CN102363617B - Ertapenem monosodium salt crystal and preparation method thereof - Google Patents
Ertapenem monosodium salt crystal and preparation method thereof Download PDFInfo
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- CN102363617B CN102363617B CN 201110351370 CN201110351370A CN102363617B CN 102363617 B CN102363617 B CN 102363617B CN 201110351370 CN201110351370 CN 201110351370 CN 201110351370 A CN201110351370 A CN 201110351370A CN 102363617 B CN102363617 B CN 102363617B
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- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
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Abstract
The invention discloses an ertapenem monosodium salt crystal and a preparation method thereof. The ertapenem monosodium salt crystal has a powder X-ray diffraction spectrum shown by a figure 1. The preparation method of the crystal comprises: dissolving an ertapenem monosodium salt serving as a raw material and a sodium-containing inorganic salt in water at 0 to 5 DEG C; cooling to -2 to 10 DEG C, regulating the pH value to 5 to 6 by using an acidic solution, adding active carbon for decolorization, and filtering; adding methanol and cooling to 0 to -40 DEG C; dripping normal propyl alcohol, stirring and crystallizing; and filtering, washing a filter cake by using an organic solvent, and pumping the solvent completely by using an oil pump. The ertapenem monosodium salt provided by the invention has the advantages of low residual solvent content, high stability and the like. The preparation method disclosed by the invention has the advantages of simple process, low preparation cost, suitability for industrial production and the like and has an industrial application value.
Description
Technical field
The present invention relates to a kind of xln of ertapenem list sodium salt and preparation method thereof, belong to technical field of organic chemistry.
Background technology
Ertapenem list sodium salt (Ertapenem Sodium) is to be invented by Britain AstraZeneca company, after transfer Merck ﹠ Co., Inc. and do further research and development, it is the new injection broad-spectrum long-acting carbapenem antibiotic that has 4 (R) methyl, 2002 in U.S.'s Initial Public Offering, has has a broad antifungal spectrum, stable to dehydropeptidase of kidney-1 (DHP-1), pharmacokinetic parameters is good, clinical therapeutic efficacy is good, better tolerance, untoward reaction is few, long half time, characteristics such as can be administered once in one day, be used for the treatment of adult's moderate clinically to the responsive microbial infection of severe, can obtain satisfactory effect to the acquired polyinfection of community.The structural formula of ertapenem list sodium salt is as follows:
Unformed ertapenem list sodium salt is disclosed among the patent documentation WO2008062279, this unformed material instability, variable color and purity are low easily.
Patent documentation WO03026572 discloses ertapenem list sodium salt A type and Type B crystallization, the preparation method of A type crystallization joins the part n-propyl alcohol in the ertapenem list sodium-salt aqueous solution earlier, be cooled to-5 ℃, with acid for adjusting pH value=5～6, add 0.5～3 times of amount methyl alcohol (volume of water relatively) and the crystallization of 0.5～3 times of amount n-propyl alcohol subsequently.The preparation method of Type B crystallization gets the crystallization of A type with containing the washed with isopropyl alcohol of 5～25% moisture.
Patent documentation CN1821248 discloses the crystallization of ertapenem list sodium salt C type, and the preparation method gets with being selected from the organic solvent washing A type of methyl acetate, acetonitrile, tetrahydrofuran (THF), acetone or its aqueous mixture or Type B crystallization.This patent also discloses a kind of reduction crystal form A, and the method for residual solvent among B and the C is about to nitrogen gas stream at low temperatures by wet crystal, obtains meeting the product of medicinal standard.
Patent documentation WO2009150630 discloses the crystallization of ertapenem list sodium salt D type, the preparation method joins part methyl alcohol in the ertapenem list sodium-salt aqueous solution earlier, with acid for adjusting pH value=5～6, adds an amount of methyl alcohol and n-propyl alcohol crystallization subsequently, filtration is also used washing with acetone, and vacuum-drying obtains.
All contain residual organic solvent in A, the B of the ertapenem list sodium salt of having reported, C and four kinds of crystal formations of D, wherein crystal form A, B and C can be reduced to residual solvent through the nitrogen gas stream drying and meet medicinal standard, but do not report whether crystal formation keeps and consequent stability problem.And amorphous ertapenem list sodium salt poor stability.Therefore be necessary still to study that the preparation method is simple, residual solvent is low, good stability, the new crystal of the ertapenem list sodium salt of suitability for industrialized production smoothly, to guarantee bulk drug and preparation thereof the stability in preparation and storage, to improve drug quality and the clinical effectiveness of ertapenem list sodium salt.
Summary of the invention
At existing in prior technology the problems referred to above and defective, the purpose of this invention is to provide that a kind of residual solvent is low, the novel ertapenem list sodium salt crystal body of good stability and provide that a kind of technology is simple, preparation cost is cheap, be fit to the preparation method of this xln of suitability for industrialized production.
For achieving the above object, the technical solution used in the present invention is as follows:
Ertapenem list sodium salt crystal body of the present invention has powder x-ray diffraction spectrogram shown in Figure 1.
Furtherly, ertapenem list sodium salt crystal body of the present invention also has FT-IR spectrogram shown in Figure 2.
Furtherly, ertapenem list sodium salt crystal body of the present invention is under powder x-ray diffraction, it is 4.4 ° ± 0.1 ° at angle of diffraction 2 θ, 5.2 ° ± 0.1 °, 7.4 ° ± 0.1 °, 8.1 ° ± 0.1 °, 10.9 ° ± 0.1 °, 12.6 ° ± 0.1 °, 14.7 ° ± 0.1 °, 15.5 ° ± 0.1 °, 17.3 ° ± 0.1 °, located main peak for 19.3 ° ± 0.1 °.
A kind of preparation method of ertapenem list sodium salt crystal body of the present invention comprises the steps:
A) at 0～5 ℃, with ertapenem list sodium salt raw material with to contain the sodium mineral alkali soluble in water;
B) be cooled to-2～10 ℃, regulate pH=5～6 (preferred pH=5.4～5.6) with acidic solution, add activated carbon decolorizing, filtration again;
C) add methyl alcohol, be cooled to 0～-40 ℃ (preferred-5～-20 ℃); Wherein the methyl alcohol volume of Jia Ruing is 0.5～3 times of volume of step a) institute water;
D) drip n-propyl alcohol, stirring and crystallizing; Wherein the n-propyl alcohol volume of Di Jiaing is 0.5～3 times of volume of step a) institute water;
E) filter, use the organic solvent washing filter cake, oil pump is drained solvent, namely gets described ertapenem list sodium salt crystal body.
As preferred version, the preparation method of described ertapenem list sodium salt crystal body comprises the steps:
A) at 0～5 ℃, with ertapenem list sodium salt raw material with to contain the sodium mineral alkali soluble in water;
B) be cooled to-2～10 ℃, regulate pH=5～6 with acidic solution, add activated carbon decolorizing, filtration again;
C) add methyl alcohol, be cooled to 0～-40 ℃; Wherein the methyl alcohol volume of Jia Ruing is 0.5～3 times of volume of step a) institute water;
D) add crystal seed, drip n-propyl alcohol then, stirring and crystallizing; Wherein the n-propyl alcohol volume of Di Jiaing is 0.5～3 times of volume of step a) institute water;
E) filter, use the organic solvent washing filter cake, oil pump is drained solvent, and logical dew point is moisture inert gas 4～48h of 0～30 ℃ at last, namely obtains described ertapenem list sodium salt crystal body.
Described ertapenem list sodium salt raw material is any known crystal formation or unformed ertapenem list sodium salt or their mixture.
The described sodium mineral alkali that contains is recommended as yellow soda ash, sodium bicarbonate or sodium hydroxide, preferred sodium bicarbonate or yellow soda ash.
Described ertapenem list sodium salt raw material is 1: 1～1: 4 with the mol ratio that contains the sodium mineral alkali.
The quality of step a) institute water is 6～12 times of ertapenem list sodium salt raw materials quality, preferred 8～10 times.
Described acidic solution is selected from any one in the organic alcoholic solution of C1～C4 of formic acid, acetic acid, propionic acid, hydrochloric acid or formic acid, acetic acid, propionic acid, hydrochloric acid, the methanol solution of preferable formic acid or acetic acid.
The volumetric molar concentration of described acidic solution is recommended as 1～25mol/L, is preferably 3～10mol/L.
Described organic solvent is selected from any one or a few the mixed solvent in acetone, ethyl acetate, tetrahydrofuran (THF), ether, methyl tertiary butyl ether, methylene dichloride, methyl alcohol, the ethanol.
Compared with prior art, ertapenem list sodium salt crystal body provided by the invention has advantages such as the low and good stability of residual solvent amount.In addition, the preparation method of ertapenem list sodium salt crystal body provided by the invention has advantages such as technology is simple, preparation cost is cheap, suitable suitability for industrialized production.
Description of drawings
Fig. 1 is the powder x-ray diffraction spectrogram of ertapenem list sodium salt crystal body provided by the invention;
Fig. 2 is the FT-IR spectrogram of ertapenem list sodium salt crystal body provided by the invention;
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of ertapenem list sodium salt crystal body provided by the invention;
Fig. 4 is the mass spectrum of ertapenem list sodium salt crystal body provided by the invention;
Fig. 5 is that ertapenem list sodium salt crystal body provided by the invention is in the powder x-ray diffraction spectrogram of-18 ℃ of placements after 6 months.
Fig. 6 is the powder x-ray diffraction spectrogram of ertapenem list sodium salt crystal body provided by the invention before logical inert gas.
Embodiment
The present invention is further detailed explanation below in conjunction with drawings and Examples.
Used ertapenem list sodium salt raw material can be the ertapenem list sodium salt of unformed or known arbitrary crystal formation or their mixture among the embodiment, its preparation method can be with reference to US6504027, WO2002057266, WO2008062279, CN200510030660, CN200710045327, " China Medicine University's journal ", described in 2007,38 (4): 305～310 documents such as grade.
Analytical instrument model and condition determination used among the embodiment are as follows:
1. powder x-ray diffraction analysis
Instrument: Dedye-Scherrer INEL CPS-120 powder x-ray diffraction.
The condition of scanning: source of radiation α
1(wavelength
), α
2(wavelength
), strength ratio α
1/ α
2Be 0.5, Cu (40KV, 30mA).
2.FT-IR analyze
Instrument: Perkin-Elmer, the Spectrum type.
Condition determination: KBr compressing tablet.
3.
1H-NMR analyzes
Instrument: Brooker,Switzerland AV400,400MHz nmr analysis instrument.
Measure solvent: D
2O.
4.MS analyze
Instrument: the UPLC-TQD of Waters company type liquid chromatography mass combined instrument.
Mass spectrum condition: positive ion full scan pattern (ESI ion source), molecular weight ranges: 100～1500amu.Capillary voltage :+3.5/-3.0 (KV); Taper hole voltage :+20/-25 (V); Secondary taper hole voltage: ± 3 (V); Six grades of bar voltages: ± 0.3 (V); Source temperature: 150 ℃; Desolventizing temperature: 350 ℃; Desolventizing air-flow: 800L/Hr; Taper hole air-flow: 50L/Hr.
With 1.86g NaHCO
3Be dissolved in the 60ml distilled water; Be cooled to 0～5 ℃, add ertapenem list sodium salt raw material 10.0g, molten clear; Regulate pH=5.5 at 0～5 ℃ of acetic acid with 3mol/L-methanol solution; Add 2g activated carbon decolorizing 20min, filtering gac under argon shield and ice-water bath; Add 100ml methyl alcohol, be cooled to-20～-15 ℃, Dropwise 5 0ml n-propyl alcohol stirs 40min at a slow speed, has a large amount of solids to separate out, and drips remaining 100ml n-propyl alcohol again, drips complete stirring and crystallizing 40min; Filter, use the small amount of acetone washing leaching cake, oil pump is drained solvent, gets the 7.4g white solid; Lead to the moisture argon gas stream 24h of 4～6 ℃ of dew points at last, namely obtain described ertapenem list sodium salt crystal body 7.2g.
0.88g NaOH is dissolved in the 120ml distilled water; Be cooled to 0～5 ℃, add ertapenem list sodium salt raw material 10.0g, molten clear; Regulate pH=5.5 at 0～5 ℃ of acetic acid with 3mol/L-methanol solution; Add 2g activated carbon decolorizing 20min, filtering gac under argon shield and ice-water bath; Add 100ml methyl alcohol, be cooled to-20～-15 ℃, add the 0.1g crystal seed, and drip the 150ml n-propyl alcohol, drip complete stirring and crystallizing 40min; Filter, use the small amount of acetone washing leaching cake, oil pump is drained solvent, gets the 7.2g white solid; Logical dew point is 0～4 ℃ moisture argon gas stream 24h at last, namely obtains described ertapenem list sodium salt crystal body 7.0g (be designated as batch 1).
Repeat twice again according to above step, can obtain ertapenem list sodium salt crystal body 7.4g (be designated as batch 2) and 7.1g (be designated as batch 3) respectively.
The solvent residual amount of 3 batches the ertapenem list sodium salt crystal body that present embodiment is prepared is shown in Table 1.
Table 1 solvent residual amount (unit is ppm)
| Sample | Methyl alcohol | Acetone | N-propyl alcohol | Ethyl acetate | Tetrahydrofuran (THF) |
| |
213 | 390 | 993 | | ND |
| Batches | |||||
| 2 | 206 | 153 | ND | ND | ND |
| Batches 3 | 240 | 238 | ND | ND | ND |
By table 1 as seen: the solvent residual amount of the ertapenem list sodium salt crystal body of present embodiment preparation is low, meets medicinal standard.
3 batches the ertapenem list sodium salt crystal body that present embodiment is prepared was deposited 6 months at-18 ℃ respectively, detected the purity of an ertapenem list sodium salt every other month, and detected result is shown in Table 2.
The purity of table 2 ertapenem list sodium salt
| Sample | 0 |
1 |
2 months | 3 months | 6 |
| Batch | |||||
| 1 | 98.3 | 98.2 | 98.2 | 98.1 | 98.0 |
| |
98.5 | 98.4 | 98.4 | 98.3 | 98.2 |
| Batches 3 | 98.6 | 98.5 | 98.4 | 98.3 | 98.3 |
By table 2 as seen: the having good stability of the ertapenem list sodium salt crystal body of present embodiment preparation.
Embodiment 3
With 4.4g Na
2CO
3Be dissolved in the 60ml distilled water, be mixed with and contain the sodium inorganic base aqueous solution; Be cooled to 0～5 ℃, add ertapenem list sodium salt raw material 10.0g, molten clear; Regulate pH=5.6 at 0～5 ℃ of formic acid with 3mol/L-methanol solution; Add 2g activated carbon decolorizing 20min, filtering gac under argon shield and ice-water bath; Add 180ml methyl alcohol, be cooled to-10～-5 ℃, add the 0.1g crystal seed, drip the 180ml n-propyl alcohol, drip and finish stirring and crystallizing 40min at a slow speed; Filter, use the small amount of ethanol washing leaching cake, oil pump is drained solvent, gets the 6.9g white solid; Logical dew point is 10～14 ℃ moisture argon gas stream 6h at last, namely obtains described ertapenem list sodium salt crystal body 6.8g (be designated as batch 4).
Repeat twice again according to above step, can obtain ertapenem list sodium salt crystal body 7.0g (be designated as batch 5) and 7.1g (be designated as batch 6) respectively.
The solvent residual amount of 3 batches the ertapenem list sodium salt crystal body that present embodiment is prepared is shown in Table 3.
Table 3 solvent residual amount (unit is ppm)
| Sample | Methyl alcohol | Ethanol | N-propyl alcohol | Ethyl acetate | Tetrahydrofuran (THF) |
| Batches 4 | 24 | 828 | 986 | 6 | ND |
| Batches 5 | 100 | 1600 | 1000 | ND | ND |
| Batches 6 | 74 | 980 | 850 | ND | ND |
By table 3 as seen: the solvent residual amount of the ertapenem list sodium salt crystal body of present embodiment preparation is low, meets medicinal standard.
3 batches the ertapenem list sodium salt crystal body that present embodiment is prepared was deposited 6 months at-18 ℃ respectively, detected the purity of an ertapenem list sodium salt every other month, and detected result is shown in Table 4.
The purity of table 4 ertapenem list sodium salt
| Sample | 0 |
1 |
2 months | 3 months | 6 months |
| Batches 4 | 98.4 | 98.2 | 98.1 | 98.0 | 97.9 |
| Batches 5 | 98.6 | 98.4 | 98.3 | 98.2 | 98.0 |
| Batches 6 | 98.7 | 98.5 | 98.4 | 98.3 | 98.2 |
By table 4 as seen: the having good stability of the ertapenem list sodium salt crystal body of present embodiment preparation.
Ertapenem list sodium salt crystal body provided by the invention has powder x-ray diffraction spectrogram shown in Figure 1: be 4.43 ° at 2 θ, 5.23 °, 7.37 °, 8.14 °, 10.97 °, 12.59 °, 14.74 °, 15.46 °, located characteristic peak for 17.31 ° and 19.34 °.
Ertapenem list sodium salt crystal body provided by the invention has FT-IR spectrogram shown in Figure 2: have characteristic peak at (cm-1) 3422,2969,1751,1686,1560,1387 and 773 places.
Ertapenem list sodium salt crystal body provided by the invention have hydrogen nuclear magnetic resonance spectrogram shown in Figure 3: δ 1.03 (d, 3H, CH3, J=7.2); 1.13 (d, 3H, CH3, J=6.4); 2.04 (m, 1H, C4 '-H); 2.88 (m, 1H, C4 '-H); 3.18 (m, 1H, C3 '-H); (3.28 dd, 1H, C2 '-H, J=6.0,2.4); (3.33 dd, 1H, C5-H, J=12.0,5.2); (3.69 dd, 1H, C6-H, J=12.0,6.6); 3.92 (m, 1H, C4-H, J=6.4); (4.04 dd, 1H, C2 '-H, J=9.2,2.4); 4.08 (m, 1H, CH-OH); 4.49 (t, 1H, C5 '-H, J=8.1); 7.32 (t, 1H, C5 "-H, J=7.9); 7.49 (d, 1H, C4 "-H, J=8.1); 7.57 (d, 1H, C6 "-H, J=7.7); 7.74 (s, 1H, C2 "-H).
Ertapenem list sodium salt crystal body provided by the invention has mass spectrum shown in Figure 4 (MS, ESI) figure: 473.99 (M-H), 475.99 (M+H).
Fig. 5 is that ertapenem list sodium salt crystal body provided by the invention is in the x-ray diffractogram of powder spectrum of-18 ℃ of placements after 6 months, comparison diagram 1 and Fig. 5 be as seen: ertapenem list sodium salt crystal body provided by the invention in-18 ℃ of x-ray diffractogram of powder spectrums after placing 6 months basic do not become, have stability.
Fig. 6 is the x-ray diffractogram of powder spectrum of ertapenem list sodium salt crystal body provided by the invention before logical inert gas, comparison diagram 1 and Fig. 6 be as seen: the x-ray diffractogram of powder spectrum of ertapenem list sodium salt crystal body provided by the invention before and after logical inert gas be basic and does not become, and has stability.
Should be noted that at last: above embodiment only is used for the present invention is further specified; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.
Claims (12)
1. an ertapenem list sodium salt crystal body is characterized in that: have powder x-ray diffraction spectrogram shown in Figure 1.
2. ertapenem list sodium salt crystal body according to claim 1 is characterized in that: also have FT-IR spectrogram shown in Figure 2.
3. ertapenem list sodium salt crystal body according to claim 1, it is characterized in that: under powder x-ray diffraction, be 4.4 ° ± 0.1 ° at angle of diffraction 2 θ, 5.2 ° ± 0.1 °, 7.4 ° ± 0.1 °, 8.1 ° ± 0.1 °, 10.9 ° ± 0.1 °, 12.6 ° ± 0.1 °, 14.7 ° ± 0.1 °, 15.5 ° ± 0.1 °, 17.3 ° ± 0.1 °, located main peak for 19.3 ° ± 0.1 °.
4. the preparation method of the described ertapenem list of claim 1 a sodium salt crystal body is characterized in that, comprises the steps:
A) at 0～5 ℃, with ertapenem list sodium salt raw material with to contain the sodium mineral alkali soluble in water;
B) be cooled to-2～10 ℃, regulate pH=5～6 with acidic solution, add activated carbon decolorizing, filtration again;
C) add methyl alcohol, be cooled to 0～-40 ℃; Wherein the methyl alcohol volume of Jia Ruing is 0.5～3 times of volume of step a) institute water;
D) drip n-propyl alcohol, stirring and crystallizing; Wherein the n-propyl alcohol volume of Di Jiaing is 0.5～3 times of volume of step a) institute water;
E) filter, use the organic solvent washing filter cake, oil pump is drained solvent, namely gets described ertapenem list sodium salt crystal body; Described organic solvent is selected from any one or a few the mixed solvent in acetone, ethyl acetate, tetrahydrofuran (THF), ether, methyl tertiary butyl ether, methylene dichloride, methyl alcohol, the ethanol.
5. the preparation method of the described ertapenem list of claim 1 a sodium salt crystal body is characterized in that, comprises the steps:
A) at 0～5 ℃, with ertapenem list sodium salt raw material with to contain the sodium mineral alkali soluble in water;
B) be cooled to-2～10 ℃, regulate pH=5～6 with acidic solution, add activated carbon decolorizing, filtration again;
C) add methyl alcohol, be cooled to 0～-40 ℃; Wherein the methyl alcohol volume of Jia Ruing is 0.5～3 times of volume of step a) institute water;
D) add crystal seed, drip n-propyl alcohol then, stirring and crystallizing; Wherein the n-propyl alcohol volume of Di Jiaing is 0.5～3 times of volume of step a) institute water;
E) filter, use the organic solvent washing filter cake, oil pump is drained solvent, and logical dew point is moisture inert gas 4～48h of 0～30 ℃ at last, namely obtains described ertapenem list sodium salt crystal body; Described organic solvent is selected from any one or a few the mixed solvent in acetone, ethyl acetate, tetrahydrofuran (THF), ether, methyl tertiary butyl ether, methylene dichloride, methyl alcohol, the ethanol.
6. according to the preparation method of claim 4 or 5 described ertapenem list sodium salt crystal bodies, it is characterized in that: described ertapenem list sodium salt raw material is any known crystal formation or unformed ertapenem list sodium salt or their mixture.
7. according to the preparation method of claim 4 or 5 described ertapenem list sodium salt crystal bodies, it is characterized in that: the described sodium mineral alkali that contains is yellow soda ash, sodium bicarbonate or sodium hydroxide.
8. according to the preparation method of claim 4 or 5 described ertapenem list sodium salt crystal bodies, it is characterized in that: the quality of step a) institute water is 6～12 times of ertapenem list sodium salt raw materials quality.
9. according to the preparation method of claim 4 or 5 described ertapenem list sodium salt crystal bodies, it is characterized in that: described ertapenem list sodium salt raw material is 1:1～1:4 with the mol ratio that contains the sodium mineral alkali.
10. according to the preparation method of claim 4 or 5 described ertapenem list sodium salt crystal bodies, it is characterized in that: described acidic solution is selected from any one in the organic alcoholic solution of C1～C4 of formic acid, acetic acid, propionic acid, hydrochloric acid.
11. the preparation method of ertapenem list sodium salt crystal body according to claim 10 is characterized in that: described acidic solution is selected from the methanol solution of formic acid or the methanol solution of acetic acid.
12. according to the preparation method of claim 4 or 5 described ertapenem list sodium salt crystal bodies, it is characterized in that: the volumetric molar concentration of described acidic solution is 1～25mol/L.
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| PCT/CN2012/082886 WO2013067878A1 (en) | 2011-11-09 | 2012-10-12 | Ertapenem sodium crystal and preparation method thereof |
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| CN102363617B (en) * | 2011-11-09 | 2013-09-18 | 上海希迈医药科技有限公司 | Ertapenem monosodium salt crystal and preparation method thereof |
| CN103848832A (en) * | 2012-11-28 | 2014-06-11 | 上海创诺医药集团有限公司 | Purification method of ertapenem sodium |
| WO2014082226A1 (en) * | 2012-11-28 | 2014-06-05 | 上海创诺医药集团有限公司 | Purification method of ertapenem sodium |
| CN103159770A (en) * | 2013-03-22 | 2013-06-19 | 成都自豪药业有限公司 | Crystal form of ertapenem monosodium salt |
| WO2015087245A1 (en) | 2013-12-11 | 2015-06-18 | Unimark Remedies Ltd. | Process for preparation of ertapenem and salts thereof |
| CN110698479A (en) * | 2018-07-09 | 2020-01-17 | 武汉启瑞药业有限公司 | Synthetic method of ertapenem monosodium salt |
| CN110423237B (en) * | 2019-09-10 | 2021-12-31 | 石药集团中诺药业（石家庄）有限公司 | Method for refining ertapenem sodium |
| CN113416193B (en) | 2021-08-23 | 2021-12-17 | 凯莱英医药集团（天津）股份有限公司 | Novel ertapenem sodium crystal form and preparation method thereof |
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| CN102363617B (en) * | 2011-11-09 | 2013-09-18 | 上海希迈医药科技有限公司 | Ertapenem monosodium salt crystal and preparation method thereof |
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| CN1752090A (en) * | 2005-10-20 | 2006-03-29 | 上海交通大学 | Preparation method of ertabeinan sodium salt |
| CN101376643A (en) * | 2007-08-28 | 2009-03-04 | 上海医药工业研究院 | Preparation of carbapenem penicillin ertapenem intermediate |
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