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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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical class COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 title abstract description 6
- 239000000047 product Substances 0.000 claims abstract description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims abstract description 9
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 7
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 claims abstract description 6
- 238000001816 cooling Methods 0.000 claims abstract description 5
- 238000001914 filtration Methods 0.000 claims abstract description 5
- 238000001694 spray drying Methods 0.000 claims abstract description 5
- 239000000843 powder Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002244 precipitate Substances 0.000 claims description 9
- YPKOTWSAVCIFAM-UHFFFAOYSA-N [Na].CCC Chemical compound [Na].CCC YPKOTWSAVCIFAM-UHFFFAOYSA-N 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- CFYSVTOSOGSISU-UHFFFAOYSA-N COC1=C(N=C(N=C1OC)NCC2=CC=CC=C2)OC Chemical compound COC1=C(N=C(N=C1OC)NCC2=CC=CC=C2)OC CFYSVTOSOGSISU-UHFFFAOYSA-N 0.000 claims description 6
- AJZPCJPVGDXYNO-UHFFFAOYSA-N COC1=CC=CC=C1C(C2=NC(=NC=C2)N)(OC)OC Chemical compound COC1=CC=CC=C1C(C2=NC(=NC=C2)N)(OC)OC AJZPCJPVGDXYNO-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 229940117916 cinnamic aldehyde Drugs 0.000 claims description 5
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 229940124530 sulfonamide Drugs 0.000 abstract description 13
- 150000003456 sulfonamides Chemical class 0.000 abstract description 7
- 239000013067 intermediate product Substances 0.000 abstract description 6
- -1 alkali metal salt Chemical class 0.000 abstract description 4
- 230000003115 biocidal effect Effects 0.000 abstract description 4
- 230000007935 neutral effect Effects 0.000 abstract description 4
- 229910052783 alkali metal Inorganic materials 0.000 abstract description 3
- 239000000376 reactant Substances 0.000 abstract description 3
- 229960001082 trimethoprim Drugs 0.000 abstract description 3
- DGPQHOUOLKPORQ-UHFFFAOYSA-N 1-hydroxy-3-phenylpropane-1,3-disulfonic acid Chemical compound OS(=O)(=O)C(O)CC(S(O)(=O)=O)C1=CC=CC=C1 DGPQHOUOLKPORQ-UHFFFAOYSA-N 0.000 abstract 1
- 229940079827 sodium hydrogen sulfite Drugs 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 18
- 239000003814 drug Substances 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 11
- 239000003242 anti bacterial agent Substances 0.000 description 8
- 229940088710 antibiotic agent Drugs 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 8
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 6
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 235000014655 lactic acid Nutrition 0.000 description 4
- 239000004310 lactic acid Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- 241000287828 Gallus gallus Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000001294 propane Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 208000003495 Coccidiosis Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 206010023076 Isosporiasis Diseases 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- ODWMXYHUKDMPTR-UHFFFAOYSA-N sodium;(4-aminophenyl)sulfonyl-(6-chloropyridazin-3-yl)azanide Chemical compound [Na+].C1=CC(N)=CC=C1S(=O)(=O)[N-]C1=CC=C(Cl)N=N1 ODWMXYHUKDMPTR-UHFFFAOYSA-N 0.000 description 2
- WXUQBKOBXREBBX-UHFFFAOYSA-N sodium;(4-aminophenyl)sulfonyl-quinoxalin-2-ylazanide Chemical compound [Na+].C1=CC(N)=CC=C1S(=O)(=O)[N-]C1=CN=C(C=CC=C2)C2=N1 WXUQBKOBXREBBX-UHFFFAOYSA-N 0.000 description 2
- 229960005404 sulfamethoxazole Drugs 0.000 description 2
- 229960003264 sulfaquinoxaline sodium Drugs 0.000 description 2
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 description 1
- PTNZGHXUZDHMIQ-UHFFFAOYSA-N 4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2C(C)C(C(O)C3C(C(O)=C(C(N)=O)C(=O)C3N(C)C)(O)C3=O)C3=C(O)C2=C1O PTNZGHXUZDHMIQ-UHFFFAOYSA-N 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 230000001165 anti-coccidial effect Effects 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960004082 doxycycline hydrochloride Drugs 0.000 description 1
- YXQXDXAHCSEVSD-GCYNEOGWSA-N dynamutilin Chemical compound OC(=O)\C=C\C(O)=O.CCN(CC)CCSCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 YXQXDXAHCSEVSD-GCYNEOGWSA-N 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960003760 florfenicol Drugs 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229960004368 oxytetracycline hydrochloride Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 150000007519 polyprotic acids Polymers 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- WKSAUQYGYAYLPV-UHFFFAOYSA-N pyrimethamine Chemical compound CCC1=NC(N)=NC(N)=C1C1=CC=C(Cl)C=C1 WKSAUQYGYAYLPV-UHFFFAOYSA-N 0.000 description 1
- 229960000611 pyrimethamine Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960002135 sulfadimidine Drugs 0.000 description 1
- ASWVTGNCAZCNNR-UHFFFAOYSA-N sulfamethazine Chemical compound CC1=CC(C)=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 ASWVTGNCAZCNNR-UHFFFAOYSA-N 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229940092292 tiamulin fumarate Drugs 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
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 invention relates to a preparation method of a water-soluble derivative of 5- (3, 4, 5-trimethoxybenzyl) -2, 4-diaminopyrimidine (trimethoxybenzylaminopyrimidine for short or TMP for short), in particular to a preparation method of a water-soluble derivative of trimethoxybenzylaminopyrimidine as a synergist of sulfonamides and antibiotics.
Background
Trimethoxy benzylaminopyrimidine (TMP) is a compound applied to treatment of positive and negative gram bacteria, can be used alone, and is more commonly matched with other active substances (such as sulfonamides or antibiotics) to prepare a medical product. TMP is compatible with sulfanilamide drugs or antibiotics, and can enhance the activity of a single active substance and expand the antibacterial spectrum through synergistic action. Thus, TMP is often used as a potentiator for sulfonamides and antibiotics.
The compatibility and application of TMP and sulfanilamide medicines are wide. CN1246336A discloses a medicine for treating chicken leucocyte protozoon, which is prepared by compounding 20-30% of sulfamethoxazole, 3-7% of TMP, 1-3% of pyrimethamine and 60-70% of starch in parts by weight. CN1233467A discloses an anticoccidial drug, which is prepared by mixing 9.0-11.0% by weight of sulfadimidine and 1.0-1.5% by weight of TMP, wherein the drug is easy to dissolve in water, but 40.0-45.0% by weight of cosolvent is added, and the cosolvent is sodium hydroxide, sodium thiosulfate, industrial alcohol and propylene glycol. CN1651072A discloses a medicine for treating piglet diarrhea, which is prepared by using 2-10% of TMP and 15-40% of sulfamethoxazole in a compatible manner. The medicine is inconvenient to use, and needs to be applied to the root of the pig tongue or drenched. The detailed description of trimethoxybenzylaminopyrimidine is described in detail in the specification of patent document CN1651072A, page 3, third paragraph, and this application refers to CN1651072A as background technology in its entirety. CN101468025A discloses soluble powder for preventing and treating avian escherichia coli, which comprises 10% of sulfachlorpyridazine sodium, 2% of TMP and 88% of glucose in parts by weight, and is prepared by crushing and mixing raw materials. CN101468027A discloses soluble powder for preventing and treating coccidiosis of livestock and poultry, which comprises 15% of sulfaquinoxaline sodium, 5% of TMP and 80% of glucose in parts by weight, and is prepared by a mixing method after raw materials are crushed. TMP is also used in combination with other antibiotics. CN1086944C discloses a chicken coccidiosis control composition, which is mainly prepared by directly mixing 80% of oxytetracycline hydrochloride and 20% of TMP in parts by weight, and is used as a stirring material.
Thus, TMP is an antibacterial synergist widely applied and can be used together with various medicines to reduce the drug resistance of a single medicine. However, TMP has a low solubility in water and is limited in the formulation that can be used with sulfonamides. Pharmaceutical products of TMP with sulfonamides or antibiotics are often administered in aqueous solution, either orally, by direct oral dilution in a beverage, or by injection. Generally, water-soluble TMP products often contain many polybasic acids such as glutamic acid, aspartic acid, lactic acid, etc., which form salts with TMP in aqueous solution. CN1542003A discloses a derivative of inorganic or organic acid of TMP to improve the solubility of TMP and prepare a suitable formulation to meet the need. The pH value of the conventional lactic acid TMP soluble powder dissolved in water is 4.0-6.0. The lactic acid TMP can be used together with acid-resistant antibiotics, for example, CN1915229A discloses a medicine for treating mixed infection of chicken and pig mycoplasma and other bacteria, which is prepared by the following steps of 5-15% of florfenicol, 5-15% of tiamulin fumarate, 5-15% of doxycycline hydrochloride and 5-10% of lactic acid TMP in parts by weight, and in addition, 30% of excipient is added and directly mixed. The water solubility of the sulfa drugs is improved by adopting a sodium salt forming form, and the soluble sulfa drugs are alkaline, such as the pH value of an aqueous solution of sulfachlorpyridazine sodium is 7.2-9.2, and the pH value of an aqueous solution of sulfaquinoxaline sodium is 9.0-10.0. The compound formed by the compatibility of inorganic acid or organic acid salt of TMP and sodium salt of sulfanilamide has double decomposition reaction to form precipitate, so that the compatible product can not be used in the form of aqueous solution, and the dosage form of the product is limited.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a preparation method of a water-soluble derivative of trimethoxy benzyl aminopyrimidine (TMP) which can stably exist under neutral or alkaline conditions and is soluble in water with the pH value of 7-10. The obtained water-soluble derivative can be used together with alkaline sulfanilamide or antibiotic salt, and can be applied in oral administration or injection.
Description of terms:
5- (3, 4, 5-trimethoxy) benzyl-2, 4-diaminopyrimidine, abbreviated to trimethoxybenzylaminopyrimidine, abbreviated to TMP.
The technical scheme of the invention is as follows:
a process for preparing a compound of formula (I) having the structure shown in formula (I):
the method comprises the following steps:
(1) adding cinnamaldehyde and sodium bisulfite into water at room temperature, stirring for 1-2 h to obtain a light white solution, adding ethanol to generate a precipitate, washing for 3-5 times by using the water and ethanol solution in a mass ratio of 1: 1, and drying to obtain a white solid, namely a compound 1-hydroxy-3-phenyl-1, 3-disulfonic acid propyl sulfonate; the chemical reaction formula is as follows:
(2) dissolving 1-hydroxy-3-phenyl-1, 3-disulfonic acid sodium propane into water, adding trimethoxy benzyl aminopyrimidine (TMP), heating to 50-60 ℃ to completely dissolve the trimethoxy benzyl aminopyrimidine and the 1-hydroxy-3-phenyl-1, 3-disulfonic acid sodium propane according to the mol ratio of 1: 2-2.5, then continuously heating for 0.5-1 h to obtain milky white solution, cooling the solution, and filtering to obtain clear solution. The reaction formula is as follows:
(3) spray-drying the clear solution obtained in the step (2) into powder to obtain a product compound (I); or,
and (3) adding ethanol with the temperature of 0 ℃ into the clear solution obtained in the step (2) to completely precipitate, separating and drying the precipitate to obtain the product compound (I).
The obtained compound (I), namely the water-soluble derivative of trimethoxy benzyl aminopyrimidine, is crystalline white or slightly light yellow powder, can be dissolved in water with the pH value of 7-10, and cannot be dissolved in ethanol, diethyl ether and chloroform.
According to the invention, the charging ratio of the cinnamaldehyde to the sodium bisulfite in the step (1) is preferably 1: 2-2.2 mol ratio.
According to the invention, the feeding ratio of trimethoprim and 1-hydroxy-3-phenyl-1, 3-disulfonate propane in the step (2) is preferably 1: 2-2.5 expressed by mol.
According to the invention, preferably, the drying cost of the product obtained by adopting the precipitation separation method in the step (3) is lower.
The product obtained by the method has the TMP content of 30-31 wt% and the target compound (I) content of 98-99%. The yield is 95-97%.
The TMP content is detected by adopting a currently general method, namely a method for titrating TMP by using perchloric acid titration solution, and the TMP content in the derivative is experimentally measured to be about 30-31 wt%, and the content of the compound (I) is converted to be 98-99%. The infrared spectrum and nuclear magnetic resonance spectrum of the product are shown in figures 1 and 2.
The TMP derivative prepared by the invention is soluble in neutral and alkaline water with the pH value of 7-10, the concentration is not higher than 60%, the obtained aqueous solution can be stably stored for at least one year without deterioration, the viscosity of the solution is not high, and the TMP derivative can be orally taken, or the TMP derivative and alkali metal salt of sulfanilamide drugs or antibiotics are prepared into the aqueous solution for use.
Compared with the prior art, the invention has the following excellent effects:
1. the product compound prepared by the invention provides a TMP derivative which is dissolved in water under neutral or alkaline conditions for the first time, can be compatible with alkaline sulfanilamide or antibiotic salt, and is applied by oral administration or injection in the form of aqueous solution.
2. The invention uses sodium bisulfite, which can obviously improve the yield and purity of 1-hydroxy-3-phenyl-1, 3-disulfonate propane and broaden the pH range of the final object dissolved in water, thereby expanding the application range of the sulfonamide or antibiotic alkali metal salt water solution compatible with the sodium bisulfite.
3. The method for preparing the intermediate product (II) by using the sodium bisulfite can be carried out at room temperature without heating, has simple operation, energy conservation and cost reduction, and is more suitable for industrial production.
4. The preparation method of the TMP derivative does not need nitrogen protection in spray drying, has simple equipment and low cost, and is more suitable for industrial production.
5. The water-soluble derivative of TMP, i.e., compound (I), can be prepared in high yield using the method of the present invention. The purity of the product obtained by the method is not less than 98.0%, and the yield is 95-97%.
Drawings
FIG. 1 is an infrared spectrum of the product of example 1. FIG. 2 is a NMR carbon spectrum of the product of example 1.
Detailed Description
The present invention is further illustrated by, but not limited to, the following examples. The TMP content of the product in the examples was determined by titration of TMP with a conventional perchloric acid titrant.
Example 1.
(1) Dissolving 80.0g of cinnamaldehyde and 126.1g of sodium bisulfite in 500mL of water at room temperature, stirring for 1-2 h to obtain a light white solution, adding ethanol to generate a system precipitate, washing the precipitate for 3-5 times by using a mixed solvent of water and ethanol in a mass ratio of 1: 1, and drying to obtain about 200g of a white solid, namely a compound (II) and 1-hydroxy-3-phenyl-1, 3-disulfonic acid propyl sulfonate;
(2) the dried white solid obtained in the previous step, i.e., 100.0g of the compound (II), 1-hydroxy-3-phenyl-1, 3-disulfonic acid sodium propane, was dissolved in 150mL of water, 42.7g of TMP was added, heated to 55 ℃ until the TMP was completely dissolved, and then the heating of the reactant mixture was continued for 1 h. Thus obtaining a milky white solution, cooling and filtering to clarify the solution;
(3) finally, the obtained solution is spray-dried into powder. 131.9g of product are obtained, with a yield of 96%.
The obtained product is a water-soluble derivative of TMP with the structure of formula (I). The infrared spectrum is shown in figure 1, and the nuclear magnetic resonance carbon spectrum is shown in figure 2.
The product obtained is a white crystalline powder with a solubility in water of up to 66.3% and a pH of the aqueous solution of 7.72. Insoluble in ethanol, diethyl ether and chloroform. The TMP content of the product was 30.8%, and the derivative content was 99.0% in terms of conversion; melting point: 246-248 c, at which the compound decomposes simultaneously.
Stability test: standing at room temperature for 1 year without change, and the powder has good fluidity and no change in product content.
Example 2. preparation as described in example 1, except that:
the final step (3) is not spray-dried, but the product is precipitated by adding 250mL of ethanol at 0 ℃ to the obtained clear solution, and then separated and dried to obtain the product. 130.5g of water-soluble TMP sodium salt derivative having the structure (I) were obtained in a yield of 95%. The product was a white crystalline powder with a solubility of 65.2% in an aqueous solution at pH 9 under alkaline conditions. Standing at room temperature for 1 year without change, and the powder has good fluidity and no change in product content.
Example 3.
Compound (II), i.e., propane 1-hydroxy-3-phenyl-1, 3-disulfonate, was prepared as in step (1) of example 1.
Dissolving 110.0g of 1-hydroxy-3-phenyl-1, 3-disulfonic acid sodium propane in 150mL of water, adding 42.7g of TMP, heating to 60 ℃ until the TMP is completely dissolved, then continuing to heat the mixture of reactants for 50min to obtain a milky white solution, cooling, filtering to clarify the solution, and finally spray-drying the obtained clarified solution to powder. 133.3g of product were obtained with a yield of 97%. The TMP content of the obtained derivative was 30.4%, the derivative content was 98.0% in terms of conversion, and the purity of the obtained product was 98.0%. The product was a white crystalline powder with a solubility of 65.2% in an aqueous solution at pH 9 under alkaline conditions. Standing at room temperature for 1 year without change, and the powder has good fluidity and no change in product content.
Claims (4)
1. A process for the preparation of a compound of formula (I),
the method comprises the following steps:
(1) adding cinnamaldehyde and sodium bisulfite into water at room temperature, stirring for 1-2 h to obtain a light white solution, adding ethanol to generate a precipitate, washing for 3-5 times by using the water and ethanol solution in a mass ratio of 1: 1, and drying to obtain a white solid, namely a compound 1-hydroxy-3-phenyl-1, 3-disulfonic acid propyl sulfonate; the chemical reaction formula is as follows:
(2) dissolving 1-hydroxy-3-phenyl-1, 3-disulfonic acid sodium propane into water, adding trimethoxy benzyl aminopyrimidine (TMP), wherein the molar ratio of the TMP to the 1-hydroxy-3-phenyl-1, 3-disulfonic acid sodium propane is 1: 2-2.5, heating to 50-60 ℃ to completely dissolve the TMP, then continuously heating for 0.5-1 h to obtain a milky white solution, cooling the solution, and filtering to obtain a clear solution; the reaction formula is as follows:
(3) spray-drying the clear solution obtained in the step (2) into powder to obtain a product compound (I); or,
adding ethanol with the temperature of 0 ℃ into the clear solution obtained in the step (2) to ensure that the precipitate is complete, and then separating and drying the precipitate to obtain a product compound (I);
the obtained product, compound (I), is a crystalline powder, is soluble in water with pH 7-10, and is insoluble in ethanol, diethyl ether and chloroform.
2. The method according to claim 1, wherein the charge ratio of cinnamaldehyde to sodium bisulfite in step (1) is 1: 2 to 2.2 mol.
3. The method according to claim 1, wherein the charge ratio of trimethoxy benzylaminopyrimidine to 1-hydroxy-3-phenyl-1, 3-disulfonic acid sodium propane in mole in step (2) is 1: 2 to 2.5.
4. The method for preparing the compound according to claim 1, wherein the obtained product has a TMP content of 30 to 31 wt% and a target compound (I) content of 98 to 99%.
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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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| 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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| 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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