CN101921276B - Crystallization refining method of Meropenem - Google Patents
Crystallization refining method of Meropenem Download PDFInfo
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- CN101921276B CN101921276B CN2010102752230A CN201010275223A CN101921276B CN 101921276 B CN101921276 B CN 101921276B CN 2010102752230 A CN2010102752230 A CN 2010102752230A CN 201010275223 A CN201010275223 A CN 201010275223A CN 101921276 B CN101921276 B CN 101921276B
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Abstract
The invention relates to a crystallization refining method of Meropenem, which has low impurity content. The crystallization refining method of Meropenem comprises the following steps: a) dissolving Meropenem crude into methyl alcohol; b) decoloring, decarbonizing, degerming and filtering; c) adding the mixture of water and precipitator into filtrate, and precipitating, wherein the precipitator is the one or the mixture of two-four types of C2-C6 alcohol, C3-C8 ketone, C2-C8 ether or tetrahydrofuran at any ratio, and the volume ratio of water to precipitator is 1:3-1:5; d) filtering to obtain crystallization; e) washing the crystallization by mixed solvent of water and organic solvent of alcohol and esters; and f) drying to obtain the finished product. The invention utilizes the characteristic that Meropenem is easy to dissolve in methyl alcohol, and a small quantity of methyl alcohol can cause Meropenem to dissolve at normal temperature; same equipment can increase inventory for multiple times if being compared with the prior art, and production capability is obviously improved. Because a small quantity of methyl alcohol is used, a great quantity of crystallization solvent can be added, crystallization is complete, yield is high, and impurities can be thoroughly removed.
Description
Technical field
The present invention relates to a kind of crystal refining method of meropenem.
Background technology
The meropenem bullion is company's laboratory self-control; Be that meropenem parent nucleus MAP and side chain are docked, hydrogenation deprotection base makes bullion (bullion quality standard: total assorted≤1.0%, single assorted≤0.5%) (MAP and side chain are available from Taizhou city one inscription medication chemistry ltd) then.
With the refining impurity of removing of meropenem bullion (Beta-methyl carbapenem antibiotic), degerming obtains the method for aseptic meropenem; Adopt in the water mostly and dissolve decarbonization filtering, Sterile Filtration; Add crystallizatioies such as acetone or THF; Vacuum drying method, (remarks: 2010 editions Chinese Pharmacopoeia standards: main assorted≤0.3%, other are single assorted≤0.1%, total assorted≤1.0%, dissolvent residual meets standards of pharmacopoeia to obtain meeting the finished product of NF standard at last; USP standard: main assorted≤0.3%, other single assorted≤0.1%, other single assorted summation≤0.3%, dissolvent residual meets standards of pharmacopoeia).But the solubleness of meropenem in water is very low, needs a large amount of water as making its dissolving at normal temperatures, and a large amount of organic solvent of needs just when next step adds organic solvent crystallization can not be realized industrial production like this.Someone adds alkaline matter in water when dissolving, but product is damaged, and foreign matter content is increased; Also have the people that water temperature is raise, at high temperature make its dissolving, product is damaged, foreign matter content increases.
The traditional drying method is vacuum-drying, but residual solvent still is difficult to remove thoroughly.
Summary of the invention
The present invention provides a kind of crystal refining method of meropenem, and foreign matter content is low.
The crystal refining method of said meropenem comprises the steps:
A) the meropenem bullion is dissolved in the methyl alcohol;
B) decolouring, carbon removal, Sterile Filtration;
C) in filtrating, add the mixed solution of entry and precipitation agent, precipitate, said precipitation agent is C
2-C
6Alcohol, C
3-C
8Ketone, C
2-C
8Ether or THF in the mixture of arbitrary proportion of a kind or 2-4 kind; Wherein the volume ratio of water and precipitation agent is 1: 3～1: 5;
D) filter crystallization excessively;
E) the mixed solvent wash crystallization of water+ethanol and ester class organic solvent;
F) drying obtains finished product.
The same prior art of the concrete grammar of step b) decolouring, carbon removal, Sterile Filtration.
As preferred version, in the step a), solvent temperature is-10-40 ℃, obtains the solution of meropenem, and more preferably the consumption of methyl alcohol is 3～10 times (V/W) of meropenem bullion.
As preferred version, in the step c), precipitation temperature is-10～40 ℃, and the consumption of water and precipitation agent is 10-50 times (V/W) of meropenem bullion.
As preferred version; Wash temperature is 10---30 ℃ in the step e); Water, ethanol, ester class volume of organic solvent ratio are 1: (0.5-1.5): (0.5～1.5), said ester class organic solvent are the mixture of the arbitrary proportion of in butylacetate, isopropyl acetate, ETHYLE ACETATE, ethyl formate, isobutyl acetate, methyl acetate, the propyl acetate a kind or 2-4 kind.The consumption of the mixed solvent of water+ethanol and ester class organic solvent is preferably 3-8 times (V/W) of meropenem bullion.
As preferred version, step f) adopts warm air drying to obtain finished product, and drying temperature is 10-40 ℃.
The present invention utilizes meropenem to be soluble in the characteristic of methyl alcohol, uses the methyl alcohol of very small amount can make the meropenem dissolving, and is under the normal temperature situation, to carry out, and makes same equipment increase several times than the charging capacity of prior art, and throughput significantly improves.
Meropenem exists with three water things under normal conditions; Its will exist with the form of anhydride with methanol solution in; The amount that is used to dissolve the methyl alcohol of meropenem bullion is to be controlled to make it become the amount near state of saturation; So as long as add the mixed solution to its poorly soluble organic solvent and water, it can be separated out with the form crystallization of three water things again.Because of quantity of methyl alcohol is few, the crystallization solvent can add in a large number, makes crystallization complete, so this method yield is high, also makes Impurity removal thorough.
Part insoluble and impurity that do not remove as yet in above-mentioned crystallization solvent, the method that can adopt the mixed solvent of water+ethanol and ester class to wash makes its removal, and less loss yield.
The present invention adopts warm air drying, residual solvent is removed, and reached standard-required, so though use solvent wide in variety, residual quantity seldom.
In sum, process for purification mild condition according to the invention, easy and simple to handle; Adopt this method can make production capacity increase (4～5 times), product yield high (reaching as high as 90%), content high (>=99.8%); Foreign matter content low (single assorted＜0.1%, total assorted＜0.2%), dissolvent residual low (≤500ppm).
Embodiment
Embodiment 1
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (37ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and THF, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.82g, product yield 88.2%), assay is following:
(1) purity: 99.89%;
(2) weight loss on drying: 12.1%;
(3) maximum contaminant: 0.04%;
(4) total assorted: 0.11%;
(5) dissolvent residual: methyl alcohol 151ppm, ethanol 13ppm, ETHYLE ACETATE 15ppm, THF 175ppm.
Embodiment 2
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (37ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and Virahol, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.83g, product yield 88.3%), assay is following:
(1) purity: 99.87%;
(2) weight loss on drying: 12.6%;
(3) maximum contaminant: 0.06%;
(4) total assorted: 0.13%;
(5) dissolvent residual: methyl alcohol 172ppm, ethanol 17ppm, ETHYLE ACETATE 13ppm, Virahol 211ppm.
Embodiment 3
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (36ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and secondary hexyl alcohol, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.86g, product yield 88.6%), assay is following:
(1) purity: 99.83%;
(2) weight loss on drying: 12.2%;
(3) maximum contaminant: 0.05%;
(4) total assorted: 0.17%;
(5) dissolvent residual: methyl alcohol 165ppm, ethanol 19ppm, ETHYLE ACETATE 15ppm, n-hexyl alcohol 196ppm.
Embodiment 4
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (37ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.93g, product yield 89.3%), assay is following:
(1) purity: 99.85%;
(2) weight loss on drying: 11.9%;
(3) maximum contaminant: 0.04%;
(4) total assorted: 0.15%;
(5) dissolvent residual: methyl alcohol 163ppm, ethanol 12ppm, ETHYLE ACETATE 14ppm, acetone 209ppm.
Embodiment 5
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (38ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and secondary octanone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.94g, product yield 89.4%), assay is following:
(1) purity: 99.86%;
(2) weight loss on drying: 12.9%;
(3) maximum contaminant: 0.04%;
(4) total assorted: 0.14%;
(5) dissolvent residual: methyl alcohol 173ppm, ethanol 15ppm, ETHYLE ACETATE 16ppm, secondary octanone 221ppm.
Embodiment 6
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (36ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and ether, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.87g, product yield 88.7%), assay is following:
(1) purity: 99.83%;
(2) weight loss on drying: 13.1%;
(3) maximum contaminant: 0.06%;
(4) total assorted: 0.17%;
(5) dissolvent residual: methyl alcohol 181ppm, ethanol 13ppm, ETHYLE ACETATE 16ppm, ether 203ppm.
Embodiment 7
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (38ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and n-butyl ether, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.81g, product yield 88.1%), assay is following:
(1) purity: 99.84%;
(2) weight loss on drying: 12.2%;
(3) maximum contaminant: 0.06%;
(4) total assorted: 0.16%;
(5) dissolvent residual: methyl alcohol 175ppm, ethanol 17ppm, ETHYLE ACETATE 16ppm, n-butyl ether 201ppm.
Embodiment 8
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (36ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and THF, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-methyl acetates of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.82g, product yield 88.2%), assay is following:
(1) purity: 99.90%;
(2) weight loss on drying: 11.8%;
(3) maximum contaminant: 0.04%;
(4) total assorted: 0.10%;
(5) dissolvent residual: methyl alcohol 181ppm, ethanol 15ppm, methyl acetate 19ppm, THF 192ppm.
Embodiment 9
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (38ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-methyl acetates of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.86g, product yield 88.6%), assay is following:
(1) purity: 99.86%;
(2) weight loss on drying: 12.1%;
(3) maximum contaminant: 0.05%;
(4) total assorted: 0.14%;
(5) dissolvent residual: methyl alcohol 178ppm, ethanol 12ppm, methyl acetate 11ppm, acetone 233ppm.
Embodiment 10
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (37ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-butylacetates of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.81g, product yield 88.1%), assay is following:
(1) purity: 99.88%;
(2) weight loss on drying: 12.4%;
(3) maximum contaminant: 0.04%;
(4) total assorted: 0.12%;
(5) dissolvent residual: methyl alcohol 173ppm, ethanol 14ppm, butylacetate 16ppm, acetone 223ppm.
Embodiment 11
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (36ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-isobutyl acetates of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.89g, product yield 88.9%), assay is following:
(1) purity: 99.82%;
(2) weight loss on drying: 12.7%;
(3) maximum contaminant: 0.05%;
(4) total assorted: 0.18%;
(5) dissolvent residual: methyl alcohol 182ppm, ethanol 17ppm, isobutyl acetate 15ppm, acetone 199ppm.
Embodiment 12
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (38ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-isopropyl acetates of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.88g, product yield 88.8%), assay is following:
(1) purity: 99.89%;
(2) weight loss on drying: 13.1%;
(3) maximum contaminant: 0.06%;
(4) total assorted: 0.11%;
(5) dissolvent residual: methyl alcohol 176ppm, ethanol 14ppm, isopropyl acetate 12ppm, acetone 23lppm.
Embodiment 13
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (37ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-propyl acetates of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.85g, product yield 88.5%), assay is following:
(1) purity: 99.87%;
(2) weight loss on drying: 12.8%;
(3) maximum contaminant: 0.05%;
(4) total assorted: 0.13%;
(5) dissolvent residual: methyl alcohol 173ppm, ethanol 19ppm, propyl acetate 17ppm, acetone 226ppm.
Embodiment 14
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (37ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ethyl formates of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.86g, product yield 88.6%), assay is following:
(1) purity: 99.84%;
(2) weight loss on drying: 12.1%;
(3) maximum contaminant: 0.05%;
(4) total assorted: 0.16%;
(5) dissolvent residual: methyl alcohol 180ppm, ethanol 18ppm, ethyl formate 19ppm, acetone 225ppm.
Embodiment 15
1, in the 100ml there-necked flask, add anhydrous methanol 35ml, middling speed stirs, and is cooled to-8～-10 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and heats up and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (37ml) is poured in the four-hole bottle of 500ml.
4, stir and to be cooled to-8～-10 ℃, keep temperature-8～-10 ℃, at the uniform velocity add mixed solvent (1: the 4) 200ml of entry and acetone, the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.92g, product yield 89.2%), assay is following:
(1) purity: 99.83%;
(2) weight loss on drying: 12.4%;
(3) maximum contaminant: 0.05%;
(4) total assorted: 0.17%;
(5) dissolvent residual: methyl alcohol 171ppm, ethanol 14ppm, ETHYLE ACETATE 17ppm, acetone 217ppm.
Embodiment 16
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is warming up to 38-40 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and lowers the temperature and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (36ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 38-40 ℃, keeps 38-40 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.80g, product yield 88.0%), assay is following:
(1) purity: 99.86%;
(2) weight loss on drying: 12.7%;
(3) maximum contaminant: 0.04%;
(4) total assorted: 0.14%;
(5) dissolvent residual: methyl alcohol 165ppm, ethanol 19ppm, ETHYLE ACETATE 18ppm, acetone 209ppm.
Embodiment 17
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (38ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 28-30 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.93g, product yield 89.3%), assay is following:
(1) purity: 99.85%;
(2) weight loss on drying: 11.9%;
(3) maximum contaminant: 0.04%;
(4) total assorted: 0.15%;
(5) dissolvent residual: methyl alcohol 167ppm, ethanol 16ppm, ETHYLE ACETATE 15ppm, acetone 219ppm.
Embodiment 18
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (37ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 10 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.89g, product yield 88.9%), assay is following:
(1) purity: 99.82%;
(2) weight loss on drying: 13.2%;
(3) maximum contaminant: 0.06%;
(4) total assorted: 0.18%;
(5) dissolvent residual: methyl alcohol 193ppm, ethanol 20ppm, ETHYLE ACETATE 29ppm, acetone 241ppm.
Embodiment 19
1, in the 250ml there-necked flask, add anhydrous methanol 100ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (97ml) is poured in the four-hole bottle of 1L.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 500ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (7.58g, product yield 75.8%), assay is following:
(1) purity: 99.91%;
(2) weight loss on drying: 12.5%;
(3) maximum contaminant: 0.04%;
(4) total assorted: 0.09%;
(5) dissolvent residual: methyl alcohol 193ppm, ethanol 15ppm, ETHYLE ACETATE 17ppm, acetone 196ppm.
Embodiment 20
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (37ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 3) 200ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.86g, product yield 88.6%), assay is following:
(1) purity: 99.84%;
(2) weight loss on drying: 12.2%;
(3) maximum contaminant: 0.05%;
(4) total assorted: 0.16%;
(5) dissolvent residual: methyl alcohol 163ppm, ethanol 16ppm, ETHYLE ACETATE 21ppm, acetone 191ppm.
Embodiment 21
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (38ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 5) 200ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.87g, product yield 88.7%), assay is following:
(1) purity: 99.86%;
(2) weight loss on drying: 12.8%;
(3) maximum contaminant: 0.05%;
(4) total assorted: 0.14%;
(5) dissolvent residual: methyl alcohol 173ppm, ethanol 13ppm, ETHYLE ACETATE 19ppm, acetone 281ppm.
Embodiment 22
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (37ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 0.5: 0.5) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.89g, product yield 88.9%), assay is following:
(1) purity: 99.82%;
(2) weight loss on drying: 12.4%;
(3) maximum contaminant: 0.07%;
(4) total assorted: 0.18%;
(5) dissolvent residual: methyl alcohol 176ppm, ethanol 14ppm, ETHYLE ACETATE 18ppm, acetone 224ppm.
Embodiment 23
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (36ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 1.5: 0.5) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.87g, product yield 88.7%), assay is following:
(1) purity: 99.85%;
(2) weight loss on drying: 12.9%;
(3) maximum contaminant: 0.06%;
(4) total assorted: 0.15%;
(5) dissolvent residual: methyl alcohol 181ppm, ethanol 11ppm, ETHYLE ACETATE 17ppm, acetone 217ppm.
Embodiment 24
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (38ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 0.5: 1.5) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.86g, product yield 88.6%), assay is following:
(1) purity: 99.84%;
(2) weight loss on drying: 12.1%;
(3) maximum contaminant: 0.05%;
(4) total assorted: 0.16%;
(5) dissolvent residual: methyl alcohol 177ppm, ethanol 13ppm, ETHYLE ACETATE 17ppm, acetone 231ppm.
Embodiment 25
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (38ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 1.5: 1.5) mixing solutions washing by soaking filter cake, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.84g, product yield 88.4%), assay is following:
(1) purity: 99.83%;
(2) weight loss on drying: 12.6%;
(3) maximum contaminant: 0.05%;
(4) total assorted: 0.17%;
(5) dissolvent residual: methyl alcohol 166ppm, ethanol 13ppm, ETHYLE ACETATE 15ppm, acetone 219ppm.
Embodiment 26
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (36ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 30ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.89g, product yield 88.9%), assay is following:
(1) purity: 99.81%;
(2) weight loss on drying: 12.3%;
(3) maximum contaminant: 0.07%;
(4) total assorted: 0.19%;
(5) dissolvent residual: methyl alcohol 171ppm, ethanol 13ppm, ETHYLE ACETATE 16ppm, acetone 237ppm.
Embodiment 27
1, in the 100ml there-necked flask, add anhydrous methanol 40ml, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem bullion is added in the there-necked flask, stirs and makes abundant dissolving.
2, in clarifying feed liquid, add the 1.5g gac, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrating filters twice with 0.45 μ m hydrophilic filter membrane, and filtrating (37ml) is poured in the four-hole bottle of 500ml.
4, stirring is cooled to 10 ± 1 ℃, keeps 10 ± 1 ℃ of temperature, at the uniform velocity adds mixed solvent (1: the 4) 200ml of entry and acetone, and the control dropping time dripped and finishes to stop stirring about 2 hour, left standstill crystallization 1 hour.
5, with crystallization suspension vacuum filtration, with water-ethanol-ETHYLE ACETATE of 15 ± 2 ℃ (1: 1: 1) mixing solutions washing by soaking filter cake, washed twice is used 80ml at every turn altogether, drains with vacuum.
6, the article of wetting are put into glass culture dish, place Hotaircirculatingoven, 40 ℃ of warm air dryings 2 hours, meropenem highly finished product (8.83g, product yield 88.3%), assay is following:
(1) purity: 99.86%;
(2) weight loss on drying: 12.8%;
(3) maximum contaminant: 0.05%;
(4) total assorted: 0.14%;
(5) dissolvent residual: methyl alcohol 173ppm, ethanol 15ppm, ETHYLE ACETATE 19ppm, acetone 231ppm.
It below is the quality synopsis of embodiment 1-27 gained meropenem highly finished product and bought-in article-1～4.
| Lot identification mark | Maximum single assorted (%) | Total assorted (%) | Purity (%) | Total residual solvent (ppm) |
| Bought-in article-1 | 0.21 | 0.35 | 99.65 | ?3558 |
| Bought-in article-2 | 0.25 | 0.42 | 99.58 | ?3617 |
| Bought-in article-3 | 0.15 | 0.28 | 99.72 | ?3359 |
| Bought-in article-4 | 0.17 | 0.32 | 99.68 | ?3830 |
| Embodiment-1 | 0.04 | 0.11 | 99.89 | ?354 |
| Embodiment-2 | 0.06 | 0.13 | 99.87 | ?413 |
| Embodiment-3 | 0.05 | 0.17 | 99.83 | ?395 |
| Embodiment-4 | 0.04 | 0.15 | 99.85 | ?398 |
| Embodiment-5 | 0.04 | 0.14 | 99.86 | ?425 |
| Embodiment-6 | 0.06 | 0.17 | 99.83 | 413 |
| Embodiment-7 | 0.06 | 0.16 | 99.84 | 409 |
| Embodiment-8 | 0.04 | 0.10 | 99.90 | 407 |
| Embodiment-9 | 0.05 | 0.14 | 99.86 | 434 |
| Embodiment-10 | 0.04 | 0.12 | 99.88 | 426 |
| Embodiment-11 | 0.05 | 0.18 | 99.82 | 413 |
| Embodiment-12 | 0.06 | 0.11 | 99.89 | 433 |
| Embodiment-13 | 0.05 | 0.13 | 99.87 | 435 |
| Embodiment-14 | 0.05 | 0.16 | 99.84 | 442 |
| Embodiment-15 | 0.05 | 0.17 | 99.83 | 419 |
| Embodiment-16 | 0.04 | 0.14 | 99.86 | 411 |
| Embodiment-17 | 0.04 | 0.15 | 99.85 | 417 |
| Embodiment-18 | 0.06 | 0.18 | 99.82 | 483 |
| Embodiment-19 | 0.04 | 0.09 | 99.91 | 421 |
| Embodiment-20 | 0.05 | 0.16 | 99.84 | 391 |
| Embodiment-21 | 0.05 | 0.14 | 99.86 | 486 |
| Embodiment-22 | 0.07 | 0.18 | 99.82 | 432 |
| Embodiment-23 | 0.06 | 0.15 | 99.85 | 426 |
| Embodiment-24 | 0.05 | 0.16 | 99.84 | 438 |
| Embodiment-25 | 0.05 | 0.17 | 99.83 | 413 |
| Embodiment-26 | 0.07 | 0.19 | 99.81 | 437 |
| Embodiment-27 | 0.05 | 0.14 | 99.86 | 438 |
Claims (7)
1. the crystal refining method of a meropenem is characterized in that, comprises the steps:
A) the meropenem bullion is dissolved in the methyl alcohol;
B) decolouring, carbon removal, Sterile Filtration;
C) in filtrating, add the mixed solution of entry and precipitation agent, precipitate, said precipitation agent is C
2-C
6Alcohol, C
3-C
8Ketone, C
2-C
8Ether or THF in the mixture of arbitrary proportion of a kind or 2-4 kind; Wherein the volume ratio of water and precipitation agent is 1:3 ~ 1:5;
D) filter crystallization excessively;
E) the mixed solvent wash crystallization of water+ethanol and ester class organic solvent; Wash temperature is 10 ~ 30 ℃; Water, ethanol, ester class volume of organic solvent ratio are 1: (0.5 ~ 1.5): (0.5 ~ 1.5), said ester class organic solvent are the mixture of the arbitrary proportion of in butylacetate, isopropyl acetate, ETHYLE ACETATE, ethyl formate, isobutyl acetate, methyl acetate, the propyl acetate a kind or 2-4 kind;
F) drying obtains finished product.
2. the crystal refining method of meropenem as claimed in claim 1 is characterized in that in the step a), and solvent temperature is-10 ~ 40 ℃, obtains the solution of meropenem.
3. the crystal refining method of meropenem as claimed in claim 2, the consumption that it is characterized in that methyl alcohol is 3 ~ 10 times (V/W) of meropenem bullion.
4. the crystal refining method of meropenem as claimed in claim 1 is characterized in that in the step c), and precipitation temperature is-10 ~ 40 ℃, and the consumption of water and precipitation agent is 10 ~ 50 times (V/W) of meropenem bullion.
5. the crystal refining method of meropenem as claimed in claim 1 is characterized in that in the said step e) washing times at least 1 time, and the consumption of the water+ethanol of each washing and the mixed solvent of ester class organic solvent is 3 ~ 8 times (V/W) of meropenem bullion.
6. the crystal refining method of meropenem as claimed in claim 5 is characterized in that washing times is 2 times in the said step e).
7. the crystal refining method of meropenem as claimed in claim 1 is characterized in that said step f) adopts warm air drying to obtain finished product, and drying temperature is 10 ~ 40 ℃.
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| CN102702203B (en) * | 2012-06-19 | 2014-06-04 | 浙江海翔药业股份有限公司 | Meropenem refining method |
| CN103570718B (en) * | 2012-07-31 | 2016-06-29 | 深圳市海滨制药有限公司 | A kind of meropenem crude drug, its preparation method and comprise its pharmaceutical composition |
| CN103570719B (en) * | 2012-07-31 | 2016-03-02 | 深圳市海滨制药有限公司 | A kind of meropenem bulk drug, its preparation method and comprise its pharmaceutical composition |
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| CN102964348A (en) * | 2012-12-21 | 2013-03-13 | 卫宏远 | New meropenem crystal form and preparation method thereof |
| KR101331762B1 (en) * | 2012-12-28 | 2013-11-20 | 주식회사 대웅제약 | Process for preparing meropenem.trihydrate |
| CN105294693A (en) * | 2015-11-27 | 2016-02-03 | 上海新亚药业有限公司 | Novel meropenem refining method |
| CN113185515A (en) * | 2020-01-14 | 2021-07-30 | 重庆圣华曦药业股份有限公司 | Preparation method of meropenem trihydrate |
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