoles is insoluble in water, slightly soluble in acetone, methyl alcohol, chloroform, only dissolves in formic acid and acetic acid.Because solvability is poor, cause Anthelmintic imidazoles bioavailability general not high.In addition, according to " serious adverse reaction of Anthelmintic imidazoles: observational study after listing " of " pharmacoepidemiology magazine " the 06th phase report in 2004, the serious adverse reaction of such medicine can relate to multiple organ and the system of whole body, front three is followed successively by nerve, skin allergy, blood etc., but the clinical application at home and abroad of such insect repellent is extensive, accounts for the first place (80 ~ 90%) of the insect repellent market share.Therefore, be necessary that Anthelmintic imidazoles pharmaceutically acceptable salt is prepared in exploitation, make it to increase solvability, improve bioavailability, reduce the dosage used, thus reduce the generation of untoward reaction, accomplish safe medication.
" auxiliary chemicals " one published in December, 2009 disclose a kind of synthesizing benzimidazole-2-Urethylane method in book, and briefly mention this substances soluble in the organic acid such as inorganic salt and acetic acid, and form corresponding salt, but saying is more general, there is no specific embodiment and preparation method, do not mention the purposes done so yet.
Summary of the invention
For the deficiencies in the prior art, the present invention's first object is to provide a kind of Anthelmintic imidazoles pharmaceutically acceptable salt, and the present invention's second object is to provide the preparation method of described salt, and the present invention's the 3rd object is to provide the application of described salt.
In order to realize above-mentioned first object, present invention employs following technical scheme:
A kind of Anthelmintic imidazoles pharmaceutically acceptable salt, it is characterized in that, its structure formula I is:
Wherein, in compound (Ι) R be rosickyite base, thiophenyl, benzoyl, to fluoro benzoyl, benzene sulfoxide group, propoxy-, butyl, to fluorobenzene sulphur ester group, preferred benzoyl, to fluoro benzoyl, propoxy-; X is acid.
As further improvement, described X is any one in Hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, trichoroacetic acid(TCA), trifluoroacetic acid, lactic acid, vitamin B13, aspartic acid, pamoic acid, glucose phosphate, Phosphoric acid glycerol esters, glactaric acid, 2-amino-ethyl sulfonic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, tartrate, toxilic acid, citric acid, xitix, oxalic acid, methylsulfonic acid, Phenylsulfonic acid and dextrocamphoric acid, any one in preferred methylsulfonic acid, sulfuric acid;
As further improvement, described Anthelmintic imidazoles pharmaceutically acceptable salt compound (Ι) can exist with the form of hydrate.
In order to realize above-mentioned second object, present invention employs following technical scheme:
The preparation method of a kind of Anthelmintic imidazoles as claimed in claim 1 pharmaceutically acceptable salt, it is characterized in that, compound (I) be by compound (II) in the mixture of organic solvent or organic solvent and water, in the presence of a catalyst, react with pharmaceutically acceptable sour X and change into its additive salt, and optionally compound (Ι) is changed into its hydrate;
The structural formula of compound (II) is:
Wherein, R be rosickyite base, thiophenyl, benzoyl, to fluoro benzoyl, benzene sulfoxide group, propoxy-, butyl, to any one in fluorobenzene sulphur ester group, preferred benzoyl, to any one in fluoro benzoyl, propoxy-.
As further improvement, the described Anthelmintic imidazoles pharmaceutically concrete preparation method of acceptable salt is:
A: drop into compound (II) in reactor, organic solvent or organic solvent and water, be warming up to backflow;
B: drip sour X and solvent solution, time for adding 0.5-1 hour;
C: drip and finish, insulation backflow 2-5 hour;
D: after insulation terminates, be cooled to less than 20 DEG C, suction filtration, organic solvent rinsing, dries
Described compound (II) is 1:1.2 ~ 2.0 with the molar ratio of sour X, and insulation reflux temperature is 50 ~ 120 DEG C; Described catalyzer is one or several the combination in pyridine, triethylamine, dimethylamine, DMF, DMAP; Catalyst levels is the 0.72%-1.83% of compound (II) quality; Solvent load is 2.8-7.8 times of compound (II) quality; In solvent, the mass ratio of organic solvent and water is: 1.6:1-56.3:1; In steps A, the consumption of organic solvent or organic solvent and water is 2.0-4.8 times of compound (II) quality; In step B, solvent load is 1.3-4.9 times of sour X quality.
As further improvement, described sour X is any one in Hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, trichoroacetic acid(TCA), trifluoroacetic acid, lactic acid, vitamin B13, aspartic acid, pamoic acid, glucose phosphate, Phosphoric acid glycerol esters, glactaric acid, 2-amino-ethyl sulfonic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, tartrate, toxilic acid, citric acid, xitix, oxalic acid, methylsulfonic acid, Phenylsulfonic acid and dextrocamphoric acid, any one in preferred methylsulfonic acid, sulfuric acid.
As further improvement, described solvent selected from methanol, ethanol, n-propyl alcohol, Virahol, acetone, butanone, ethyl acetate, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dioxane, chloroform, N, one or several combination in dinethylformamide, the combination of a kind of in preferred acetone, butanone or two kinds.
In order to realize above-mentioned 3rd object, present invention employs following technical scheme:
A kind of Anthelmintic imidazoles pharmaceutically acceptable salt with reasonably pharmaceutically acceptable pharmaceutical excipient for the preparation of the purposes of tablet, capsule, granule, pill, suspensoid, pre-mixture.
Adopt technical scheme provided by the invention, possess following beneficial effect:
(1) the invention provides novel compound (I)
(2) compound (Ι) preparation technology is simple, and yield is high;
(3) compound (Ι) solubleness in water, ethanol is about 6-10 doubly to formula II compound, and this higher solubility is significant, because it makes this active compound have preferably bioavailability.
Embodiment
The synthesis mechanism of the compounds of this invention (I) is: in the secondary amine in compound (I), in 1 lone electron pair of nitrogen and solution, hydrogen ion forms coordinate bond, is that acid ion in a kind of coordination ion and acid exists in solution and the salt that formed simultaneously.
The compound (I) of the present invention's synthesis is by being attached on tubulin, the formation of spindle body in interference mitotic division, cause cell mitogen normally not carry out, cause Chromosomal ploidy abnormal (aneuploid), thus reach the object of sterilization.
Below by specific embodiment, be described in detail the present invention, but the invention is not restricted to above-described embodiment, all any simple, equivalent variations of doing above-described embodiment according to technical spirit of the present invention or modification, all belong within the scope of the technology of the present invention.
Embodiment 1
The preparation of Vermox mesylate
50.00g Vermox (M is dropped in 500mL four-hole bottle
w=295.30g/mol), the acetone of 68.50g, 0.36g pyridine, 31.50g water, is warming up to backflow, drips 19.52g methylsulfonic acid (M
w=96.10g/mol) and the mixing solutions of 40.00g acetone, time for adding 0.5 hour, drips and finishes, and insulation backflow 4-5 hour, insulation terminates, and is cooled to less than 20 DEG C, suction filtration, Acetone rinse, dries to obtain white powder solid.Yield 94.85%, purity 99.30%, moisture content 4.4%, containing 1 crystal water.
Employing Perkin-Elmer PE2400 elemental analyser records results of elemental analyses and is: S measured by C:49.72, H:4.34, N:10.12, DIOENX-500 type ion chromatograph is 7.81.
According to 10 times that the solubleness of test determines Vermox mesylate in water and ethanol of solubleness in " Chinese Pharmacopoeia " 2010 editions is corresponding compound (II).
Embodiment 2
The preparation of Oxibendazole vitriol
30.00g Oxibendazole (M is dropped in 500mL four-hole bottle
w=249.27g/mol), 144.00g Virahol, the DMAP of 0.55g, is warming up to backflow, drips 18.37g sulfuric acid (M
w=98.08g/mol) and the mixing solutions of 90.00g water, time for adding 1 hour, drips and finishes, and insulation backflow 2 hours, insulation terminates, and is cooled to less than 20 DEG C, suction filtration, isopropyl alcohol, dries to obtain light yellow solid.Yield 92.2%, purity 99.5%.
Perkin-Elmer PE2400 elemental analyser is adopted to record results of elemental analyses: S measured by C:41.53, H:4.87, N:12.15, DIOENX-500 type ion chromatograph is 9.18.
According to 6 times that the solubleness of test determines Oxibendazole vitriol in water and ethanol of solubleness in " Chinese Pharmacopoeia " 2010 editions is corresponding compound (II).
Embodiment 3
The preparation of Flubendazole mesylate
50.00g Flubendazole (M is dropped in 500mL four-hole bottle
w=313.28g/mol), the ethanol of 157.00g, 0.40g triethylamine, 3.50g water, is warming up to backflow, drips 30.70g methylsulfonic acid (M
w=96.10g/mol) and the mixing solutions of 40.00g ethanol, time for adding 0.5 hour, drips and finishes, and insulation backflow 4-5 hour, insulation terminates, and is cooled to less than 20 DEG C, suction filtration, ethanol rinse, dries to obtain white powder solid.Yield 92.65%, purity 98.30%, moisture content 3.7%, containing 1 crystal water.
Employing Perkin-Elmer PE2400 elemental analyser records results of elemental analyses and is: S measured by C:47.81, H:4.33, N:9.68, DIOENX-500 type ion chromatograph is 7.51.
According to 7.5 times that the solubleness of test determines Vermox mesylate in water and ethanol of solubleness in " Chinese Pharmacopoeia " 2010 editions is corresponding compound (II).
Claims (10)
1. an Anthelmintic imidazoles pharmaceutically acceptable salt, it is characterized in that, its structural formula is:
Wherein, in compound (Ι), R is rosickyite base, thiophenyl, benzoyl, to fluoro benzoyl, benzene sulfoxide group, propoxy-, butyl, to fluorobenzene sulphur ester group, X is acid.
2. Anthelmintic imidazoles pharmaceutically acceptable salt as claimed in claim 1, is characterized in that,
X is any one in Hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, trichoroacetic acid(TCA), trifluoroacetic acid, lactic acid, vitamin B13, aspartic acid, pamoic acid, glucose phosphate, Phosphoric acid glycerol esters, glactaric acid, 2-amino-ethyl sulfonic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, tartrate, toxilic acid, citric acid, xitix, oxalic acid, methylsulfonic acid, Phenylsulfonic acid and dextrocamphoric acid, and Anthelmintic imidazoles pharmaceutically acceptable salt compound (Ι) can exist with the form of hydrate.
3. Anthelmintic imidazoles pharmaceutically acceptable salt as claimed in claim 1, is characterized in that, R is benzoyl, to any one in fluoro benzoyl, propoxy-, and X is any one in methylsulfonic acid, sulfuric acid.
4. the preparation method of an Anthelmintic imidazoles as claimed in claim 1 pharmaceutically acceptable salt, it is characterized in that, compound (I) be by compound (II) in the mixture of organic solvent or organic solvent and water, in the presence of a catalyst, react with pharmaceutically acceptable sour X and change into its additive salt, and optionally compound (Ι) is changed into its hydrate;
The structural formula of compound (II) is:
Wherein, R be rosickyite base, thiophenyl, benzoyl, to fluoro benzoyl, benzene sulfoxide group, propoxy-, butyl, to fluorobenzene sulphur ester group.
5. the preparation method of Anthelmintic imidazoles as claimed in claim 4 pharmaceutically acceptable salt, it is characterized in that, its concrete preparation method is:
A: drop into compound (II) in reactor, organic solvent or organic solvent and water, be warming up to backflow;
B: the mixing solutions dripping sour X and solvent, time for adding 0.5-1 hour;
C: drip and finish, insulation backflow 2-5 hour, insulation terminates;
D: be cooled to less than 20 DEG C, suction filtration, organic solvent rinsing, dries
Described compound (II) is 1:1.2 ~ 2.0 with the molar ratio of sour X, and insulation reflux temperature is 50 ~ 120 DEG C; Described catalyzer is one or several the combination in pyridine, triethylamine, dimethylamine, DMF, DMAP, and catalyst levels is the 0.72%-1.83% of compound (II) quality; Solvent load is 2.8-7.8 times of compound (II) quality; In solvent, the mass ratio of organic solvent and water is: 1.6:1-56.3:1; In steps A, the consumption of organic solvent or organic solvent and water is 2.0-4.8 times of compound (II) quality; In step B, solvent load is 1.3-4.9 times of sour X quality.
6. the preparation method of the pharmaceutically acceptable salt of the Anthelmintic imidazoles as described in claim 4 or 5, it is characterized in that, sour X is any one in Hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, trichoroacetic acid(TCA), trifluoroacetic acid, lactic acid, vitamin B13, aspartic acid, pamoic acid, glucose phosphate, Phosphoric acid glycerol esters, glactaric acid, 2-amino-ethyl sulfonic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, tartrate, toxilic acid, citric acid, xitix, oxalic acid, methylsulfonic acid, Phenylsulfonic acid and dextrocamphoric acid.
7. the preparation method of the pharmaceutically acceptable salt of the Anthelmintic imidazoles as described in claim 4 or 5; it is characterized in that; R is benzoyl in compound (II), to any one in fluoro benzoyl, propoxy-, described pharmaceutically acceptable sour X is any one in methylsulfonic acid, sulfuric acid.
8. the preparation method of the pharmaceutically acceptable salt of the Anthelmintic imidazoles as described in claim 4 or 5, it is characterized in that, organic solvent is selected from one or several the combination in methyl alcohol, ethanol, n-propyl alcohol, Virahol, acetone, butanone, ethyl acetate, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dioxane, chloroform, DMF.
9. the preparation method of the pharmaceutically acceptable salt of the Anthelmintic imidazoles as described in claim 4 or 5, is characterized in that, organic solvent is selected from the combination of a kind of in acetone, butanone or two kinds.
10. the Anthelmintic imidazoles as described in any one of claim 1 to 9 pharmaceutically acceptable salt with reasonably pharmaceutically acceptable pharmaceutical excipient for the preparation of the purposes of tablet, capsule, granule, pill, suspensoid, pre-mixture.
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| CN1419450A (en) * | 2000-01-26 | 2003-05-21 | 尼科克斯公司 | Nitrite salts of antimicrobial agents |
| CN1582925A (en) * | 2003-08-19 | 2005-02-23 | 王玉万 | Powder injection of benzimidazole hydrochloride, etc. for animals |
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| WO2011041914A1 (en) * | 2009-10-09 | 2011-04-14 | University Health Network (Uhn) | Use of flubendazole and vinca alkaloids for treatment of hematological diseases |
| CN103601685A (en) * | 2013-12-05 | 2014-02-26 | 常州亚邦齐晖医药化工有限公司 | Preparation method of oxibendazole |
-
2014
- 2014-12-05 CN CN201410737508.XA patent/CN104478808A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1419450A (en) * | 2000-01-26 | 2003-05-21 | 尼科克斯公司 | Nitrite salts of antimicrobial agents |
| CN1376467A (en) * | 2001-03-26 | 2002-10-30 | 王玉万 | Veterinary medicine containing oxfendazole |
| CN1582925A (en) * | 2003-08-19 | 2005-02-23 | 王玉万 | Powder injection of benzimidazole hydrochloride, etc. for animals |
| CN1966495A (en) * | 2006-09-15 | 2007-05-23 | 常州亚邦齐晖医药化工有限公司 | Method for preparing 5-(4- fluobenzene sulphonyloxy) benzimidazole-2-amido methyl formate |
| WO2011041914A1 (en) * | 2009-10-09 | 2011-04-14 | University Health Network (Uhn) | Use of flubendazole and vinca alkaloids for treatment of hematological diseases |
| CN103601685A (en) * | 2013-12-05 | 2014-02-26 | 常州亚邦齐晖医药化工有限公司 | Preparation method of oxibendazole |
Non-Patent Citations (11)
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