CN101880282A - Purification method of pyrrolidine carbapenem antibiotics - Google Patents
Purification method of pyrrolidine carbapenem antibiotics Download PDFInfo
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- CN101880282A CN101880282A CN200910031291XA CN200910031291A CN101880282A CN 101880282 A CN101880282 A CN 101880282A CN 200910031291X A CN200910031291X A CN 200910031291XA CN 200910031291 A CN200910031291 A CN 200910031291A CN 101880282 A CN101880282 A CN 101880282A
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- 238000000034 method Methods 0.000 title claims abstract description 22
- 238000000746 purification Methods 0.000 title claims abstract description 19
- -1 pyrrolidine carbapenem Chemical compound 0.000 title abstract description 5
- 239000003242 anti bacterial agent Substances 0.000 title abstract description 4
- 229940088710 antibiotic agent Drugs 0.000 title abstract description 4
- 238000002425 crystallisation Methods 0.000 claims abstract description 36
- 230000008025 crystallization Effects 0.000 claims abstract description 36
- 239000007864 aqueous solution Substances 0.000 claims abstract description 25
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000000243 solution Substances 0.000 claims description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 52
- 239000013078 crystal Substances 0.000 claims description 21
- 238000001035 drying Methods 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 238000001816 cooling Methods 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 230000001476 alcoholic effect Effects 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 3
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 abstract description 32
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 abstract description 4
- 229960000895 doripenem Drugs 0.000 abstract description 4
- 238000001953 recrystallisation Methods 0.000 abstract description 4
- 238000003756 stirring Methods 0.000 description 37
- 229960002429 proline Drugs 0.000 description 31
- 229930182821 L-proline Natural products 0.000 description 16
- 239000012043 crude product Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- OTTZHAVKAVGASB-UHFFFAOYSA-N hept-2-ene Chemical compound CCCCC=CC OTTZHAVKAVGASB-UHFFFAOYSA-N 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 description 1
- 229930182820 D-proline Natural products 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 101150116596 dhp-1 gene Proteins 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
Landscapes
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a purification method of pyrrolidine carbapenem antibiotics, and in particular to a method for purifying Doripenem through crystallization or re-crystallization. In the method, the Doripenem is separated out from aqueous solution containing Doripenem and proline.
Description
Technical field
The present invention relates to a kind of purification process of S-4661, specifically, relate to a kind of method of coming the purifying S-4661 by crystallization or recrystallization.
Background technology
S-4661 (Doripenem is the carbapenems Broad spectrum antibiotics of the also adopted company of Japanese salt exploitation S-4661), have has a broad antifungal spectrum, to most β-Nei Xiananmeis are stable, PBPSs avidity is strong, anti-microbial activity is high, to characteristics such as DHP-1 are stable.Its chemical being called (4R, 5S, 6S)-3-[((3S, 5S)-and the 5-[[(sulphonamide) amino] methyl]-the 3-pyrrolidyl) sulfydryl]-6-[(1R)-and the 1-hydroxyethyl] 4-methyl-7-Oxy-1-azabicyclic [3.2.0] hept-2-ene"-2-carboxylic acid, structural formula is as follows.
Two kinds of stable crystal form II I, IV of S-4661 and preparation method thereof are disclosed among the patent documentation CN1432016A.In preparation process, S-4661 is dissolved in comparatively high temps (as the 55 ℃) pure water, is prepared into the solution of the S-4661 that contains 5～40% weight, by adding corresponding crystal seed and means such as cooling, stirring, separates out crystal, reaches the purpose of purifying.But carbapenem compound is less stable in the aqueous solution, especially under higher concentration and temperature; stability is poorer, usually can darken, side reaction such as product polymerization, degraded, thereby the finished product can exist purity on the low side; problems such as by product is residual, this is disadvantageous.
The present invention is in the purifying of S-4661, when S-4661 when crystallization or recrystallization, can significantly increase the stability of S-4661, thereby improve the purity and the yield of the finished product from the aqueous solution that contains proline(Pro).
Summary of the invention
The invention provides a kind of purification process of S-4661, S-4661 is to separate out from the aqueous solution (also claiming crystal water solution) that contains S-4661 and proline(Pro) in this method.
Concrete, the purification process of S-4661 provided by the invention may further comprise the steps:
(1) S-4661 and proline(Pro) are dissolved in the water, obtain containing the aqueous solution (promptly preparing crystal water solution) of S-4661 and proline(Pro);
(2) the S-4661 crystallization is separated out in cooling from the aqueous solution of (1) gained;
(3) with (2) gained Crystallization Separation, drying.
The purification process of above-mentioned S-4661, wherein the concentration of S-4661 in crystal water solution is 0.02～0.2g/mL, preferred 0.05～0.1g/mL; The concentration of proline(Pro) in crystal water solution is 0.01～0.25g/mL, is preferably 0.02～0.1g/mL.
Wherein, in the process of step (1) crystal water formulations prepared from solutions, the order of dissolving S-4661, proline(Pro) is unrestricted, can successively or dissolve operation simultaneously, and is preferred, and the aqueous solution of preparation proline(Pro) adds the S-4661 dissolving then earlier; Wherein S-4661 can also can be its hydrate for anhydrous form, and it can also can be the S-4661 crossed of purifying for the crude product of S-4661; In the dissolved process, crystal water solution heats or maintains between 40～55 ℃ more preferably 45～50 ℃.After preparing the crystal water solution of S-4661, optionally, can add gac and stir decolouring.
In the step (2), impel S-4661 from solution, to separate out, can be aided with any methods that help crystallization such as stirring, adding crystal seed by cooling.For those skilled in the art, can by water-bath or naturally method such as cooling cool off.Preferably, under whipped state, in about 0～25 ℃ of cooling down; More preferably, under whipped state, about 0～10 ℃ of cooling down; Preferred, under whipped state, in about 0～5 ℃ of cooling down.After crystallization is separated out, preferably keep solution temperature to continue to stir 1～10h slaking, better 1～3h.
Lock out operation in the step (3) can be this areas such as centrifugation or filtration separation method commonly used, the preferred filtration; Optionally, separate the back to S-4661 crystallization wash, washing can be with the alcohol or the pure aqueous solution; The exsiccant condition is 20～60 ℃ of following drying under reduced pressure 1～10 hour, and pressure is 20～30mmHg; Preferably 30 ℃ of following drying under reduced pressure 4 hours.The difference of drying conditions can obtain the different S-4661 of water content, and water content is preferably 4～8%.
The purification process of preferred S-4661 provided by the invention may further comprise the steps:
(1) S-4661 and proline(Pro) are dissolved in the water, obtain containing the aqueous solution (promptly preparing crystal water solution) of S-4661 and proline(Pro);
(2) the S-4661 crystallization is separated out in cooling from the aqueous solution of (1) gained;
(3) add alcoholic solvent to containing in the S-4661 crystalline aqueous solution of (2);
(4) with (3) gained Crystallization Separation, drying.
The purification process of above-mentioned S-4661, wherein the concentration of S-4661 in crystal water solution is 0.02～0.2g/mL, preferred 0.05～0.1g/mL; The concentration of proline(Pro) in crystal water solution is 0.01～0.25g/mL, is preferably 0.02～0.1g/mL.
Wherein, in the process of step (1) crystal water formulations prepared from solutions, the order of dissolving S-4661, proline(Pro) is unrestricted, can successively or dissolve operation simultaneously, and is preferred, and the aqueous solution of preparation proline(Pro) adds the S-4661 dissolving then earlier; Wherein S-4661 can also can be its hydrate for anhydrous form, and it can also can be the S-4661 crossed of purifying for the crude product of S-4661; In the dissolved process, crystal water solution heats or maintains between 40～55 ℃ more preferably 45～50 ℃.After preparing the crystal water solution of S-4661, optionally, can add gac and stir decolouring.
In the step (2), impel S-4661 from solution, to separate out, can be aided with any methods that help crystallization such as stirring, adding crystal seed by cooling.For those skilled in the art, can by water-bath or naturally method such as cooling cool off.Preferably, under whipped state, in about 0～25 ℃ of cooling down; More preferably, under whipped state, about 0～10 ℃ of cooling down.Preferred, under whipped state, in about 0～5 ℃ of cooling down.After crystallization is separated out, preferably keep solution temperature to continue to stir 1～10h slaking, better 1～3h.
Alcoholic solvent in the step (3) is one or several the mixed solvent in methyl alcohol, ethanol, Virahol, n-propyl alcohol, the primary isoamyl alcohol etc., the more preferably mixed solvent of one or both in ethanol, the Virahol, most preferred ethanol.Wherein the volume ratio of the alcoholic solvent and the aqueous solution is 0.1: 1～20: 1, is preferably 2: 1～5: 1.Preferably under whipped state, slowly add in the process of adding alcoholic solvent, for example drip.Stir 1～10h slaking, preferred 1～3h after adding alcoholic solvent.The temperature of solution should remain on 0～10 ℃ during stirring, preferred 0～5 ℃.Optionally, solution can be spent the night 0～-10 ℃ of stirring.
Lock out operation in the step (4) can be this areas such as centrifugation or filtration separation method commonly used, the preferred filtration; Optionally, separate the back to S-4661 crystallization wash, washing can be with the alcohol or the pure aqueous solution; The exsiccant condition is 20～60 ℃ of following drying under reduced pressure 1～10 hour, and pressure is 20～30mmHg; Preferably 30 ℃ of following drying under reduced pressure 4 hours.The difference of drying conditions can obtain the different S-4661 of water content, and water content is preferably 4～8%.
By the S-4661 that purification process of the present invention obtains, the method for utilization high performance liquid chromatography (HPLC) is measured, and adopts area normalization method, wherein the purity of S-4661 is greater than 99.0%, and preferred, purity is greater than 99.4%, preferred, purity is greater than 99.6%.
Proline(Pro) of the present invention can be L-proline(Pro), D-proline(Pro), D, the mixture of one or more in the L-proline(Pro).Preferred L-proline(Pro), D, one or both mixture of L-proline(Pro).
The present invention compared with prior art by adding proline(Pro) in crystal water solution, thereby has significantly increased the stability of S-4661 in crystallization or recrystallization process, and and then obtains the S-4661 of high purity and high yield.
Embodiment
To help to understand the present invention by following embodiment, but not limit content of the present invention.
Product purity adopts the HPLC method to measure (area normalization method) among the embodiment, and concrete condition determination is as follows:
Instrument: Agilent 1100
Chromatographic column: Phenomenex Hyperclone 5 μ BDS C18
Column temperature: 25 ℃
Wavelength: 210nm
Moving phase: 10mmol/L KH
2PO
4Solution (pH=6.0): acetonitrile=95: 5.
Content also adopts above-mentioned HPLC method to measure, and relative content adopts peak area and S-4661 reference substance peak area ratio to determine.Wherein, in the purified S-4661 product that obtains, increase the detection of L-proline(Pro), adopt high performance liquid chromatography, nh 2 column separates, and the differential detector checks that in each batch sample, it is residual all not detect the L-proline(Pro).
Embodiment 1: the preparation of S-4661 crude product
100 gram DN-8 are (referring to document organic process research ﹠amp; Development 2003,7, the preparation of 649-654 method) is dissolved in water (450mL) and THF (800mL), adds 100 gram Pd/C (water content 66%), be heated under 25 ℃, under the 20-24kg pressure, reacted 2 hours, heat release in the hydrogenation process is kept temperature of reaction 30-40 ℃ of reaction, reaction finishes, suction filtration is with 150mL (THF: water=2: 1) wash palladium carbon, with ethyl acetate (750mL * 2) washing water layer, propyl carbinol (500mL * 2) washing water layer, water layer is cooled to 0 ℃, has faint yellow solid to separate out, and is incubated 0-5 ℃ of stirring and spends the night, suction filtration, 25 ℃ of following drying under reduced pressure 15 hours, S-4661 crude product (32 grams, yield 65%, water content 6.1%, purity 96.2%).
Embodiment 2: stability of solution is investigated
Get 1 gram S-4661 crude product, be dissolved in the pure water of 50ml, the L-proline(Pro) aqueous solution of 0.05g/mL, the L-proline(Pro) aqueous solution of 0.1g/mL respectively, stirring and dissolving is to obtaining clear liquid.Get 10ml respectively and place under 25 ℃ of room temperatures, 40 ℃, the 50 ℃ environment, get 10min respectively, 20min, solution behind the 30min detects through HPLC, with room temperature 0min peak area in contrast, calculates the relative peak area ratio, calculate relative content, thereby investigate its stability of solution.As can be seen, behind the adding proline(Pro), when comparatively high temps (40 ℃ and 50 ℃), the stability of S-4661 in solution is significantly improved from following table.
Embodiment 3
S-4661 crude product (1.0g) is added in the L-proline(Pro) solution (20mL) of 0.05g/mL, stir heating down, to 50 ℃ of dissolvings down, its solution is maintained 50～55 ℃, add gac (50mg) and stir decolouring 5min, filter, get filtrate and be cooled to 0～5 ℃ of stirring, there is solid to separate out in about 1 hour, keeps 0～5 ℃ of slaking 2 hours.Splash into Virahol 10mL, keep 0～5 ℃ of slaking 2 hours ,-10 ℃ of stirrings are spent the night, and leach the gained crystallization then.After the gained crystallization was washed with 80% isopropanol water solution (5mL), drying was 4 hours under 30 ℃ of water pumps (20-30mmHg) reduced pressure, obtains S-4661 0.91g (yield 91%, water content 5.93%), purity: 99.65%.
Embodiment 4 (reference literature CN1432016A relatively uses with embodiment 3)
S-4661 crude product (1.0g) is added in the distilled water (20mL), stir heating down, to 50 ℃ of dissolvings down, its solution is maintained 50～55 ℃, cross the suction funnel that is covered with gac (50mg), filter, get filtrate and be cooled to 0～5 ℃ of stirring, have solid to separate out in about 1 hour, keep 0～5 ℃ of slaking 2 hours, splash into Virahol 10mL, keep 0～5 ℃ of slaking 2 hours.-10 ℃ of stirrings are spent the night, and leach the gained crystallization then.After the gained crystallization was washed with 80% isopropanol water solution (5mL), (drying was 4 hours under 20～30mmHg) reduced pressure, obtains S-4661 0.75g (yield 74%, water content 7.3%), purity: 98.95% at 30 ℃ of water pumps.
Embodiment 5
S-4661 crude product (1.0g) is added in the L-proline(Pro) solution (30mL) of 0.05g/mL, stir heating down, to 40 ℃ of dissolvings down, its solution is maintained 40 ℃, add gac (50mg) and stir decolouring 5min, filter, get filtrate and be cooled to 0～5 ℃ of stirring, there is solid to separate out in about 1 hour, keeps 0～5 ℃ of slaking 2 hours.Ethanol (90mL) was splashed into wherein in about 1 hour, keep 0～5 ℃ of slaking 2 hours, leach the gained crystallization then.After the gained crystallization was washed with 80% aqueous ethanolic solution (5mL), drying was 4 hours under 30 ℃ of water pumps (20-30mmHg) reduced pressure, obtains S-4661 0.84g (yield 84%, water content 6.02%), product purity: 99.41%.
Embodiment 6
S-4661 crude product (1.0g) is added in the L-proline(Pro) solution (15mL) of 0.1g/mL, stir heating down, to 45 ℃ of dissolvings down, its solution is maintained 45 ℃, add gac (50mg) and stir decolouring 5min, filter, get filtrate and be cooled to 0～5 ℃ of stirring, there is solid to separate out in about 1 hour, keeps 0～5 ℃ of slaking 2 hours.Ethanol (30mL) was splashed into wherein in about 1 hour, keep 0～5 ℃ of slaking 2 hours, leach the gained crystallization then.After the gained crystallization was washed with 80% aqueous ethanolic solution (5mL), drying was 4 hours under 30 ℃ of water pumps (20-30mmHg) reduced pressure, obtains S-4661 0.88g (yield 88%, water content 5.96%), product purity: 99.55%.
Embodiment 7
S-4661 crude product (1.0g) is added in the L-proline(Pro) solution (10mL) of 0.25g/mL, stir heating down, to 42 ℃ of dissolvings down, its solution is maintained 42 ℃, add gac (50mg) and stir decolouring 5min, filter, get filtrate and be cooled to 0～5 ℃ of stirring, there is solid to separate out in about 1 hour, keeps 0～5 ℃ of slaking 2 hours.Ethanol (20mL) was splashed into wherein in about 1 hour, keep 0～5 ℃ of slaking 2 hours, leach the gained crystallization then.After the gained crystallization was washed with 80% aqueous ethanolic solution (5mL), drying was 4 hours under 30 ℃ of water pumps (20-30mmHg) reduced pressure, obtains S-4661 0.85g (yield 85%, water content 6.01%), product purity: 99.48%.
Embodiment 8
S-4661 crude product (1.0g) is added in the L-proline(Pro) solution (15mL) of 0.03g/mL, stir heating down,, its solution is maintained 50 ℃, be cooled to 0～5 ℃ of stirring, have solid to separate out in about 1 hour, keep 0～5 ℃ of slaking 2 hours to 50 ℃ of dissolvings down.Virahol (30mL) was splashed into wherein in about 1 hour, keep 0～5 ℃ of slaking 2 hours, leach the gained crystallization then.After the gained crystallization was washed with 80% isopropanol water solution (5mL), drying was 4 hours under 30 ℃ of water pumps (20-30mmHg) reduced pressure, obtains S-4661 0.93g (yield 93%, water content 5.93%), product purity: 99.67%.
Embodiment 9
S-4661 crude product (1.0g) is added in the L-proline(Pro) solution (30mL) of 0.03g/mL, stir heating down,, its solution is maintained 40 ℃, be cooled to 0～5 ℃ of stirring, have solid to separate out in about 1 hour, keep 0～5 ℃ of slaking 2 hours to 40 ℃ of dissolvings down.Virahol (90mL) was splashed into wherein in about 1 hour, keep 0～5 ℃ of slaking 2 hours, leach the gained crystallization then.After the gained crystallization was washed with 80% isopropanol water solution (5mL), drying was 4 hours under 30 ℃ of water pumps (20-30mmHg) reduced pressure, obtains S-4661 0.89g (yield 89%, water content 5.88%), product purity: 99.49%.
Embodiment 10
S-4661 crude product (1.0g) is added in the L-proline(Pro) solution (15mL) of 0.1g/mL, stir heating down,, its solution is maintained 45 ℃, be cooled to 0～5 ℃ of stirring, have solid to separate out in about 1 hour, keep 0～5 ℃ of slaking 2 hours to 45 ℃ of dissolvings down.Virahol (30mL) was splashed into wherein in about 1 hour, keep 0～5 ℃ of slaking 2 hours, leach the gained crystallization then.After the gained crystallization was washed with 80% isopropanol water solution (5mL), drying was 4 hours under 30 ℃ of water pumps (20-30mmHg) reduced pressure, obtains S-4661 0.92g (yield 92%, water content 5.72%), product purity: 99.71%.
Embodiment 11
S-4661 crude product (1.5g) is added in the L-proline(Pro) solution (10mL) of 0.1g/mL, stir heating down, to 45 ℃ of dissolvings down, its solution is maintained 42 ℃, add gac (50mg) and stir decolouring 5min, filter, get filtrate and be cooled to 0～5 ℃ of stirring, there is solid to separate out in about 1 hour, keeps 0～5 ℃ of slaking 2 hours.N-propyl alcohol (100mL) was splashed into wherein in about 1 hour, keep 0～5 ℃ of slaking 2 hours, leach the gained crystallization then.After the gained crystallization was washed with the 80% n-propyl alcohol aqueous solution (5mL), drying was 4 hours under 30 ℃ of water pumps (20-30mmHg) reduced pressure, obtains S-4661 0.88g (yield 88%, water content 6.01%), product purity: 99.63%.
Claims (9)
1. the purification process of a S-4661, S-4661 is to separate out from the aqueous solution that contains S-4661 and proline(Pro) in this method.
2. the purification process of claim 1 may further comprise the steps:
(1) S-4661 and proline(Pro) are dissolved in the water, obtain containing the aqueous solution of S-4661 and proline(Pro);
(2) the S-4661 crystallization is separated out in cooling from the aqueous solution of (1) gained;
(3) with (2) gained Crystallization Separation, drying.
3. the purification process of claim 1 may further comprise the steps:
(1) S-4661 and proline(Pro) are dissolved in the water, obtain containing the aqueous solution of S-4661 and proline(Pro);
(2) the S-4661 crystallization is separated out in cooling from the aqueous solution of (1) gained;
(3) add alcoholic solvent to containing in the S-4661 crystalline aqueous solution of (2);
(4) with (3) gained Crystallization Separation, drying.
4. the purification process of claim 3, wherein alcoholic solvent is one or several the mixed solvent in methyl alcohol, ethanol, Virahol, n-propyl alcohol, the primary isoamyl alcohol.
5. the purification process of claim 4, wherein the volume ratio of the alcoholic solvent and the aqueous solution is 0.1: 1～20: 1.
6. the described purification process of arbitrary claim among the claim 1-5, wherein the concentration of S-4661 in crystal water solution is 0.02～0.2g/mL.
7. the described purification process of arbitrary claim among the claim 1-5, wherein the concentration of proline(Pro) in crystal water solution is 0.01～0.25g/mL.
8. the described purification process of arbitrary claim among the claim 2-5, wherein in the step (1) temperature of the aqueous solution between 40～55 ℃.
9. the described purification process of arbitrary claim among the claim 2-5, wherein in the step (2) the refrigerative temperature between 0～25 ℃.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102731505A (en) * | 2011-04-13 | 2012-10-17 | 石药集团中奇制药技术（石家庄）有限公司 | Preparation method of doripenem |
| CN106255694A (en) * | 2014-04-28 | 2016-12-21 | Jw制药公司 | Novel donipenem crystal and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100536843C (en) * | 2006-05-10 | 2009-09-09 | 鲁南制药集团股份有限公司 | Pharmaceutical composition for injection containing faropenem |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102731505A (en) * | 2011-04-13 | 2012-10-17 | 石药集团中奇制药技术（石家庄）有限公司 | Preparation method of doripenem |
| CN102731505B (en) * | 2011-04-13 | 2015-09-02 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of preparation method of S-4661 |
| CN106255694A (en) * | 2014-04-28 | 2016-12-21 | Jw制药公司 | Novel donipenem crystal and preparation method thereof |
| US9840506B2 (en) | 2014-04-28 | 2017-12-12 | Jw Pharmaceutical Corporation | Crystal of doripenem, and preparation method therefor |
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