CN103319505A - Method for crystallizing and producing cefpiramide sodium crystals - Google Patents
Method for crystallizing and producing cefpiramide sodium crystals Download PDFInfo
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Abstract
The invention discloses a method for crystallizing and producing cefpiramide sodium crystals. The method comprises the steps that: (a) cefpiramide acid and an transamination agent are dissolved in a solvent I, wherein the transamination agent is any one selected from triethylamine, diisopropylamine, and isopropylamine; and a temperature is controlled, and the materials are stirred until completely dissolved; (b) a salt-forming agent is added into a solvent II, wherein when the salt-forming agent is sodium ethylhexanoate, the solvent II is an acetone solvent, and when the salt-forming agent is sodium hydroxide, the solvent II is any one or a mixture of two selected from methanol and tetrahydrofuran; and the materials are stirred until completely dissolved; (c) the salt-forming agent solution is uniformly added into the solution of cefpiramide amine salt; the temperature is controlled, and crystal seeds are added; curing crystallization is carried out; acetone is added into the crystallization system for regulating the pH value of the crystallization system and for carrying out solvent-out crystallization; and filtering, washing, and drying are carried out, such that the cefpiramide sodium crystals are obtained. The method provided by the invention has the advantages of simple operation, uniform crystals, high purity, low impurity content, good stability, easy storage, and the like.
Description
Technical field
The present invention relates to a kind of field of medicine and chemical technology and produce the method for preparation, specifically a kind of method of producing the cefpiramide sodium crystal with crystallization method.
Background technology
The chemistry of Wy-44635 is called (6R, 7R)-7-[(R)-2-(4-hydroxyl-6-methyl-3-pyridine hydroxyl amino)-2-(p-hydroxybenzene) kharophen]-3-[[(1-methyl isophthalic acid H-tetrazolium-5-yl) sulphur] methyl]-8-oxo-5-thia-1 azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid sodium salt.Molecular formula: C
25H
23N
8NaO
7S
2, its structural formula is:
This product is the Third generation Cephalosporins microbiotic, is used for responsive microbial septicemia, pneumonia pulmonary suppuration disease, prostatitis, acute/chronic bronchitis, cholecystitis, the intra-uterine infections etc. such as Staphylococcus, Peptococcus, enterobacter, proteus, hemophilus influenza, streptococcus.
Mainly contain the imported product from Slovenia Lai Ke company and SUMITOMO CHEMICAL pharmacy on the present domestic cefpiramide preparation of sodium market, preparation is expensive.Because the technical difficulty of this kind is larger, the producer of the aseptic Wy-44635 of domestic production is less, and only adopt lyophilization production, the quality of the pharmaceutical preparations that lyophilization is produced is generally relatively poor, shows as that purity is on the low side, its related substances is high, product stability is poor, is difficult for preserving.
China Patent Publication No. CN101037444A discloses a kind of synthetic method of compound of cefpiramide sodium.The method adopt Cefpiramide Acid and triethylamine, diethylamine, quadrol in organic solvent ,-10～40 ℃ of reactions, drip weight percent in the mixture that after reaction, obtains and be the acetone soln of 10%～15% sodium salt, adjust pH to 6～8, then filtration, drying obtain Wy-44635.The amine agent that turns of adopting in this patent is triethylamine, diethylamine, quadrol, and their toxicity is larger, and the amine salt of generation solvability in its solvent system is relatively poor, easily separates out.Adopt respectively sodium-acetate, Sodium.alpha.-hydroxypropionate, Sodium Thiocyanate 99, Sodium isooctanoate etc. to do salt forming agent in this patent, the product stability of production is poor, and specific volume is large, and poor fluidity is difficult for packing.
Summary of the invention
The technical issues that need to address of the present invention provide the method that a kind of product purity is high, the cefpiramide sodium crystal is produced in the crystallization of good stability.
For solving the problems of the technologies described above the technical solution used in the present invention be:
The method of cefpiramide sodium crystal is produced in crystallization, comprises following process:
(a) preparation process of cefpiramide amine salt solution: with Cefpiramide Acid with turn the amine agent and be dissolved in the solvent I, the control temperature is stirred to fully dissolving at 0～25 ℃, described turn the amine agent be in triethylamine, Diisopropylamine, the Isopropylamine any one; Cefpiramide Acid weight grams and the solvent I volume milliliter ratio of counting are 1:4～1:20;
(b) dissolution process of salt forming agent: salt forming agent is added in the solvent II, be stirred to fully dissolving, described salt forming agent is the wherein a kind of of Sodium isooctanoate or sodium hydroxide; When described salt forming agent was Sodium isooctanoate, the solvent II was acetone solvent; When described salt forming agent was sodium hydroxide, the solvent II was that any one or two kinds mix arbitrarily in methyl alcohol, the tetrahydrofuran (THF); Salt forming agent weight grams and the solvent II volume milliliter ratio of counting are 1:10～1:50;
(c) Crystallization Process: salt forming agent solution is evenly joined in the solution of cefpiramide amine salt, the control temperature is at 0～45 ℃, then add after the cefpiramide sodium crystal carries out growing the grain as crystal seed, add again acetone in the crystallizing system and regulate the pH value and carry out dilution crystallization, then to crystal filter, wash, drying obtains the cefpiramide sodium crystal.
Further improvement of the present invention is: the solvent I is the wherein mixing of one or more of methyl alcohol, acetone, acetonitrile, N,N-dimethylacetamide, DMF, tetrahydrofuran (THF), water in the preparation process of described cefpiramide amine salt solution.
Further improvement of the present invention is: Cefpiramide Acid weight grams and the solvent I volume milliliter ratio of counting are 1:5～1:15 in the preparation process of described cefpiramide amine salt solution.
Further improvement of the present invention is: salt forming agent weight grams and the solvent II volume milliliter ratio of counting are 1:25～1:40 in the dissolution process of described salt forming agent.
Further improvement of the present invention is: when salt forming agent was Sodium isooctanoate in the described Crystallization Process, the molar ratio of Sodium isooctanoate and Cefpiramide Acid was 1:1, and when salt forming agent was sodium hydroxide, the molar ratio of sodium hydroxide and Cefpiramide Acid was 1.15:1.
Further improvement of the present invention is: salt forming agent solution joins evenly that the used time is 20～30min in the cefpiramide amine salt solution in the described Crystallization Process.
Further improvement of the present invention is: adding crystal seed weight in the described Crystallization Process is 1 ‰ of Cefpiramide Acid weight～5 ‰; Rearing crystal time is 5～30min.
Further improvement of the present invention is: when adding acetone carries out dilution crystallization the pH value of crystallizing system is regulated, when salt forming agent is sodium hydroxide, crystallizing system pH value is adjusted to 10.5～11.5, and when salt forming agent was Sodium isooctanoate, crystallizing system pH value was adjusted to 8.5～9.5.
Further improvement of the present invention is: the dry vacuum-drying mode that adopts of the crystal in the described Crystallization Process, drying temperature is 30～50 ℃.
Owing to having adopted technique scheme, the obtained technical progress of the present invention is:
What the method transfer amine agent of crystallization production cefpiramide sodium crystal was adopted is triethylamine, Isopropylamine, Diisopropylamine, the cefpiramide amine salt solvability in solvent I of the present invention that generates is good, be difficult for separating out, provide favourable condition for follow-up adding salt forming agent reaction generates the cefpiramide sodium crystal.If Cefpiramide Acid weight grams and the solvent I volume milliliter ratio of counting exceed the scope of 1:4～1:20, it is unstable that reaction system will become, and exceed the scope of 1:5～1:15, and the cefpiramide amine salt can be separated out with crystalline form in 12 hours.
Because invention has changed kind and the proportioning of crystallizing system solvent and changed salt forming agent, overcome that the product stability that prior art produces is poor, specific volume large, poor fluidity, be difficult for the packing shortcoming.The present invention adopts sodium hydroxide and Sodium isooctanoate as salt forming agent, the Wy-44635 product of producing, and specific volume is little, between 1.6～1.8, good fluidity, is easy to packing.After amino acid transfers an amine amine salt to, be slightly soluble in methyl alcohol, be dissolved in hardly acetone, acetonitrile, N, N-N,N-DIMETHYLACETAMIDE, N, any solvent such as dinethylformamide, tetrahydrofuran (THF), the present invention not only can make solubilizing reaction fully dissolve after Cefpiramide Acid weight grams and the solvent I volume milliliter ratio of counting are made into 1:5～1:15, and solution-stabilized, even can not separate out in 24 hours 20-25 ℃ of stirring yet.
The present invention joins the used time qualified 20～30min of being in the cefpiramide amine salt solution with salt forming agent solution, and the add-on of crystal seed and rearing crystal time are defined as 1 ‰～5 ‰ and 5～30min, and crystal is evenly separated out, and purity is good, and product is easily dry.
Solvent I, the solvent II of reasonably having selected different steps to use in the method for the present invention, and solvent I and Cefpiramide Acid amount ratio have rationally been determined, the ratio of solvent II and salt forming agent Sodium isooctanoate, sodium hydroxide, make the cefpiramide amine salt solution more stable, be difficult for separating out, can improve the yield of product.In crystallisation process, add again acetone, Wy-44635 solubleness in crystallizing system is reduced, thereby separate out fast, and regulated respectively the pH value of solution according to different salt forming agents, can guarantee the maximum yield of product.
Product that this technique is done and lyophilization done the acceleration situation compares respectively under product initial mass and the same terms, concrete data see Table 1, table 2, table 3.
This technique of table 1 and the contrast of freeze-drying prods primary data
| Technique | Purity/% | Single largest impurity/% | Impurity summation/% | MMT/% |
| This handicraft product | 99.5 | 0.14 | 0.53 | 0.05 |
| Freeze-drying prods | 97.3 | 0.31 | 2.70 | 0.20 |
This handicraft product of table 2 and freeze-drying prods accelerate 3 months Data Comparisons
| Technique | Purity/% | Single largest impurity/% | Impurity summation/% | MMT/% |
| This handicraft product | 99.4 | 0.16 | 0.61 | 0.07 |
| Freeze-drying prods | 90.8 | 1.55 | 9.23 | 0.75 |
This handicraft product of table 3 and freeze-drying prods accelerate 6 months Data Comparisons
| Technique | Purity/% | Single largest impurity/% | Impurity summation/% | MMT/% |
| This handicraft product | 98.5 | 0.31 | 1.50 | 0.20 |
| Freeze-drying prods | 81.6 | 7.78 | 18.3 | 2.94 |
Can find out from above-mentioned data, products obtained therefrom of the present invention has that purity is high, foreign matter content is low, good stability, is easy to the advantages such as preservation.
Embodiment
The method of cefpiramide sodium crystal is produced in a kind of crystallization, comprise following process: (a) preparation process of cefpiramide amine salt solution: be the Cefpiramide Acid of 1:1 with molar ratio and turn the amine agent and be dissolved in the solvent I, the control temperature is at 0～25 ℃, be stirred to fully dissolving, described turn the amine agent be in triethylamine, Diisopropylamine, the Isopropylamine any one; Cefpiramide Acid weight grams and the solvent I volume milliliter ratio of counting are 1:4～1:20, are preferably 1:5～1:15; Described solvent I is the wherein mixing of one or more of methyl alcohol, acetone, acetonitrile, N,N-dimethylacetamide, DMF, tetrahydrofuran (THF), water.
(b) dissolution process of salt forming agent: salt forming agent is added in the solvent II, be stirred to fully dissolving, described salt forming agent is the wherein a kind of of Sodium isooctanoate or sodium hydroxide; When described salt forming agent was Sodium isooctanoate, the solvent II was acetone solvent; When described salt forming agent was sodium hydroxide, the solvent II was that any one or two kinds mix arbitrarily in methyl alcohol, the tetrahydrofuran (THF); Salt forming agent weight grams and the solvent II volume milliliter ratio of counting are 1:10～1:50, are preferably 1:25～1:40.
(c) Crystallization Process: salt forming agent solution is evenly joined in the solution of cefpiramide amine salt, salt forming agent solution joins that the used time is 20～30min in the cefpiramide amine salt solution; When salt forming agent was Sodium isooctanoate, the molar ratio of Sodium isooctanoate and Cefpiramide Acid was 1:1, and when salt forming agent was sodium hydroxide, the molar ratio of sodium hydroxide and Cefpiramide Acid was 1.15:1; The control temperature is at 0～45 ℃ in the adition process, and then adds after the cefpiramide sodium crystal carries out growing the grain as crystal seed, and crystal seed weight is 1 ‰ of Cefpiramide Acid weight～5 ‰; Rearing crystal time is 5～30min.And then add acetone in the crystallizing system and carry out dilution crystallization, and regulate the pH value of crystallizing system, and when salt forming agent was sodium hydroxide, crystallizing system pH value was adjusted to 10.5～11.5, and when salt forming agent was Sodium isooctanoate, crystallizing system pH value was adjusted to 8.5～9.5.Then to crystallizing system filter, wash, drying obtains the cefpiramide sodium crystal.The dry vacuum-drying mode that adopts of crystal, drying temperature is 30～50 ℃.
Below in conjunction with embodiment the present invention is described in further details.
Embodiment 1
Accurately measure Cefpiramide Acid 20g, methyl alcohol 60ml, acetone 40ml, acetonitrile 20ml, triethylamine 4.6ml is put in the four-hole bottle, the molar ratio of Cefpiramide Acid and triethylamine is 1:1, the volume milliliter ratio of counting of the weight grams of Cefpiramide Acid and solvent I is 1:6, in 20 ℃ of isothermal reactions are bathed, be stirred to fully dissolving, form the cefpiramide amine salt solution for subsequent use.Accurately measure sodium hydroxide 1.5g, methyl alcohol 40ml is put in the Erlenmeyer flask, the add-on of sodium hydroxide is that to make the molar ratio of sodium hydroxide and Cefpiramide Acid be 1.15:1, is stirred to fully dissolving, forms sodium hydroxide solution for subsequent use.In 20 ℃ of isothermal reactions are bathed, with 20 minutes sodium hydroxide solution is evenly joined in the cefpiramide amine salt solution, then add the cefpiramide sodium crystal 0.03g as crystal seed, growing the grain 10 minutes.Then adding 300ml acetone in the crystallizing system makes crystallizing system carry out dilution crystallization, regulating crystallizing system pH value is 10.5, then crystallizing system is filtered, use again twice of washing with acetone filter cake, under 40 ℃, vacuum condition, filter cake is carried out drying, until make the moisture of filter cake, residual fused lattice.Cefpiramide sodium crystal yield in the present embodiment: 94.0%, purity: 99.7%, specific volume: 1.67, single largest impurity: 0.15%, impurity summation: 0.54%, MMT (5-sulfydryl-1-methyl tetrazolium): 0.04%.
Embodiment 2
Accurately measure Cefpiramide Acid 20g, methyl alcohol 60ml, acetone 40ml, acetonitrile 20ml, Diisopropylamine 4.6ml is put in the four-hole bottle, the molar ratio of Cefpiramide Acid and Diisopropylamine is 1:1, the volume milliliter ratio of counting of the weight grams of Cefpiramide Acid and solvent I is 1:6, in 10 ℃ of isothermal reactions are bathed, be stirred to fully dissolving, form the cefpiramide amine salt solution for subsequent use.Accurately measure Sodium isooctanoate 5.42g, acetone 150ml is put in the Erlenmeyer flask, the consumption of Sodium isooctanoate is that to make the molar ratio of Sodium isooctanoate and Cefpiramide Acid be 1:1, is stirred to fully dissolving, forms the Sodium isooctanoate solution for standby.In 25 ℃ of isothermal reactions are bathed, with 25 minutes Sodium isooctanoate solution is evenly joined in the cefpiramide amine salt solution, then add the cefpiramide sodium crystal 0.02g as crystal seed, growing the grain 25 minutes.Then in crystallizing system, add 150ml acetone dilution crystallization, regulating crystallizing system pH value is 9.5, then crystallizing system is filtered, and uses twice of washing with acetone filter cake again, under 45 ℃, vacuum condition, filter cake is carried out drying, until make the moisture of filter cake, residual fused lattice.Cefpiramide sodium crystal yield in the present embodiment: 95.4%, purity: 99.4%, specific volume: 1.78, single largest impurity: 0.19%, impurity summation: 0.48%, MMT:0.06%.
Embodiment 3
Accurately measure Cefpiramide Acid 20g, methyl alcohol 60ml, acetone 40ml, water 10ml, Diisopropylamine 4.6ml is put in the four-hole bottle, the molar ratio of Cefpiramide Acid and Diisopropylamine is 1:1, the volume milliliter ratio of counting of the weight grams of Cefpiramide Acid and solvent I is 1:5.5, in 20 ℃ of isothermal reactions are bathed, be stirred to fully dissolving, form the cefpiramide amine salt solution for subsequent use.Accurately measure Sodium isooctanoate 5.42g, acetone 150ml is put in the Erlenmeyer flask, the consumption of Sodium isooctanoate is that to make the molar ratio of Sodium isooctanoate and Cefpiramide Acid be 1:1, is stirred to fully dissolving, forms the Sodium isooctanoate solution for standby.In 15 ℃ of isothermal reactions are bathed, with 30 minutes Sodium isooctanoate solution is evenly joined in the cefpiramide amine salt solution, then add the cefpiramide sodium crystal 0.04g as crystal seed, growing the grain 15 minutes.Then add 150ml acetone in the crystallizing system and carry out dilution crystallization, regulating crystallizing system pH value is 9.0, then crystallizing system is filtered, and uses twice of washing with acetone filter cake again, under 50 ℃, vacuum condition, filter cake is carried out drying, until make the moisture of filter cake, residual fused lattice.Cefpiramide sodium crystal yield in the present embodiment: 96.2%, purity: 99.8%, specific volume: 1.90, single largest impurity: 0.14%, impurity summation: 0.53%, MMT:0.05%.
Embodiment 4
Accurately measure Cefpiramide Acid 20g, methyl alcohol 60ml, acetone 40ml, water 10ml, triethylamine 4.6ml is put in the four-hole bottle, the molar ratio of Cefpiramide Acid and triethylamine is 1:1, the volume milliliter ratio of counting of the weight grams of Cefpiramide Acid and solvent I is 1:5.5, in 20 ℃ of isothermal reactions are bathed, be stirred to fully dissolving, form the cefpiramide amine salt solution for subsequent use.Accurately measure sodium hydroxide 1.5g, methyl alcohol 60ml is put in the Erlenmeyer flask, the add-on of sodium hydroxide is that to make the molar ratio of sodium hydroxide and Cefpiramide Acid be 1.15:1, is stirred to fully dissolving, forms sodium hydroxide solution for subsequent use.In 10 ℃ of isothermal reactions are bathed, with 22 minutes sodium hydroxide solution is evenly joined in the cefpiramide amine salt solution, then add the cefpiramide sodium crystal 0.1g as crystal seed, growing the grain 5 minutes.Then add 300ml acetone and carry out dilution crystallization, regulating crystallizing system pH value is 11.0, then crystallizing system is filtered, and uses washing with acetone filter cake twice again, under 35 ℃, vacuum condition filter cake is carried out drying, until make the moisture of filter cake, residual fused lattice.Cefpiramide sodium crystal yield in the present embodiment: 94.8%, purity: 99.5%, specific volume: 1.72, single largest impurity: 0.13% impurity summation: 0.55%, MMT:0.06%.
Embodiment 5
Accurately measure Cefpiramide Acid 20g, acetone 100ml, DMA (N, the N-N,N-DIMETHYLACETAMIDE) 25ml, triethylamine 4.6ml are put in the four-hole bottle, the molar ratio of Cefpiramide Acid and triethylamine is 1:1, the volume milliliter ratio of counting of the weight grams of Cefpiramide Acid and solvent I is 1:6.25, in 5 ℃ of isothermal reactions are bathed, be stirred to fully dissolving, form the cefpiramide amine salt solution for subsequent use.Accurately measure sodium hydroxide 1.5g, methyl alcohol 50ml is put in the Erlenmeyer flask, the add-on of sodium hydroxide is that to make the molar ratio of sodium hydroxide and Cefpiramide Acid be 1.15:1, is stirred to fully dissolving, forms sodium hydroxide solution for subsequent use.In 30 ℃ of isothermal reactions are bathed, with 28 minutes sodium hydroxide solution is evenly joined in the cefpiramide amine salt solution, then add the cefpiramide sodium crystal 0.08g as crystal seed, growing the grain 20 minutes.Then in crystallizing system, add 300ml acetone dilution crystallization, regulating crystallizing system pH value is 11.5, then crystallizing system is filtered, and uses twice of washing with acetone filter cake again, under 40 ℃, vacuum condition, filter cake is carried out drying, until make the moisture of filter cake, residual fused lattice.Cefpiramide sodium crystal yield in the present embodiment: 95.6%, purity: 99.9%, specific volume: 1.81, single largest impurity: 0.13%, impurity summation: 0.58%, MMT:0.07%.
Embodiment 6
Accurately measure Cefpiramide Acid 20g, acetone 100ml, DMF (N, dinethylformamide) 25ml, Diisopropylamine 4.6ml are put in the four-hole bottle, the molar ratio of Cefpiramide Acid and Diisopropylamine is 1:1, the volume milliliter ratio of counting of the weight grams of Cefpiramide Acid and solvent I is 1:6.25, in 0 ℃ of isothermal reaction is bathed, be stirred to fully dissolving, form the cefpiramide amine salt solution for subsequent use.Accurately measure Sodium isooctanoate 5.42g, acetone 150ml is put in the Erlenmeyer flask, the add-on of Sodium isooctanoate is that to make the molar ratio of Sodium isooctanoate and Cefpiramide Acid be 1:1, is stirred to fully dissolving, forms the Sodium isooctanoate solution for standby.In 40 ℃ of isothermal reactions are bathed, with 22 minutes Sodium isooctanoate solution evenly is added in the cefpiramide amine salt solution, then add the cefpiramide sodium crystal 0.06g as crystal seed, growing the grain 25 minutes.Then in crystallizing system, add 150ml acetone dilution crystallization, regulating crystallizing system pH value is 8.5, then crystallizing system is filtered, and uses twice of washing with acetone filter cake again, under 45 ℃, vacuum condition, filter cake is carried out drying, until make the moisture of filter cake, residual fused lattice.Cefpiramide sodium crystal yield in the present embodiment: 93.8%, purity: 99.2%, specific volume: 1.85, single largest impurity: 0.23% impurity summation: 0.65%, MMT:0.06%.
Embodiment 7
Accurately measure Cefpiramide Acid 20g, methyl alcohol 60ml, acetonitrile 20ml, DMA (N, the N-N,N-DIMETHYLACETAMIDE) 25ml, Diisopropylamine 4.6ml are put in the four-hole bottle, the molar ratio of Cefpiramide Acid and Diisopropylamine is 1:1, the volume milliliter ratio of counting of the weight grams of Cefpiramide Acid and solvent I is 1:5.25, in 15 ℃ of isothermal reactions are bathed, be stirred to fully dissolving, form the cefpiramide amine salt solution for subsequent use.Accurately measure sodium hydroxide 1.5g, methyl alcohol 40ml, THF (tetrahydrofuran (THF)) 30ml is put in the Erlenmeyer flask, the add-on of sodium hydroxide is that to make the molar ratio of sodium hydroxide and Cefpiramide Acid be 1.15:1, be stirred to fully dissolving, form sodium hydroxide solution for subsequent use.In 20 ℃ of constant temperature stirring reactions are bathed, with 24 minutes sodium hydroxide solution is evenly joined in the cefpiramide amine salt solution, then add the cefpiramide sodium crystal 0.05g as crystal seed, growing the grain 30 minutes.Then add 300ml acetone in the crystallizing system and carry out dilution crystallization, regulating crystallizing system pH value is 10.6, then crystallizing system is filtered, and uses twice of washing with acetone filter cake again, under 30 ℃, vacuum condition, filter cake is carried out drying, until make the moisture of filter cake, residual fused lattice.Cefpiramide sodium crystal yield in the present embodiment: 95.7%, purity: 98.9%, specific volume: 1.90, single largest impurity: 0.14%, impurity summation: 0.58%, MMT:0.06%.
Embodiment 8
Accurately measure Cefpiramide Acid 20g, methyl alcohol 100ml, acetonitrile 50ml, THF (tetrahydrofuran (THF)) 50ml, Diisopropylamine 4.6ml are put in the four-hole bottle, the molar ratio of Cefpiramide Acid and Diisopropylamine is 1:1, the weight grams of Cefpiramide Acid and the volume milliliter of solvent I are counted ratio 1:10, in 15 ℃ of isothermal reactions are bathed, be stirred to fully dissolving, form the cefpiramide amine salt solution for subsequent use.Accurately measure Sodium isooctanoate 5.42g, acetone 200ml is put in the Erlenmeyer flask, the add-on of Sodium isooctanoate is that to make the molar ratio of Sodium isooctanoate and Cefpiramide Acid be 1:1, is stirred to fully dissolving, forms the Sodium isooctanoate solution for standby.In 25 ℃ of constant temperature stirring reactions are bathed, with 20 minutes Sodium isooctanoate solution is evenly joined in the cefpiramide amine salt solution, then add the cefpiramide sodium crystal 0.1g as crystal seed, growing the grain 10 minutes.Then in crystallizing system, add 150ml acetone dilution crystallization, regulating crystallizing system pH value is 9.2, then crystallizing system is filtered, and uses twice of washing with acetone filter cake again, under 48 ℃, vacuum condition, filter cake is carried out drying, until make the moisture of filter cake, residual fused lattice.Cefpiramide sodium crystal yield in the present embodiment: 96.8%, purity: 98.5%, specific volume: 1.65, single largest impurity: 0.23%, impurity summation: 0.85%, MMT:0.07%.
Embodiment 9
Accurately measure Cefpiramide Acid 20g, methyl alcohol 50ml, acetone 40ml, water 10ml, Isopropylamine 2.8ml is put in the four-hole bottle, the molar ratio of Cefpiramide Acid and Isopropylamine is 1:1, the volume milliliter ratio of counting of the weight grams of Cefpiramide Acid and solvent I is 1:5, in 15 ℃ of isothermal reactions are bathed, be stirred to fully dissolving, form the cefpiramide amine salt solution for subsequent use.Accurately measure Sodium isooctanoate 5.42g, acetone 150ml is put in the Erlenmeyer flask, the add-on of Sodium isooctanoate is that to make the molar ratio of Sodium isooctanoate and Cefpiramide Acid be 1:1, is stirred to fully dissolving, forms the Sodium isooctanoate solution for standby.In 25 ℃ of isothermal reactions are bathed, with 20 minutes Sodium isooctanoate solution evenly is added in the cefpiramide amine salt solution, then add the cefpiramide sodium crystal 0.05g as crystal seed, growing the grain 8 minutes.Then in crystallizing system, add 150ml acetone dilution crystallization, regulating crystallizing system pH value is 9.4, then crystallizing system is filtered, and uses twice of washing with acetone filter cake again, under 30 ℃, vacuum condition, filter cake is carried out drying, until make the moisture of filter cake, residual fused lattice.Cefpiramide sodium crystal yield in the present embodiment: 94.3%, purity: 99.1%, specific volume: 1.82, single largest impurity: 0.20%, impurity summation: 0.75%, MMT:0.08%.
Embodiment 10
Accurately measure Cefpiramide Acid 20g, acetone 100ml, DMF (N, dinethylformamide) 25ml, Isopropylamine 2.8ml are put in the four-hole bottle, the molar ratio of Cefpiramide Acid and Isopropylamine is 1:1, the volume milliliter ratio of counting of the weight grams of Cefpiramide Acid and solvent I is 1:6.25, in 5 ℃ of isothermal reactions are bathed, be stirred to fully dissolving, form the cefpiramide amine salt solution for subsequent use.Accurately measure Sodium isooctanoate 5.42g, acetone 135.5ml is put in the Erlenmeyer flask, the add-on of Sodium isooctanoate is that to make the molar ratio of Sodium isooctanoate and Cefpiramide Acid be 1:1, is stirred to fully dissolving, forms Sodium isooctanoate solution.In 25 ℃ of isothermal reactions are bathed, with 20 minutes Sodium isooctanoate solution evenly is added in the cefpiramide amine salt solution, then add the cefpiramide sodium crystal 0.05g as crystal seed, growing the grain 16 minutes.Then in crystallizing system, add 150ml acetone dilution crystallization, regulating crystallizing system pH value is 9.1, then crystallizing system is filtered, and uses twice of washing with acetone filter cake again, under 40 ℃, vacuum condition, filter cake is carried out drying, until make the moisture of filter cake, residual fused lattice.Cefpiramide sodium crystal yield in the present embodiment: 93.9%, purity: 99.5%, specific volume: 1.72, single largest impurity: 0.18%, impurity summation: 0.80%, MMT:0.07%.
Embodiment 11
Accurately measure Cefpiramide Acid 20g, acetone 55ml, DMF (N, dinethylformamide) 25ml, Isopropylamine 2.8ml are put in the four-hole bottle, the molar ratio of Cefpiramide Acid and Isopropylamine is 1:1, the volume milliliter ratio of counting of the weight grams of Cefpiramide Acid and solvent I is 1:4, in 20 ℃ of isothermal reactions are bathed, be stirred to fully dissolving, form the cefpiramide amine salt solution for subsequent use.Accurately measure sodium hydroxide 1.5g, methyl alcohol 75ml, the add-on of sodium hydroxide is that to make the molar ratio of sodium hydroxide and Cefpiramide Acid be 1.15:1, is stirred to fully dissolving, forms sodium hydroxide solution for subsequent use.In 0 ℃ of isothermal reaction is bathed, with 20 minutes sodium hydroxide solution evenly is added in the cefpiramide amine salt solution, then add the cefpiramide sodium crystal 0.08g as crystal seed, growing the grain 8 minutes.Then in crystallizing system, add 150ml acetone dilution crystallization, regulating crystallizing system pH value is 11.0, then crystallizing system is filtered, and uses twice of washing with acetone filter cake again, under 40 ℃, vacuum condition, filter cake is carried out drying, until make the moisture of filter cake, residual fused lattice.Cefpiramide sodium crystal yield in the present embodiment: 93.5%, purity: 99.4%, specific volume: 1.75, single largest impurity: 0.19%, impurity summation: 0.81%, MMT:0.09%.
Embodiment 12
Accurately weighing Cefpiramide Acid 20g, methyl alcohol 120ml, acetone 280ml, triethylamine 4.6ml are put in the four-hole bottle, the molar ratio of Cefpiramide Acid and triethylamine is 1:1, the volume milliliter ratio of counting of the weight grams of Cefpiramide Acid and solvent I is 1:20, in 5 ℃ of isothermal reactions are bathed, be stirred to fully dissolving, form the cefpiramide amine salt solution for subsequent use.Accurately measure sodium hydroxide 1.5g, methyl alcohol 15ml, the add-on of sodium hydroxide is that to make the molar ratio of sodium hydroxide and Cefpiramide Acid be 1.15:1, is stirred to fully dissolving, forms sodium hydroxide solution for subsequent use.In 45 ℃ of isothermal reactions are bathed, with 20 minutes sodium hydroxide solution evenly is added in the cefpiramide amine salt solution, then add the cefpiramide sodium crystal 0.04g as crystal seed, growing the grain 20 minutes.Then in crystallizing system, add 150ml acetone dilution crystallization, regulating crystallizing system pH value is 10.8, then crystallizing system is filtered, and uses twice of washing with acetone filter cake again, under 40 ℃, vacuum condition, filter cake is carried out drying, until make the moisture of filter cake, residual fused lattice.Cefpiramide sodium crystal yield in the present embodiment: 96.6%, purity: 98.4%, specific volume: 1.66, single largest impurity: 0.22%, impurity summation: 0.89%, MMT:0.04%.
Embodiment 13
Accurately measure Cefpiramide Acid 20g, methyl alcohol 60ml, acetone 40ml, acetonitrile 20ml, Diisopropylamine 4.6ml is put in the four-hole bottle, the molar ratio of Cefpiramide Acid and Diisopropylamine is 1:1, the volume milliliter ratio of counting of the weight grams of Cefpiramide Acid and solvent I is 1:6, in 10 ℃ of isothermal reactions are bathed, be stirred to fully dissolving, form the cefpiramide amine salt solution for subsequent use.Accurately measure Sodium isooctanoate 5.42g, acetone 54.2ml is put in the Erlenmeyer flask, the add-on of Sodium isooctanoate solution is that to make the molar ratio of Sodium isooctanoate and Cefpiramide Acid be 1:1, is stirred to fully dissolving, forms the Sodium isooctanoate solution for standby.In 25 ℃ of isothermal reactions are bathed, with 25 minutes Sodium isooctanoate solution evenly is added in the cefpiramide amine salt solution, then add the cefpiramide sodium crystal 0.02g as crystal seed, growing the grain 15 minutes.Then in crystallizing system, add 250ml acetone dilution crystallization, regulating crystallizing system pH value is 9.5, then crystallizing system is filtered, and uses twice of washing with acetone filter cake again, under 45 ℃, vacuum condition, filter cake is carried out drying, until make the moisture of filter cake, residual fused lattice.Cefpiramide sodium crystal yield in the present embodiment: 95.1%, purity: 99.6%, specific volume: 1.79, single largest impurity: 0.18% impurity summation: 0.49%, MMT:0.06%.
Embodiment 14
Accurately measure Cefpiramide Acid 20g, methyl alcohol 160ml, acetonitrile 70ml, THF (tetrahydrofuran (THF)) 70ml, Diisopropylamine 4.6ml are put in the four-hole bottle, the molar ratio of Cefpiramide Acid and Diisopropylamine is 1:1, the volume milliliter ratio of counting of the weight grams of Cefpiramide Acid and solvent I is 1:15, in 15 ℃ of isothermal reactions are bathed, be stirred to fully dissolving, form the cefpiramide amine salt solution for subsequent use.Accurately measure Sodium isooctanoate 5.42g, acetone 271ml is put in the Erlenmeyer flask, the add-on of Sodium isooctanoate solution is that to make the molar ratio of Sodium isooctanoate and Cefpiramide Acid be 1:1, is stirred to fully dissolving, forms the Sodium isooctanoate solution for standby.In 25 ℃ of isothermal reactions are bathed, with 20 minutes Sodium isooctanoate solution evenly is added in the cefpiramide amine salt solution, then add the cefpiramide sodium crystal 0.1g as crystal seed, growing the grain 10 minutes.Then add 50ml acetone dilution crystallization in the crystallizing system, regulating crystallizing system pH value is 9.2, then crystallizing system is filtered, and uses washing with acetone filter cake twice again, and dry cake under 48 ℃, vacuum condition is until make the moisture of filter cake, residual fused lattice.Cefpiramide sodium crystal yield in the present embodiment: 96.7%, purity: 98.6%, specific volume: 1.64, single largest impurity: 0.25%, impurity summation: 0.86%, MMT:0.09%.
Embodiment 15
Accurately measure Cefpiramide Acid 20g, methyl alcohol 80ml, acetonitrile 30ml, DMA (N, the N-N,N-DIMETHYLACETAMIDE) 25ml, Diisopropylamine 4.6ml are put in the four-hole bottle, the molar ratio of Cefpiramide Acid and Diisopropylamine is 1:1, the volume milliliter ratio of counting of the weight grams of Cefpiramide Acid and solvent I is 1:6.75, in 15 ℃ of isothermal reactions are bathed, be stirred to fully dissolving, form the cefpiramide amine salt solution for subsequent use.Accurately measure sodium hydroxide 1.5g, methyl alcohol 10ml, THF (tetrahydrofuran (THF)) 5ml is put in the Erlenmeyer flask, the add-on of sodium hydroxide is that to make the molar ratio of sodium hydroxide and Cefpiramide Acid be 1.15:1, be stirred to fully dissolving, form sodium hydroxide solution for subsequent use.In 20 ℃ of isothermal reactions are bathed, with 26 minutes sodium hydroxide solution evenly is added in the cefpiramide amine salt solution, then add the cefpiramide sodium crystal 0.05g as crystal seed, growing the grain 25 minutes.Then in crystallizing system, add 300ml acetone dilution crystallization, regulating crystallizing system pH value is 10.8, then crystallizing system is filtered, and uses twice of washing with acetone filter cake again, dry cake under 35 ℃, vacuum condition is until make the moisture of filter cake, residual fused lattice.Cefpiramide sodium crystal yield in the present embodiment: 95.8%, purity: 98.7%, specific volume: 1.91, single largest impurity: 0.15%, impurity summation: 0.56%, MMT:0.05%.
The solvent I of using in the preparation process of the amine salt solution of cefpiramide described in above-described embodiment can also be methyl alcohol, acetone, acetonitrile, N, N-N,N-DIMETHYLACETAMIDE, N, the mixing of wherein a kind of or any several arbitrary proportions of dinethylformamide, tetrahydrofuran (THF), water is enumerated in an embodiment no longer one by one.In addition, although the embodiment of specification sheets has only enumerated above-mentioned part embodiment and numerical range, on the basis of above-described embodiment, spirit according to the present invention is expanded and is revised above-described embodiment, all can reach the object of the invention.
Claims (9)
1. the method for cefpiramide sodium crystal is produced in a crystallization, it is characterized in that comprising following process:
(a) preparation process of cefpiramide amine salt solution: with Cefpiramide Acid with turn the amine agent and be dissolved in the solvent I, the control temperature is stirred to fully dissolving at 0～25 ℃, described turn the amine agent be in triethylamine, Diisopropylamine, the Isopropylamine any one; Cefpiramide Acid weight grams and the solvent I volume milliliter ratio of counting are 1:4～1:20;
(b) dissolution process of salt forming agent: salt forming agent is added in the solvent II, be stirred to fully dissolving, described salt forming agent is the wherein a kind of of Sodium isooctanoate or sodium hydroxide; When described salt forming agent was Sodium isooctanoate, the solvent II was acetone solvent; When described salt forming agent was sodium hydroxide, the solvent II was that any one or two kinds mix arbitrarily in methyl alcohol, the tetrahydrofuran (THF); Salt forming agent weight grams and the solvent II volume milliliter ratio of counting are 1:10～1:50;
(c) Crystallization Process: salt forming agent solution is evenly joined in the solution of cefpiramide amine salt, the control temperature is at 0～45 ℃, then add after the cefpiramide sodium crystal carries out growing the grain as crystal seed, add again acetone in the crystallizing system and carry out dilution crystallization, then to crystal filter, wash, drying obtains the cefpiramide sodium crystal.
2. the method for cefpiramide sodium crystal is produced in crystallization according to claim 1, it is characterized in that the solvent I is methyl alcohol, acetone, acetonitrile, N in the preparation process of described cefpiramide amine salt solution, the wherein mixing of one or more of N-N,N-DIMETHYLACETAMIDE, DMF, tetrahydrofuran (THF), water.
3. according to claim 1 or 2 each described crystallizations method of producing the cefpiramide sodium crystals, it is characterized in that: Cefpiramide Acid weight grams and the solvent I volume milliliter ratio of counting are 1:5～1:15 in the preparation process of described cefpiramide amine salt solution.
4. the method for cefpiramide sodium crystal is produced in crystallization according to claim 1, and it is characterized in that: salt forming agent weight grams and the solvent II volume milliliter ratio of counting are 1:25～1:40 in the dissolution process of described salt forming agent.
5. the method for cefpiramide sodium crystal is produced in crystallization according to claim 1, when it is characterized in that salt forming agent is Sodium isooctanoate in the described Crystallization Process, the molar ratio of Sodium isooctanoate and Cefpiramide Acid is 1:1, when salt forming agent was sodium hydroxide, the molar ratio of sodium hydroxide and Cefpiramide Acid was 1.15:1.
6. the method for cefpiramide sodium crystal is produced in crystallization according to claim 1, it is characterized in that in the described Crystallization Process that salt forming agent solution joins evenly that the used time is 20～30min in the cefpiramide amine salt solution.
7. the method for cefpiramide sodium crystal is produced in crystallization according to claim 1, it is characterized in that adding crystal seed weight in the described Crystallization Process is 1 ‰ of Cefpiramide Acid weight～5 ‰; Rearing crystal time is 5～30min.
8. the method for cefpiramide sodium crystal is produced in crystallization according to claim 1, it is characterized in that: when adding acetone carries out dilution crystallization the pH value of crystallizing system is regulated, when salt forming agent is sodium hydroxide, crystallizing system pH value is adjusted to 10.5～11.5, when salt forming agent was Sodium isooctanoate, crystallizing system pH value was adjusted to 8.5～9.5.
9. the method for cefpiramide sodium crystal is produced in crystallization according to claim 1, it is characterized in that the dry vacuum-drying mode that adopts of crystal in the described Crystallization Process, and drying temperature is 30～50 ℃.
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| CN110143972A (en) * | 2018-02-12 | 2019-08-20 | 罗欣药业(上海)有限公司 | A kind of Cefazedone sodium novel crystal form and preparation method thereof |
| CN111072688A (en) * | 2019-12-30 | 2020-04-28 | 湖北凌晟药业有限公司 | Method for refining cefpiramide acid |
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| CN112442048A (en) * | 2020-11-10 | 2021-03-05 | 华北制药河北华民药业有限责任公司 | Preparation method of cefpiramide sodium |
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Inventor after: Wei Qingjie Inventor after: Hu Limin Inventor after: Gao Zhigang Inventor after: Chen Jianjun Inventor after: Qiao Junhua Inventor after: Zhao Honge Inventor after: Liu Hua Inventor after: Zhang Chunbo Inventor after: Li Huifen Inventor after: Cai Qiuqin Inventor before: Wei Qingjie Inventor before: Gao Zhigang Inventor before: Chen Jianjun Inventor before: Zhang Chunbo Inventor before: Li Huifen Inventor before: Cai Qiuqin Inventor before: Hu Limin |
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