CN101671347B - Carboxylic acid penicillin amine salt and application thereof in preparing high-purification sodium oxacillin salt - Google Patents
Carboxylic acid penicillin amine salt and application thereof in preparing high-purification sodium oxacillin salt Download PDFInfo
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Abstract
The invention relates to a carboxylic acid penicillin dibenzyl (substituting benzyl) ethylenediamine salt compound and an application thereof in preparing a high-purification sodium oxacillin salt. The carboxylic acid penicillin dibenzyl (substituting benzyl) ethylenediamine salt compound has a structure as the formula II, and carboxylic acid penicillin comprises ticacillin, carbenicillin and thelike, wherein R is thiofuran-3-group or phenyl; R1, R2 and R3 are respectively independent H, alkyls of C1-C5, halogens and nitryl; and substituent groups of the substituted alkyl are selected from the halogens and alkoxy groups of C1-C5.
Description
Technical field
The present invention relates to the application in preparation high purity penicillin sodium salt of a kind of carboxylic acid penicillium mould dibenzyl (substituted benzyl) ethylenediamine salt compound and this compound.
Background technology
In the penicillium mould classification, ticarcillin and Gepcillin are wide spectrum semi-synthetic penicillins microbiotic, contain two carboxyls in the molecular structure, belong to the carboxylic acid PCs, shown in I,
Wherein, R is thiene-3-yl-
or phenyl
; M1 and M2 can be identical or different groups, like sodium ion, potassium ion, amino or suitable amido etc.
Ticarcillin is a kind of new thiophene alkene penicillin carboxy of Beecham company exploitation; It influences the synthetic of bacteria cell wall through disturbing the mucopeptide cross bracing, causes the defective or the weakness of cell walls, and bacterium presents deformity; It is dead with rapid dissolving to continue, thereby reaches anti-microbial effect.Ticarcillin is a kind of Broad spectrum antibiotics, to multiple gram-positive microorganism (G+), Gram-negative bacteria (G-) sensitivity, is mainly used in the treatment gram-negative bacteria and infects.For charrin's disease, often need and the aminoglycoside antibiotics combined utilization.
Gepcillin is the semi-synthetic anti-pseudomonas penicillium mould of a kind of wide spectrum; Its mechanism of action causes the defective or the weakness of cell walls for through disturbing the mucopeptide cross bracing to influence the synthetic of bacteria cell wall, and bacterium presents deformity; It is dead with rapid dissolving to continue, and plays anti-microbial effect.Its antimicrobial spectrum is similar with penbritin basically, and characteristics are strong to Pseudomonas aeruginosa and the effect of indole-positive Bacillus proteus, and these article are the penicillin resistant enzyme not, and are invalid to the resistance gold-coloured staphylococci.
Ticarcillin and Gepcillin clinically mainly with its double sodium salt and beta-lactamase inhibitor system as: process compound preparation with Clavulanic Potassium and sulbactam; Both cooperations had both enlarged antimicrobial spectrum; Strengthen anti-microbial activity again, thereby played good anti-microbial effect.Carboxylic acid penicillium mould double sodium salt structural formula is shown in the formula III:
Wherein, R is thiene-3-yl-or phenyl.
Have two carboxyls on the formula III double sodium salt compound structure, two the equal ability of carboxyl salifies, but salifiable kinetic rate is different, forms the mixture of single sodium salt and double sodium salt in the salification process easily, and crystal formation is bad, is non-medicinal forms.In addition, formula III double sodium salt compound is relatively more responsive to temperature and pH, has very high water absorbability, is prone to decompose.Therefore, be difficult to prepare carboxylic acid penicillium mould double sodium salt with conventional solvent method.Lyophilization and the spray-drying processes of adopting prepare double sodium salt more in the data of literatures; Adopt the common meeting of lyophilization because impurity is in the aqueous solution in synthetic preparation; All impurity and product are separated out simultaneously after the lyophilize; Cause that the finished product look level is higher, purity is lower, less stable, influenced the final quality of product.
U.K.pat.No1004670 and US.pat.No4066664 disclose the synthetic and preparation method of Ticarcillin Disodium, and wherein lyophilization is adopted in the preparation of final step sodium salt, and products obtained therefrom is of poor quality, is not suitable for suitability for industrialized production.
In order to address the above problem and provide a kind of preparation method who is suitable for large-scale commercial prodn, the researchist has proposed various improved methods.
Proposed in the CN101070326A patent to prepare the carboxylic acid penicillin sodium salt: carboxylic acid penicillium mould compound is turned to sodium salt in Transfer in Aqueous Solution with solvent crystallization; Be added drop-wise to then in alcohols or the organic solvent of ketone and separate out product, filtering also, vacuum-drying obtains the carboxylic acid penicillin sodium salt.There is following shortcoming in this method: 1) adopt mixed solvent, products obtained therefrom does not have crystal formation, and the look level is high, and less stable, product purity are merely about 95%; 2) yield of preparation sodium salt is merely about 60%.
The preparation method of the carboxylic acid penicillin sodium salt of mentioning among the CN1696133A (200410037727.3); Comprise step .1) with the isopropyl ether solvent; Mix the generation chlorination reaction to 3-thiophene ethyl malonate and thionyl chloride, preserve subsequent use behind the reaction solution concentrating under reduced pressure.2) 6-amino-penicillanic acid, sodium hydroxide, acetone and step 1) is made reaction solution mixes the generation acylation reaction; With the reaction solution phase-splitting; Make the water decolouring, filter, filtrating merges the back and adds Hydrogen chloride and MIBK, and the solution phase-splitting is extracted; The acetone soln and the crystal seed that in the organic phase of gained, add Sodium isooctanoate, growing the grain.3) solution after the crystallization is filtered, filter cake washing is also dry, obtains ticarcillin list sodium salt.4) be mixed with the aqueous solution to ticarcillin list sodium salt and sodium hydroxide, with promptly getting the ticarcillin sodium salt after its decolouring, filtration, the freeze-drying.This method forms single sodium salt in the preparation process, and uses mixed solvent, finally obtains product with freeze drying process, and products obtained therefrom look level is high, and purity is on the low side, and quality product does not meet the European Pharmacopoeia standard.
Among the preparation method of the disclosed carboxylic acid penicillin sodium salt of CN100486978C (200610132419.8), in penicillium mould free acid solution, behind the adding solvent cut, use activated carbon decolorizing, filter; Add salt forming agent ,-10～-50 ℃ with agitation condition under growing the grain, complete until crystallization, filter, washing obtains carboxylic acid penicillium mould double sodium salt after the vacuum-drying.This crystallization process is compared its shortcoming with lyophilization outstanding equally, complete for crystallization, adds a large amount of organic solvents; Gained carboxylic acid penicillium mould double sodium salt is no crystal formation powder, poor stability.In actually operating, gained is carboxylic acid penicillium mould list sodium salt and double sodium salt mixture, has caused product p H defective, is not suitable for suitability for industrialized production.
China's pharmaceutical chemistry magazine, 2005,3 (16), 178-180 has reported that the Ticarcillin Disodium synthetic improves technology, adopts solvent to subtract in synthesizing and steams the back freeze-drying, obtains the ticarcillin sodium salt.This technology exists that production stage is long, yield is low, the high quality problems of product look level.
The method for preparing the carboxylic acid penicillin sodium salt in the above document not only has limitation on industrial scale, and the carboxylic acid penicillin sodium salt look level that obtains is high, specific optical rotation is low, purity difference, does not reach the requirement of European Pharmacopoeia.
Summary of the invention
To the defective that exists in the synthetic preparation of carboxylic acid penicillin sodium salt in the prior art, the present invention provides a kind of method for preparing high purity carboxylic acid penicillin sodium salt.
For reaching the foregoing invention purpose, the present invention at first provides a kind of carboxylic acid penicillium mould dibenzyl ethylenediamine salt or carboxylic acid penicillium mould substituted benzyl ethylenediamine salt, and its preparation method is provided.Can directly prepare high purity, high-load penicillin sodium salt by carboxylic acid penicillium mould dibenzyl or substituted benzyl ethylenediamine salt compound; For the storage and the safe handling of medicine provides better guarantee; Solve the problem of quality aspects such as carboxylic acid Veticillin purity salt, solvability, thereby accomplished task of the present invention.
Technical scheme of the present invention is following:
Carboxylic acid penicillium mould dibenzyl ethylenediamine salt or carboxylic acid penicillium mould substituted benzyl ethylenediamine salt, structural formula are suc as formula II:
Wherein, R is thiene-3-yl-or phenyl, and R1, R2, R3 are H, C1～C5 alkyl or substituted alkyl, halogen, nitro independently of one another, and the substituting group on the said substituted alkyl is selected from the alkoxy grp of halogen and C1～C5.
The preparation method of carboxylic acid penicillium mould dibenzyl ethylenediamine salt or carboxylic acid penicillium mould substituted benzyl ethylenediamine salt compound among the present invention; Comprise and make carboxylic acid penicillium mould raw material and N; N-dibenzyl (or substituted benzyl) ethylenediamine salt reacts production II midbody compound.N, the structural formula of N-dibenzyl (or substituted benzyl) ethylenediamine salt is suc as formula shown in the IV:
Wherein, R1, R2, R3 are H, C1～C5 alkyl or substituted alkyl, halogen, nitro independently of one another, and the substituting group on the said substituted alkyl is selected from halogen and C1～C5 alkoxy grp.
Above-mentioned carboxylic acid penicillium mould raw material can be metal-salt, ammonium salt, organic amine salt, mineral acid or the organic acid salt of carboxylic acid penicillium mould;
Above-mentioned N, N-dibenzyl or substituted benzyl ethylenediamine salt can be unhindered amina, mineral acid or organic acid form, like N, N-dibenzyl-ethylenediamin diacetate salt or N, N-dibenzyl-ethylenediamin dihydrochloride etc.
The preparation method of carboxylic acid penicillium mould midbody formula II compound of the present invention, step is following:
(1) the carboxylic acid penicillin solution is regulated pH2.0～10.0, adds N, N-dibenzyl ethylenediamine salt or N, and N-substituted benzyl ethylenediamine salt, 0～100 ℃ of temperature of reaction forms formula II carboxylic acid penicillium mould benzyl salt compound.Carboxylic acid penicillium mould and N, the mol ratio of N-dibenzyl ethylenediamine salt or N-substituted benzyl ethylenediamine salt is 1: 1.0～10.0, preferred 1: 1.0～8.0.
Preferable reaction temperature is 0～50 ℃ in this step (1).
(2) add appropriate solvent and make carboxylic acid penicillium mould benzyl salt crystallization complete, the crystallization time range is 1～20 hour, and filtering separation obtains formula II carboxylic acid penicillium mould benzyl salt compound.
The preferred crystallization time is 1～10 hour in this step (2).
Carboxylic acid penicillin solution preferred aqueous solutions described in the preparation process (1) also can be the mixing solutions of water-alcohol or water-ketone.Conventional mineral acid, mineral alkali or organic bases are selected in the pH regulator agent of carboxylic acid penicillin solution for use, preferred hydrochloric acid, acetate, sodium hydroxide, ammoniacal liquor, triethylamine or Tributylamine.
The solvent that adds in the step (2) can be single organic solvent or water-pure mixed solvent or water-ketone mixed solvent.Described alcohol is selected from methyl alcohol, ethanol, propyl alcohol, isopropylcarbinol, propyl carbinol or 2-butanols, and described ketone is selected from acetone, butanone or MIBK, particular methanol or acetone.
Its reaction process is following:
The result detects:
Warp
1The HNMR analytical proof, N in the gained formula II carboxylic acid penicillium mould benzyl salt compound, N-dibenzyl-ethylenediamin or N, N-substituted benzyl quadrol and carboxylic acid penicillium mould existence form are that their mol ratio is 1: 1; High-pressure liquid phase (HPLC) detects its purity>=98%.
As synthesis of carboxylic acid penicillin sodium salt useful as intermediates, formula II carboxylic acid penicillium mould dibenzyl or substituted benzyl ethylenediamine salt compound have the purity height, and characteristics such as purification are stablized, are easy to chemical property.
Another innovative point of the present invention is formula II compound carboxylic acid penicillium mould benzyl or the application of substituted benzyl ethylenediamine salt in preparation carboxylic acid penicillin sodium salt.
The invention further relates to method by formula II compound high purity carboxylic acid penicillin sodium salt.This method is included in uses strongly acidic cationic exchange resin to handle formula II carboxylic acid penicillium mould dibenzyl (substituted benzyl) ethylenediamine salt compound in the solvent, remove by filter resin, in filtrating, adds the sodium exchanger then, obtains the carboxylic acid penicillin sodium salt.Reaction process by formula II compound carboxylic acid penicillin sodium salt is following:
By the method for formula II compound high purity carboxylic acid penicillin sodium salt, concrete steps are following:
(1) formula II compound is suspended in the solvent, the ratio of formula II compound and solvent is 1: 2～1: 100g/ml gets suspension;
(2) add strongly acidic cationic exchange resin in the suspension, stir down at 0～30 ℃ and made formula II compound dissolution in 3-10 hour, N is wherein removed in resin cation(R.C.) absorption, and N-dibenzyl or substituted benzyl ethylenediamine salt obtain free carboxy acid's penicillinic acid solution;
(3) solution that makes of filtration step (2) to be removing Zeo-karb wherein, and filtrating is decoloured and handled the back and add the sodium exchanger and handle, and keeps 0～50 ℃ of treatment temp, and crystallization filters, carboxylic acid Veticillin product salt.
Preferred 0～40 ℃ of recrystallization temperature treats that carboxylic acid penicillium mould dibenzyl or the complete after-filtration of substituted benzyl ethylenediamine salt crystallization go out product.
Solvent in the step (1) is selected from the mixed solvent of ethanol, ETHYLE ACETATE, THF, water, ethanol and water volume ratio 1/1, THF and water volume ratio 1/1, the mixed solvent of preferred alcohol and water volume ratio 1/1.
The ratio preferred 1: 5～1 of step (1) Chinese style II compound and solvent: 50g/ml, further preferred proportion is 1: 10～1: 20g/ml.
The amount of the strongly acidic cationic exchange resin that adds in the step (2) and the ratio of formula II compound are (1～100): 1 mass ratio, preferred mass is than being (2～50): 1.
Step (2) strongly acidic cationic exchange resin is selected from Amberlite IR-120, Duolite ES-280 or ThermaxT-54, but market is bought.
Sodium exchanger described in the step (3) is selected from sodium hydrogencarbonate, yellow soda ash, Sodium.alpha.-hydroxypropionate, Sodium isooctanoate, sodium-acetate or sodium methylate, wherein preferred Sodium isooctanoate or sodium hydrogencarbonate.
The mol ratio of the dosage of the sodium exchanger described in the step (3) and formula II compound is a formula II compound: sodium exchanger=1: (1～10), preferable range 1: (2～5).
Excellent results of the present invention:
The present invention is with carboxylic acid penicillium mould and N; The reaction of N-dibenzyl ethylenediamine salt or substituted benzyl ethylenediamine salt obtains a kind of carboxylic acid penicillium mould benzyl salt compound of brand new, i.e. carboxylic acid penicillium mould dibenzyl ethylenediamine salt or substituted benzyl ethylenediamine salt (structural formula II), and this compound crystal formation is good, purity is high, stable in properties; And this carboxylic acid penicillium mould benzyl salt compound reacts with the sodium exchanger after Zeo-karb is handled again; Preparation carboxylic acid penicillin sodium salt, simple to operate, convenient processing; Compare with known method about the synthesis of carboxylic acid penicillin sodium salt, the prepared carboxylic acid Veticillin purity salt of method provided by the invention is up to more than 98%.
The inventor finds that carboxylic acid penicillium mould dibenzyl or substituted benzyl ethylenediamine salt compound (structural formula II) solubleness in water and most organic solvent is less; And dibenzyl or substituted benzyl diethyl amine salt can form the adsorptivity that double charge strengthens itself and Zeo-karb; Make dibenzyl or substituted benzyl diethylamine be adsorbed more thoroughly; In carboxylic acid penicillium mould and dibenzyl or substituted benzyl quadrol salification process, maintain under the weak acid environment simultaneously; Avoid the degraded of carboxylic acid penicillium mould effectively, thereby guaranteed in the preparation process, to form highly purified carboxylic acid penicillin sodium salt.
Therefore, one of innovative point of the present invention is the preparation of important intermediate compound-carboxylic acid penicillium mould dibenzyl or substituted benzyl ethylenediamine salt (structural formula II).As the important intermediate of synthesis of carboxylic acid penicillin sodium salt, this benzyl salt has that purity height, look level are good, stable in properties, can long-term storage, be easy to advantages such as purification.Prepare penicillin sodium salt by penicillium mould benzyl salt, can adopt more economical solvent method in the industrial production, solved the production cost and the quality problems that exist in the freeze-drying of carboxylic acid penicillin sodium salt, and be easy to amplify and carry out scale prodn.
Description of drawings
Fig. 1 is embodiment 1 a gained ticarcillin benzyl ethylenediamine salt infared spectrum.X-coordinate is wave number (cm among the figure
-1), ordinate zou is transmitance %.
Fig. 2 is embodiment 1 a gained ticarcillin dibenzyl ethylenediamine salt HPLC collection of illustrative plates, and X-coordinate is time (min of unit) among the figure.
Fig. 3 is embodiment 4 gained Gepcillin dibenzyl ethylenediamine salt HPLC collection of illustrative plates, and X-coordinate is time (min of unit) among the figure.
Embodiment
Following embodiment is used to further specify the present invention, but does not show any restriction to the present invention.
One, the preparation of midbody formula II compound
The preparation of embodiment 1 ticarcillin dibenzyl ethylenediamine salt
Ticarcillin sodium salt 21g (0.05mol) is dissolved in the 190ml water, adds the 200ml acetone diluted, treats that solid dissolves after-filtration fully.Gained filtrating is stirred down fast, adds N, N-dibenzyl-ethylenediamin diacetate solution (18g (0.05mol) N, the N-dibenzyl-ethylenediamin diacetate is dissolved in the 150ml water).Separate out the white crystalline solid.Stir 1 hour after-filtration, water washing, 35 ℃ of following dryings of gained ticarcillin dibenzyl ethylenediamine salt solid 24 hours obtain solid weight 30g.Yield 86.9%.Mp226～230 ℃ (decomposition).It is 99.5% (Fig. 2) that high-pressure liquid phase (HPLC) detects purity.
1The mol ratio of dibenzyl-ethylenediamin and ticarcillin is a dibenzyl-ethylenediamin in the HNMR analytical proof gained ticarcillin dibenzyl ethylenediamine salt compound: ticarcillin=1: 1.
1HNMR(400MHz，DMSO)δ8.56(d，1H)，8.04(d，1H)，7.45～7.30(m，6H)，6.75～6.73(m，1H)，5.69～5.56(m，1H)，5.01(d，1H)，4.22(dd，2H)，3.94(s，1H)，3.82(s，3H)，2.95(s，1H)。
The preparation of embodiment 2 ticarcillin dibenzyl ethylenediamine salts
Ticarcillin sodium salt 4.2g (0.01mol) is dissolved in the 40ml water, in feed liquid, adds N, the solution of N-dibenzyl-ethylenediamin diacetate 3.6g and 40ml water.Ticarcillin benzyl ethylenediamine salt is separated out immediately, stirs 2 hours after-filtration, water washing, 35 ℃ of vacuum-drying 24 hours.Obtain ticarcillin dibenzyl ethylenediamine salt 6g, yield 79.5%.Mp225～228 ℃, HPLC detects its purity 99.7%.Structure is identical with embodiment 1.
The preparation of embodiment 3 ticarcillin dibenzyl ethylenediamine salts
Ticarcillin Disodium 84g (0.2mol) is dissolved in the 420ml water, and room temperature is stirred to dissolution filter for a short time.N, N-dibenzyl-ethylenediamin dihydrochloride 61.5g (0.2mol) is dissolved in the 720ml water, joins in the ticarcillin sodium solution under stirring fast.Add the back and in feed liquid, add 780ml acetone.Stirred 30 minutes, and filtered, water washing, 35 ℃ of following vacuum-drying 48 hours obtains ticarcillin dibenzyl ethylenediamine salt 130g.Yield 97%.Mp226～228 ℃, HPLC detects its purity 99.2%.Structure is identical with embodiment 1.
The preparation of embodiment 4 Gepcillin dibenzyl ethylenediamine salts
Carbenicillin sodium 4.2g (0.01mol) is dissolved in the 40ml water, adds the dilution of 40ml methyl alcohol.After treating dissolving fully, in feed liquid, add N, the solution of N-dibenzyl-ethylenediamin diacetate 3.6g (0.01mol) and 40ml water.Gepcillin benzyl salt is separated out immediately.Stir 30 minutes after-filtration fast, use water washing, drain 35 ℃ of following vacuum-dryings 24 hours, obtain Gepcillin dibenzyl ethylenediamine salt 6g.Yield 83.3%.Mp201～205 ℃, HPLC detects its purity 99.0% (Fig. 3).
1The mol ratio of dibenzyl-ethylenediamin and Gepcillin is a dibenzyl-ethylenediamin in the HNMR analytical proof Gepcillin dibenzyl ethylenediamine salt compound: carboxylic acid penicillium mould=1: 1.
1HNMR(400MHz，DMSO)δ8.06(d，1H)，8.04(d，1H)，7.05～7.00(m，6H)，6.25～6.13(m，1H)，5.10～5.15(m，1H)，4.11(dd，2H)，3.56(s，1H)，3.15(s，3H)，2.75(s，1H)。
The preparation of embodiment 5 ticarcillin dibenzyl ethylenediamine salts
Join N to the ethyl acetate solution 20ml that contains ticarcillin acid 3.05g (0.07mol); In the acetone soln of N-dibenzyl-ethylenediamin diacetate [1.7g (0.07mol) N, the N-dibenzyl-ethylenediamin diacetate is dissolved in the 100ml acetone], white solid is separated out immediately; Stir 30 minutes after-filtration; Water washing, 35 ℃ of following vacuum-drying 24 hours obtains Gepcillin dibenzyl ethylenediamine salt 4.5g.Yield 97%.Mp224～228 ℃, HPLC detects its purity 99.3%.Structure is identical with embodiment 1.
The preparation of embodiment 6 Gepcillin dibenzyl ethylenediamine salts
The methanol solution 50ml that contains Gepcillin acid 3.05g (0.007mol) adds N, the solution of N-dibenzyl-ethylenediamin dihydrochloride 1.78g and 50ml methyl alcohol; White solid is separated out immediately, stirs 30 minutes, filters; Methanol wash; 35 ℃ of following vacuum-drying 24 hours obtains Gepcillin dibenzyl ethylenediamine salt 5g, yield 99%.Structure is identical with embodiment 4.
Two, the preparation of carboxylic acid penicillin sodium salt
Zeo-karb Amberlyst 15, the Amberlite200C that uses in following examples is Rohmhass Rhom and Hass product.
The preparation of embodiment 7. ticarcillin double sodium salts
The ticarcillin dibenzyl ethylenediamine salt 20g (0.03mol) of embodiment 1 preparation is suspended in the 350ml methyl alcohol, keeps 5～10 ℃ of temperature.In feed liquid, add Amberlyst 15 resin 12.5g, stir 2 hours, remove by filter resin to feed clarification.Filtrating keeps 5～10 ℃ of temperature, adds Sodium isooctanoate and regulates pH8.0, is cooled to 0 ℃ then, leaves standstill 20 hours, separates out the white crystalline solid, filter, and the cold methanol washing, 30～35 ℃ of following vacuum-dryings obtain ticarcillin double sodium salt 11g, yield 85.3%.HPLC detects its purity 99.1%.
1H-NMR(400MHz，DMSO)δ：1.54(S，6H)，4.28(s，1H)，4.67(s，1H)，5.50(d，1H，J＝4.0Hz)，5.58(m，1H)，7.12(m，2H).MS-ESI?m/z?429.4[M+1]+。
The preparation of embodiment 8. ticarcillin double sodium salts
The ticarcillin dibenzyl ethylenediamine salt 180g (27.2mol) of embodiment 3 preparations is suspended in the 200ml THF; Add entry 30ml, strongly acidic cationic exchange resin Amberlite 200C 200g, holding temperature is no more than 10 ℃; Stir 3～5 hours to feed liquid reaction clarification; Remove by filter resin, gained filtrating added the 2g activated carbon decolorizing 30 minutes, removed by filter gac.Add sodium-acetate 50g in the gained filtrating, be stirred to solid and separate out, filter, 35 ℃ of following vacuum-dryings of gained solid obtain ticarcillin double sodium salt 130g, yield 88%.HPLC detects its purity 99.2%.
The preparation of the two sodium of embodiment 9. Gepcillins
With the Gepcillin dibenzyl ethylenediamine salt 20g of preparation among the embodiment 4,, obtain Gepcillin double sodium salt 15g, yield 85% according to operation among the embodiment 7.HPLC detects its purity 99.3%.
Claims (10)
1. be the method for the carboxylic acid penicillin sodium salt more than 98% by formula II compound purity, said formula II structural formula of compound is following:
Wherein, R is thiene-3-yl-or phenyl; R1, R2, R3 are H, C1～C5 alkyl or substituted alkyl, halogen, nitro independently of one another, and the substituting group on the said substituted alkyl is selected from the alkoxy grp of halogen and C1～C5;
Step is following:
(1) formula II compound is suspended in the solvent, the ratio of formula II compound and solvent is 1: 2～1: 100g/ml gets suspension;
(2) add strongly acidic cationic exchange resin in the suspension; Under 0～30 ℃, stir and made formula II compound dissolution in 3-10 hour, N wherein, N-dibenzyl ethylenediamine salt or N are removed in resin cation(R.C.) absorption; N-substituted benzyl ethylenediamine salt obtains free carboxy acid's penicillinic acid solution;
(3) solution that makes of filtration step (2) to be removing Zeo-karb wherein, and filtrating is decoloured and handled the back and add the sodium exchanger and handle, and keeps crystallization under 0～50 ℃ of condition of temperature, filter, carboxylic acid Veticillin product salt.
2. preparing purity according to claim 1 is the method for the carboxylic acid penicillin sodium salt more than 98%, it is characterized in that said recrystallization temperature is 0～40 ℃.
3. preparing purity according to claim 1 is the method for the carboxylic acid penicillin sodium salt more than 98%, it is characterized in that the solvent in the step (1) is selected from the ethanol of ethanol, ETHYLE ACETATE, THF, water, volume ratio 1/1 and the THF and the water mixed solvent of water mixed solvent or volume ratio 1/1.
4. preparing purity according to claim 1 is the method for the carboxylic acid penicillin sodium salt more than 98%, it is characterized in that the solvent in the step (1) is second alcohol and water 1/1 a mixed solvent by volume.
5. preparing purity according to claim 1 is the method for the carboxylic acid penicillin sodium salt more than 98%, and the ratio that it is characterized in that step (1) Chinese style II compound and solvent is 1: 5～1: 50g/ml.
6. preparing purity according to claim 1 is the method for the carboxylic acid penicillin sodium salt more than 98%, and the ratio that it is characterized in that step (1) Chinese style II compound and solvent is 1: 10～1: 20g/ml.
7. preparing purity according to claim 1 is the method for the carboxylic acid penicillin sodium salt more than 98%, it is characterized in that the amount of the strongly acidic cationic exchange resin of adding in the step (2) and the ratio of formula II compound are (1～100): 1 mass ratio.
8. preparing purity according to claim 1 is the method for the carboxylic acid penicillin sodium salt more than 98%, it is characterized in that the amount of the strongly acidic cationic exchange resin of adding in the step (2) and the mass ratio of formula II compound are (2～50): 1.
9. preparing purity according to claim 1 is the method for the carboxylic acid penicillin sodium salt more than 98%, it is characterized in that the sodium exchanger described in the step (3) is selected from Sodium isooctanoate or sodium hydrogencarbonate.
10. preparing purity according to claim 1 is the method for the carboxylic acid penicillin sodium salt more than 98%, it is characterized in that the dosage of the sodium exchanger described in the step (3) and the mol ratio of formula II compound are formula II compound: sodium exchanger=1: (1～10).
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES374402A1 (en) * | 1969-12-10 | 1972-01-01 | Lafarquim S A Lab | Procedure for obtaining an insoluble salt in water. (Machine-translation by Google Translate, not legally binding) |
| US4066664A (en) * | 1975-04-08 | 1978-01-03 | Recherche Et Industrie Therapeutiques | Intermediates for preparing α-carboxy-α-(3-thienyl)penicillin and cephalosporin derivatives |
| CN1696133A (en) * | 2004-05-10 | 2005-11-16 | 河北张药股份有限公司 | Method for synthesizing ticarcillin sodium |
-
2009
- 2009-09-29 CN CN2009100184907A patent/CN101671347B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES374402A1 (en) * | 1969-12-10 | 1972-01-01 | Lafarquim S A Lab | Procedure for obtaining an insoluble salt in water. (Machine-translation by Google Translate, not legally binding) |
| US4066664A (en) * | 1975-04-08 | 1978-01-03 | Recherche Et Industrie Therapeutiques | Intermediates for preparing α-carboxy-α-(3-thienyl)penicillin and cephalosporin derivatives |
| CN1696133A (en) * | 2004-05-10 | 2005-11-16 | 河北张药股份有限公司 | Method for synthesizing ticarcillin sodium |
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| CN101671347A (en) | 2010-03-17 |
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