CN102617485A - Preparation method for water-soluble derivative of trimethoprim - Google Patents
Preparation method for water-soluble derivative of trimethoprim Download PDFInfo
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- CN102617485A CN102617485A CN2012100708073A CN201210070807A CN102617485A CN 102617485 A CN102617485 A CN 102617485A CN 2012100708073 A CN2012100708073 A CN 2012100708073A CN 201210070807 A CN201210070807 A CN 201210070807A CN 102617485 A CN102617485 A CN 102617485A
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Abstract
The invention relates to a preparation method for a water-soluble derivative of trimethoprim, which includes the steps: firstly, leading cinnamyl aldehyde to react with sodium hydrogen sulfite to prepare 1-hydroxy-3-phenyl-1, 3-propane disulfonic acid, then leading an intermediate product to react with the trimethoprim, and subjecting obtained reactant solution to cooling in added low-temperature ethanol, filtering, drying or direct spray drying so that a target product compound (I), namely the water-soluble derivative of the trimethoprim is prepared and is soluble in water under the neutral or alkaline conditions, and water solution can be stably stored. The water solution can be taken orally conveniently, or prepared with sulfonamide or antibiotic alkali metal salt to water solution for use.
Description
Technical field
The present invention relates to 5-(3; 4; 5-trimethoxy benzyl)-2; The preparation method of a kind of soluble derivative of 4-di-amino-pyrimidine (be called for short trimethoxy benzylamino pyrimidine, or be abbreviated as TMP) is particularly as the preparation method of the soluble derivative of the trimethoxy benzylamino pyrimidine of sulfa drugs and microbiotic synergistic agent.
Background technology
Trimethoxy benzylamino pyrimidine (TMP) is the compound that is applied to treat positive and negative gram-bacteria, and this compound can use separately, more commonly with other active substances (like sulfa drugs or microbiotic) compatibility, makes pharmaceutical prod.TMP and sulfa drugs or microbiotic compatibility use, and through synergy, can strengthen the activity of single active substance, also can enlarge antimicrobial spectrum.Therefore, TMP is usually as sulfa drugs and antibiotic synergistic agent.
TMP and sulfa drugs compatibility use application wider.CN1246336A discloses a kind of medicine of treating chicken leucocyte protozoon, is that 20～30% sulfamethoxazole, 3～7% TMP, 1～3% Pyrimethamine hcl and 60～70% starch complex form by mass fraction.CN1233467A discloses a kind of anticoccidial medicament; Using mass fraction is 9.0～11.0% sulphamethazine and 1.0～1.5% TMP compatibility; Though this medicament is soluble in water; But wherein added 40.0～45.0% solubility promoter, institute adds solubility promoter has sodium hydroxide, Sulfothiorine, industrial spirit, Ucar 35.CN1651072A discloses a kind of medicine of treating baby pig diarrhoea, and to use mass fraction be 2～10% TMP and 15～40% sulfamethoxazole compatibility use.This drug use is inconvenient, need be applied on the pig root of the tongue or the filling clothes.Relevant trimethoxy benzylamino pyrimidine is described in detail in the 3rd section of patent document CN1651072A Instructions Page 3 has write up, the application to quote CN1651072A full text technology as a setting.CN101468025A discloses a kind of soluble powder that is used to prevent and treat avian escherichia coli, comprises Prinzone (Squibb), 2% TMP and 88% the glucose of mass fraction 10%, adopt raw material pulverizing after the blended mode prepare.CN101468027A discloses a kind of soluble powder that is used to prevent and treat coccidiosis of livestock and poultry, comprises Sulfaquinoxaline Sodium CP2000,5% TMP and 80% the glucose of mass fraction 15%, carries out the blending means preparation again after adopting raw material pulverizing.TMP also is used for using with other microbiotic compatibilities.CN1086944C has opened a kind of composition for treating and preventing coccidiosis of chicken, mainly directly is mixed by the TMP of the tetramycin hydrochloride of mass fraction 80% and 20% and processes, and uses as spice.
It is thus clear that TMP is a kind of widely used Trimethoprim, can use with a variety of compatibility of drugs, to reduce the resistance of single medicine.But the solubleness of TMP in water is very little and the sulfa drugs compatibility when using the available formulation be restricted.TMP and sulfa drugs or antibiotic pharmaceutical prod often will be with the forms of the aqueous solution, through directly oral, be diluted in the beverage mode oral or injection and use.Generally, often contain a lot of polyprotonic acids in the water-soluble TMP product, like L-glutamic acid, aspartic acid, lactic acid etc., these acid and TMP salify in the aqueous solution.CN1542003A discloses a kind of TMP mineral acid or organic acid verivate, and to improve the solubleness of TMP, the suitable formulation of preparation is satisfied the demand.PH value after lactic acid TMP soluble powder commonly used at present is water-soluble is 4.0～6.0.This lactic acid TMP can use with acid proof microbiotic compatibility; A kind of medicine of treating chicken and pig Mycoplasma and other bacteria mixed infections is disclosed like CN1915229A; Form by the florfenicol of mass fraction 5～15%, 5～15% fumaric acid tiamulin, 5～15% Vibramycin hydrochloride and 5～10% lactic acid TMP; Add 30% vehicle in addition, directly mixed.And that sulfa drugs adopts the form that forms sodium salt to improve usually is water-soluble, and soluble sulfa drugs is generally alkalescence, is 7.2～9.2 like the pH value of water solution of Prinzone (Squibb), and the pH value of water solution of Sulfaquinoxaline Sodium CP2000 is 9.0～10.0.Dual decomposition reaction can take place in the compsn of the sodium salt compatibility of the mineral acid of TMP or organic acid salt and sulfamido formation like this, forms deposition, makes these compatibility products not use with the mode of the aqueous solution, has limited the formulation of product.
Summary of the invention
In order to overcome the deficiency of prior art, the present invention provide a kind of can stable existence under neutrality or the alkaline condition, in the preparation method of pH soluble derivative of soluble trimethoxy benzylamino pyrimidine (being TMP) in 7～10 water.The products obtained therefrom soluble derivative can use with the sulfanilamide (SN) or the antibiotic salt compatibility of alkalescence, uses with oral or injection injection system.
The term explanation:
5-(3,4, the 5-trimethoxy) benzyl-2, the 4-di-amino-pyrimidine is called for short trimethoxy benzylamino pyrimidine, is abbreviated as TMP.
Technical scheme of the present invention is following:
The preparation method of a kind of formula (I) compound, said compound has the structure shown in the formula (I):
Step is following:
(1) under the room temperature phenylacrolein and sodium sulfite anhy 96 are added to the water, stir 1～2h, obtain shallow white solution; Add ethanol; Produce throw out, using mass ratio is 1: 1 water and alcoholic acid solution washing 3～5 times, must white solid after the drying; Be compound 1-hydroxyl-3-phenyl-1,3-sodium disulfonate propane; Reaction formula is following:
(2) with 1-hydroxyl-3-phenyl-1,3-sodium disulfonate propane is soluble in water, adds trimethoxy benzylamino pyrimidine (TMP); Trimethoxy benzylamino pyrimidine and 1-hydroxyl-3-phenyl-1,3-sodium disulfonate propane is 1: 2～2.5 in molar ratio, is warming up to 50～60 ℃ trimethoxy benzylamino pyrimidine is dissolved fully; Continue heating 0.5～1h then, get milky solution, with this solution cooling; Filter, get settled solution.Reaction formula is following:
(3) step (2) gained settled solution is spray dried to powder, gets product compound (I); Perhaps,
In step (2) gained settled solution, add temperature and make deposition fully,, promptly get product compound (I) again with precipitate and separate, drying at 0 ℃ ethanol.
Products obtained therefrom compound (I) is the soluble derivative of trimethoxy benzylamino pyrimidine, is the white or the slightly flaxen powder of crystal form, dissolves in the water of pH=7～10, is insoluble to ethanol, EC.
According to the present invention, preferred, the phenylacrolein in the step (1) and the feed ratio of sodium sulfite anhy 96 are 1: 2～2.2 mol ratios.
According to the present invention, preferred, trimethoprim and 1-hydroxyl-3-phenyl-1 in the step (2), the feed ratio that 3-sodium disulfonate propane is represented by mole is 1: 2～2.5.
According to the present invention, preferred, the drying cost that step (3) employing precipitate and separate method obtains product is lower.
The content of TMP is 30～31wt% in the products therefrom according to the method for the invention, and target compound (I) content is 98～99%.Productive rate 95～97%.
The present method in common of the employing of TMP content detection, the method for promptly deciding TMP with the perchloric acid titration drop, experiment records that TMP content is about 30～31wt% in this verivate, and converting and obtaining compound (I) content is 98～99%.The detection spectrogram of the ir spectra of product and nuclear magnetic resonance spectrum is seen Fig. 1 and Fig. 2.
The TMP verivate that the present invention makes is solvable in 7～10 neutrality and the alkaline water at pH; Concentration is not higher than under 60% the condition; The resulting aqueous solution can be stablized and deposits at least one year never degenerate; This soltion viscosity is not high, and taking orally is used, and perhaps it is mixed with the aqueous solution with sulfa drugs or antibiotic an alkali metal salt and uses.
Excellent results compared with prior art of the present invention is following:
1, the product compound of the present invention preparation, provide first a kind of under neutrality or alkaline condition TMP verivate soluble in water, can with the sulfanilamide (SN) or the antibiotic salt compatibility of alkalescence, with oral way or with the form infusion application of the aqueous solution.
2, the present invention uses sodium sulfite anhy 96; Can significantly improve compound 1-hydroxyl-3-phenyl-1; The productive rate and the purity of 3-sodium disulfonate propane; Widened the water-soluble pH scope of ultimate aim thing, therefore expanded can with the range of application of the sulfa drugs or the microbiotic aqueous solution of alkali metal salt of its compatibility.
3, the present invention uses sodium sulfite anhy 96 to prepare intermediate product (II) can at room temperature to carry out, and need not heating, and simple to operate, save energy, cost reduce, and are more suitable for suitability for industrialized production.
4, do not need nitrogen protection in the TMP derivative preparation method spraying drying of the present invention, equipment is simple, cost reduces, and is more suitable for suitability for industrialized production.
5, use the inventive method can prepare highly purified TMP soluble derivative with high yield, i.e. compound (I).Products obtained therefrom purity of the present invention is not less than 98.0%, productive rate 95～97%.
Description of drawings
Fig. 1 is the ir spectra spectrogram of the product of embodiment 1.Fig. 2 is the carbon-13 nmr spectra of the product of embodiment 1.
Embodiment
Below in conjunction with specific embodiment the present invention is further specified, but be not limited thereto.The method that general perchloric acid titration drop is decided TMP is adopted in the detection of product TMP content among the embodiment.
(1) sodium sulfite anhy 96 with 80.0g phenylacrolein and 126.1g at room temperature is dissolved in the water of 500mL, stirs 1～2h, obtains shallow white solution; Add ethanol, system produces throw out, and using mass ratio is 1: 1 water and ethanol mixed solvent washing precipitate 3～5 times; Get the about 200g of white solid after the drying; Be compound (II), 1-hydroxyl-3-phenyl-1,3-sodium disulfonate propane;
(2) will go up the dried white solid thing of a step gained; Be compound (II) 1-hydroxyl-3-phenyl-1,3-sodium disulfonate propane 100.0g is dissolved in the 150mL water, adds 42.7g TMP; Be heated to 55 ℃ and dissolve fully, continue the mixture 1h of reacting by heating thing then until TMP.Obtained milky solution like this, cooling is filtered and is made the solution clarification;
(3) at last the solution spray that obtains is dried to powder.Obtain the 131.9g product, productive rate is 96%.
Products obtained therefrom is the soluble derivative with TMP of formula (I) structure.The ir spectra spectrogram is as shown in Figure 1, and carbon-13 nmr spectra is as shown in Figure 2.
Products obtained therefrom is the crystalline powder of white, and the solubleness in water can reach 66.3%, and pH value of aqueous solution is 7.72.Be insoluble to ethanol, EC.TMP content is 30.8% in the product, and converting and obtaining derivative content is 99.0%; Fusing point: 246 ℃～248 ℃, this compound decomposes under this temperature simultaneously.
Stability experiment: 1 year no change of normal temperature held, powder flowbility is fine, the product content no change.
Embodiment 2. is like embodiment 1 described preparation method, and different is:
Spray-drying process is not adopted in final step (3), but at 0 ℃ ethanol product is precipitated out through in the gained settled solution, adding the 250mL temperature, separates drying again and obtains product.Obtain the water-soluble TMP sodium salt derivative of 130.5g, productive rate 95% with structure (I).Product is the crystalline powder of white, is that solubleness is 65.2% in the aqueous solution under 9 alkaline conditions in the pH value.1 year no change of normal temperature held, powder flowbility is fine, the product content no change.
Embodiment 3.
Compound (II), i.e. 1-hydroxyl-3-phenyl-1, the preparation of 3-sodium disulfonate propane is with embodiment 1 step (1).
With 110.0g 1-hydroxyl-3-phenyl-1,3-sodium disulfonate propane is dissolved in the 150mL water, adds 42.7g TMP; Being heated to 60 ℃ dissolves until TMP fully; Continue the mixture 50min of reacting by heating thing then, get milky white solution, cooling; Filtration makes the solution clarification, at last the settled solution that obtains is spray dried to powder.Obtain the 133.3g product, productive rate is 97%.TMP content is 30.4% in the gained verivate, and converting and obtaining derivative content is 98.0%, products obtained therefrom purity 98.0%.Product is the crystalline powder of white, is that solubleness is 65.2% in the aqueous solution under 9 alkaline conditions in the pH value.1 year no change of normal temperature held, powder flowbility is fine, the product content no change.
Claims (4)
1. the preparation method of a formula (I) compound,
Step is following:
(1) under the room temperature phenylacrolein and sodium sulfite anhy 96 are added to the water, stir 1～2h, obtain shallow white solution; Add ethanol; Produce throw out, using mass ratio is 1: 1 water and alcoholic acid solution washing 3～5 times, must white solid after the drying; Be compound 1-hydroxyl-3-phenyl-1,3-sodium disulfonate propane; Reaction formula is following:
(2) with 1-hydroxyl-3-phenyl-1,3-sodium disulfonate propane is soluble in water, adds trimethoxy benzylamino pyrimidine (TMP); TMP and 1-hydroxyl-3-phenyl-1,3-sodium disulfonate propane is 1: 2～2.5 in molar ratio, is warming up to 50～60 ℃ TMP is dissolved fully; Continue heating 0.5～1h then, get milky solution, with this solution cooling; Filter, get settled solution; Reaction formula is following:
(3) step (2) gained settled solution is spray dried to powder, gets product compound (I); Perhaps,
In step (2) gained settled solution, add temperature and make deposition fully,, promptly get product compound (I) again with precipitate and separate, drying at 0 ℃ ethanol;
Products obtained therefrom compound (I) is the powder of crystal form, dissolves in the water of pH=7～10, is insoluble to ethanol, EC.
2. the preparation method of compound as claimed in claim 1 is characterized in that phenylacrolein and the feed ratio of sodium sulfite anhy 96 in the step (1) is 1: 2～2.2 mol ratios.
3. the preparation method of compound as claimed in claim 1 is characterized in that trimethoxy benzylamino pyrimidine and 1-hydroxyl-3-phenyl-1 in the step (2), and the feed ratio that 3-sodium disulfonate propane is represented by mole is 1: 2～2.5.
4. the preparation method of compound as claimed in claim 1 is characterized in that, the content of TMP is 30～31wt% in the products therefrom, and target compound (I) content is 98～99%.
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| CN 201110073461 CN102180839A (en) | 2011-03-25 | 2011-03-25 | Water-soluble trimethoprim derivative and preparation method thereof |
| CN2012100708073A CN102617485A (en) | 2011-03-25 | 2012-03-16 | Preparation method for water-soluble derivative of trimethoprim |
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| CN115785718A (en) * | 2022-11-25 | 2023-03-14 | 四川大学 | Metal coordination antibacterial coating with multiple substrate surfaces and preparation method thereof |
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| CN103601688A (en) * | 2013-11-25 | 2014-02-26 | 四川大学 | Synthetic method of trimethoprim impurity |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH654300A5 (en) * | 1983-05-06 | 1986-02-14 | Massague Vendrell Antonio J | Water-soluble derivative of 2,4-diamino-5-((3,4,5-trimethoxyphenyl)methyl)pyrimidine and processes for the manufacture of this derivative |
| ES2007537A6 (en) * | 1988-07-21 | 1989-06-16 | Cenavisa S A | Sulpha methoxy- pyridazine and sulpha-methoxazole deriv. prepn. |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH654300A5 (en) * | 1983-05-06 | 1986-02-14 | Massague Vendrell Antonio J | Water-soluble derivative of 2,4-diamino-5-((3,4,5-trimethoxyphenyl)methyl)pyrimidine and processes for the manufacture of this derivative |
| ES2007537A6 (en) * | 1988-07-21 | 1989-06-16 | Cenavisa S A | Sulpha methoxy- pyridazine and sulpha-methoxazole deriv. prepn. |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115785718A (en) * | 2022-11-25 | 2023-03-14 | 四川大学 | Metal coordination antibacterial coating with multiple substrate surfaces and preparation method thereof |
| CN115785718B (en) * | 2022-11-25 | 2023-08-22 | 四川大学 | Metal coordination antibacterial coating on multi-substrate surface and preparation method thereof |
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Application publication date: 20120801 |