CN101921276A - Crystallization refining method of Meropenem - Google Patents
Crystallization refining method of Meropenem Download PDFInfo
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- CN101921276A CN101921276A CN 201010275223 CN201010275223A CN101921276A CN 101921276 A CN101921276 A CN 101921276A CN 201010275223 CN201010275223 CN 201010275223 CN 201010275223 A CN201010275223 A CN 201010275223A CN 101921276 A CN101921276 A CN 101921276A
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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 crude product is company's laboratory self-control; be that meropenem parent nucleus MAP and side chain are docked, hydrogenation deprotection base makes crude product (crude product quality standard: total assorted≤1.0%, single assorted≤0.5%) (MAP and side chain are available from Taizhou city one inscription medication chemistry company limited) then.
With the refining impurity of removing of meropenem crude product (Beta-methyl carbapenem antibiotic), degerming, obtain the method for aseptic meropenem, adopt in the water mostly and dissolve decarbonization filtering, Sterile Filtration, add crystallizatioies such as acetone or tetrahydrofuran (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 state-promulgated pharmacopoeia 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 invention provides a kind of crystal refining method of meropenem, foreign matter content is low.
The crystal refining method of described meropenem comprises the steps:
A) the meropenem crude product is dissolved in the methyl alcohol;
B) decolouring, carbon removal, Sterile Filtration;
C) in filtrate, add the mixed solution of entry and precipitation agent, precipitation, described precipitation agent is C
2-C
6Alcohol, C
3-C
8Ketone, C
2-C
8Ether or a kind or the mixture of the arbitrary proportion of 2-4 kind in the tetrahydrofuran (THF); Wherein the volume ratio of water and precipitation agent is 1: 3～1: 5;
D) filter crystallization;
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 crude product.
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 crude product.
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), described ester class organic solvent are the mixture of the arbitrary proportion of in butylacetate, isopropyl acetate, ethyl 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 crude product.
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 very a spot of methyl alcohol can make the meropenem dissolving, and is to carry out under the normal temperature situation, 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 crude product is to be controlled to make it become amount near state of saturation, so need only the mixed solution that adds 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 height also makes Impurity removal thorough.
Part is insoluble and impurity that do not remove as yet can adopt the method for the mixed solvent washing of water+ethanol and ester class to make its removal in above-mentioned crystallization solvent, 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 of the present invention, easy and simple to handle, adopt this method can make production capacity increase (4～5 times), product yield height (reaching as high as 90%), content height (〉=99.8%), foreign matter content low (single assorted＜0.1%, total assorted＜0.2%), dissolvent residual low (≤500ppm).
Embodiment
Embodiment 1
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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 tetrahydrofuran (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-ethyl 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 product 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 as follows:
(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, ethyl acetate 15ppm, tetrahydrofuran (THF) 175ppm.
Embodiment 2
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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-ethyl 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 product 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 as follows:
(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, ethyl acetate 13ppm, Virahol 211ppm.
Embodiment 3
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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-ethyl 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 product 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 as follows:
(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, ethyl acetate 15ppm, n-hexyl alcohol 196ppm.
Embodiment 4
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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 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 product 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 as follows:
(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, ethyl acetate 14ppm, acetone 209ppm.
Embodiment 5
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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-ethyl 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 product 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 as follows:
(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, ethyl acetate 16ppm, secondary octanone 221ppm.
Embodiment 6
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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-ethyl 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 product 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 as follows:
(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, ethyl acetate 16ppm, ether 203ppm.
Embodiment 7
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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-ethyl 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 product 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 as follows:
(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, ethyl acetate 16ppm, n-butyl ether 201ppm.
Embodiment 8
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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 tetrahydrofuran (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 product 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 as follows:
(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, tetrahydrofuran (THF) 192ppm.
Embodiment 9
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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 product 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 as follows:
(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, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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 product 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 as follows:
(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, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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 product 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 as follows:
(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, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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 product 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 as follows:
(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, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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 product 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 as follows:
(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, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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 product 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 as follows:
(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, add anhydrous methanol 35ml in the 100ml there-necked flask, middling speed stirs, and is cooled to-8～-10 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, 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 filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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-ethyl 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 product 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 as follows:
(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, ethyl acetate 17ppm, acetone 217ppm.
Embodiment 16
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is warming up to 38-40 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, 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 filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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-ethyl 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 product 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 as follows:
(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, ethyl acetate 18ppm, acetone 209ppm.
Embodiment 17
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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-ethyl acetate (1: 1: 1) mixing solutions washing by soaking filter cake of 28-30 ℃, washed twice is used 50ml at every turn altogether, drains with vacuum.
6, the product 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 as follows:
(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, ethyl acetate 15ppm, acetone 219ppm.
Embodiment 18
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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 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 product 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 as follows:
(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, ethyl acetate 29ppm, acetone 241ppm.
Embodiment 19
1, add anhydrous methanol 100ml in the 250ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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-ethyl 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 product 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 as follows:
(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, ethyl acetate 17ppm, acetone 196ppm.
Embodiment 20
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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-ethyl 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 product 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 as follows:
(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, ethyl acetate 21ppm, acetone 191ppm.
Embodiment 21
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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-ethyl 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 product 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 as follows:
(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, ethyl acetate 19ppm, acetone 281ppm.
Embodiment 22
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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 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 product 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 as follows:
(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, ethyl acetate 18ppm, acetone 224ppm.
Embodiment 23
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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-ethyl 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 product 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 as follows:
(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, ethyl acetate 17ppm, acetone 217ppm.
Embodiment 24
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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-ethyl 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 product 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 as follows:
(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, ethyl acetate 17ppm, acetone 231ppm.
Embodiment 25
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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-ethyl 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 product 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 as follows:
(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, ethyl acetate 15ppm, acetone 219ppm.
Embodiment 26
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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-ethyl 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 product 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 as follows:
(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, ethyl acetate 16ppm, acetone 237ppm.
Embodiment 27
1, add anhydrous methanol 40ml in the 100ml there-necked flask, middling speed stirs, and is cooled to 15 ± 2 ℃, and 10g meropenem crude product is added in the there-necked flask, stirs and makes abundant dissolving.
2, add the 1.5g gac in clarifying feed liquid, middling speed stirs, and is incubated 15 ± 2 ℃, decolouring 20min.
3, decolouring finishes, and uses the filter paper filtering carbon removal, and filtrate filters twice with 0.45 μ m hydrophilic filter membrane, and filtrate (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 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 product 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 as follows:
(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, ethyl 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 (8)
1. the crystal refining method of a meropenem is characterized in that, comprises the steps:
A) the meropenem crude product is dissolved in the methyl alcohol;
B) decolouring, carbon removal, Sterile Filtration;
C) in filtrate, add the mixed solution of entry and precipitation agent, precipitation, described precipitation agent is C
2-C
6Alcohol, C
3-C
8Ketone, C
2-C
8Ether or a kind or the mixture of the arbitrary proportion of 2-4 kind in the tetrahydrofuran (THF); Wherein the volume ratio of water and precipitation agent is 1: 3～1: 5;
D) filter crystallization;
E) the mixed solvent wash crystallization of water+ethanol and ester class organic solvent;
F) drying obtains finished product.
2. as the crystal refining method of claims 1 described meropenem, it is characterized in that in the step a) that solvent temperature is-10-40 ℃, obtain the solution of meropenem.
3. as the crystal refining method of claims 2 described meropenems, the consumption that it is characterized in that methyl alcohol is 3～10 times (V/W) of meropenem crude product.
4. as the crystal refining method of claims 1 described meropenem, it is characterized in that in the step c) that precipitation temperature is-10～40 ℃, the consumption of water and precipitation agent is 10-50 times (V/W) of meropenem crude product.
5. as the crystal refining method of claims 1 described meropenem, it is characterized in that 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), described ester class organic solvent are the mixture of the arbitrary proportion of in butylacetate, isopropyl acetate, ethyl acetate, ethyl formate, isobutyl acetate, methyl acetate, the propyl acetate a kind or 2-4 kind.
6. as the crystal refining method of claims 1 described meropenem, it is characterized in that in the described step e) washing times at least 1 time, the water+ethanol of each washing is 3-8 times (V/W) of meropenem crude product with the consumption of the mixed solvent of ester class organic solvent.
7. as the crystal refining method of claims 6 described meropenems, it is characterized in that washing times is 2 times in the described step e).
8. as the crystal refining method of claims 1 described meropenem, it is characterized in that described step f) adopts warm air drying to obtain finished product, drying temperature is 10-40 ℃.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702203A (en) * | 2012-06-19 | 2012-10-03 | 浙江海翔药业股份有限公司 | Meropenem refining method |
| CN102964348A (en) * | 2012-12-21 | 2013-03-13 | 卫宏远 | New meropenem crystal form and preparation method thereof |
| CN103570719A (en) * | 2012-07-31 | 2014-02-12 | 深圳市海滨制药有限公司 | Meropenem raw medicine, preparation method thereof and pharmaceutical composition containing same |
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| CN103570720A (en) * | 2012-07-31 | 2014-02-12 | 新乡海滨药业有限公司 | Meropenem raw medicine, preparation method thereof and pharmaceutical composition containing same |
| WO2014104583A1 (en) | 2012-12-28 | 2014-07-03 | Daewoong Pharmaceutical Co., Ltd. | 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 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070197781A1 (en) * | 2005-07-29 | 2007-08-23 | Neera Tewari | Processes for the preparation of carbapenems |
| JP2009215270A (en) * | 2008-03-13 | 2009-09-24 | Savior Lifetec Corp | Crystalline carbapenem compound and process for producing the same |
| WO2009138847A2 (en) * | 2008-05-14 | 2009-11-19 | Orchid Chemicals And Pharmaceuticals Ltd. | An improved process for the preparation of cefozopran |
-
2010
- 2010-09-07 CN CN2010102752230A patent/CN101921276B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070197781A1 (en) * | 2005-07-29 | 2007-08-23 | Neera Tewari | Processes for the preparation of carbapenems |
| JP2009215270A (en) * | 2008-03-13 | 2009-09-24 | Savior Lifetec Corp | Crystalline carbapenem compound and process for producing the same |
| WO2009138847A2 (en) * | 2008-05-14 | 2009-11-19 | Orchid Chemicals And Pharmaceuticals Ltd. | An improved process for the preparation of cefozopran |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102702203B (en) * | 2012-06-19 | 2014-06-04 | 浙江海翔药业股份有限公司 | Meropenem refining method |
| CN102702203A (en) * | 2012-06-19 | 2012-10-03 | 浙江海翔药业股份有限公司 | Meropenem refining method |
| CN103570720B (en) * | 2012-07-31 | 2016-02-10 | 新乡海滨药业有限公司 | A kind of meropenem bulk drug, its preparation method and comprise its pharmaceutical composition |
| CN103570718A (en) * | 2012-07-31 | 2014-02-12 | 深圳市海滨制药有限公司 | Meropenem raw medicine, preparation method thereof and pharmaceutical composition containing same |
| CN103570720A (en) * | 2012-07-31 | 2014-02-12 | 新乡海滨药业有限公司 | Meropenem raw medicine, preparation method thereof and pharmaceutical composition containing same |
| CN103570719A (en) * | 2012-07-31 | 2014-02-12 | 深圳市海滨制药有限公司 | Meropenem raw medicine, preparation method thereof and pharmaceutical composition containing same |
| 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 |
| 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 |
| CN102964348A (en) * | 2012-12-21 | 2013-03-13 | 卫宏远 | New meropenem crystal form and preparation method thereof |
| WO2014104583A1 (en) | 2012-12-28 | 2014-07-03 | Daewoong Pharmaceutical Co., Ltd. | Process for preparing meropenem trihydrate |
| CN104903324A (en) * | 2012-12-28 | 2015-09-09 | 大熊制药株式会社 | Process for preparing meropenem trihydrate |
| JP2016504371A (en) * | 2012-12-28 | 2016-02-12 | デウン ファーマシューティカル カンパニー リミテッド | Method for producing meropenem trihydrate |
| EP2938617A4 (en) * | 2012-12-28 | 2016-05-11 | Dae Woong Pharma | 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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| CN101921276B (en) | 2012-07-18 |
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