CN108395379A - A kind of semisynthesis of mitoxantrone - Google Patents
A kind of semisynthesis of mitoxantrone Download PDFInfo
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- CN108395379A CN108395379A CN201810296342.0A CN201810296342A CN108395379A CN 108395379 A CN108395379 A CN 108395379A CN 201810296342 A CN201810296342 A CN 201810296342A CN 108395379 A CN108395379 A CN 108395379A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
- C07C2603/24—Anthracenes; Hydrogenated anthracenes
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Abstract
The invention discloses a kind of semisynthesis of mitoxantrone, and the synthesis of bulk pharmaceutical chemicals is carried out by one-step method, subsequent process for refining is then carried out, obtains mitoxantrone hydrochloride drug, and synthesis step is simple, and synthesis cycle is short, and reaction condition is mild, and product yield is high.
Description
Technical field
The invention belongs to chemical fields, and in particular to a kind of semisynthesis of mitoxantrone.
Background technology
Mitoxantrone is the antitumor class drug of a line of a kind of research and development seventies in last century, and clinic is injected using its hydrochloride
Liquid is applied to the treatment of malignant lymphoma, breast cancer and acute leukemia.Mitoxantrone is by acting on the double helix knot of DNA
Structure leads to the cracking of DNA chain, may act on the tumour cell of any cell cycle, relative to a line anticancer drug such as adriamycin,
The antitumor action of mitoxantrone is strong, high water solubility, it is cardio-toxicity it is low, bone marrow inhibition is small, have broad application prospects.On
Mainly by import, existing domestic existing multiple commercial vendors produce for the use of the end of the century drug, still, the conjunction for medicine material medicine
Patent report is there is no at the technique country.
Mitoxantrone is a kind of chemicals, is prepared by chemical synthesis, and the product is documented and its derivative is female
The synthetic route of core is as follows.
1) synthesis of 1,4- dihydroxy -6- aminoethyls -9,10- anthraquinones.
2) synthesis of 1,4- dihydroxy -2- (4- butylamine base) -9,10- anthraquinones.
Long for fully synthetic routine synthetic steps, route is complicated, and low yield, by-product is more, and energy consumption is high, production cost
Height is unsuitable for the production of pharmaceutical raw material medicine.
Invention content
The method of the present invention proposes a kind of meter of support anthracene the technical problem to be solved is that, the shortcomings that being directed to the above prior art
The semisynthesis of quinone, synthetic line is simple, and yield is high, and production cost is low, and work efficiency is high.
In order to solve the above-mentioned technical problem, the present invention is achieved in the following ways：
Step 1: the synthesis of bulk pharmaceutical chemicals：
1. the Isosorbide-5-Nitrae of 10-12g at room temperature, is added in 250ml three-necked bottles, then 5,8- tetra hydroxyanthraquinone leuco compounds are used
The air in 250ml three-necked bottles is emptied containing the balloon of nitrogen or argon gas；
2. after emptying the air in 250ml three-necked bottles, the Isosorbide-5-Nitrae dioxane of 54-66ml is added, starts to stir, until 1,
4,5,8- tetra hydroxyanthraquinone leuco compounds are dissolved completely in 1,4 dioxane；
3. complete it is above-mentioned 2. after, constant pressure titrate funnel in be added 32-40g N- (2- ethoxys) ethylenediamine, then
N- (2- ethoxys) ethylenediamine is added dropwise into 250ml three-necked bottles, continuous stirring, time for adding 13-18 during being added dropwise
Minute, after completion of dropwise addition, obtain paste thick liquid；
4. complete it is above-mentioned 3. after, the 250ml three-necked bottles equipped with paste thick liquid are placed in water-bath and are heated, control temperature
Degree is 50 DEG C -55 DEG C, reacts 2-3 hours at such a temperature, after reaction, obtains blue brown or bluish violet oily liquids, i.e.,
Product D；
5. obtained product D is poured into tool plug wide-mouth bottle, and 150-200ml absolute ethyl alcohols are added, and record at this time
Then tool plug wide-mouth bottle is put into water-bath by liquid scale, it is 55 DEG C -60 DEG C to control hot temperature, and is constantly filled in tool
It is passed through in wide-mouth bottle with the dried dry oxygen of dead plaster, and at a temperature of 55 DEG C -60 DEG C, it is small slowly to aoxidize 4-6
When, until the color transition of reaction liquid is sapphirine；
6. letting cool obtained sapphirine liquid to room temperature, and ethanol balance is supplemented in tool fills in wide-mouth bottle, until above-mentioned
5. liquid scale, at room temperature stand 12-36 hours, then sapphirine liquid is poured into and carries out decompression suction filtration in Buchner funnel
Obtain blue bulk pharmaceutical chemicals crystal, i.e. product E；
Step 2: bulk pharmaceutical chemicals is refined：
It is 3 according to the volume ratio of absolute ethyl alcohol and n-hexane 1. in beaker:1 ratio prepares mixed liquor 150ml-
200ml；
2. weigh the product E of 8-12g, pour into tool plug three-necked bottle in, then to tool fill in three-necked bottle in pour into it is above-mentioned 1. in
Tool plug three-necked bottle is put into water-bath by mixed liquor, is stirred dissolving, solution temperature control is 53-56 DEG C, is completely dissolved
Afterwards, it then is filled in three-necked bottle to tool and activated carbon is added, constantly stir and carry out hot reflux, the temperature control of heat reflux is 65-70
DEG C, the time control of heat reflux is 15-30 minutes, after heat reflux, carries out decompression suction filtration immediately, obtains filtrate, will obtain
Filtrate let cool, precipitated crystal overnight by ice bath, then carry out decompression filter obtaining drug crystal；
3. configure again it is above-mentioned 1. in mixed liquor, then obtained drug crystal is repeatedly rinsed, until product
In the bronzing color spot blue colored crystal that is visible by naked eyes have apparent gloss, and at single-size shape, crystal is put after flushing
It is dried in thermostatic drying chamber, drying temperature is 105 DEG C, and drying time is 1.8-2.2 hours, and essence is obtained after drying
Drug after system, i.e. mitoxantrone hydrochloride.
The beneficial effects of the invention are as follows：Experimental procedure is simple, and synthesis cycle is short, and the primary throwing sample production cycle is 3-5 days, can
Meeting the needs of industrialized production, the organic solvent type applied in experiment is few, and a kind of solvent is not used during chemical combination,
1.4- dioxane is easy to volatilize, and residual quantity is small after the multiple washing and drying of absolute ethyl alcohol, meets organic molten in drug in GMP
The remaining standard of agent, meets the regulation of drug safety, and reaction condition is mild, and reaction temperature is relatively low, and control is suitable anti-
Answer temperature on the one hand can effectively reduce side reaction product yield amount, it is in addition comparatively safe and reduce energy consumption and environmental pollution, it originates
The prices of raw materials are cheap, abundance, are easy to buy, and the yield of product is high.
Description of the drawings
Fig. 1 is the synthetic route chart of the present invention.
Specific implementation mode
The present invention is described in further detail below；
Embodiment 1
A kind of semisynthesis of mitoxantrone provided in this embodiment, including；
Step 1: the synthesis of bulk pharmaceutical chemicals：
1. the Isosorbide-5-Nitrae of 10g at room temperature, is added in 250ml three-necked bottles, 5,8- tetra hydroxyanthraquinone leuco compounds, then with containing
The balloon of nitrogen or argon gas empties the air in 250ml three-necked bottles；
2. after emptying the air in 250ml three-necked bottles, the Isosorbide-5-Nitrae dioxane of 54ml is added, starts to stir, until Isosorbide-5-Nitrae, 5,
8- tetra hydroxyanthraquinone leuco compounds are dissolved completely in 1,4 dioxane；
3. complete it is above-mentioned 2. after, constant pressure titrate funnel in be added 32g N- (2- ethoxys) ethylenediamine, then to
N- (2- ethoxys) ethylenediamine is added dropwise in 250ml three-necked bottles, the continuous stirring during being added dropwise, time for adding is 13 minutes,
After completion of dropwise addition, paste thick liquid is obtained；
4. complete it is above-mentioned 3. after, the 250ml three-necked bottles equipped with paste thick liquid are placed in water-bath and are heated, control temperature
Degree is 50 DEG C, reacts 2 hours at such a temperature, after reaction, obtains blue brown or bluish violet oily liquids, i.e. product D；
5. obtained product D is poured into tool plug wide-mouth bottle, and 150ml absolute ethyl alcohols are added, and record liquid at this time
Then tool plug wide-mouth bottle is put into water-bath by scale, it is 55 DEG C to control hot temperature, and constantly fills in wide-mouth bottle and lead to tool
Enter the dry oxygen for using dead plaster dried, and at a temperature of 55 DEG C, slowly oxidation 4 hours, until reaction liquid
Color transition is sapphirine；
6. letting cool obtained sapphirine liquid to room temperature, and ethanol balance is supplemented in tool fills in wide-mouth bottle, until above-mentioned
5. liquid scale, at room temperature stand 12 hours, then sapphirine liquid is poured into Buchner funnel carry out decompression filter
To blue bulk pharmaceutical chemicals crystal, i.e. product E；
Step 2: bulk pharmaceutical chemicals is refined：
It is 3 according to the volume ratio of absolute ethyl alcohol and n-hexane 1. in beaker:1 ratio prepares mixed liquor 150ml；
2. weigh the product E of 8g, pour into tool plug three-necked bottle in, then to tool fill in three-necked bottle in pour into it is above-mentioned 1. in mixing
Tool plug three-necked bottle is put into water-bath, is stirred dissolving by liquid, and solution temperature control is 53 DEG C, after being completely dissolved, then to tool
Activated carbon is added in plug three-necked bottle, constantly stirs and carry out hot reflux, the temperature control of heat reflux is 65 DEG C, heat reflux when
Between control be 15 minutes, heat reflux after, carry out decompression suction filtration immediately, obtain filtrate, obtained filtrate is let cool, ice is passed through
Bath precipitates crystal overnight, then carries out decompression suction filtration and obtains drug crystal；
3. configure again it is above-mentioned 1. in mixed liquor, then obtained drug crystal is repeatedly rinsed, until product
In the bronzing color spot blue colored crystal that is visible by naked eyes have apparent gloss, and at single-size shape, crystal is put after flushing
It is dried in thermostatic drying chamber, drying temperature is 105 DEG C, and drying time is 1.8 hours, after being refined after drying
Drug, i.e. mitoxantrone hydrochloride.
The measurement that content is carried out to obtained mitoxantrone hydrochloride drug measures content using HPLC-UV, and yield is
30%.
Embodiment 2
Step 1: the synthesis of bulk pharmaceutical chemicals：
1. the Isosorbide-5-Nitrae of 12g at room temperature, is added in 250ml three-necked bottles, 5,8- tetra hydroxyanthraquinone leuco compounds, then with containing
The balloon of nitrogen or argon gas empties the air in 250ml three-necked bottles；
2. after emptying the air in 250ml three-necked bottles, the Isosorbide-5-Nitrae dioxane of 66ml is added, starts to stir, until Isosorbide-5-Nitrae, 5,
8- tetra hydroxyanthraquinone leuco compounds are dissolved completely in 1,4 dioxane；
3. complete it is above-mentioned 2. after, constant pressure titrate funnel in be added 40g N- (2- ethoxys) ethylenediamine, then to
N- (2- ethoxys) ethylenediamine is added dropwise in 250ml three-necked bottles, the continuous stirring during being added dropwise, time for adding is 18 minutes,
After completion of dropwise addition, paste thick liquid is obtained；
4. complete it is above-mentioned 3. after, the 250ml three-necked bottles equipped with paste thick liquid are placed in water-bath and are heated, control temperature
Degree is 55 DEG C, reacts 3 hours at such a temperature, after reaction, obtains blue brown or bluish violet oily liquids, i.e. product D；
5. obtained product D is poured into tool plug wide-mouth bottle, and 200ml absolute ethyl alcohols are added, and record liquid at this time
Then tool plug wide-mouth bottle is put into water-bath by scale, it is 60 DEG C to control hot temperature, and constantly fills in wide-mouth bottle and lead to tool
Enter the dry oxygen for using dead plaster dried, and at a temperature of 60 DEG C, slowly oxidation 6 hours, until reaction liquid
Color transition is sapphirine；
6. letting cool obtained sapphirine liquid to room temperature, and ethanol balance is supplemented in tool fills in wide-mouth bottle, until above-mentioned
5. the liquid scale recorded in stands 36 hours at room temperature, then pours into Buchner funnel sapphirine liquid and depressurize
Suction filtration obtains blue bulk pharmaceutical chemicals crystal, i.e. product E；
Step 2: bulk pharmaceutical chemicals is refined：
It is 3 according to the volume ratio of absolute ethyl alcohol and n-hexane 1. in beaker:1 ratio prepares mixed liquor 200ml；
2. weighing the product E of 12g, pour into tool plug three-necked bottle, then filled in tool poured into three-necked bottle it is above-mentioned 1. in it is mixed
Liquid to be closed, tool plug three-necked bottle is put into water-bath, is stirred dissolving, solution temperature control is 56 DEG C, after being completely dissolved, then to
Activated carbon is added in tool plug three-necked bottle, constantly stirs and carry out hot reflux, the temperature control of heat reflux is 70 DEG C, heat reflux
Time control is 30 minutes, after heat reflux, carries out decompression suction filtration immediately, obtains filtrate, obtained filtrate is let cool, is passed through
Ice bath precipitates crystal overnight, then carries out decompression suction filtration and obtains drug crystal；
3. configure again it is above-mentioned 1. in mixed liquor, then obtained drug crystal is repeatedly rinsed, until product
In the bronzing color spot blue colored crystal that is visible by naked eyes have apparent gloss, and at single-size shape, crystal is put after flushing
It is dried in thermostatic drying chamber, drying temperature is 105 DEG C, and drying time is 2.2 hours, after being refined after drying
Drug, i.e. mitoxantrone hydrochloride.
The measurement that content is carried out to obtained mitoxantrone hydrochloride drug measures content using HPLC-UV, and yield is
32%.
Embodiment 3
Step 1: the synthesis of bulk pharmaceutical chemicals：
1. the Isosorbide-5-Nitrae of 11g at room temperature, is added in 250ml three-necked bottles, 5,8- tetra hydroxyanthraquinone leuco compounds, then with containing
The balloon of nitrogen or argon gas empties the air in 250ml three-necked bottles；
2. after emptying the air in 250ml three-necked bottles, the Isosorbide-5-Nitrae dioxane of 60ml is added, starts to stir, until Isosorbide-5-Nitrae, 5,
8- tetra hydroxyanthraquinone leuco compounds are dissolved completely in 1,4 dioxane；
3. complete it is above-mentioned 2. after, constant pressure titrate funnel in be added 35g N- (2- ethoxys) ethylenediamine, then to
N- (2- ethoxys) ethylenediamine is added dropwise in 250ml three-necked bottles, the continuous stirring during being added dropwise, time for adding is 15 minutes,
After completion of dropwise addition, paste thick liquid is obtained；
4. complete it is above-mentioned 3. after, the 250ml three-necked bottles equipped with paste thick liquid are placed in water-bath and are heated, control temperature
Degree is 52 DEG C, reacts 2.5 hours at such a temperature, after reaction, obtains blue brown or bluish violet oily liquids, i.e. product D；
5. obtained product D is poured into tool plug wide-mouth bottle, and 180ml absolute ethyl alcohols are added, and record liquid at this time
Then tool plug wide-mouth bottle is put into water-bath by scale, it is 57 DEG C to control hot temperature, and constantly fills in wide-mouth bottle and lead to tool
Enter the dry oxygen for using dead plaster dried, and at a temperature of 57 DEG C, slowly oxidation 5 hours, until reaction liquid
Color transition is sapphirine；
6. letting cool obtained sapphirine liquid to room temperature, and ethanol balance is supplemented in tool fills in wide-mouth bottle, until above-mentioned
5. the liquid scale recorded in stands 24 hours at room temperature, then pours into Buchner funnel sapphirine liquid and depressurize
Suction filtration obtains blue bulk pharmaceutical chemicals crystal, i.e. product E；
Step 2: bulk pharmaceutical chemicals is refined：
It is 3 according to the volume ratio of absolute ethyl alcohol and n-hexane 1. in beaker:1 ratio prepares mixed liquor 180ml；
2. weighing the product E of 10g, pour into tool plug three-necked bottle, then filled in tool poured into three-necked bottle it is above-mentioned 1. in it is mixed
Liquid to be closed, tool plug three-necked bottle is put into water-bath, is stirred dissolving, solution temperature control is 55 DEG C, after being completely dissolved, then to
Activated carbon is added in tool plug three-necked bottle, constantly stirs and carry out hot reflux, the temperature control of heat reflux is 68 DEG C, heat reflux
Time control is 20 minutes, after heat reflux, carries out decompression suction filtration immediately, obtains filtrate, obtained filtrate is let cool, is passed through
Ice bath precipitates crystal overnight, then carries out decompression suction filtration and obtains drug crystal；
3. configure again it is above-mentioned 1. in mixed liquor, then obtained drug crystal is repeatedly rinsed, until product
In the bronzing color spot blue colored crystal that is visible by naked eyes have apparent gloss, and at single-size shape, crystal is put after flushing
It is dried in thermostatic drying chamber, drying temperature is 105 DEG C, and drying time is 2.0 hours, after being refined after drying
Drug, i.e. mitoxantrone hydrochloride.
The measurement that content is carried out to obtained mitoxantrone hydrochloride drug measures content using HPLC-UV, and yield is
35%.
Embodiment 4
Step 1: the synthesis of bulk pharmaceutical chemicals：
1. the Isosorbide-5-Nitrae of 10.5g at room temperature, is added in 250ml three-necked bottles, then 5,8- tetra hydroxyanthraquinone leuco compounds are used
The air in 250ml three-necked bottles is emptied containing the balloon of nitrogen or argon gas；
2. after emptying the air in 250ml three-necked bottles, the Isosorbide-5-Nitrae dioxane of 59ml is added, starts to stir, until Isosorbide-5-Nitrae, 5,
8- tetra hydroxyanthraquinone leuco compounds are dissolved completely in 1,4 dioxane；
3. complete it is above-mentioned 2. after, constant pressure titrate funnel in be added 38g N- (2- ethoxys) ethylenediamine, then to
N- (2- ethoxys) ethylenediamine is added dropwise in 250ml three-necked bottles, the continuous stirring during being added dropwise, time for adding is 14 minutes,
After completion of dropwise addition, paste thick liquid is obtained；
4. complete it is above-mentioned 3. after, the 250ml three-necked bottles equipped with paste thick liquid are placed in water-bath and are heated, control temperature
Degree is 53 DEG C, reacts 2.2 hours at such a temperature, after reaction, obtains blue brown or bluish violet oily liquids, i.e. product D；
5. obtained product D is poured into tool plug wide-mouth bottle, and 170ml absolute ethyl alcohols are added, and record liquid at this time
Then tool plug wide-mouth bottle is put into water-bath by scale, it is 59 DEG C to control hot temperature, and constantly fills in wide-mouth bottle and lead to tool
Enter the dry oxygen for using dead plaster dried, and at a temperature of 59 DEG C, slowly oxidation 5.5 hours, until reaction liquid
Color transition be sapphirine；
6. letting cool obtained sapphirine liquid to room temperature, and ethanol balance is supplemented in tool fills in wide-mouth bottle, until above-mentioned
5. the liquid scale recorded in stands 30 hours at room temperature, then pours into Buchner funnel sapphirine liquid and depressurize
Suction filtration obtains blue bulk pharmaceutical chemicals crystal, i.e. product E；
Step 2: bulk pharmaceutical chemicals is refined：
It is 3 according to the volume ratio of absolute ethyl alcohol and n-hexane 1. in beaker:1 ratio prepares mixed liquor 180ml；
2. weigh the product E of 9g, pour into tool plug three-necked bottle in, then to tool fill in three-necked bottle in pour into it is above-mentioned 1. in mixing
Tool plug three-necked bottle is put into water-bath, is stirred dissolving by liquid, and solution temperature control is 54 DEG C, after being completely dissolved, then to tool
Activated carbon is added in plug three-necked bottle, constantly stirs and carry out hot reflux, the temperature control of heat reflux is 68 DEG C, heat reflux when
Between control be 22 minutes, heat reflux after, carry out decompression suction filtration immediately, obtain filtrate, obtained filtrate is let cool, ice is passed through
Bath precipitates crystal overnight, then carries out decompression suction filtration and obtains drug crystal；
3. configure again it is above-mentioned 1. in mixed liquor, then obtained drug crystal is repeatedly rinsed, until product
In the bronzing color spot blue colored crystal that is visible by naked eyes have apparent gloss, and at single-size shape, crystal is put after flushing
It is dried in thermostatic drying chamber, drying temperature is 105 DEG C, and drying time is 1.9 hours, after being refined after drying
Drug, i.e. mitoxantrone hydrochloride.
The measurement that content is carried out to obtained mitoxantrone hydrochloride drug measures content using HPLC-UV, and yield is
38%.
Above example is merely illustrative of the invention's technical idea, and protection scope of the present invention cannot be limited with this, every
According to technological thought proposed by the present invention, any change done on the basis of technical solution each falls within the scope of the present invention
Within.
Claims (1)
1. a kind of semisynthesis of mitoxantrone, it is characterised in that：The preparation method carries out according to the following steps：
Step 1: the synthesis of bulk pharmaceutical chemicals：
At room temperature, the Isosorbide-5-Nitrae of 10-12g, 5,8- tetra hydroxyanthraquinone leuco compounds, then with nitrogenous are added in 250ml three-necked bottles
The balloon of gas or argon gas empties the air in 250ml three-necked bottles；
2. after emptying the air in 250ml three-necked bottles, the Isosorbide-5-Nitrae dioxane of 54-66ml is added, starts to stir, until Isosorbide-5-Nitrae,
5,8- tetra hydroxyanthraquinone leuco compounds are dissolved completely in 1,4 dioxane；
3. complete it is above-mentioned 2. after, constant pressure titrate funnel in be added 32-40g N-（2- ethoxys）Ethylenediamine, then to
N- is added dropwise in 250ml three-necked bottles（2- ethoxys）Ethylenediamine, the continuous stirring during being added dropwise, time for adding is 13-18 points
Clock after completion of dropwise addition, obtains paste thick liquid；
4. complete it is above-mentioned 3. after, the 250ml three-necked bottles equipped with paste thick liquid are placed in water-bath and are heated, control temperature
It is 50 DEG C -55 DEG C, reacts 2-3 hours at such a temperature, after reaction, obtain blue brown or bluish violet oily liquids, that is, produce
Object D；
5. obtained product D is poured into tool plug wide-mouth bottle, and 150-200ml absolute ethyl alcohols are added, and record liquid at this time
Then tool plug wide-mouth bottle is put into water-bath by scale, it is 55 DEG C -60 DEG C to control hot temperature, and constantly fills in wide-mouth to tool
It is passed through in bottle with the dried dry oxygen of dead plaster, and at a temperature of 55 DEG C -60 DEG C, slowly oxidation 4-6 hours,
Until the color transition of reaction liquid is sapphirine；
6. letting cool obtained sapphirine liquid to room temperature, and ethanol balance is supplemented in tool fills in wide-mouth bottle, until it is above-mentioned 5.
Liquid scale, at room temperature stand 12-36 hour, then sapphirine liquid is poured into Buchner funnel carry out decompression suction filtration obtain
Blue bulk pharmaceutical chemicals crystal, i.e. product E；
Step 2: bulk pharmaceutical chemicals is refined：
It is 3 according to the volume ratio of absolute ethyl alcohol and n-hexane 1. in beaker:1 ratio prepares mixed liquor 150ml-200ml；
2. weigh the product E of 8-12g, pour into tool plug three-necked bottle in, then to tool fill in three-necked bottle in pour into it is above-mentioned 1. in mixing
Tool plug three-necked bottle is put into water-bath by liquid, is stirred dissolving, and solution temperature control is 53-56 DEG C, after being completely dissolved, then
It is filled in three-necked bottle to tool and activated carbon is added, constantly stir and carry out hot reflux, the temperature control of heat reflux is 65-70 DEG C, heat
The time control of reflux is 15-30 minutes, after heat reflux, carries out decompression suction filtration immediately, obtains filtrate, the filtrate that will be obtained
It lets cool, is precipitated crystal overnight by ice bath, then carry out decompression suction filtration and obtain drug crystal；
3. configure again it is above-mentioned 1. in mixed liquor, then obtained drug crystal is repeatedly rinsed, until product in nothing
Macroscopic bronzing color spot blue colored crystal has apparent gloss, and at single-size shape, crystal is placed on perseverance after flushing
It is dried in warm drying box, drying temperature is 105 DEG C, and drying time is 1.8-2.2 hours, after being refined after drying
Drug, i.e. mitoxantrone hydrochloride.
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| CN201810296342.0A CN108395379A (en) | 2018-03-30 | 2018-03-30 | A kind of semisynthesis of mitoxantrone |
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| CN201810296342.0A CN108395379A (en) | 2018-03-30 | 2018-03-30 | A kind of semisynthesis of mitoxantrone |
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4138415A (en) * | 1978-05-05 | 1979-02-06 | American Cyanamid Company | 1,4-Bis(aminoalkylamino)-anthraquinones and leuco derivatives thereof |
| US4197249A (en) * | 1977-08-15 | 1980-04-08 | American Cyanamid Company | 1,4-Bis(substituted-amino)-5,8-dihydroxyanthraquinones and leuco bases thereof |
| CS231079B1 (en) * | 1982-07-16 | 1984-09-17 | Libuse Havlickova | Processing method of pharmaceuticaly effective 1,4-diamino antraquinone derivative |
| CS264757B1 (en) * | 1985-03-26 | 1989-09-12 | Havlickova Libuse | Process for preparing pharmacologic active derivatives of 1,4-diaminoantraquinone |
| SU1811159A1 (en) * | 1990-06-26 | 1996-03-27 | Уральский политехнический институт им.С.М.Кирова | Method of synthesis of 1,4-dihydroxy-5,8-bis- {{2-[(2-hydroxyethyl) -amino]ethyl}amino}- 9, 10-anthracenedione dihydrochloride |
| US6465522B1 (en) * | 1998-12-24 | 2002-10-15 | De Montford University | Anthraquinone anticancer drugs |
| CN1927839A (en) * | 2006-09-25 | 2007-03-14 | 天津理工大学 | Compound of 1,4-di(arylamido substituted alkylamino)-5,8-dihydroxyanthraquinone and preparation method thereof |
| WO2008062252A1 (en) * | 2006-11-21 | 2008-05-29 | Access Pharmaceuticals, Inc | N-oxides of cytotoxic anthraquinones as hypoxia-targeting prodrugs in cancer treatment |
-
2018
- 2018-03-30 CN CN201810296342.0A patent/CN108395379A/en not_active Withdrawn
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4197249A (en) * | 1977-08-15 | 1980-04-08 | American Cyanamid Company | 1,4-Bis(substituted-amino)-5,8-dihydroxyanthraquinones and leuco bases thereof |
| US4138415A (en) * | 1978-05-05 | 1979-02-06 | American Cyanamid Company | 1,4-Bis(aminoalkylamino)-anthraquinones and leuco derivatives thereof |
| CS231079B1 (en) * | 1982-07-16 | 1984-09-17 | Libuse Havlickova | Processing method of pharmaceuticaly effective 1,4-diamino antraquinone derivative |
| CS264757B1 (en) * | 1985-03-26 | 1989-09-12 | Havlickova Libuse | Process for preparing pharmacologic active derivatives of 1,4-diaminoantraquinone |
| SU1811159A1 (en) * | 1990-06-26 | 1996-03-27 | Уральский политехнический институт им.С.М.Кирова | Method of synthesis of 1,4-dihydroxy-5,8-bis- {{2-[(2-hydroxyethyl) -amino]ethyl}amino}- 9, 10-anthracenedione dihydrochloride |
| US6465522B1 (en) * | 1998-12-24 | 2002-10-15 | De Montford University | Anthraquinone anticancer drugs |
| CN1927839A (en) * | 2006-09-25 | 2007-03-14 | 天津理工大学 | Compound of 1,4-di(arylamido substituted alkylamino)-5,8-dihydroxyanthraquinone and preparation method thereof |
| WO2008062252A1 (en) * | 2006-11-21 | 2008-05-29 | Access Pharmaceuticals, Inc | N-oxides of cytotoxic anthraquinones as hypoxia-targeting prodrugs in cancer treatment |
Non-Patent Citations (3)
| Title |
|---|
| CHICCARELLI, F. S.等: "Identification of human urinary mitoxantrone metabolites", 《CANCER RESEARCH》 * |
| KALEAGASIOGLU, FERDA等: "Cytotoxic activity of a new hydroxy anthraquinone derivative 1,4-bis[(2-aminoethyl)amino]-5,8-dihydroxy anthraquinone, compared to that of mitoxantrone", 《ACTA PHARMACEUTICA TURCICA》 * |
| ZEE-CHENG, ROBERT K. Y.等: "Antineoplastic agents. Structure-activity relationship study of bis(substituted aminoalkylamino)anthraquinones", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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