CN101880290A - Preparation method of cefamandole nafate - Google Patents
Preparation method of cefamandole nafate Download PDFInfo
- Publication number
- CN101880290A CN101880290A CN 201010212928 CN201010212928A CN101880290A CN 101880290 A CN101880290 A CN 101880290A CN 201010212928 CN201010212928 CN 201010212928 CN 201010212928 A CN201010212928 A CN 201010212928A CN 101880290 A CN101880290 A CN 101880290A
- Authority
- CN
- China
- Prior art keywords
- sodium
- formylcefamole
- preparation
- reaction
- hours
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a preparation method of cefamandole nafate, which comprises the following steps: (1) suspending 7-amino-3-[(1-methyl-1H-tetrazol-5-yl) S-methyl] -3-cephem-4-carboxylic acid and sodium bicarbonate in an acetone water solution, adding the acetone solution of alpha-formylmandeloyl chloride to carry out a condensation reaction, and preparing 7-D-(2-formyloxy phenylacetamide)-3- [(1-methyl-1H-tetrazol-5-yl) S-methyl]-3-cephem-4-carboxylic acid; and (2) dissolving the 7-D-(2-formyloxy phenylacetamide)-3- [(1-methyl-1H-tetrazol-5-yl) S-methyl]-3-cephem-4-carboxylic acid in acetone to carry out a salification reaction with the acetone solution of organic acid sodium to prepare the cefamandole nafate. The method has the advantages of simple technology, high product yield, high purity, high reaction selectivity and use of no special equipment in production, and is suitable for industrialized production.
Description
Technical field
The present invention relates to the material medicine preparation field, be specifically related to a kind of preparation method of Sodium O-formylcefamole.
Background technology
Sodium O-formylcefamole, chemical name is: thiomethyl 7-D-(2-methanoyl phenylacetyl amido)-8-oxo-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl)]-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid sodium salt or 7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-3-cephem-4-carboxylic acid sodium salt, molecular formula: C
19H
17N
6NaO
6S
2, molecular weight: 512.50, CAS number: 42540-40-9, chemical structural formula is as follows:
At present, existing more Mandokef preparation of sodium.For example, the injection of the spore bacteriums derivative of U.S. Eli Lilly company exploitation: cefamandole nafate for inj.September nineteen eighty-three, Shionogi was obtained the approval of the cefadole preparation of sodium of commodity kefdole by name in Japan.Homemade injection cefadole, commodity cefamandole sodium by name was copied successfully by Shanghai No. 3 Pharmaceutical Factory in 1979, with its methyl esters sodium (Cafamandole nafate) as clinical preparation.
Sodium O-formylcefamole is the cephalosporins of s-generation injection, and has a broad antifungal spectrum is to beta-lactam enzyme stability height, Plasma Concentration height, transformation period is short, and tissue distribution is wide, especially concentration height in kidney and bile, toxicity is low, and side effect is little, and protein binding rate is 78%.Clinical being used for by the septicemia due to the sensitive organism and lower respiratory tract, liver and gall, peritonaeum, urinary system and skin soft-tissue infection etc.The mechanism of action of Sodium O-formylcefamole is: Sodium O-formylcefamole can combine with the penicillin-binding protein (PBPs) on the bacterial cell membrane; make the transpeptidase acidylate; suppress in the bacterium synthetic every with cell walls; the intersection that influences the cell wall mucopeptide composition links; the division and the growth of cell are suppressed; cause ne ar elongated, dissolving at last and dead.
At present, the synthetic method of Sodium O-formylcefamole has a lot of documents and patent report.Mainly be with 7-amino-cephalosporanic acid (7-ACA) in the document or 7-amino-3-(1-methyl isophthalic acid H-tetrazole-5-yl)-thiomethyl-3-cephalo-4-carboxylic acid (7-ATCA) is a starting raw material, method or chloride method by active ester synthesize.A kind of synthetic method of Sodium O-formylcefamole is disclosed in the U.S. Pat 4351947; with formyl mandelic acid and 1-methyl-5-sulfydryl-1; 2; 3; active ester is made in the reaction of 4-tetrazole; with 7-ACA or 7-ATCA reaction, obtain Mandokef acid again, obtain Sodium O-formylcefamole through salt-forming reaction again.Similar method is also disclosed among the Chinese patent CN200810009182.3.This kind method complex process, and synthesis yield is not high, unstable product quality; In addition, use toxicant such as toluene, bisbenzothiazole etc., and do not established the link of removing toxicant, caused toxicant residual, unfavorable to human body.
Publication number is to disclose a kind of Cefamandole nafate compounds and synthetic method thereof in the Chinese patent application of CN101475580A; earlier synthetic formyl mandelic acid (being D-(-)-2-methanoyl-toluylic acid); again formyl mandelic acid and isopropyl chlorocarbonate, N-methyl piperidine are reacted in organic solvent and obtain D-(-)-2-methanoyl-phenyllacetyl chloride; then D-(-)-2-methanoyl-phenyllacetyl chloride and 7-ATCA reaction are obtained Mandokef acid, change into Sodium O-formylcefamole at last as required.This method complex process, and used molecular sieve, molecular sieve not only cost an arm and a leg but also can the absorption reaction products, although be the adsorbed molecules diameter smaller or equal to
Reaction product, but also can cause product yield to reduce; Moreover need to remove molecular sieve after the reaction end, as remove not exclusively, also can cause the purity of last gross product undesirable.
A kind of synthetic method of antibiotics cefamandole nafate is disclosed among the Chinese patent CN200710024283.3; 7-amino-3-(1-methyl isophthalic acid H-tetrazole-5-yl)-thiomethyl-3-cephalo-4-carboxylic acid is a raw material in employing, obtains cephalo broad-mouthed receptacle for holding liquid polyester sodium solid through silicon alkyl reaction, acylation reaction, hydrolysis reaction, decolouring and salt-forming reaction successively.This method technological operation complexity, and silicon amine alkane is easy to generate the by product ammonia, has influence on the quality of the yield and the finished product of product.
Therefore, be necessary to study the novel synthesis of the simple and Sodium O-formylcefamole that product yield is high, purity is high of a kind of technology.
Summary of the invention
The invention provides the preparation method of the simple and Sodium O-formylcefamole that cost is low of a kind of technology, this method selectivity is good, the yield height of product, purity height.
A kind of preparation method of Sodium O-formylcefamole comprises step:
(1) with 7-amino-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-3-cephem-4-carboxylic acid and sodium bicarbonate be suspended in the aqueous acetone solution, the acetone soln that adds α-formyl mandelic acid chloride carries out condensation reaction, makes 7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-3-cephem-4-carboxylic acid;
(2) with 7-D-(2-methanoyl the phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl that makes in the step (1)) thiomethyl]-3-cephem-4-carboxylic acid is dissolved in acetone, is carried out to reactant salt with the acetone soln of organic acid sodium, makes Sodium O-formylcefamole.
As preferably:
In the step (1), the condition of described condensation reaction is: 4 ℃～6 ℃ insulated and stirred reactions 1 hour～2 hours, be warmed up to 18 ℃～22 ℃ again and continued stirring reaction 1.5 hours～2 hours; More preferably:, be warmed up to 20 ℃ again and continued stirring reaction 2 hours 5 ℃ of insulated and stirred reactions 1 hour; Be for condensation reaction is carried out in the environment of a gentleness, reaction more fully and the by product of reaction less, guarantee that the ultimate aim product has higher transformation efficiency.
In order to improve the purity of condensation reaction products, in the step (1), described condensation reaction finishes back pressure reducing and steaming acetone, raffinate obtains extracting solution through ethyl acetate extraction, extracting solution is evaporated to the dried faint yellow oily thing that obtains behind anhydrous sodium sulfate drying, oily matter makes 7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl through the organic solvent recrystallization) thiomethyl]-3-cephem-4-carboxylic acid.
Described organic solvent can be selected this area recrystallization solvent commonly used for use, further preferred ether.
Described organic acid sodium is selected C for use
1～C
10Alkyl acid sodium, as Sodium isooctanoate, be more conducive to the carrying out of salt-forming reaction.
In the step (2), the condition of described salt-forming reaction was :-1 ℃～0 ℃ stirring reaction 3 hours～5 hours.Carry out in relatively mild environment to guarantee salt-forming reaction.
In order to improve the salt-forming reaction degree of purity of production, in the step (2), after described salt-forming reaction finishes, reaction product is filtered gained filter cake washing with acetone, again in 35 ℃～50 ℃ drying under reduced pressure 3 hours～6 hours, be dissolved in dehydrated alcohol then, the mixing solutions washing after drying through activated carbon decolorizing, ethyl acetate crystallization, anhydrous methanol and ethyl acetate makes Sodium O-formylcefamole.
The volume ratio of anhydrous methanol and ethyl acetate is 1: 1 in the mixing solutions of described anhydrous methanol and ethyl acetate, can reach best washing effect.
In the step of the present invention (1), the reaction equation of condensation reaction is as follows:
In the step (2), be example with the Sodium isooctanoate, the reaction equation of salt-forming reaction is as follows:
The not strict qualification of the consumption of reaction raw materials among the present invention; generally measure than reacting according to chemical reaction; also but α-formyl mandelic acid chloride or organic acid sodium are excessive, or 7-amino-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-the 3-cephem-the 4-carboxylic acid is excessive to react.
The not strict qualification of the consumption of sodium bicarbonate, acetone, water among the present invention can be according to the consumption adjustment of reaction mass, as long as generally guarantee that sodium bicarbonate is suspended in the aqueous acetone solution.
Compared with prior art, the present invention has following advantage:
Preparation method of the present invention; in advance with 7-amino-3-[(1-methyl isophthalic acid H-tetrazolium-5 base) thiomethyl]-3-cephem-4-carboxylic acid and sodium bicarbonate be suspended in the aqueous acetone solution; after forming the reaction system of suspension; acetone soln with α-formyl mandelic acid chloride carries out condensation reaction again; reduce the generation of side reaction effectively, guaranteed the high conversion of target product.Simultaneously, because the by product of reaction is dissolved in the reaction system of above-mentioned suspendible mostly, target product is insoluble to the reaction system of above-mentioned suspendible substantially, conveniently carries out aftertreatment, to improve degree of purity of production.
The yield of preparation method's final product Sodium O-formylcefamole of the present invention reaches more than 92.6%.In the Sodium O-formylcefamole standard that " British Pharmacopoeia " records, require the content of Cefamandole free acid (free Cefamandole) must not surpass 9.5% (quality percentage composition), if the content of Cefamandole is many,, can influence the solubleness of product because its solubleness is poor; By the improvement of reaction system, the content of Cefamandole free acid in the product Sodium O-formylcefamole of gained (3.8%, the quality percentage composition) compared with prior art reduces greatly among the preparation method of the present invention.
Preparation method of the present invention can remove unreacted reactant and most of by product by simple aftertreatment, as adopt the ether recrystallization and Sodium O-formylcefamole crude product (salt reaction product) is being carried out adopt anhydrous methanol and the washing of ethyl acetate mixed solution in the purified process, can effectively remove the Cefamandole free acid, improve degree of purity of production, make purity reach (with reference to the method under the 2010 Chinese Pharmacopoeia Sodium O-formylcefamole test items, HLPC area normalization method) more than 94.2%.
Residual organic solvent content is low in the gained Sodium O-formylcefamole product of the present invention, is lower than significantly all that " two ones of Chinese pharmacopoeia versions in 2005 are to the limited amount in the regulation of residual solvent.
Preparation method's operating procedure of the present invention is simple, and cost is low, and production need not any specific installation, the yield of product and purity height, and the selectivity height of reaction (can reach 89.4%) is fit to suitability for industrialized production.
Embodiment
Embodiment 1
7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-preparation of 3-cephem-4-carboxylic acid
With 258g (0.798mol) 7-amino-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-3-cephem-4-carboxylic acid and 375g sodium bicarbonate be suspended in by being pre-chilled in the mixed solution that 5 ℃ 7500ml water and 7500mL acetone forms, add 1000ml then and contain the acetone soln of 148.8g (0.75mol) α-formyl mandelic acid chloride, 5 ℃ of insulated and stirred were reacted 1 hour, be warmed up to 20 ℃ then and continued stirring reaction 2 hours, reaction finishes the back in 20 ℃ of pressure reducing and steaming acetone, adding ethyl acetate in raffinate extracts, extract 2 times, the consumption of each ethyl acetate is 6L, merge extracted twice liquid, through anhydrous sodium sulfate drying, 20 ℃ are evaporated to dried faint yellow oily thing; Faint yellow oily thing is got pale yellow powder 383g with the ether recrystallization, and purity is: 89.4%.Molar yield is 93.27%, and reaction preference is 94.3%.
Above-mentioned pale yellow powder is carried out ultimate analysis, the result is as follows: C:46.6%, H:3.6%, N:17.2%, O:19.4%, S:13.2% (being mass percent), with 7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-theoretical value of 3-cephem-4-carboxylic acid: C:46.5%, H:3.7%, N:17.1%, O:19.6%, S:13.1% (being mass percent) conforms to.
Show that above-mentioned pale yellow powder is 7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-3-cephem-4-carboxylic acid.
Embodiment 2
7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-preparation of 3-cephem-4-carboxylic acid sodium salt
The pale yellow powder 383g that embodiment 1 is made is dissolved in the 1.5L acetone, add 1.2L then and contain the acetone soln of 92g (0.55mol) Sodium isooctanoate, ice bath is cooled to 0 ℃, continued stirring reaction 3 hours, filter filter cake washing with acetone, 40 ℃ of following drying under reduced pressure 5 hours, make crude product 276.2g, fusing point (mp) is 183 ℃-185 ℃.Molar yield is 93.8%.
Above-mentioned crude product is carried out ultimate analysis, and the result is as follows: C:44.7%, H:3.5%, N:16.3%, O:18.6%, S:12.5%, Na:4.4% (being mass percent), with 7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-theoretical value of 3-cephem-4-carboxylic acid sodium salt: C:44.5%, H:3.4%, N:16.4%, O:18.7%, S:12.5%, Na:4.5% (being mass percent) conforms to.
The main component that shows above-mentioned crude product is 7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-3-cephem-4-carboxylic acid sodium salt, i.e. Sodium O-formylcefamole.The quality percentage composition of Sodium O-formylcefamole is 95.8% in the above-mentioned crude product, and the quality percentage composition of Cefamandole free acid is 3.8% in the Sodium O-formylcefamole.
Embodiment 3
The preparation of Sodium O-formylcefamole highly finished product
The 276.2g crude product that makes among the embodiment 2 is dissolved in the anhydrous methanol of 5000ml, stir and add gac 10g down, stir decolouring 30 minutes, filtration obtains filtrate, filtrate is slowly joined in the 15000ml ethyl acetate, at room temperature continued stirring and crystallizing 4 hours, filter, filter cake washs with the mixing solutions (volume ratio of anhydrous methanol and ethyl acetate is 1: 1) of anhydrous methanol and ethyl acetate, collect filter cake, 40 ℃ of following vacuum-dryings obtain Sodium O-formylcefamole highly finished product 256.3g, and yield 92.8%, the mp of Sodium O-formylcefamole highly finished product are 189 ℃-190.5 ℃.
Embodiment 4
7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-preparation of 3-cephem-4-carboxylic acid
With 258g (0.798mol) 7-amino-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-3-cephem-4-carboxylic acid and 375g sodium bicarbonate be suspended in by being pre-chilled in the mixed solution that 4 ℃ 7500ml water and 7500mL acetone forms, add 1000ml then and contain the acetone soln of 148.8g (0.75mol) α-formyl mandelic acid chloride, 4 ℃ of insulated and stirred were reacted 2 hours, be warmed up to 18 ℃ then and continued stirring reaction 2 hours, reaction finishes the back in 20 ℃ of pressure reducing and steaming acetone, adding ethyl acetate in raffinate extracts, extract 2 times, the consumption of each ethyl acetate is 6L, merge extracted twice liquid, through anhydrous sodium sulfate drying, 20 ℃ are evaporated to dried faint yellow oily thing; Faint yellow oily thing is got pale yellow powder 380g with the ether recrystallization, and purity is: 88.4%.Molar yield is 91.50%, and reaction preference is 93.7%.
7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-preparation of 3-cephem-4-carboxylic acid sodium salt, except pale yellow powder is 380g, ice bath is cooled to-1 ℃, outside the continuation stirring reaction 5 hours, all the other operations are with embodiment 2, make crude product 278.4g, the crude product yield is 92.8%, and fusing point (mp) is 183.4 ℃-184 ℃.
Above-mentioned crude product is carried out ultimate analysis, and main component result is as follows: C:44.7%, H:3.5%, N:16.2%, O:18.7%, S:12.5%, Na:4.4%, theoretical value with Sodium O-formylcefamole: C:44.5%, H:3.4%, N:16.4%, O:18.7%, S:12.5%, Na:4.5% conforms to.
The main component that shows above-mentioned crude product is 7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-3-cephem-4-carboxylic acid sodium salt, i.e. cephalo broad-mouthed receptacle for holding liquid polyester sodium.The quality percentage composition of Sodium O-formylcefamole is 92.8% in the above-mentioned crude product, and the quality percentage composition of Cefamandole free acid is 3.8% in the Sodium O-formylcefamole.
The preparation of Sodium O-formylcefamole highly finished product, except crude product is 278.4g, all the other are operated with embodiment 3, make Sodium O-formylcefamole highly finished product 258.7g, and yield 92.9%, the mp of Sodium O-formylcefamole highly finished product are 188.5 ℃-189.5 ℃.
Embodiment 5
7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-preparation of 3-cephem-4-carboxylic acid
With 258g (0.798mol) 7-amino-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-3-cephem-4-carboxylic acid and 375g sodium bicarbonate be suspended in by being pre-chilled in the mixed solution that 6 ℃ 7500ml water and 7500mL acetone forms, add 1000ml then and contain the acetone soln of 148.8g (0.75mol) α-formyl mandelic acid chloride, 6 ℃ of insulated and stirred were reacted 1 hour, be warmed up to 22 ℃ then and continued stirring reaction 1.5 hours, reaction finishes the back in 20 ℃ of pressure reducing and steaming acetone, adding ethyl acetate in raffinate extracts, extract 2 times, the consumption of each ethyl acetate is 6L, merge extracted twice liquid, through anhydrous sodium sulfate drying, 20 ℃ are evaporated to dried faint yellow oily thing; Faint yellow oily thing is got pale yellow powder 382g with the ether recrystallization, and purity is: 88.29%.Molar yield is 91.86%, and reaction preference is 92.7%.
7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-preparation of 3-cephem-4-carboxylic acid sodium salt, except pale yellow powder is 382g, ice bath is cooled to 0 ℃, outside the continuation stirring reaction 4 hours, all the other operations are with embodiment 2, make crude product 279.8g, the crude product yield is 93.8%, and fusing point (mp) is 183.6 ℃-184.8 ℃.
Above-mentioned crude product is carried out ultimate analysis, and main component result is as follows: C:44.7%, H:3.3%, N:16.3%, O:18.7%, S:12.4%, Na:4.6%, theoretical value with Sodium O-formylcefamole: C:44.5%, H:3.4%, N:16.4%, O:18.7%, S:12.5%, Na:4.5% conforms to.The main component that shows above-mentioned crude product is 7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-3-cephem-4-carboxylic acid sodium salt, i.e. Sodium O-formylcefamole.The quality percentage composition of Sodium O-formylcefamole is 92.3% in the above-mentioned crude product, and the quality percentage composition of Cefamandole free acid is 3.8% in the Sodium O-formylcefamole.
The preparation of Sodium O-formylcefamole highly finished product, except crude product is 279.8g, all the other are operated with embodiment 3, make Sodium O-formylcefamole highly finished product 261.4g, and yield 93.4%, the mp of Sodium O-formylcefamole highly finished product are 189.8 ℃-190.4 ℃.
Differentiate
(1) HPLC differentiates: the Sodium O-formylcefamole highly finished product of getting embodiment 3,4 and 5 preparations are prepared need testing solution respectively, get Sodium O-formylcefamole standard substance preparation reference substance solution, respectively need testing solution and reference substance solution are carried out the HPLC detection, the preparation of need testing solution and reference substance solution and HPLC detection method differentiate that with reference to 2010 editions two Sodium O-formylcefamoles of Chinese Pharmacopoeia item down.The result shows: the retention time of need testing solution main peak is consistent with the retention time of reference substance solution main peak, so (promptly meet 2010 editions two Sodium O-formylcefamoles of Chinese Pharmacopoeia and differentiate item regulation down) up to specification.
(2) get embodiment 3,4 and the 5 Sodium O-formylcefamole highly finished product that prepare, be dissolved in water respectively and make the solution that contains 20 μ g Sodium O-formylcefamole highly finished product among every 1ml respectively, with reference to " the spectrophotometry among 2005 editions two appendix IVA of Chinese pharmacopoeia, solution has maximum absorption at the wavelength place of 269nm as a result, meets the ultraviolet spectrum characteristic (promptly meet 2010 editions two Sodium O-formylcefamoles of Chinese Pharmacopoeia and differentiate item ultraviolet spectrum characteristic down) of Sodium O-formylcefamole.
(3) get embodiment 3,4 and the 5 Sodium O-formylcefamole highly finished product that prepare, with reference to " flame reaction of sodium salt is differentiated among two appendix III of Chinese pharmacopoeia version in 2000, the result shows that the flame reaction of Sodium O-formylcefamole highly finished product of embodiment 3,4 and 5 preparations is positive reaction, meets in the Chinese Pharmacopoeia regulation about the flame reaction of sodium salt.
(4) the Sodium O-formylcefamole highly finished product of embodiment 3,4 and 5 preparations are white powder; Odorless, have draw moist, easily molten in water, molten in the methyl alcohol part omitted, soluble,very slightly in ethanol, insoluble in acetone or vinyl acetic monomer.Conform to the physico-chemical property of Sodium O-formylcefamole.
(5) the Sodium O-formylcefamole highly finished product of embodiment 3,4 and 5 preparations, after testing, its hydrogen spectrum (
1H-NMR:400MHz, DMSO-d6) result such as table 1, the carbon spectrum (
13C-NMR:100MHz, DMSO-d6) result such as table 2:
The hydrogen spectrum measurement result of table 1. Sodium O-formylcefamole highly finished product
| Chemical shift (ppm) | Proton number | Peak shape | Relevant chemical shift of proton (ppm) | Ownership | Remarks |
| ??9.36 | ??1H | ??d | ??5.54 | ??H13(-NH-??) | J=8.3Hz, heavy water exchange back disappears |
| ??8.37 | ??1H | ??s | ??/ | ??H16 | |
| ??7.52 | ??2H | ??m | ??7.39 | ??2H18 | |
| ??7.39 | ??3H | ??m | ??7.52 | ??2H19，??H20 | |
| ??6.14 | ??1H | ??s | ??/ | ??H15 | |
| ??5.54 | ??1H | ??dd | ??9.36，4.89 | ??H7 | J=4.8,8.3Hz, heavy water exchange back is the dd peak |
| ??4.89 | ??1H | ??d | ??5.54 | ??H6 | ??J＝4.8Hz |
| ??4.46 | ??1H | ??d | ??4.20 | ??H10 | ??J＝12.3Hz |
| ??4.20 | ??1H | ??d | ??4.46 | ??H10 | ??J＝12.3Hz |
| ??3.91 | ??3H | ??s | ??/ | ??H12 | |
| ??3.51 | ??1H | ??d | ??3.33 | ??H4 | ??J＝17.5Hz |
| ??3.33 | ??1H | ??d | ??3.51 | ??H4 | ??J＝17.5Hz |
The carbon spectrum measurement result of table 2. Sodium O-formylcefamole highly finished product
| Chemical shift (ppm) | Carbon type | Ownership | Relevant chemical shift of proton (ppm) | Long-range relevant chemical shift of proton (ppm) |
| ?168.4 | Season C | ??C14 | ??/ | ??9.36，6.14，5.54 |
| ?164.5 | Season C | ??C9 | ??/ | ??/ |
| ?162.8 | Season C | ??C8 | ??/ | ??9.36，5.54，4.89 |
| ?161.1 | Uncle C | ??C16 | ??8.37 | ??6.14 |
| Chemical shift (ppm) | Carbon type | Ownership | Relevant chemical shift of proton (ppm) | Long-range relevant chemical shift of proton (ppm) |
| ?154.6 | Season C | ??C11 | ??/ | ??4.46，4.20，3.91 |
| ?134.9 | Season C | ??C17 | ??/ | ??7.39，6.14 |
| ?133.1 | Season C | ??C3 | ??/ | ??4.46，4.20，3.51，3.331 |
| ?128.8 | Uncle C | ??C20 | ??7.39 | ??7.52 |
| ?128.4 | Uncle C | ??2C19 | ??7.39 | ??7.52 |
| ?127.4 | Uncle C | ??2C18 | ??7.52 | ??6.14 |
| ?116.3 | Season C | ??C2 | ??/ | ??4.46，4.20，3.51，3.33 |
| ?73.6 | Uncle C | ??C15 | ??6.14 | ??8.37，7.52 |
| ?58.0 | Uncle C | ??C7 | ??5.54 | ??9.36 |
| ?57.4 | Uncle C | ??C6 | ??4.89 | ??5.54，3.33 |
| ?36.6 | Secondary C | ??C10 | ??4.46，4.20 | ??3.33 |
| ?33.6 | Uncle C | ??C12 | ??3.91 | ??/ |
| ?26.3 | Secondary C | ??C4 | ??3.51，3.33 | ??4.46，4.20 |
Above-mentioned hydrogen spectrum conforms to the carbon spectrum with the hydrogen spectrum of Sodium O-formylcefamole with the carbon spectrum, shows that the inventive method obtains Sodium O-formylcefamole.
Related substance
Related substance according to " high effective liquid chromatography for measuring among two attached VD of Chinese pharmacopoeia version in 2000:
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is weighting agent; Mobile phase A is triethylamine phosphoric acid solution-water (volume ratio 1: 2); Mobile phase B is triethylamine phosphoric acid solution-acetonitrile-methyl alcohol (volume ratio 1: 1: 1); Flow velocity is per minute 1.0ml, linear gradient elution; The detection wavelength is 254nm; Number of theoretical plate calculates by the Mandokef peak and is not less than 6000.
Detection method: get the Sodium O-formylcefamole highly finished product of embodiment 3,4 and 5 preparations, add respectively that mixed solvent [with 10% triethylamine (V/V) solution (with phosphorus acid for adjusting pH value to 2.5)-acetonitrile (volume ratio 75: 18)] dissolves and dilute make contain 0.8mg Sodium O-formylcefamole highly finished product among every 1ml approximately solution as need testing solution; Precision is measured need testing solution 1ml, puts in the 100ml measuring bottle, adds mixed solvent and is diluted to scale, shakes up, in contrast solution.Precision is measured need testing solution and each 20 μ l of contrast solution, injects liquid chromatograph respectively, the record color atlas.If any impurity peaks, single impurity peak area must not be greater than the main peak area (1.0%) of contrast solution in the color atlas of need testing solution; Each impurity peak area summation must not be greater than 5.0 times (5.0%) of contrast solution main peak area.
The result is as follows: single impurity is respectively 0.83%, 0.85%, 0.82% (single impurity peak area is with respect to the per-cent of the main peak area of contrast solution) in the Sodium O-formylcefamole highly finished product of embodiment 3,4 and 5 preparations; Total impurities is respectively 2.81%, 2.90%, 2.85% (the total impurities peak area is with respect to the per-cent of the main peak area of contrast solution); Measurement result shows: single impurity peak area is less than the main peak area (1.0%) of contrast solution in the color atlas of Sodium O-formylcefamole highly finished product solution of the present invention; Each impurity peak area summation meets the requirements less than 5.0 times (5.0%) of contrast solution main peak area.
The investigation of stability high spot reviews project
One, gets a batch sample according to " 2005 editions second influence factor test methods of Chinese pharmacopoeia are carried out the investigation of stable high spot reviews project.This test is to carry out under the condition fiercer than accelerated test.
(1) high temperature test
The Sodium O-formylcefamole highly finished product of getting embodiment 3 preparations are as trial-product, opening places clean weighing bottle, places 10 days under 60 ℃ of temperature, takes a sample respectively with 10 days in the 5th day, by " 2005 editions second influence factor test methods of Chinese pharmacopoeia are measured, and the results are shown in Table 3.
Table 3 high temperature test result
(2) high wet test
The Sodium O-formylcefamole highly finished product of getting embodiment 3 preparation are as trial-product, and opening places temperature is housed is 25 ℃ KNO
3In the close drying device of saturated solution (relative humidity is 92.5%), placed 10 days, in sampling in the 5th and the 10th day, by " detection method in 2005 editions second influence factor test methods of Chinese pharmacopoeia is measured, the weight of this product before and after accurately weighing is tested simultaneously, to investigate the moisture absorption deliquescence performance of this product, the results are shown in Table 4.
Table 4 high humidity test-results
(3) strong illumination test
The Sodium O-formylcefamole highly finished product of getting embodiment 3 preparations are as trial-product, opening was placed in the adjustable light box that illumination is 4500lx illumination 10 days, in the 5th day and sampling respectively in the 10th day, by " detection method in 2005 editions second influence factor test methods of Chinese pharmacopoeia is measured, and the results are shown in Table 5.
Table 5 highlight test result
From above-mentioned influence factor test as can be seen, Sodium O-formylcefamole highly finished product of the present invention were placed 10 days under the condition of above-mentioned high temperature, high humidity, high light, moisture absorption in 5 days weightening finish is 1.74%, moisture absorption in 10 days weightening finish is 3.86%, in 5%, other quality index does not have considerable change substantially yet, illustrates that Sodium O-formylcefamole highly finished product quality of the present invention is comparatively stable.
Two, get the Sodium O-formylcefamole highly finished product of embodiment 3 preparations, three duplicate samples of div in par aeq, lot number is respectively: 20091001,20091002 and 20091003, sample is respectively according to " 2005 editions second accelerated tests methods of Chinese pharmacopoeia are that 40 ± 2 ℃, relative humidity are to place 6 months under 75 ± 5% the condition in temperature.In 1st month, 2 months, 3 months, 6 each sampling at the end of month of duration of test once, detect, the results are shown in Table 6 by stable high spot reviews project:
Table 6 accelerated test measurement result
The Sodium O-formylcefamole highly finished product of embodiment 4 and 5 preparations are carried out stability test according to above-mentioned " investigation of stable high spot reviews project ", and test result is similar to the test result of the Sodium O-formylcefamole highly finished product of embodiment 3 preparations.
From above-mentioned accelerated test result as can be seen, Sodium O-formylcefamole highly finished product of the present invention are that 40 ± 2 ℃, relative humidity are to place 6 months under 75 ± 5% the condition in temperature, the content of related substance increases slightly but changes little, the Mandokef sodium content descends slightly but changes little, other quality index are substantially almost constant, and Sodium O-formylcefamole highly finished product steady quality of the present invention is described.
Claims (8)
1. the preparation method of a Sodium O-formylcefamole comprises step:
(1) with 7-amino-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-3-cephem-4-carboxylic acid and sodium bicarbonate be suspended in the aqueous acetone solution, the acetone soln that adds α-formyl mandelic acid chloride carries out condensation reaction, makes 7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl) thiomethyl]-3-cephem-4-carboxylic acid;
(2) with 7-D-(2-methanoyl the phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl that makes in the step (1)) thiomethyl]-3-cephem-4-carboxylic acid is dissolved in acetone, is carried out to reactant salt with the acetone soln of organic acid sodium, makes Sodium O-formylcefamole.
2. the preparation method of Sodium O-formylcefamole according to claim 1, it is characterized in that, in the step (1), the condition of described condensation reaction is: 4 ℃～6 ℃ insulated and stirred reactions 1 hour～2 hours, be warmed up to 18 ℃～22 ℃ again and continued stirring reaction 1.5 hours～2 hours.
3. the preparation method of Sodium O-formylcefamole according to claim 2 is characterized in that, in the step (1), the condition of described condensation reaction is: 5 ℃ of insulated and stirred reactions 1 hour, be warmed up to 20 ℃ again and continued stirring reaction 2 hours.
4. the preparation method of Sodium O-formylcefamole according to claim 1, it is characterized in that, in the step (1), described condensation reaction finishes back pressure reducing and steaming acetone, raffinate obtains extracting solution through ethyl acetate extraction, extracting solution is evaporated to the dried faint yellow oily thing that obtains behind anhydrous sodium sulfate drying, oily matter makes 7-D-(2-methanoyl phenylacetamide)-3-[(1-methyl isophthalic acid H-tetrazolium-5-yl through the organic solvent recrystallization) thiomethyl]-3-cephem-4-carboxylic acid.
5. the preparation method of Sodium O-formylcefamole according to claim 4 is characterized in that, described organic solvent is an ether.
6. the preparation method of Sodium O-formylcefamole according to claim 1 is characterized in that, described organic acid sodium is selected C for use
1～C
10Alkyl acid sodium.
7. the preparation method of Sodium O-formylcefamole according to claim 1 is characterized in that, in the step (2), the condition of described salt-forming reaction is :-1 ℃～0 ℃ stirring reaction 3 hours～5 hours.
8. the preparation method of Sodium O-formylcefamole according to claim 1, it is characterized in that, in the step (2), after described salt-forming reaction finishes, reaction product is filtered gained filter cake washing with acetone, in 35 ℃～45 ℃ drying under reduced pressure 3 hours～6 hours, be dissolved in dehydrated alcohol then again, mixing solutions washing after drying through activated carbon decolorizing, ethyl acetate crystallization, anhydrous methanol and ethyl acetate makes Sodium O-formylcefamole.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102129288A CN101880290B (en) | 2010-06-28 | 2010-06-28 | Preparation method of cefamandole nafate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102129288A CN101880290B (en) | 2010-06-28 | 2010-06-28 | Preparation method of cefamandole nafate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101880290A true CN101880290A (en) | 2010-11-10 |
| CN101880290B CN101880290B (en) | 2012-03-07 |
Family
ID=43052452
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010102129288A Active CN101880290B (en) | 2010-06-28 | 2010-06-28 | Preparation method of cefamandole nafate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101880290B (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102766148A (en) * | 2012-08-06 | 2012-11-07 | 夏智红 | Cefamandole nafate compound and composite thereof |
| WO2013057196A1 (en) * | 2011-10-20 | 2013-04-25 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Process for the preparation of cefamandole nafate |
| CN105001240A (en) * | 2015-05-28 | 2015-10-28 | 浙江长典医药有限公司 | Cefamandole nafate compound entity used for children and preparation thereof |
| CN105030786A (en) * | 2015-05-28 | 2015-11-11 | 浙江长典医药有限公司 | Juvenile Cefamandole Nafate and low-sodium carrier pharmaceutical composition |
| CN105037392A (en) * | 2015-08-13 | 2015-11-11 | 青岛蓝盛洋医药生物科技有限责任公司 | Bactericidal medicine efamandole nafate compound and preparing method of bactericidal medicine efamandole nafate compound |
| CN105399754A (en) * | 2015-12-17 | 2016-03-16 | 苏州中联化学制药有限公司 | Preparation method for sodium cefamandole |
| CN106565750A (en) * | 2016-11-09 | 2017-04-19 | 哈药集团制药总厂 | Synthesis method for dextrorotation cefamandole nafate |
| CN106565749A (en) * | 2016-09-30 | 2017-04-19 | 华北制药河北华民药业有限责任公司 | Method for improving quality of cemandil sodium by using three-dimensional column plate to purify solvent |
| CN106562972A (en) * | 2016-09-30 | 2017-04-19 | 华北制药河北华民药业有限责任公司 | Method for preparing cefamandole nafate powder preparation for injection |
| CN110241167A (en) * | 2019-07-02 | 2019-09-17 | 苏州盛达药业有限公司 | A kind of method that enzyme process prepares Mandokef sodio-derivative |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3928592A (en) * | 1974-02-22 | 1975-12-23 | Lilly Co Eli | Antibiotic pharmaceutical compositions |
| CN101108856A (en) * | 2007-07-27 | 2008-01-23 | 苏州中联化学制药有限公司 | Method for synthesizing antibiotic cefamandole nafate |
| CN101475580A (en) * | 2009-01-21 | 2009-07-08 | 海南美大制药有限公司 | Cefamandole nafate compounds and synthesizing method thereof |
-
2010
- 2010-06-28 CN CN2010102129288A patent/CN101880290B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3928592A (en) * | 1974-02-22 | 1975-12-23 | Lilly Co Eli | Antibiotic pharmaceutical compositions |
| CN101108856A (en) * | 2007-07-27 | 2008-01-23 | 苏州中联化学制药有限公司 | Method for synthesizing antibiotic cefamandole nafate |
| CN101475580A (en) * | 2009-01-21 | 2009-07-08 | 海南美大制药有限公司 | Cefamandole nafate compounds and synthesizing method thereof |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013057196A1 (en) * | 2011-10-20 | 2013-04-25 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Process for the preparation of cefamandole nafate |
| CN102766148A (en) * | 2012-08-06 | 2012-11-07 | 夏智红 | Cefamandole nafate compound and composite thereof |
| CN105001240A (en) * | 2015-05-28 | 2015-10-28 | 浙江长典医药有限公司 | Cefamandole nafate compound entity used for children and preparation thereof |
| CN105030786A (en) * | 2015-05-28 | 2015-11-11 | 浙江长典医药有限公司 | Juvenile Cefamandole Nafate and low-sodium carrier pharmaceutical composition |
| CN105037392A (en) * | 2015-08-13 | 2015-11-11 | 青岛蓝盛洋医药生物科技有限责任公司 | Bactericidal medicine efamandole nafate compound and preparing method of bactericidal medicine efamandole nafate compound |
| CN105399754B (en) * | 2015-12-17 | 2018-05-15 | 苏州中联化学制药有限公司 | A kind of preparation method of Cefamandole Nafate |
| CN105399754A (en) * | 2015-12-17 | 2016-03-16 | 苏州中联化学制药有限公司 | Preparation method for sodium cefamandole |
| CN106565749A (en) * | 2016-09-30 | 2017-04-19 | 华北制药河北华民药业有限责任公司 | Method for improving quality of cemandil sodium by using three-dimensional column plate to purify solvent |
| CN106562972A (en) * | 2016-09-30 | 2017-04-19 | 华北制药河北华民药业有限责任公司 | Method for preparing cefamandole nafate powder preparation for injection |
| CN106565750A (en) * | 2016-11-09 | 2017-04-19 | 哈药集团制药总厂 | Synthesis method for dextrorotation cefamandole nafate |
| CN106565750B (en) * | 2016-11-09 | 2018-09-11 | 哈药集团制药总厂 | A kind of synthetic method of dextrorotation Mandokef acid |
| CN110241167A (en) * | 2019-07-02 | 2019-09-17 | 苏州盛达药业有限公司 | A kind of method that enzyme process prepares Mandokef sodio-derivative |
| CN110241167B (en) * | 2019-07-02 | 2023-12-26 | 苏州盛达药业有限公司 | Method for preparing cefamandole nafate derivative by enzyme method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101880290B (en) | 2012-03-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101880290B (en) | Preparation method of cefamandole nafate | |
| EP3995611A1 (en) | High throughput method for constructing and screening compound library and reaction device | |
| WO2022171044A1 (en) | Oxa-azaspiro compound, salt form thereof and crystal form thereof | |
| CN114621310A (en) | Targeted Prdx2 degradation agent based on tripterine, and preparation method and medical application thereof | |
| CN102321100B (en) | Preparation method of cefminox sodium | |
| CN109053724A (en) | The purification process and purposes of the preparation method and Tadalafei of a kind of impurity prepared during Tadalafei and the impurity | |
| CN111606925A (en) | Preparation method of cefixime delta 3 isomer impurity | |
| CN108794489B (en) | Derivatization reagent and preparation method and application thereof | |
| JP6974788B2 (en) | Imidazopyrroloquinoline salt and its manufacturing method, as well as pharmaceuticals, cosmetics and foods | |
| CN109134380A (en) | Chloro aminooimidazole class compound and preparation method thereof, purposes and detection method | |
| CN109824534B (en) | Synthesis method of N-alkanoyl memantine | |
| CN102643293A (en) | Cefdinir ternary complex and method for preparing cefdinir by using same | |
| CN110964022A (en) | Fluorescent probe for detecting peroxynitrite ions and preparation method and application thereof | |
| JP3746181B2 (en) | Phenyldiazirine compounds and photoaffinity labeling reagents | |
| JP2663105B2 (en) | 14α-hydroxy-4-androstene-3,6,17-trione hydrate crystal and method for producing the same | |
| CN112110862B (en) | Preparation method and application of 1,4,5, 6-tetrahydro-5-hydroxypyrimidine compound and hydrochloride thereof | |
| CN114989147B (en) | Benzopyrimidine compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof | |
| CN113045573B (en) | Probe compound resistant to carbapenem antibiotic germs and application | |
| CN112920241B (en) | Benzimidazole derivative BI308 and preparation method and application thereof | |
| CN117355528B (en) | Salt type pyrrolotriazine compound, crystal form and preparation method thereof | |
| US11708357B2 (en) | Crystal form of pyrrolidinyl urea derivative and application thereof | |
| CN109081847A (en) | A kind of 1/2 water cefotaxime sodium compound | |
| CN114956997B (en) | Vanilmandelic acid hapten derivative and synthetic method thereof, vanillylmandelic acid antigen and preparation method thereof, antibody and kit | |
| CN110092799B (en) | Cyclic compound, preparation method and application thereof | |
| CN109134505A (en) | 1/2 water cefoperazone sodium compound of one kind and its drug combination preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee |
Owner name: HAINAN GOURD DOLL PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: HAINAN XINZHONGZHENG PHARMACEUTICAL CO., LTD. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: 570216, East B District, No. 6, Haikou Free Trade Zone, No. 168 Nanhai Road, Hainan, Haikou Patentee after: Hainan Gourd Doll Pharmaceutical Co., Ltd. Address before: 570216, East B District, No. 6, Haikou Free Trade Zone, No. 168 Nanhai Road, Hainan, Haikou Patentee before: Hainan Xinzhongzheng Pharmaceutical Co., Ltd. |
|
| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 570216, East B District, No. 6, Haikou Free Trade Zone, No. 168 Nanhai Road, Hainan, Haikou Patentee after: HAINAN HULUWA PHARMACEUTICAL GROUP CO., LTD. Address before: 570216, East B District, No. 6, Haikou Free Trade Zone, No. 168 Nanhai Road, Hainan, Haikou Patentee before: Hainan Gourd Doll Pharmaceutical Co., Ltd. |