CN104861014B - A kind of preparation method of Farmorubine Hydrochloride crystallization - Google Patents
A kind of preparation method of Farmorubine Hydrochloride crystallization Download PDFInfo
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- CN104861014B CN104861014B CN201510298163.7A CN201510298163A CN104861014B CN 104861014 B CN104861014 B CN 104861014B CN 201510298163 A CN201510298163 A CN 201510298163A CN 104861014 B CN104861014 B CN 104861014B
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
The present invention relates to the preparation method of Farmorubine Hydrochloride crystallization, the preparation method comprises the following steps：(a) mixed solvent of ester, ether and water is provided, (b) amorphous substance of Farmorubine Hydrochloride is formed into suspension in the in the mixed solvent of step (a) and be beaten, and (c) collects Farmorubine Hydrochloride crystallization from the suspension.The Farmorubine Hydrochloride crystallization purity obtained by preparation method of the present invention is high, and without the impurity such as dimer and catabolite, storage stability is good.
Description
（One）Technical field
The present invention relates to pharmaceutical chemistry synthesis technical field, and in particular to a kind of preparation side of Farmorubine Hydrochloride crystallization
Method.
（Two）Background technology
Epi-ADM and its acid-addition salts, such as Farmorubine Hydrochloride, belonged to anthracycline compound, from 80 years last century
It has been used as treating the cytostatics of a variety of solid tumor types since generation.
The structural formula of Farmorubine Hydrochloride is as follows：
。
American documentation literature US5,091,373 discloses the purposes that Epi-ADM is used to treat tumour.
The preparation method of Epi-ADM, example are described in american documentation literature US4,112,076 and US5,874,550
Such as, Epi-ADM and its acid-addition salts can chemically be synthesized by daunorubicin starting.European patent document EP1990405A1
Epi-ADM can also be prepared by microbial fermentation processes by disclosing.When preparing Epi-ADM, it will usually produce it is organic and
Inorganic impurity, the 25% of the at most reachable prepared product mixtures weight of their ratio.Therefore, to table Ah mould after preparation
It is necessary that element and its acid-addition salts, which carry out purification,.
The method that american documentation literature US4,861,870 provides purification Farmorubine Hydrochloride.Wherein, by means of acetone
Farmorubine Hydrochloride is precipitated out in the aqueous solution and obtain amorphous substance.It is said that can obtain with the method pure hydrochloric acid table Ah
Mycin amorphous substance.
Describe and penetrated by X- in american documentation literature US 7,485,707 and international patent application WO 2010/039159
The some crystal forms for the Farmorubine Hydrochloride that ray diffraction diagram stave is levied, the Farmorubine Hydrochloride known relative to oneself shows to change
Kind heat endurance.The preparation method of these crystal forms is：Hydrophilic organic solvent is added into Farmorubine Hydrochloride, from molten
Crystallization is separated out in liquid or gel.But, when the present inventor repeats the method for these patent documents description, find what is provided in document
Under the conditions of can not obtain the crystallization Farmorubine Hydrochloride with the X-ray diffracting spectrum.
In addition, from prior art, can be formed when preparing or crystallizing Farmorubine Hydrochloride undesirable dimer or
The impurity such as catabolite, the purity for crystallizing Farmorubine Hydrochloride is low.
Therefore, this area stills need to develop the preparation method of the crystallization Farmorubine Hydrochloride of high-purity.
（Three）The content of the invention
There is provided the preparation method that Farmorubine Hydrochloride is crystallized, the system in order to make up the deficiencies in the prior art by the present invention
Preparation Method process is easy, can operate at room temperature.
The present invention is achieved through the following technical solutions：
The preparation method of the Farmorubine Hydrochloride crystallization of the present invention, comprises the following steps：(a) the mixed of ester, ether and water is provided
Bonding solvent, the in the mixed solvent formation of (b) by Farmorubine Hydrochloride amorphous substance in step (a) and is beaten suspension, and (c) from
Farmorubine Hydrochloride crystallization is collected in the suspension.
Preferably, the ester be selected from C3 ~ C5 esters, C3 ~ C5 esters 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；It is highly preferred that C3 ~ C5 esters are selected from ethyl acetate or isopropyl acetate.
Preferably, the ether is selected from C3~C6 ethers, and C3~C6 ethers can be methyl ethyl ether, methyl-propyl ether, first
Base isopropyl ether, ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, 1,4- dioxane, propyl ether or isopropyl ether；It is highly preferred that described
C3~C6 ethers are selected from methyl tertiary butyl ether(MTBE), tetrahydrofuran or isopropyl ether.
Preferably, the percent by volume of step (a) mixed solvent reclaimed water is 5% ~ 30%；It is highly preferred that step (a) mixing is molten
The percent by volume of agent reclaimed water is 10% ~ 20%.
Preferably, the volume ratio of step (a) in the mixed solvent C3 ~ C5 esters and C3~C6 ethers is 3:1~1:3；It is highly preferred that
The volume ratio of step (a) in the mixed solvent C3 ~ C5 esters and C3~C6 ethers is 1:1~1:2.
Preferably, the mass volume ratio of Farmorubine Hydrochloride amorphous substance and mixed solvent is 1g in step (b):2mL~
1g:15mL；It is highly preferred that the mass volume ratio of Farmorubine Hydrochloride amorphous substance and mixed solvent is 1g in step (b):4mL~
1 g:8mL。
Preferably, the temperature of step (b) mashing is 20 DEG C ~ 40 DEG C, and the time of mashing is 2 ~ 6 hours.
Preferably, after the completion of step (b) mashing, suspension is cooled to 0 DEG C ~ -20 DEG C, and be kept stirring at such a temperature
8 ~ 15 hours；It is highly preferred that the cooldown rate of the suspension is 10 DEG C/h ~ 20 DEG C/h.
In step (c), the crystallization separated out in suspension is separated and dried using the conventional method of this area.It is described
Separation, using the conventional method of this area such as filtering, centrifuge；The concrete operations of filtering are：The sample for being intended to separation is placed in
On filter paper, suction filtration is depressurized；The concrete operations of centrifugation are：Be intended to separation sample be placed in centrifuge tube, afterwards at a high speed rotation until
Solid is all sink to centrifugation bottom of the tube.Selectively, solid is washed with suitable solvent, cleaning solvent such as acetone.It is described dry
It is dry, using this area conventional method such as forced air drying or be dried under reduced pressure；Drying equipment is convection oven or vacuum drying oven；It is dry
Dry to be carried out in the case where depressurizing or not depressurizing, preferably pressure is less than 0.09Mpa；Drying temperature is room temperature（About 10 DEG C ~ 30 DEG C）；
Drying time is 10 ~ 72 hours, preferably 10 ~ 48 hours.
The initiation material Farmorubine Hydrochloride amorphous substance of the present invention, can be according to patent document US4,861,870 disclosures
Method prepare.Through high performance liquid chromatography（HPLC）Detection, its purity is about 90% ~ 93%.
The preparation method process of the present invention is easy, can operate at room temperature.Detect, obtained by preparation method of the present invention through HPLC
The purity for the Farmorubine Hydrochloride crystallization arrived is high, and its purity is free of the impurity such as dimer and catabolite up to more than 99%.
After being preserved 2 months under 40 DEG C, 75% relative humidities, its purity is basically unchanged, and still keeps original crystalline state.
（Four）Embodiment
The present invention is limited with further reference to following examples, and the preparation method of the present invention is described in detail in the embodiment.It is right
It should be apparent to those skilled in the art that many changes for preparation condition can be without departing from the present invention
Implement.
Unless otherwise instructed, various reagents used in embodiment are commercially available.
Unless otherwise instructed, the temperature in embodiment is room temperature.
Embodiment 1
Take 10.0 g Farmorubine Hydrochloride amorphous substances（Purity 92.0%）It is suspended in 20ml ethyl acetate, 30 ml tetrahydrochysene furans
The in the mixed solvent muttered with 10ml water.At 30 DEG C, the suspension is beaten 4 hours.Afterwards, progressively with 10 DEG C/h of speed
The suspension is cooled to -10 DEG C, and is kept for -10 DEG C stir 12 hours.Filtering, crystallization is washed with acetone, then is dried in vacuo 24
Hour, obtain Farmorubine Hydrochloride crystallization.Yield 92%, purity 99.3%, the impurity without dimer or catabolite.
Embodiment 2
Take 10.0 g Farmorubine Hydrochloride amorphous substances（Purity 92.0%）It is suspended in 36ml ethyl acetate, 36ml methyl- terts
The in the mixed solvent of butyl ether and 8ml water.At 40 DEG C, the suspension is beaten 3 hours.Afterwards, progressively with 10 DEG C/h of speed
The suspension is cooled to 0 DEG C by rate, and is kept for 0 DEG C stir 10 hours.Filtering, crystallization washed with acetone, then to be dried in vacuo 36 small
When, obtain Farmorubine Hydrochloride crystallization.Yield 91%, purity 99.0%, the impurity without dimer or catabolite.
Embodiment 3
Take 10.0 g Farmorubine Hydrochloride amorphous substances（Purity 92.0%）It is suspended in 11ml ethyl acetate, 22ml tetrahydrochysene furans
The in the mixed solvent muttered with 7ml water.At 20 DEG C, the suspension is beaten 6 hours.Afterwards, progressively will with 15 DEG C/h of speed
The suspension is cooled to -10 DEG C, and is kept for -10 DEG C stir 15 hours.Filtering, crystallization washed with acetone, then to be dried in vacuo 24 small
When, obtain Farmorubine Hydrochloride crystallization.Yield 92%, purity 99.2%, the impurity without dimer or catabolite.
Embodiment 4
Take 10.0 g Farmorubine Hydrochloride amorphous substances（Purity 92.0%）It is suspended in 60ml isopropyl acetates, 30 ml tetrahydrochysenes
The in the mixed solvent of furans and 10ml water.At 30 DEG C, the suspension is beaten 5 hours.Afterwards, progressively with 20 DEG C/h of speed
The suspension is cooled to -20 DEG C by rate, and is kept for -20 DEG C stir 12 hours.Filtering, crystallization is washed with acetone, then is dried in vacuo
36 hours, obtain Farmorubine Hydrochloride crystallization.Yield 90%, purity 99.1%, the impurity without dimer or catabolite.
Embodiment 5
Take 10.0 g Farmorubine Hydrochloride amorphous substances（Purity 92.0%）It is suspended in 12ml ethyl acetate, 12ml isopropyl ethers
With the in the mixed solvent of 6ml water.At 25 DEG C, the suspension is beaten 5 hours.Afterwards, progressively should with 10 DEG C/h of speed
Suspension is cooled to -15 DEG C, and is kept for -15 DEG C stir 8 hours.Filtering, crystallization is washed with acetone, then is dried in vacuo 36 hours,
Obtain Farmorubine Hydrochloride crystallization.Yield 93%, purity 99.0%, the impurity without dimer or catabolite.
Embodiment 6
Take 10.0 g Farmorubine Hydrochloride amorphous substances（Purity 92.0%）It is suspended in 24ml ethyl acetate, 36 ml tetrahydrochysene furans
The in the mixed solvent muttered with 10ml water.At 30 DEG C, the suspension is beaten 4 hours.Afterwards, progressively with 10 DEG C/h of speed
The suspension is cooled to -10 DEG C, and is kept for -10 DEG C stir 12 hours.Filtering, crystallization is washed with acetone, then is dried in vacuo 24
Hour, obtain Farmorubine Hydrochloride crystallization.Yield 91%, purity 99.3%, the impurity without dimer or catabolite.
Embodiment 7
Take 10.0 g Farmorubine Hydrochloride amorphous substances（Purity 92.0%）It is suspended in 30ml Ethyl formates, 10ml methyl second
The in the mixed solvent of base ether and 2ml water.At 40 DEG C, the suspension is beaten 0.4 hour.Afterwards, progressively with 20 DEG C/h of speed
The suspension is cooled to -20 DEG C by rate, and is kept for -20 DEG C stir 2 hours.Filtering, crystallization is washed with acetone, then convection oven is dry
Dry 10 hours, obtain Farmorubine Hydrochloride crystallization.Yield 91.4%, purity 99.4%, the impurity without dimer or catabolite.
Embodiment 8
Take 10.0 g Farmorubine Hydrochloride amorphous substances（Purity 92.0%）It is suspended in 20ml methyl acetates, 60ml methyl-props
The in the mixed solvent of base ether and 34ml water.At 40 DEG C, the suspension is beaten 2 hours.Afterwards, progressively with 20 DEG C/h of speed
The suspension is cooled to -20 DEG C by rate, and is kept for -20 DEG C stir 12 hours.Filtering, crystallization is washed with acetone, then convection oven
Dry 10 hours, obtain Farmorubine Hydrochloride crystallization.Yield 91.8%, purity 99.4% is miscellaneous without dimer or catabolite
Matter.
Embodiment 9
C3 ~ C5 esters are propyl formates.
C3~C6 ethers are methyl isopropyl ethers.
Other steps are same as Example 1.
Embodiment 10
C3 ~ C5 esters are methyl propionates.
C3~C6 ethers are ether.
Other steps are same as Example 1.
Embodiment 11
C3 ~ C5 esters are isopropyl formates.
C3~C6 ethers are methyl tertiary butyl ether(MTBE)s.
Other steps are same as Example 1.
Embodiment 12
C3 ~ C5 esters are isopropyl acid methyl esters.
C3~C6 ethers are 1,4- dioxane.
Other steps are same as Example 1.
Embodiment 12
C3 ~ C5 esters are isopropyl acetates.
C3~C6 ethers are propyl ether.
Other steps are same as Example 1.
Embodiment 13
C3 ~ C5 esters are ethyl propionates.
Other steps are same as Example 1.
Embodiment 14
C3 ~ C5 esters are isopropyl acetoacetic esters.
Other steps are same as Example 1.
Claims (6)
1. a kind of preparation method of Farmorubine Hydrochloride crystallization, it is characterised in that：Comprise the following steps：
The mixed solvent of ester, ether and water is provided, the percent by volume of mixed solvent reclaimed water is 5% ~ 30%, the volume ratio of ester and ether is
3:1~1:3；
The ester is selected from C3 ~ C5 esters, and the ether is selected from C3~C6 ethers；
C3 ~ C5 esters are Ethyl formate, methyl acetate, ethyl acetate, propyl formate, methyl propionate, isopropyl formate, isopropyl
Sour methyl esters, propyl acetate, isopropyl acetate, ethyl propionate or isopropyl acetoacetic ester；
C3~C6 ethers are methyl ethyl ether, methyl-propyl ether, methyl isopropyl ether, ether, methyl tertiary butyl ether(MTBE), tetrahydrochysene furan
Mutter, 1,4- dioxane, propyl ether or isopropyl ether；
(b) by Farmorubine Hydrochloride amorphous substance is in the in the mixed solvent formation suspension of step (a) and is beaten；
The temperature of mashing is 20 DEG C ~ 40 DEG C, and after the completion of mashing, suspension is cooled into 0 DEG C ~ -20 DEG C；
(c) Farmorubine Hydrochloride crystallization is collected from the suspension.
2. the preparation method of Farmorubine Hydrochloride crystallization according to claim 1, it is characterised in that：Hydrochloric acid in step (b)
The mass volume ratio of Epi-ADM amorphous substance and mixed solvent is 1g:2mL~1g:15mL.
3. the preparation method of Farmorubine Hydrochloride crystallization according to claim 1, it is characterised in that：Step (b) mashing
Time is 2 ~ 6 hours.
4. the preparation method of Farmorubine Hydrochloride crystallization according to claim 1, it is characterised in that：Step (b) has been beaten
Cheng Hou, 0 DEG C ~ -20 DEG C are cooled to by suspension, and are kept stirring at such a temperature 8 ~ 15 hours.
5. the preparation method of Farmorubine Hydrochloride crystallization according to claim 1, it is characterised in that：The suspension it is cold
But speed is 10 DEG C/h ~ 20 DEG C/h.
6. the preparation method of Farmorubine Hydrochloride crystallization according to claim 1, it is characterised in that：In step (c), use
The crystallization separated out in suspension is separated and dried by the conventional method of this area.
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| CN109666050B (en) * | 2017-10-16 | 2023-09-12 | 鲁南制药集团股份有限公司 | Epirubicin hydrochloride crystal form III 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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| IT1275953B1 (en) * | 1995-03-22 | 1997-10-24 | Sicor Spa | PROCEDURE FOR THE PREPARATION OF ANTIBIOTICS OF THE CLASS OF ANTHRACYCLINES |
| ATE195526T1 (en) * | 1996-12-16 | 2000-09-15 | Pharmachemie Bv | METHOD FOR PRODUCING EPIRUBICIN OR ADDITIONAL SALTS THEREOF, DAUNORUBICIN |
| CN100412084C (en) * | 2003-07-02 | 2008-08-20 | 獀洛克斯股份有限公司 | Thermally stable crystalline epirubicin hydrochloride and method of making the same |
| US7388083B2 (en) * | 2005-03-07 | 2008-06-17 | Solux Corporation | Epimerization of 4′-C bond and modification of 14-CH3-(CO)-fragment in anthracyclin antibiotics |
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| DE102011103751A1 (en) * | 2011-05-31 | 2012-12-06 | Heraeus Precious Metals Gmbh & Co. Kg | Crystallization of epirubicin hydrochloride |
| EP2778171A1 (en) * | 2013-03-15 | 2014-09-17 | Synbias Pharma Ltd. | Crystalline monohydrate of epirubicin hydrochloride |
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