CN102285988B - Doripenem hydrate crystal and preparation method thereof - Google Patents
Doripenem hydrate crystal and preparation method thereof Download PDFInfo
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- 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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Abstract
The invention discloses a doripenem hydrate crystal and a preparation method thereof. An X-ray diffraction spectrum of powder of the crystal is shown as a figure 1; and the moisture measured value in the crystal is 4.4-5.5 percent. The preparation method of the crystal comprises the following steps of: dissolving a doripenem rough product in water at 40-70 DEG C; cooling to 0-25 DEG C; adding activated carbon; stirring and decoloring for 5-15 minutes; filtering; cooling filtrate to 0-10 DEG C; separating solid out; preserving heat and stirring for 1-2 hours; filtering; washing filter cakes by using mixture of isopropanol and water in a ratio of 4:1; and drying at the temperature of 40-60 DEG C under the condition of 5-10mmHG until the moisture measured value in the crystal is 4.4-5.5 percent. The doripenem hydrate crystal provided by the invention has the advantages of high purity, low residual solvent, high stability, high safety in medication and the like. In addition, the preparation method of the doripenem hydrate crystal provided by the invention has the advantages of simple process, low preparation cost, being suitable for industrial production and the like.
Description
Technical field
The present invention relates to a kind of S-4661 hydrate crystal and preparation method thereof, belongs to technical field of organic chemistry.
Background technology
S-4661 (Doripenem) is the novel beta-methylcarbapenem antibiotics of Japanese Shionogi company exploitation, on September 16th, 2005 in Japan's listing, commodity are called Finibax.S-4661 on October 15th, 2007 by drugs approved by FDA, be used for infecting and the complicacy urinary tract infections in the clinical treatment complicacy abdomen.Synthetic through suppressing cell walls, demonstrate wide spectrum, anti-microbial activity efficiently, the activity to Pseudomonas aeruginosa is better than existing carbapenem antibiotics especially.Its chemical structural formula is following:
Chinese patent (patent No. is ZL92111069.3 and ZL95104834.1) discloses the preparation method of unformed S-4661; As everyone knows; Unformed material is difficult for preserving, in order to overcome these defectives usually than the crystal-form substances poor stability; Japan Shionogi company discloses four kinds of S-4661 crystallizations (crystal formation I, crystal form II, crystal form II I and form IV) and preparation method thereof in succession, and the specifying information of described four kinds of crystalline compounds is seen shown in the table 1.
Table 1
In above-mentioned four kinds of crystal formations; I, II, three kinds of crystal formations of III stable bad, having only form IV is wherein stable best crystal formation, still; Form IV can not directly obtain; After must obtaining crystal form II I earlier, obtain through drying under reduced pressure again, have defectives such as complicated process of preparation, preparation cost height undoubtedly.
Chinese patent (patent No. is ZL200610028746.9) discloses two kinds of S-4661 crystallizations (crystal form V and crystal form V I) and preparation method thereof again in succession, and the specifying information of described two kinds of crystalline compounds is seen shown in the table 2.
Table 2
Chinese patent (patent No. is ZL200710127224.9) discloses another kind of S-4661 crystal form V, contains 2 molecular crystal water, and the specifying information of described crystalline compounds is seen shown in the table 3.
Table 3
Although the report of existing above-mentioned multiple crystal formation; But still be necessary to study conveniently be easy to get, thermodynamic stability is good, S-4661 new crystal suitability for industrialized production smoothly; To guarantee bulk drug and preparation thereof the stability in preparation and storage, to improve the drug quality and the clinical efficacy of S-4661.
Summary of the invention
The purpose of this invention is to provide that a kind of purity is high, residual solvent is low, the S-4661 hydrate crystal of good stability and provide that a kind of technology is simple, preparation cost is cheap, be fit to this crystalline preparation method of suitability for industrialized production.
For realizing the foregoing invention purpose, the technical scheme that the present invention adopts is following:
S-4661 hydrate crystal of the present invention, its powder x-ray diffraction spectrogram is as shown in Figure 1, and the moisture determination value in the crystal is 4.4～5.5%.
Furtherly, S-4661 hydrate crystal of the present invention also has DSC spectrogram shown in Figure 2, TG spectrogram shown in Figure 3 and IR spectrogram shown in Figure 4.
Furtherly, S-4661 hydrate crystal of the present invention under powder x-ray diffraction, is 6.43 ° ± 0.2 ° at 2 θ, 13.02 ° ± 0.2 °, and 14.96 ° ± 0.2 °; 15.27 ° ± 0.2 °, 15.85 ° ± 0.2 °, 16.60 ° ± 0.2 °, 17.46 ° ± 0.2 °, 20.60 ° ± 0.2 °; 21.04 ° ± 0.2 °, 22.18 ° ± 0.2 °, 23.88 ° ± 0.2 °, 25.35 ° ± 0.2 °, 26.04 ° ± 0.2 °; 28.19 ° ± 0.2 °, 29.00 ° ± 0.2 °, 31.65 ° ± 0.2 °, 34.09 ° ± 0.2 °, located main peak for 34.90 ° ± 0.2 °; At 2 θ is 10.86 ° ± 0.2 °, 11.22 ° ± 0.2 °, and 18.05 ° ± 0.2 °, 18.43 ° ± 0.2 °, 18.92 ° ± 0.2 °; 19.62 ° ± 0.2 °, 23.10 ° ± 0.2 °, 23.40 ° ± 0.2 °, 33.34 ° ± 0.2 °, 36.44 ° ± 0.2 °; 37.21 ° ± 0.2 °, 38.04 ° ± 0.2 °, 39.77 ° ± 0.2 °, 41.22 ° ± 0.2 °, located secondary peaks for 45.22 ° ± 0.2 °.
Furtherly, the Virahol residual volume≤500ppm in the S-4661 hydrate crystal of the present invention.
Furtherly, the Virahol residual volume≤300ppm in the S-4661 hydrate crystal of the present invention.
A kind of preparation method of S-4661 hydrate crystal of the present invention comprises the steps:
A) the S-4661 bullion is dissolved in the water of 40～70 ℃ (being preferably 50～60 ℃);
B) be cooled to 0～25 ℃ (being preferably 10～25 ℃), add gac, stir decolouring 5～15 minutes;
C) filter, filtrating is cooled to 0～10 ℃, have solid to separate out, insulated and stirred 1～2 hour;
D) filter, with isopropanol=4: 1 washing leaching cakes;
E) at 40～60 ℃, the moisture determination value that is dried under 5～10mmHg in the crystal is 4.4～5.5% (being preferably 4.7～5.2%), promptly gets described S-4661 hydrate crystal.
Further, the preparation method of S-4661 hydrate crystal of the present invention comprises the steps:
A) the S-4661 bullion is dissolved in the water of 40～70 ℃ (being preferably 50～60 ℃);
B) be cooled to 0～25 ℃ (being preferably 10～25 ℃), add gac, stir decolouring 5～15 minutes;
C) filter, adding S-4661 hydrate crystal of the present invention has solid to separate out as crystal seed in filtrating, stirs and drips organic solvent after 0.5～1 hour, drips to finish to be cooled to-5～15 ℃, continues to stir 1～2 hour;
D) filter, with isopropanol=4: 1 washing leaching cakes;
E) at 40～60 ℃, the moisture determination value that is dried under 5～10mmHg in the crystal is 4.4～5.5% (being preferably 4.7～5.2%), promptly gets described S-4661 hydrate crystal.
Described S-4661 bullion can be unformed or known arbitrary crystal formation.
The HPLC purity of described S-4661 bullion preferably >=95%.
The S-4661 bullion in the step a) and the mass ratio of water be preferably 1: 10～and 1: 30.
Described organic solvent is recommended as C
1～4Lower alcohol (as: methyl alcohol, ethanol, Virahol, propyl carbinol etc.), THF, acetone and acetonitrile in any one; Be preferably Virahol.
The volume ratio of described organic solvent and step a) institute water is recommended as 0.1: 1～and 3: 1; Be preferably 0.4: 1～2: 1.
Compared with prior art, S-4661 hydrate crystal provided by the invention has following advantage: purity high (HPLC purity is greater than 99.8%); Residual solvent low (the Virahol residual volume is no more than 500ppm, generally is lower than 300ppm) is stipulated about the limit that the isopropanol solvent residual volume is no more than 5000ppm well below ICH, has guaranteed the drug safety of S-4661 preparation greatly; Good stability is 75% environment held 6 months at 40 ℃ with relative humidity, and proterties, content, related substance and the moisture of being investigated sample have no significant change.In addition, the preparation method of S-4661 hydrate crystal 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 S-4661 hydrate crystal of the present invention;
Fig. 2 is the DSC spectrogram of S-4661 hydrate crystal of the present invention;
Fig. 3 is the TG spectrogram of S-4661 hydrate crystal of the present invention;
Fig. 4 is infrared (IR) spectrogram of S-4661 hydrate crystal of the present invention.
Embodiment
Below in conjunction with accompanying drawing and embodiment the present invention is done further detailed explanation.
The S-4661 bullion that is used for embodiment can be unformed or known arbitrary crystal formation; Preferred HPLC purity >=95%, its preparation method can be with reference to described in the documents such as ZL92111069.3, ZL95104834.1, ZL95193672.7, ZL01810309.X, ZL200610028746.9, ZL200710127224.9.
The condition determination of powder x-ray diffraction spectrogram is: the source of radiation of the wavelength α 2 of wavelength α 1,1.54439 dusts
of 1.5460 dusts
; Strength ratio α 1/ α 2 is 0.5; The Dedye-Scherrer INEL CPS-120 equipment of 40kV voltage and 30mA strength of current, the measuring error of angle of diffraction 2 θ is about ± and 0.2.
The DSC condition determination: in airtight container, logical 50ml/min nitrogen gas stream, under 20～320 ℃, heating rate is 10 ℃/min, uses DSC Q 2000 (U.S. TA company) equipment.
The TGA condition determination: in encloses container, the nitrogen gas stream of logical 100ml/min, under 20～320 ℃, heating rate is 10 ℃/min, uses SDT Q600 (U.S. TA company) equipment.
The condition determination of infrared (IR) spectrogram is: under 24 ℃, 40% humidity, in PE Spectrum RX equipment, measuring behind the pressing potassium bromide troche.
5g S-4661 bullion is dissolved in 50～55 ℃ the 100mL zero(ppm) water, water-bath is cooled to 25 ℃ then, adds the 0.5g gac, stirs decolouring 15 minutes; Suction filtration is cooled to about 0～10 ℃ with filtrating, has solid to separate out, and stirs suction filtration after two hours, with isopropanol=4: 1 washing leaching cakes; Under 50～60 ℃, 5mmHg dry 1.5 hours, 2g S-4661 hydrate crystal of the present invention.
Detect gained crystalline HPLC purity with reference to method described in " Journal of Chromatography B, 853 (2007), 123～126 "; Detect the Virahol residual volume in the gained crystal with reference to method described in " Chinese microbiotic magazine, 3 (31), 2006,187～189 ".
Detection is learnt: present embodiment gained crystalline HPLC purity is 99.85%, and wherein the Virahol residual volume is 219ppm.
The moisture that utilizes Ka Er-Fei Xie (KF) method to measure in the crystal is 4.83%.
Present embodiment gained crystalline powder x-ray diffraction spectrogram is as shown in Figure 1: at 2 θ is 6.43 °, 13.02 °, and 14.96 °, 15.27 °, 15.85 °; 16.60 °, 17.46 °, 20.60 °, 21.04 °, 22.18 °; 23.88 °, 25.35 °, 26.04 °, 28.19 °; 29.00 °, 31.65 °, 34.09 °, located main peak for 34.90 °; At 2 θ is 10.86 °, 11.22 °, 18.05 °, 18.43 °, 18.92 °, 19.62 °, 23.10 °, 23.40 °, 33.34 °, 36.44 °, 37.21 °, 38.04 °, 39.77 °, 41.22 °, has located secondary peaks for 45.22 °.
Present embodiment gained crystalline DSC spectrogram is as shown in Figure 2: at 110～160 ℃ an endotherm(ic)peak is arranged, Onset value (starting temperature) is 137.17 ℃; At 170～200 ℃ an exothermic peak is arranged, Onset value (starting temperature) is 179.02 ℃.
Present embodiment gained crystalline TG spectrogram is as shown in Figure 3: the measured value of thermogravimetic analysis (TGA) is 4.86%.Present embodiment gained crystalline infrared (IR) spectrogram is as shown in Figure 4:
| Absorption peak wave number (cm -1) | Absorption peak strength | Group and oscillatory type |
| 3541.1 | s | Intramolecular hydrogen bond association O-H stretching vibration |
| 3393.8 | m | Pyrrole ring N-H stretching vibration |
| 3261.5 | s | Intramolecular hydrogen bond association O-H stretching vibration |
| 3083.5 | m | The C-H asymmetrical stretching vibration that links to each other with nitrogen-atoms |
| 2977.7 | m | C-H asymmetrical stretching vibration in the methyl |
| 2964.5 | m | |
| 1715.7 | s | C=O stretching vibration in the carboxyl |
| 1635.6 | m | C=O stretching vibration in the beta-lactam |
| 1568.9 | s | The C=C stretching vibration |
| 1456.2 | m | C-H asymmetrical deformation vibration in the methyl |
| 1364.7 | m | C-H symmetrical deformation vibration in the methyl |
| 1366.6 | m | C-H symmetrical deformation vibration in the methyl |
| 1350.4 | m | |
| 1279 | m | ?-SO 2-asymmetrical stretching vibration |
| 1264.2 | m | |
| 1162.6 | m | ?-SO 2-symmetrical stretching vibration |
| 1091.7 | m | Secondary alcohol C-O stretching vibration |
| 1071.9 | m | The C-N stretching vibration of tertiary amine |
| 930.1 | m | OH on-plane surface angle vibration in the carboxyl |
| 765.1 | m | Pyrrole ring N-H on-plane surface waves |
10g S-4661 bullion is dissolved in 50～55 ℃ the 200mL zero(ppm) water, water-bath is cooled to 25 ℃ then, adds the 1.0g gac, stirs decolouring 15 minutes; Suction filtration is cooled to about 0～10 ℃ with filtrating, and the 0.1g crystal that adds embodiment 1 gained has solid to separate out as crystal seed, stirs to drip the 100ml Virahol after 1 hour, drips to finish and stirs suction filtration after 2 hours, with isopropanol=4: 1 washing leaching cakes; Under 50～60 ℃, 10mmHg dry 2 hours, the 8.2g crystal.
Detection is learnt: present embodiment gained crystalline HPLC purity is 99.86%, and Virahol residual volume wherein is 205ppm, and the moisture that utilizes Ka Er-Fei Xie (KF) method to measure is 4.79%; And have powder x-ray diffraction spectrogram shown in Figure 1, DSC spectrogram shown in Figure 2, TG spectrogram shown in Figure 3 and infrared (IR) chromatogram characteristic shown in Figure 4.
Embodiment 3
10g S-4661 bullion is dissolved in 55～60 ℃ the 110mL zero(ppm) water, water-bath is cooled to 15 ℃ then, adds the 1.0g gac, stirs decolouring 15 minutes; Suction filtration, the 0.1g crystal that adds embodiment 1 gained has solid to separate out as crystal seed; Stir and drip the 200ml Virahol after 1 hour; Drip to finish and to be cooled to 0～5 ℃, stir suction filtration after 2 hours, with isopropanol=4: 1 washing leaching cakes; Under 50～60 ℃, 10mmHg dry 1.5 hours, the 8.0g crystal.
Detection is learnt: present embodiment gained crystalline HPLC purity is 99.83%, and Virahol residual volume wherein is 259ppm, and the moisture that utilizes Ka Er-Fei Xie (KF) method to measure is 4.81%; And have powder x-ray diffraction spectrogram shown in Figure 1, DSC spectrogram shown in Figure 2, TG spectrogram shown in Figure 3 and infrared (IR) chromatogram characteristic shown in Figure 4.
Embodiment 4
10g S-4661 bullion is dissolved in 50～55 ℃ the 220mL zero(ppm) water, water-bath is cooled to 20 ℃ then, adds the 1.0g gac, stirs decolouring 15 minutes; Suction filtration, the 0.1g crystal that adds embodiment 1 gained has solid to separate out as crystal seed; Stir after 1 hour and to drip the 200ml Virahol, drip to finish and be cooled to 10～15 ℃, stir suction filtration after 2 hours; With isopropanol=4: 1 washing leaching cakes, under 40～50 ℃, 5mmHg dry 3 hours, the 8.1g crystal.
Detection is learnt: present embodiment gained crystalline HPLC purity is 99.84%, and Virahol residual volume wherein is 235ppm, and the moisture that utilizes Ka Er-Fei Xie (KF) method to measure is 4.76%; And have powder x-ray diffraction spectrogram shown in Figure 1, DSC spectrogram shown in Figure 2, TG spectrogram shown in Figure 3 and infrared (IR) chromatogram characteristic shown in Figure 4.
Embodiment 5
10g S-4661 bullion is dissolved in 55～60 ℃ the 150mL zero(ppm) water, water-bath is cooled to 10 ℃ then, adds the 1.0g gac, stirs decolouring 15 minutes; Suction filtration, the 0.1g crystal that adds embodiment 1 gained has solid to separate out as crystal seed; Stir after 1 hour and to drip the 300ml Virahol, drip to finish and be cooled to 0～5 ℃, stir suction filtration after 2 hours; With isopropanol=4: 1 washing leaching cakes, under 50～55 ℃, 10mmHg dry 2 hours, the 8.0g crystal.
Detection is learnt: present embodiment gained crystalline HPLC purity is 99.87%, and Virahol residual volume wherein is 165ppm, and the moisture that utilizes Ka Er-Fei Xie (KF) method to measure is 4.78%; And have powder x-ray diffraction spectrogram shown in Figure 1, DSC spectrogram shown in Figure 2, TG spectrogram shown in Figure 3 and infrared (IR) chromatogram characteristic shown in Figure 4.
Embodiment 6
10g S-4661 bullion is dissolved in 50～55 ℃ the 300mL zero(ppm) water, water-bath is cooled to 10～15 ℃ then, adds the 1.0g gac, stirs decolouring 15 minutes; Suction filtration, the 0.1g crystal that adds embodiment 1 gained has solid to separate out as crystal seed; Stir after 1 hour and to drip the 200ml Virahol, drip to finish and be cooled to 0～5 ℃, stir suction filtration after 2 hours; With isopropanol=4: 1 washing leaching cakes, under 40～45 ℃, 10mmHg dry 5 hours, the 7.8g crystal.
Detection is learnt: present embodiment gained crystalline HPLC purity is 99.88%, and Virahol residual volume wherein is 265ppm, and the moisture that utilizes Ka Er-Fei Xie (KF) method to measure is 5.01%; And have powder x-ray diffraction spectrogram shown in Figure 1, DSC spectrogram shown in Figure 2, TG spectrogram shown in Figure 3 and infrared (IR) chromatogram characteristic shown in Figure 4.
Embodiment 7
10g S-4661 bullion is dissolved in 50～55 ℃ the 200mL zero(ppm) water, water-bath is cooled to 20～25 ℃ then, adds the 1.0g gac, stirs decolouring 15 minutes; Suction filtration is cooled to about 0～5 ℃ with filtrating, and the 0.1g crystal that adds embodiment 1 gained is as crystal seed; There is solid to separate out, stirs after 1 hour and to drip the 200ml Virahol, drip to finish and be cooled to-5～0 ℃; Stir suction filtration after 2 hours; With isopropanol=4: 1 washing leaching cakes, under 55～60 ℃, 5mmHg dry 1 hour, the 7.88g crystal.
Detection is learnt: present embodiment gained crystalline HPLC purity is 99.82%, and Virahol residual volume wherein is 275ppm, and the moisture that utilizes Ka Er-Fei Xie (KF) method to measure is 4.87%; And have powder x-ray diffraction spectrogram shown in Figure 1, DSC spectrogram shown in Figure 2, TG spectrogram shown in Figure 3 and infrared (IR) chromatogram characteristic shown in Figure 4.
Embodiment 8
Investigate the stability of S-4661 hydrate crystal of the present invention: it is 75% moisture eliminator that gained S-4661 hydrate crystal of the present invention is placed relative humidity; Place 40 ℃ of thermostatic drying chambers; After 0,1,2,3,6 month, take a sample; The proterties of check and analysis sample, content, related substance and moisture are measured the result and are seen shown in the table 4.
Table 4
Visible by table 4: S-4661 hydrate crystal of the present invention is in 6 months probation, and its proterties, content, related substance and moisture have no significant change, and have satisfactory stability property.
Be necessary to be pointed out that at this: above embodiment only is used for the present invention is further specified; Can not be interpreted as the restriction to protection domain of the present 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 (7)
1. S-4661 hydrate crystal, it is characterized in that: said crystalline powder x-ray diffraction spectrogram is as shown in Figure 1, and the moisture determination value in the crystal is 4.4 ~ 5.5%.
2. S-4661 hydrate crystal according to claim 1 is characterized in that: said crystal also has DSC spectrogram shown in Figure 2, TG spectrogram shown in Figure 3 and IR spectrogram shown in Figure 4.
3. S-4661 hydrate crystal according to claim 1 and 2 is characterized in that: the Virahol residual volume≤500ppm in the said crystal.
4. the preparation method of the described S-4661 hydrate crystal of claim 1 is characterized in that, comprises the steps:
A) the S-4661 bullion is dissolved in 40 ~ 70 ℃ the water; Described S-4661 bullion is unformed or known arbitrary crystal formation, HPLC purity >=95%;
B) be cooled to 0 ~ 25 ℃, add gac, stir decolouring 5 ~ 15 minutes;
C) filter, filtrating is cooled to 0 ~ 10 ℃, have solid to separate out, insulated and stirred 1 ~ 2 hour;
D) filter, with isopropanol=4:1 washing leaching cake;
E) at 40 ~ 60 ℃, the moisture determination value that is dried under 5 ~ 10mmHg in the crystal is 4.4 ~ 5.5%, promptly gets described S-4661 hydrate crystal.
5. the preparation method of S-4661 hydrate crystal according to claim 4 is characterized in that: the S-4661 bullion in the step a) and the mass ratio of water are 1:10 ~ 1:30.
6. the preparation method of the described S-4661 hydrate crystal of claim 1 is characterized in that, comprises the steps:
A) the S-4661 bullion is dissolved in 40 ~ 70 ℃ the water; Described S-4661 bullion is unformed or known arbitrary crystal formation, HPLC purity >=95%;
B) be cooled to 0 ~ 25 ℃, add gac, stir decolouring 5 ~ 15 minutes;
C) filter, the described S-4661 hydrate crystal of adding claim 1 has solid to separate out as crystal seed in filtrating, stirs and drips Virahol after 0.5 ~ 1 hour, drips to finish to be cooled to-5 ~ 15 ℃, continues to stir 1 ~ 2 hour;
D) filter, with isopropanol=4:1 washing leaching cake;
E) at 40 ~ 60 ℃, the moisture determination value that is dried under 5 ~ 10mmHg in the crystal is 4.4 ~ 5.5%, promptly gets described S-4661 hydrate crystal.
7. the preparation method of S-4661 hydrate crystal according to claim 6 is characterized in that: the volume ratio of described organic solvent and step a) institute water is 0.1:1 ~ 3:1.
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| CN201110266374A CN102285988B (en) | 2011-09-08 | 2011-09-08 | Doripenem hydrate crystal and preparation method thereof |
| PCT/CN2012/081064 WO2013034087A1 (en) | 2011-09-08 | 2012-09-06 | Doripenem hydrate crystal and preparation method therefor |
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| CN102285988B (en) * | 2011-09-08 | 2012-09-05 | 上海希迈医药科技有限公司 | Doripenem hydrate crystal and preparation method thereof |
| CN102702201B (en) * | 2012-03-26 | 2013-12-25 | 深圳市海滨制药有限公司 | Doripenem intermediate compound, preparation method and application of doripenem intermediate compound and preparation method for doripenem |
| CN104072497B (en) * | 2013-03-29 | 2017-10-03 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of newly crystallization and preparation method thereof of donipenem |
| WO2015167148A1 (en) | 2014-04-28 | 2015-11-05 | 제이더블유중외제약 주식회사 | Novel crystal of doripenem, and preparation method therefor |
| KR20160109904A (en) * | 2015-03-13 | 2016-09-21 | 주식회사 대웅제약 | Method of preparing crystalline doripenem |
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| CN1151162A (en) * | 1994-05-02 | 1997-06-04 | 盐野义制药株式会社 | Crystal of pyrrolidylthiocarbapenem derivative, lyophilized preparation containing said crystal, and process for producing the same |
| CN101100468A (en) * | 2006-07-07 | 2008-01-09 | 上海医药工业研究院 | Doriipenem hydrate crystal and preparation method thereof |
| CN101100469A (en) * | 2006-07-03 | 2008-01-09 | 成都地奥九泓制药厂 | Novel crystal of doripenem, preparation method and use thereof |
| EP2275424A1 (en) * | 2009-07-17 | 2011-01-19 | Sandoz AG | Doripenem crystallization process |
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| BRPI0109712B8 (en) * | 2000-03-31 | 2021-05-25 | Shionogi & Co | crystal form of pyrrolidithiocarbapenem derivative |
| CN102285988B (en) * | 2011-09-08 | 2012-09-05 | 上海希迈医药科技有限公司 | Doripenem hydrate crystal and preparation method thereof |
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| CN1151162A (en) * | 1994-05-02 | 1997-06-04 | 盐野义制药株式会社 | Crystal of pyrrolidylthiocarbapenem derivative, lyophilized preparation containing said crystal, and process for producing the same |
| CN101100469A (en) * | 2006-07-03 | 2008-01-09 | 成都地奥九泓制药厂 | Novel crystal of doripenem, preparation method and use thereof |
| CN101100468A (en) * | 2006-07-07 | 2008-01-09 | 上海医药工业研究院 | Doriipenem hydrate crystal and preparation method thereof |
| EP2275424A1 (en) * | 2009-07-17 | 2011-01-19 | Sandoz AG | Doripenem crystallization process |
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