CN104861014A - Preparing method of epirubicin hydrochloride crystals - Google Patents
Preparing method of epirubicin hydrochloride crystals Download PDFInfo
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- CN104861014A CN104861014A CN201510298163.7A CN201510298163A CN104861014A CN 104861014 A CN104861014 A CN 104861014A CN 201510298163 A CN201510298163 A CN 201510298163A CN 104861014 A CN104861014 A CN 104861014A
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- ether
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- farmorubine hydrochloride
- ester
- suspension
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- 238000000034 method Methods 0.000 title claims abstract description 12
- 239000013078 crystal Substances 0.000 title abstract description 5
- MWWSFMDVAYGXBV-FGBSZODSSA-N (7s,9s)-7-[(2r,4s,5r,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydron;chloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-FGBSZODSSA-N 0.000 title abstract 5
- 229960003265 epirubicin hydrochloride Drugs 0.000 title abstract 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000000725 suspension Substances 0.000 claims abstract description 28
- 239000012046 mixed solvent Substances 0.000 claims abstract description 22
- 150000002148 esters Chemical class 0.000 claims abstract description 20
- 239000000126 substance Substances 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 51
- 238000002425 crystallisation Methods 0.000 claims description 40
- 230000008025 crystallization Effects 0.000 claims description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- 238000002360 preparation method Methods 0.000 claims description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical group CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 6
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 5
- 229940011051 isopropyl acetate Drugs 0.000 claims description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- RMGHERXMTMUMMV-UHFFFAOYSA-N 2-methoxypropane Chemical compound COC(C)C RMGHERXMTMUMMV-UHFFFAOYSA-N 0.000 claims description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 3
- RMOUBSOVHSONPZ-UHFFFAOYSA-N Isopropyl formate Chemical compound CC(C)OC=O RMOUBSOVHSONPZ-UHFFFAOYSA-N 0.000 claims description 3
- XOBKSJJDNFUZPF-UHFFFAOYSA-N Methoxyethane Chemical group CCOC XOBKSJJDNFUZPF-UHFFFAOYSA-N 0.000 claims description 3
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 claims description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 3
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 3
- 125000004494 ethyl ester group Chemical group 0.000 claims description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 3
- VNKYTQGIUYNRMY-UHFFFAOYSA-N methoxypropane Chemical compound CCCOC VNKYTQGIUYNRMY-UHFFFAOYSA-N 0.000 claims description 3
- 150000004702 methyl esters Chemical class 0.000 claims description 3
- 229940017219 methyl propionate Drugs 0.000 claims description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 2
- 238000010009 beating Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 2
- 229940090181 propyl acetate Drugs 0.000 claims description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 12
- 238000000354 decomposition reaction Methods 0.000 abstract description 2
- 238000004537 pulping Methods 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 20
- 239000000539 dimer Substances 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- 230000015556 catabolic process Effects 0.000 description 9
- 238000006731 degradation reaction Methods 0.000 description 9
- 238000005406 washing Methods 0.000 description 8
- 238000001291 vacuum drying Methods 0.000 description 7
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical class O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 229960000641 zorubicin Drugs 0.000 description 2
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparing method of epirubicin hydrochloride crystals. The preparing method comprises the following steps: a, providing a mixed solvent of ester, ether and water; b, filling the amorphous substance of epirubicin hydrochloride in the mixed solvent in step a to form a suspension and pulping; c, collecting epirubicin hydrochloride crystals from the suspension. The epirubicin hydrochloride crystals obtained by the preparing method are high in purity, do not contain impurities such as dipolymer and decomposition products and are great in storing stability.
Description
(1) technical field
The present invention relates to pharmaceutical chemistry synthesis technical field, be specifically related to a kind of preparation method of Farmorubine Hydrochloride crystallization.
(2) background technology
Pidorubicin and acid salt thereof, such as Farmorubine Hydrochloride, belong to anthracycline compound, used as the cytostatics of the multiple solid tumor types for the treatment of since the 80's of last century.
The structural formula of Farmorubine Hydrochloride is as follows:
。
American documentation literature US5,091,373 disclose the purposes that pidorubicin is used for the treatment of tumour.
American documentation literature US4,112,076 and US5,874, describe the preparation method of pidorubicin in 550, such as, pidorubicin and acid salt thereof chemically can synthesize by daunorubicin is initial.European patent document EP1990405A1 discloses also can by microbial fermentation processes preparation table Zorubicin.When preparation table Zorubicin, usually can produce organic and inorganic impurity, their ratio can reach at most 25% of prepared product mixtures weight.Therefore, it is necessary for purifying to pidorubicin and acid salt thereof after the production.
American documentation literature US4,861,870 methods providing purification Farmorubine Hydrochloride.Wherein, make Farmorubine Hydrochloride by being precipitated out in the aqueous solution and obtaining amorphous substance by means of acetone.It is said and can obtain pure Farmorubine Hydrochloride amorphous substance by this method.
Describe some crystallized form of the Farmorubine Hydrochloride characterized by X-ray diffracting spectrum in american documentation literature US 7,485,707 and international patent application WO 2010/039159, relative to the Farmorubine Hydrochloride that oneself knows, show the thermostability of improvement.The preparation method of these crystallized forms is: in Farmorubine Hydrochloride, add hydrophilic organic solvent, crystallization from solution or gel.But, when the present inventor repeats the method for these patent documentations description, under finding the condition provided at document, the crystallization Farmorubine Hydrochloride with described X-ray diffracting spectrum can not be obtained.
In addition, from prior art, can form the impurity such as undesirable dimer or degradation production when preparation or crystallization Farmorubine Hydrochloride, the purity of crystallization Farmorubine Hydrochloride is low.
Therefore, this area still needs the preparation method developing highly purified crystallization Farmorubine Hydrochloride.
(3) summary of the invention
The present invention, in order to make up the deficiencies in the prior art, provides the preparation method of Farmorubine Hydrochloride crystallization, and described preparation method's operation is easy, can at room temperature operate.
The present invention is achieved through the following technical solutions:
The preparation method of Farmorubine Hydrochloride crystallization of the present invention, comprise the following steps: (a) provides the mixed solvent of ester, ether and water, b Farmorubine Hydrochloride amorphous substance is formed suspension and pulls an oar by () in the mixed solvent of step (a), and (c) collects Farmorubine Hydrochloride crystallization from described suspension.
Preferably, described ester is selected from C3 ~ C5 ester, and described C3 ~ C5 ester can be ethyl formate, methyl acetate, ethyl acetate, propyl formate, methyl propionate, isopropyl formate, isopropyl acid methyl esters, propyl acetate, isopropyl acetate, ethyl propionate or isopropyl acid ethyl ester; More preferably, described C3 ~ C5 ester is selected from ethyl acetate or isopropyl acetate.
Preferably, described ether is selected from C3 ~ C6 ether, and described C3 ~ C6 ether can be methyl ethyl ether, methyl-propyl ether, methyl isopropyl ether, ether, methyl tertiary butyl ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, propyl ether or isopropyl ether; More preferably, described C3 ~ C6 ether is selected from methyl tertiary butyl ether, tetrahydrofuran (THF) or isopropyl ether.
Preferably, in step (a) mixed solvent, the volume percent of water is 5% ~ 30%; More preferably, in step (a) mixed solvent, the volume percent of water is 10% ~ 20%.
Preferably, in step (a) mixed solvent, the volume ratio of C3 ~ C5 ester and C3 ~ C6 ether is 3:1 ~ 1:3; More preferably, in step (a) mixed solvent, the volume ratio of C3 ~ C5 ester and C3 ~ C6 ether is 1:1 ~ 1:2.
Preferably, in step (b), the mass volume ratio of Farmorubine Hydrochloride amorphous substance and mixed solvent is 1g:2mL ~ 1g:15mL; More preferably, in step (b), the mass volume ratio of Farmorubine Hydrochloride amorphous substance and mixed solvent is 1g:4mL ~ 1 g:8mL.
Preferably, the temperature that step (b) is pulled an oar is 20 DEG C ~ 40 DEG C, and the time of making beating is 2 ~ 6 hours.
Preferably, after step (b) has been pulled an oar, suspension is cooled to 0 DEG C ~-20 DEG C, and keeps stirring 8 ~ 15 hours at such a temperature; More preferably, the rate of cooling of described suspension is 10 DEG C/h ~ 20 DEG C/h.
In step (c), the ordinary method of this area is adopted the crystallization of separating out in suspension to be carried out being separated and drying.Described separation, adopts the ordinary method of this area such as to filter, centrifugal etc.; The concrete operations of filtering are: be placed on filter paper by the sample for being separated, decompress filter; Centrifugal concrete operations are: the sample for being separated is placed in centrifuge tube, and high speed rotating is until solid is all sink to bottom centrifuge tube afterwards.Selectively, the suitable solvent wash of solid, cleaning solvent is acetone such as.Described drying, adopts the ordinary method such as forced air drying or drying under reduced pressure of this area; Drying plant is convection oven or vacuum drying oven; Drying in decompression or can be carried out under not reducing pressure, and is preferably pressure and is less than 0.09Mpa; Drying temperature is room temperature (about 10 DEG C ~ 30 DEG C); Time of drying is 10 ~ 72 hours, is preferably 10 ~ 48 hours.
Starting raw material Farmorubine Hydrochloride amorphous substance of the present invention, can according to patent documentation US4, and 861, method preparation disclosed in 870.Detect through high performance liquid chromatography (HPLC), its purity is about 90% ~ 93%.
Preparation method's operation of the present invention is easy, can at room temperature operate.Detect through HPLC, the purity of the Farmorubine Hydrochloride crystallization obtained by preparation method of the present invention is high, and its purity can reach more than 99%, and not containing impurity such as dimer Sum decomposition products.40 DEG C, preserve 2 months under 75% relative humidities after, its purity is substantially constant, and still keeps original crystal form.
(4) embodiment
The present invention limits with further reference to following examples, and described embodiment describes preparation method of the present invention in detail.It will be apparent for a person skilled in the art that the many changes for preparation condition can be implemented without departing from the present invention.
If no special instructions, all ingredients used in embodiment is commercially available.
If no special instructions, the temperature in embodiment is room temperature.
Embodiment 1
Get 10.0 g Farmorubine Hydrochloride amorphous substances (purity 92.0%) to be suspended in the mixed solvent of 20ml ethyl acetate, 30 ml tetrahydrofuran (THF)s and 10ml water.At 30 DEG C, this suspension 4 hours of pulling an oar.Afterwards, progressively with the speed of 10 DEG C/h, this suspension is cooled to-10 DEG C, and keeps-10 DEG C to stir 12 hours.Filter, crystallization washing with acetone, then vacuum-drying 24 hours, obtain Farmorubine Hydrochloride crystallization.Yield 92%, purity 99.3%, does not contain the impurity of dimer or degradation production.
Embodiment 2
Get 10.0 g Farmorubine Hydrochloride amorphous substances (purity 92.0%) to be suspended in the mixed solvent of 36ml ethyl acetate, 36ml methyl tertiary butyl ether and 8ml water.At 40 DEG C, this suspension 3 hours of pulling an oar.Afterwards, progressively with the speed of 10 DEG C/h, this suspension is cooled to 0 DEG C, and keeps 0 DEG C to stir 10 hours.Filter, crystallization washing with acetone, then vacuum-drying 36 hours, obtain Farmorubine Hydrochloride crystallization.Yield 91%, purity 99.0%, does not contain the impurity of dimer or degradation production.
Embodiment 3
Get 10.0 g Farmorubine Hydrochloride amorphous substances (purity 92.0%) to be suspended in the mixed solvent of 11ml ethyl acetate, 22ml tetrahydrofuran (THF) and 7ml water.At 20 DEG C, this suspension 6 hours of pulling an oar.Afterwards, progressively with the speed of 15 DEG C/h, this suspension is cooled to-10 DEG C, and keeps-10 DEG C to stir 15 hours.Filter, crystallization washing with acetone, then vacuum-drying 24 hours, obtain Farmorubine Hydrochloride crystallization.Yield 92%, purity 99.2%, does not contain the impurity of dimer or degradation production.
Embodiment 4
Get 10.0 g Farmorubine Hydrochloride amorphous substances (purity 92.0%) to be suspended in the mixed solvent of 60ml isopropyl acetate, 30 ml tetrahydrofuran (THF)s and 10ml water.At 30 DEG C, this suspension 5 hours of pulling an oar.Afterwards, progressively with the speed of 20 DEG C/h, this suspension is cooled to-20 DEG C, and keeps-20 DEG C to stir 12 hours.Filter, crystallization washing with acetone, then vacuum-drying 36 hours, obtain Farmorubine Hydrochloride crystallization.Yield 90%, purity 99.1%, does not contain the impurity of dimer or degradation production.
Embodiment 5
Get 10.0 g Farmorubine Hydrochloride amorphous substances (purity 92.0%) to be suspended in the mixed solvent of 12ml ethyl acetate, 12ml isopropyl ether and 6ml water.At 25 DEG C, this suspension 5 hours of pulling an oar.Afterwards, progressively with the speed of 10 DEG C/h, this suspension is cooled to-15 DEG C, and keeps-15 DEG C to stir 8 hours.Filter, crystallization washing with acetone, then vacuum-drying 36 hours, obtain Farmorubine Hydrochloride crystallization.Yield 93%, purity 99.0%, does not contain the impurity of dimer or degradation production.
Embodiment 6
Get 10.0 g Farmorubine Hydrochloride amorphous substances (purity 92.0%) to be suspended in the mixed solvent of 24ml ethyl acetate, 36 ml tetrahydrofuran (THF)s and 10ml water.At 30 DEG C, this suspension 4 hours of pulling an oar.Afterwards, progressively with the speed of 10 DEG C/h, this suspension is cooled to-10 DEG C, and keeps-10 DEG C to stir 12 hours.Filter, crystallization washing with acetone, then vacuum-drying 24 hours, obtain Farmorubine Hydrochloride crystallization.Yield 91%, purity 99.3%, does not contain the impurity of dimer or degradation production.
Embodiment 7
Get 10.0 g Farmorubine Hydrochloride amorphous substances (purity 92.0%) to be suspended in the mixed solvent of 30ml ethyl formate, 10ml methyl ethyl ether and 2ml water.At 40 DEG C, this suspension 0.4 hour of pulling an oar.Afterwards, progressively with the speed of 20 DEG C/h, this suspension is cooled to-20 DEG C, and keeps-20 DEG C to stir 2 hours.Filter, crystallization washing with acetone, drier 10 hours of convection oven, obtain Farmorubine Hydrochloride crystallization.Yield 91.4%, purity 99.4%, does not contain the impurity of dimer or degradation production.
Embodiment 8
Get 10.0 g Farmorubine Hydrochloride amorphous substances (purity 92.0%) to be suspended in the mixed solvent of 20ml methyl acetate, 60ml methyl-propyl ether and 34ml water.At 40 DEG C, this suspension 2 hours of pulling an oar.Afterwards, progressively with the speed of 20 DEG C/h, this suspension is cooled to-20 DEG C, and keeps-20 DEG C to stir 12 hours.Filter, crystallization washing with acetone, drier 10 hours of convection oven, obtain Farmorubine Hydrochloride crystallization.Yield 91.8%, purity 99.4%, does not contain the impurity of dimer or degradation production.
Embodiment 9
C3 ~ C5 ester is propyl formate.
Described C3 ~ C6 ether is methyl isopropyl ether.
Other steps are identical with embodiment 1.
Embodiment 10
C3 ~ C5 ester is methyl propionate.
Described C3 ~ C6 ether is ether.
Other steps are identical with embodiment 1.
Embodiment 11
C3 ~ C5 ester is isopropyl formate.
Described C3 ~ C6 ether is methyl tertiary butyl ether.
Other steps are identical with embodiment 1.
Embodiment 12
C3 ~ C5 ester is isopropyl acid methyl esters.
Described C3 ~ C6 ether is Isosorbide-5-Nitrae-dioxane.
Other steps are identical with embodiment 1.
Embodiment 12
C3 ~ C5 ester is isopropyl acetate.
Described C3 ~ C6 ether is propyl ether.
Other steps are identical with embodiment 1.
Embodiment 13
C3 ~ C5 ester is ethyl propionate.
Other steps are identical with embodiment 1.
Embodiment 14
C3 ~ C5 ester is isopropyl acid ethyl ester.
Other steps are identical with embodiment 1.
Claims (10)
1. a preparation method for Farmorubine Hydrochloride crystallization, is characterized in that: comprise the following steps:
A () provides the mixed solvent of ester, ether and water;
B Farmorubine Hydrochloride amorphous substance is formed suspension and pulls an oar by () in the mixed solvent of step (a);
C () collects Farmorubine Hydrochloride crystallization from described suspension.
2. the preparation method of Farmorubine Hydrochloride crystallization according to claim 1, it is characterized in that: described ester is selected from C3 ~ C5 ester, described ether is selected from C3 ~ C6 ether.
3. the preparation method of Farmorubine Hydrochloride crystallization according to claim 1 and 2, is characterized in that: described C3 ~ C5 ester is ethyl formate, methyl acetate, ethyl acetate, propyl formate, methyl propionate, isopropyl formate, isopropyl acid methyl esters, propyl acetate, isopropyl acetate, ethyl propionate or isopropyl acid ethyl ester.
4. the preparation method of Farmorubine Hydrochloride crystallization according to claim 1 and 2, it is characterized in that: described C3 ~ C6 ether is methyl ethyl ether, methyl-propyl ether, methyl isopropyl ether, ether, methyl tertiary butyl ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, propyl ether or isopropyl ether.
5. the preparation method of Farmorubine Hydrochloride crystallization according to claim 1 and 2, is characterized in that: in step (a) mixed solvent, the volume percent of water is 5% ~ 30%, and the volume ratio of ester and ether is 3:1 ~ 1:3.
6. the preparation method of Farmorubine Hydrochloride crystallization according to claim 1 and 2, is characterized in that: in step (b), the mass volume ratio of Farmorubine Hydrochloride amorphous substance and mixed solvent is 1g:2mL ~ 1g:15mL.
7. the preparation method of Farmorubine Hydrochloride crystallization according to claim 1 and 2, is characterized in that: the temperature that step (b) is pulled an oar is 20 DEG C ~ 40 DEG C, and the time of making beating is 2 ~ 6 hours.
8. the preparation method of Farmorubine Hydrochloride crystallization according to claim 1 and 2, is characterized in that: after step (b) has been pulled an oar, and suspension is cooled to 0 DEG C ~-20 DEG C, and keeps stirring 8 ~ 15 hours at such a temperature.
9. the preparation method of Farmorubine Hydrochloride crystallization according to claim 1 and 2, is characterized in that: the rate of cooling of described suspension is 10 DEG C/h ~ 20 DEG C/h.
10. the preparation method of Farmorubine Hydrochloride crystallization according to claim 1 and 2, is characterized in that: in step (c), adopts the ordinary method of this area the crystallization of separating out in suspension to be carried out being separated and drying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510298163.7A CN104861014B (en) | 2015-06-03 | 2015-06-03 | A kind of preparation method of Farmorubine Hydrochloride crystallization |
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| CN201510298163.7A CN104861014B (en) | 2015-06-03 | 2015-06-03 | A kind of preparation method of Farmorubine Hydrochloride crystallization |
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| CN104861014A true CN104861014A (en) | 2015-08-26 |
| CN104861014B CN104861014B (en) | 2017-09-29 |
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Cited By (4)
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| CN109206309A (en) * | 2018-09-13 | 2019-01-15 | 山东省食品药品检验研究院 | A kind of isolation and purification method of doxorubicin hydrochloride impurity |
| CN109384822A (en) * | 2017-08-11 | 2019-02-26 | 鲁南制药集团股份有限公司 | A kind of epirubicin hydrochloride crystal form and preparation method thereof |
| CN109666050A (en) * | 2017-10-16 | 2019-04-23 | 鲁南制药集团股份有限公司 | A kind of epirubicin hydrochloride crystal form III and preparation method thereof |
| CN109836466A (en) * | 2017-11-24 | 2019-06-04 | 鲁南制药集团股份有限公司 | A kind of crystal form of epirubicin hydrochloride and preparation method thereof |
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| CN109384822A (en) * | 2017-08-11 | 2019-02-26 | 鲁南制药集团股份有限公司 | A kind of epirubicin hydrochloride crystal form and preparation method thereof |
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| CN109836466A (en) * | 2017-11-24 | 2019-06-04 | 鲁南制药集团股份有限公司 | A kind of crystal form of epirubicin hydrochloride and preparation method thereof |
| CN109836466B (en) * | 2017-11-24 | 2024-01-19 | 鲁南制药集团股份有限公司 | Crystal form of epirubicin hydrochloride and preparation method thereof |
| CN109206309A (en) * | 2018-09-13 | 2019-01-15 | 山东省食品药品检验研究院 | A kind of isolation and purification method of doxorubicin hydrochloride impurity |
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