CN106366036A - 6, 9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5, 10-dione dimaleate and synthesis technology thereof - Google Patents
6, 9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5, 10-dione dimaleate and synthesis technology thereof Download PDFInfo
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- CN106366036A CN106366036A CN201610694524.4A CN201610694524A CN106366036A CN 106366036 A CN106366036 A CN 106366036A CN 201610694524 A CN201610694524 A CN 201610694524A CN 106366036 A CN106366036 A CN 106366036A
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- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
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Abstract
The invention discloses a synthesis technology of 6, 9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5, 10-dione dimaleate and relates to the technical field of antineoplastic drug synthesis. The synthesis technology comprises that 3, 4-pyridinedicarboxylic anhydride and hydroquinone undergo a reaction in the presence of a catalyst to produce a first intermediate, the first intermediate and N-t-butoxycarbonylethylenediamine undergo a reaction to produce a second intermediate, the second intermediate is subjected to deprotection, and the product and maleic acid undergo a salt forming reaction to produce a product. The prepared product has purity greater than 99.5% and known single impurity and unknown single impurity contents less than 0.1%. The important intermediate of the synthesis technology has stable properties and is convenient for storage. The synthesis technology allows mild reaction conditions, has simple processes, realizes a low cost and is suitable for industrial production. The invention also provides pixantrone dimaleate. The pixantrone dimaleate can be processed to form a freeze-dried powder injection for treating human aggressive non-Hodgkin's lymphoma with easy recurrence and high treatment difficulty.
Description
Technical field
The present invention relates to a kind of synthesis technical field of antineoplastic agent, and particularly to a kind of double [(the 2- amino second of 6,9-
Base) amino] benzo [g] isoquinolin -5,10- diketone 2-maleate and its synthesis technique.
Background technology
The chemical name of maleic acid Pixantrone (pixantrone dimaleate) is double [(2- amino-ethyl) ammonia of 6,9-
Base] benzo [g] isoquinolin -5,10- diketone 2-maleate, chemical structural formula isMolecular weight
For 557.5, character is Dark blue crystals powder.The dosage form of maleic acid Pixantrone mostly is freeze-dried powder injection, every
Pixantrone containing 29mg, every milliliter of solution 5.8mg containing pixantrone after redissolution, treatment adult's recurrence can be used for as single therapy medicine difficult
Control, Aggressive Non-Hodgkin's (non-hodgkin's lymphoma, nhl).
Wherein, pixantrone is a kind of cytotoxic naphthazine diones antibiotics of tool, and granted use
Anthracycline antibiotics (doxorubicin and other) and amerantrone (mitoxantrone) are different, and pixantrone is a kind of weak topology isomerase
Ii inhibitor, direct alkylation forms stable dna adduct.Further, since pixantrone not ketone group containing, and combine single miscellaneous former
Son enter ring structure, therefore, pixantrone can not possibly generate active oxidation product, will not as anthracycline antibiotics, in conjunction with from
Son forms the alcohols metabolite that may cause cardiac toxicity.Just because of this unique structure of pixantrone, with doxorubicin
Compare with mitoxantrone, the cardiac toxicity degree that pixantrone produces in animal experiment is minimum.Injection pixantrone was in 2012 5
The moon is approved for as monotherapy multiple relapse refractory, aggressive b cell nhl, trade name in European Union on the 10th
Pixuvri, is the first medicine being approved for this patient population of European Union.The result of study that the clinical iii phase studies pix 301 shows
Show: patient combines the complete response rate (20%) of Rituximab (rituximab) therapeutic scheme apparently higher than mark to pixuvri
The complete response rate (6%) of quasi- therapeutic scheme (gemcitabine joint rituximab treatment), meanwhile, using pixuvri joint
No progression of disease phase (the average out to 10.2 months) ratio of the treatment group of Rituximab (rituximab) adopts standard regimens
Treatment group the no progression of disease phase (average out to 7.6 months) long.
Notable to the therapeutic effect of aggressive b cell nhl based on pixantrone, the chemical synthesis process of maleic acid Pixantrone is standby
Paid attention to.At present, the synthetic method of maleic acid Pixantrone is summed up mainly following four routes.
Route one:
Route two:
Route three:
Route four:
Wherein, route one and route two are for initiation material with 3,4- dipicolinic acid, are prepared into 3 with acetic acid anhydride reactant,
4- picolinic acid acid anhydride；React with to fluorine hexichol again, be prepared into key intermediate 6,9- difluoro benzo [g] isoquinolin -5,10- bis-
Ketone；Again with ethylenediamine or n- tertbutyloxycarbonyl reacting ethylenediamine, it is prepared into pixantrone；It is then converted to maleic acid Pixantrone.Route
One and route two have the disadvantage in that (1) 3,4- picolinic acid acid anhydride and a large amount of strong acid corrosivity when difluorobenzene is reacted, will be used
Aluminum trichloride (anhydrous) and high boiling carcinogenic solvent Nitrobenzol, this reaction is heterogeneous reaction system, stirring difficult it is difficult to enter
Row industrial amplification production；(2) prepare intermediate 6,9- difluoro benzo [g] isoquinolin -5, during 10- diketone, with 20% send out
Cigarette sulphuric acid is reaction reagent and solvent, and condition is acutely, seriously polluted；(3) although synthesis maleic acid Pixantrone product purity energy
Enough reach 99%, the single impurity content of unknown structure is less than 0.2%, but may still not meet frozen powder for injection pin increasingly
Strict prescription.
Route three and route four are for initiation material with 3,4- pyridine diacid chloride, with hydroquinone or Isosorbide-5-Nitrae-dimethoxy benzene
Reaction is prepared into intermediate 6,9- dihydroxy benzo [g] isoquinolin -5,10- diketone, after isomery conversion, then with ethylenediamine
Reaction generates pixantrone, becomes salt maleic acid Pixantrone afterwards with maleic acid.The shortcoming of route three and route four is: 3,4- pyridine two
The conversion ratio that acyl chlorides and hydroquinone react preparation is very low, and purification difficult leads to yield very low, and 3,4- pyridine diacid chloride pole
Perishable, need now-making-now-using.In addition, after isomery conversion, more impurity can be generated with reacting ethylenediamine, and pixantrone exists
Less stable in reaction system, when removing impurity, free pixantrone can generate new impurity so that generating in this step again
Pixantrone contain more impurity, purification cost is very high.
In sum, there is presently no a kind of technique of suitable industrialized production maleic acid Pixantrone.
Content of the invention
It is an object of the invention to provide a kind of double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- two of 6,9-
The synthesis technique of ketone 2-maleate, reaction condition is gentle, simple, and purity is high, low cost, suitable industrialized production.
Another object of the present invention is to providing a kind of double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5 of 6,9-,
10- diketone 2-maleate, can be made into freeze-dried powder injection, for treatment adult's recurrence refractory, aggressive non-Hodgkin′ses
Lymphoma.
The present invention solves its technical problem and employs the following technical solutions to realize.
The present invention proposes a kind of double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone two maleic acid of 6,9-
The synthesis technique of salt, it comprises the following steps:
3,4- picolinic acid acid anhydride and hydroquinone are reacted in the presence of catalyst, obtains the first intermediate, catalyst
The silica gel load phosphoric acid being 40%～50% for load capacity, the first intermediate is 6,9- dihydroxy benzo [g] isoquinolin -5,10-
Diketone；
By the first intermediate and n- tertbutyloxycarbonyl reacting ethylenediamine, obtain the second intermediate, the second intermediate is n, n-
Tertbutyloxycarbonyl pixantrone；
Deprotection is carried out to the second intermediate, becomes salt with maleic acid, obtain double [(2- amino-ethyl) amino] benzo of 6,9-
[g] isoquinolin -5,10- diketone 2-maleate.
Further, in present pre-ferred embodiments, the mol ratio of 3,4- picolinic acid acid anhydrides and hydroquinone is 1:0.8
～1.2；The weight of 3,4- picolinic acid acid anhydride and catalyst is than for 1:1～1.4.
Further, in present pre-ferred embodiments, the concrete preparation process of catalyst is:
The silica gel of 40-100 mesh is placed in dimethylbenzene, adds triethylamine and zinc acetate, silica gel, triethylamine and zinc acetate
Than for 1:0.015～0.025:0.004～0.006, agitating heating, flow back to obtain weight the first solution；In 0.4h-0.6h
Deca strong phosphoric acid in one solution, the weight of silica gel and strong phosphoric acid, than for 1:0.8～1.2, after reflux water-dividing 2h～3h, is cooled to 8
DEG C～12 DEG C, sucking filtration, drying, obtain final product.
Further, in present pre-ferred embodiments, the concrete synthesis technique of the first intermediate is:
Add 3,4- pyridine anhydride, hydroquinone and hexamethylene in a reservoir, add catalyst, be heated to reflux a point water 4h
～6h, is cooled to temperature and is less than 10 DEG C, filters to obtain the first filtrate, and washing the first filtrate obtains organic faciess, and reduce pressure organic faciess, obtains
Grease；Add diisopropyl ether in grease, stirring separates out the first solid, filters, recrystallization, obtains final product.
Further, in present pre-ferred embodiments, using oxolane, the first solid after filtering is tied again
Brilliant.
Further, in present pre-ferred embodiments, the concrete synthesis technique of the second intermediate is:
First intermediate and n- tertbutyloxycarbonyl ethylenediamine are placed in n- methyl pyrrolidone, addition potassium carbonate, first
The mol ratio of intermediate, n- tertbutyloxycarbonyl ethylenediamine and potassium carbonate is 1:1.5～2.5:0.8～1.2, is heated to 55 DEG C～65
DEG C, react 4h～6h, cooling, obtain the second solution, the second solution is added in deionized water, the first intermediate and deionization
For 1:17～23, stirring separates out the second solid to the weight of water ratio, filters, recrystallization, obtains final product.
Further, in present pre-ferred embodiments, using the mixed liquor of the methanol for 1:1 for the volume ratio and dichloromethane
Recrystallization is carried out to the second solid after filtering.
Further, in present pre-ferred embodiments, 6,9- double [(2- amino-ethyl) amino] benzo [g] isoquinolin-
The concrete synthesis technique of 5,10- diketone 2-maleate is:
Under nitrogen protection, the second intermediate and trifluoracetic acid are added in dichloromethane, 11h～13h are stirred at room temperature,
Add ethanol, concentrating under reduced pressure at less than 60 DEG C, add deionized water dissolving, adjust ph value be 4～4.5, filter second
Filtrate, in the second filtrate add 3m maleic acid solution, adjust ph value be 3.2～3.6, stir 11h～13h, filter the 3rd
Solid, recrystallization, obtain final product.
Further, in present pre-ferred embodiments, recrystallization is carried out to the 3rd solid using 95% ethanol.
The present invention also proposes a kind of double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone two Malaysia of 6,9-
Hydrochlorate, is obtained using above-mentioned synthesis technique.
Double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone two maleic acid of the 6,9- of the embodiment of the present invention
The beneficial effect of salt and its synthesis technique is: this synthesis technique is in catalyst first by 3,4- picolinic acid acid anhydride with hydroquinone
In the presence of react, obtain the first intermediate；Secondly by the first intermediate and n- tertbutyloxycarbonyl reacting ethylenediamine, obtain second
Intermediate；Then deprotection is carried out to the second intermediate, become salt with maleic acid, obtain maleic acid Pixantrone.Prepared product is pure
Degree is higher than literature value, and purity is more than 99.5% it is known that single impurity and unknown single impurity content are respectively less than 0.1%, this synthesis
Important intermediate stable in properties involved by technique, is easy to store, and the reaction condition of this synthesis technique is gentle, simple, become
This low, industrialized production of suitable maleic acid Pixantrone；Prepared maleic acid Pixantrone, can be made into freeze-dried powder injection,
For treatment adult's recurrence refractory, Aggressive Non-Hodgkin's.
Specific embodiment
Purpose, technical scheme and advantage for making the embodiment of the present invention are clearer, below will be in the embodiment of the present invention
Technical scheme be clearly and completely described.In embodiment, unreceipted actual conditions person, builds according to normal condition or manufacturer
The condition of view is carried out.Agents useful for same or the unreceipted production firm person of instrument, being can be by the commercially available conventional product bought and obtain
Product.
Double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone two of 6,9- to the embodiment of the present invention below
Maleate and its synthesis technique are specifically described.
The embodiment of the present invention provides a kind of double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone two of 6,9-
The synthesis technique of maleate, its reaction equation is:
The synthesis technique of double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone 2-maleate of this 6,9-
Comprise the following steps:
S1 synthesizes the first intermediate: by 3,4- picolinic acid acid anhydride as initiation material, with hydroquinone catalyst work
Use lower reaction, obtain the first intermediate, the silica gel load phosphoric acid that catalyst is 40%～50% for load capacity, as 40%～
50% silica gel load phosphoric acid, the weight of wherein phosphoric acid accounts for the 40%～50% of silica gel weight, and the first intermediate is 6,9- dihydroxy
Benzo [g] isoquinolin -5,10- diketone (in reaction equation), the mol ratio of 3,4- picolinic acid acid anhydrides and hydroquinone is
1:0.8～1.2；The weight of 3,4- picolinic acid acid anhydride and catalyst is than for 1:1～1.4.The present embodiment adopts silica gel load phosphoric acid
For catalyst so that the reaction of 3,4- pyridine anhydride and hydroquinone is easily carried out, high income, mild condition.And 3,4- pyrrole
Pyridine anhydride can directly be bought in market, it is to avoid adopts the unstable raw materials such as 3,4- pyridine diacid chloride, is therefore easier to realize industry
Metaplasia is produced.
The concrete synthesis technique of the first intermediate is as follows:
3,4- pyridine anhydride, hydroquinone and solvent hexamethylene are added to container, in such as there-necked flask, add and urge
Agent 40%～50% silica gel load phosphoric acid, is heated to reflux a point water 4h～6h, be cooled to temperature be less than 10 DEG C, filter first
Filtrate, first washes with water, then washs the first filtrate with 10% sodium bicarbonate solution, and washing obtains organic faciess, and evaporated under reduced pressure has
Machine phase, obtains grease；Add diisopropyl ether in grease, stirring separates out the first solid, filters, it is preferred to use oxolane is to mistake
The first solid after filter carries out recrystallization, obtains final product.
Wherein, catalyst 40%～50% silica gel load phosphoric acid is to be obtained in advance using following synthesis techniques:
The silica gel of 40-100 mesh is placed in dimethylbenzene, adds triethylamine and zinc acetate, silica gel, triethylamine and zinc acetate
For 1:0.015～0.025:0.004～0.006, mechanical agitation heats weight ratio, and flow back to obtain the first solution；In 0.4-0.6h
Deca strong phosphoric acid in the first solution, the weight of silica gel and strong phosphoric acid ratio is for 1:0.8～1.2, after reflux water-dividing 2h～3h, cooling
To 8 DEG C～12 DEG C, sucking filtration, drying, obtain final product.
S2 synthesizes the second intermediate: the first intermediate and n- tertbutyloxycarbonyl reacting ethylenediamine obtain the second intermediate,
Second intermediate is double [(the 2-n- t-butoxycarbonyl amino ethyl) amino] benzo of n, n- tertbutyloxycarbonyl pixantrone, also known as 6,9-
[g] isoquinolin -5,10- diketone ((n-boc) pixantrone in reaction equation), first intermediate 6 of the present embodiment, 9- dihydroxy
Base benzo [g] isoquinolin -5,10- diketone and n- tertbutyloxycarbonyl reacting ethylenediamine, reaction condition is gentle, high conversion rate, impurity
Few, the second intermediate n obtaining, n- tertbutyloxycarbonyl pixantrone purity is very high.
The concrete synthesis technique of the second intermediate is as follows:
First intermediate and n- tertbutyloxycarbonyl ethylenediamine are placed in n- methyl pyrrolidone, addition potassium carbonate, first
Intermediate, n- tertbutyloxycarbonyl ethylenediamine, potassium carbonate mol ratio be 1:1.5～2.5:0.8～1.2, be heated to 55 DEG C～
65 DEG C, react 4h～6h, cooling, obtain the second solution, the second solution be slowly added in deionized water, the first intermediate and
For 1:17～23, stirring separates out the second solid to the weight of deionized water ratio, filters, it is preferred to use volume ratio be 1:1 methanol and
The mixed liquor of dichloromethane carries out recrystallization to the second solid after filtering, and obtains final product.
S3 synthesizes double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5 of 6,9-, 10- diketone 2-maleate, i.e. horse
Carry out sour pixantrone: deprotection is carried out to the second intermediate, becomes salt with maleic acid, obtain double [(2- amino-ethyl) amino] benzene of 6,9-
And [g] isoquinolin -5,10- diketone 2-maleate.The second intermediate n of the present embodiment, n- tertbutyloxycarbonyl pixantrone is in nitrogen
Deprotection under gas shielded, is directly converted into maleate by trifluoroacetate, simple to operate, effectively prevent the generation of impurity.
The concrete synthesis technique of maleic acid Pixantrone is as follows:
Under nitrogen protection, the second intermediate and trifluoracetic acid are added in dichloromethane, 11h～13h are stirred at room temperature,
Add ethanol, for dilute reaction solution, in vacuum, less than 60 DEG C at concentrating under reduced pressure, add deionized water dissolving, with 20%
Potassium hydroxide adjust ph value be 4～4.5, filter the second filtrate (main component therein be reaction equation in trifluoro vinegar
Sour pixantrone), add 3m maleic acid solution (aqueous maleic acid of 3mol/l) in the second filtrate, with 20% potassium hydroxide
It is 3.2～3.6 that solution adjusts ph value, 11h～13h is stirred at room temperature, filters to obtain the 3rd solid, using 95% ethanol to the 3rd solid
Carry out recrystallization, obtain final product.
The embodiment of the present invention provides a kind of double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone two of 6,9-
Maleate, is obtained using above-mentioned synthesis technique.
With reference to embodiments the feature and performance of the present invention is described in further detail.
Embodiment 1
Embodiment 1 provides a kind of double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone two Malaysia of 6,9-
Hydrochlorate, it synthesizes according to following processing step:
Prepare catalyst 45% silica gel load phosphoric acid: add toward in 500ml there-necked flask 40g40-100 mesh silica gel,
200ml dimethylbenzene, 0.8g triethylamine and 0.2g zinc acetate (weight of silica gel, triethylamine and zinc acetate is than for 1:0.02:
0.005), mechanical agitation heating, flow back to obtain the first solution, in 0.5h to Deca 40g strong phosphoric acid in the first solution (silica gel with dense
The weight of phosphoric acid is than for 1:1), reflux water-dividing 2.5h afterwards；It is cooled to 10 DEG C, sucking filtration, then drain after being washed twice with dimethylbenzene,
It is dried, obtain final product 72.0g45% silica gel load phosphoric acid.
Synthesize the first intermediate: by 14.9g (0.10mol, 1eq.) 3,4- pyridine anhydride, 11.0g (0.10mol, 1eq.)
Hydroquinone and 100ml hexamethylene are added in 250ml there-necked flask that (mol ratio of 3,4- picolinic acid acid anhydride and hydroquinone is
1:1), add 17.9g catalyst 45% silica gel load phosphoric acid (weight of 3,4- picolinic acid acid anhydrides and catalyst is than for 1:
1.2), it is heated to reflux a point water 5h, is cooled to less than 10 DEG C, filter to obtain the first filtrate, first respectively use 2 times first filters of 30ml water washing
Liquid, then washed once the first filtrate with 10% sodium bicarbonate solution of 30ml, the organic faciess anhydrous sodium sulfate drying obtaining, subtract
Pressure is evaporated dried organic faciess, obtains yellow oil；Add 150ml diisopropyl ether toward in grease, precipitation yellow is stirred at room temperature
First solid, filters, and washes twice filter cake with diisopropyl ether, and 60 DEG C of decompression is dried 4h, obtains 21.3g in khaki powder shape first
Solid, then with 85.2ml oxolane recrystallization, cross filter solid in 0 DEG C, obtaining 16.5g is in the first of light yellow solid powder
Mesosome, yield 67.8%, purity 98.5%.
Synthesize the second intermediate: by prepared 12.0g (0.05mol, 1eq.) first intermediate of upper step, 16.0g
(0.1mol, 2eq.) n- tertbutyloxycarbonyl ethylenediamine, 6.9g (0.05mol, 1eq.) potassium carbonate and 60ml n- methyl pyrrolidone
Add reaction bulb in (the first intermediate, n- tertbutyloxycarbonyl ethylenediamine, potassium carbonate mol ratio be 1:2:1), be heated to 60
DEG C reaction 5h, course of reaction with hplc method detect the first intermediate residual quantity, as residual rate ＜ 1%, reaction can terminate,
Obtain the second solution, treat that the second solution is slightly lowered the temperature, the second solution is poured slowly in 240ml deionized water (the first intermediate and
The weight of deionized water ratio is for 1:20), stirring separate out be in a large number royalblue the second solids, room temperature filters, and filter cake washes 3 with water
Secondary, then the mixed solvent recrystallization with 120ml methanol and dichloromethane (v/v=1:1), filter in 0～5 DEG C, obtain in the middle of second
Body, yield 80%, purity 99.5%.
Double [(2-n- t-butoxycarbonyl amino ethyl) amino] benzo [g] isoquinolin of 6,9- in gained second intermediate-
5,10- diketone are insoluble in water, and its hplc detection method is as follows:
Chromatographic column: alltima c18 4.6 × 150mm, 5um；
Mobile phase:
Flow velocity: 1.0ml/min；Wavelength: 242nm；Column temperature: 40 DEG C；Sample size: 20 μ l；
tr: 18.7min；tR (raw material): 4.3min (rrt0.23)；
Detector end time: 50min；Lc end time: 60min；
Need testing solution: 0.2mg/ml (acetonitrile).
Double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone 2-maleate of synthesis 6,9-: in nitrogen
Protection, second intermediate of the 10.6g (0.02mol, 1eq) that upper step is obtained and 23.0g (0.2mol, 10eq) trifluoracetic acid add
Enter in 106ml dichloromethane, 12h is stirred at room temperature, add 53ml ethanol, concentrating under reduced pressure at less than 60 DEG C, obtain dark blue
Color residue, after adding 42.4ml deionized water dissolving, then adjusts ph value to 4.2 with 20% potassium hydroxide, obtains navy blue
Solution, obtain the second filtrate after being removed by filtration a small amount of insoluble matter, in the second filtrate add 20ml (0.06mol, 3eq) 3m
Maleic acid solution, the potassium hydroxide solution regulation solution ph with 20% to 3.4, after 12h is stirred at room temperature, filtering must be in navy blue
The 3rd solid, with 53ml95% ethanol, recrystallization is carried out to the 3rd solid, obtains 6.5g maleic acid Pixantrone crystal, yield
58%, purity 99.7%, wherein maleic content are 40.2% (i.e. maleic acid number is 1.93).
Maleic acid Pixantrone detection method in gained maleic acid Pixantrone crystal is as follows:
Chromatographic column: alltima c18 4.6 × 150mm, 5um；
Mobile phase: 20mm sodium heptanesulfonate, is dissolved with water-acetonitrile-dioxane (75:20:5), phosphoric acid adjusts ph and is
3.0；
Flow velocity: 1.0ml/min, wavelength: 247nm, column temperature: 40 DEG C, sample size: 20 μ l,
Need testing solution: 0.5mg/ml (mobile phase)；
Run time: 60min；
In gained maleic acid Pixantrone crystal, the final detection method of maleic acid liquid content is:
Chromatographic column: inertsil ods-3 4.6 × 250mm, 5um；
Mobile phase: (0.1m sodium dihydrogen phosphate, phosphoric acid adjusts ph to 3.0)-methanol (95:5)；
Wavelength: 210nm；Flow velocity: 1ml/min；Column temperature: 35 DEG C；Sample size: 20 μ l；
Need testing solution: 0.12mg/ml (50% methanol)；
Maleic acid solution: 0.05mg/ml (50% methanol)；
tR (maleic acid): 5.5min；
Run time 15min.
Embodiment 2
Embodiment 2 provides a kind of double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone two Malaysia of 6,9-
Hydrochlorate, it synthesizes according to following processing step:
Prepare catalyst 40% silica gel load phosphoric acid: add toward in 500ml there-necked flask 40g40-100 mesh silica gel,
200ml dimethylbenzene, 0.6g triethylamine and 0.16g zinc acetate (weight of silica gel, triethylamine and zinc acetate is than for 1:0.015:
0.004), mechanical agitation heating, flow back to obtain the first solution, in 0.4h to Deca 32g strong phosphoric acid in the first solution (silica gel with dense
The weight of phosphoric acid is than for 1:0.8), reflux water-dividing 2h afterwards；It is cooled to 8 DEG C, sucking filtration, then drain after being washed twice with dimethylbenzene,
It is dried, obtain final product 70.0g 40% silica gel load phosphoric acid.
Synthesize the first intermediate: by 14.9g (0.10mol) 3,4- pyridine anhydride, 8.8g (0.08mol) hydroquinone and
100ml hexamethylene is added in 250ml there-necked flask (mol ratio of 3,4- picolinic acid acid anhydrides and hydroquinone is 1:0.8), then
Add 14.9g catalyst 40% silica gel load phosphoric acid (weight of 3,4- picolinic acid acid anhydrides and catalyst than for 1:1), be heated to reflux
Divide water 4h, be cooled to less than 10 DEG C, filter to obtain the first filtrate, first respectively use 2 the first filtrates of 30ml water washing, then with 30ml's
10% sodium bicarbonate solution washed once the first filtrate, the organic faciess anhydrous sodium sulfate drying obtaining, after evaporated under reduced pressure is dried
Organic faciess, obtain yellow oil；Add 150ml diisopropyl ether toward in grease, precipitation yellow first solid, mistake are stirred at room temperature
Filter, washes twice filter cake with diisopropyl ether, and 60 DEG C of decompression is dried 4h, obtains the first solid that 21.1g is in khaki powder shape, then uses
85.2ml oxolane recrystallization, crosses filter solid in 0 DEG C, obtains the first intermediate that 16.2g is in light yellow solid powder, yield
67.6%, purity 98.2%.
Synthesize the second intermediate: by prepared 12.0g (0.05mol) first intermediate of upper step, 16.0g (0.075mol) n-
Tertbutyloxycarbonyl ethylenediamine, 5.5g (0.04mol) potassium carbonate and 60ml n- methyl pyrrolidone add reaction bulb interior (in first
Mesosome, n- tertbutyloxycarbonyl ethylenediamine, potassium carbonate mol ratio be 1:1.5:0.8), be heated to 55 DEG C of reaction 4h, obtain the
Two solution, the second solution are poured slowly in 204ml deionized water (weight of the first intermediate and deionized water than for 1:17),
Stirring separate out be in a large number royalblue the second solids, room temperature filters, and filter cake washes with water 3 times, then with 120ml methanol and dichloromethane
The mixed solvent recrystallization of alkane (v/v=1:1), filters in 0～5 DEG C, obtains the second intermediate, yield 80%, purity 99.5%.
Double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone 2-maleate of synthesis 6,9-: in nitrogen
Protection, second intermediate of the 10.6g (0.02mol) that upper step is obtained and 23.0g (0.2mol) trifluoracetic acid are added to 106ml
In dichloromethane, 12h is stirred at room temperature, adds 53ml ethanol, concentrating under reduced pressure at less than 60 DEG C, obtain navy blue residue,
After adding 42.4ml deionized water dissolving, then adjust ph value to 4.2 with 20% potassium hydroxide, obtain navy blue solution, mistake
Obtain the second filtrate after filtering out a small amount of insoluble matter, in the second filtrate, add 20ml (0.06mol) 3m maleic acid solution, use
20% potassium hydroxide solution adjusts solution ph to 3.4, and after 11h is stirred at room temperature, filtering must be in navy blue 3rd solid, use
53ml95% ethanol carries out recrystallization to the 3rd solid, obtains 6.3g maleic acid Pixantrone crystal, yield 56%, purity 99.6%,
Wherein maleic content is 40.5%.
Embodiment 3
Embodiment 3 provides a kind of double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone two Malaysia of 6,9-
Hydrochlorate, it synthesizes according to following processing step:
Prepare catalyst 50% silica gel load phosphoric acid: add toward in 500ml there-necked flask 40g40-100 mesh silica gel,
200ml dimethylbenzene, 1g triethylamine and 0.24g zinc acetate (weight of silica gel, triethylamine and zinc acetate is than for 1:0.025:
0.006), mechanical agitation heating, flow back to obtain the first solution, in 0.6h to Deca 48g strong phosphoric acid in the first solution (silica gel with dense
The weight of phosphoric acid is than for 1:1.2), reflux water-dividing 3h afterwards；It is cooled to 12 DEG C, sucking filtration, then drain after being washed twice with dimethylbenzene,
It is dried, obtain final product 72.3g50% silica gel load phosphoric acid.
Synthesize the first intermediate: by 14.9g (0.10mol) 3,4- pyridine anhydride, 13.2g (0.12mol) hydroquinone and
100ml hexamethylene is added in 250ml there-necked flask (mol ratio of 3,4- picolinic acid acid anhydrides and hydroquinone is 1:1.2), then
Add 20.8g50% silica gel load phosphoric acid (weight of 3,4- picolinic acid acid anhydrides and catalyst than for 1:1.2), be heated to reflux a point water
6h, is cooled to less than 10 DEG C, filters to obtain the first filtrate, first respectively uses 2 the first filtrates of 30ml water washing, then 10% carbon with 30ml
Sour hydrogen sodium solution washed once the first filtrate, the organic faciess anhydrous sodium sulfate drying obtaining, and evaporated under reduced pressure is dried organic
Phase, obtains yellow oil；Add 150ml diisopropyl ether toward in grease, precipitation yellow first solid is stirred at room temperature, filters, with different
Propyl ether washes twice filter cake, and 60 DEG C of decompression is dried 4h, obtains the first solid that 21.3g is in khaki powder shape, then uses 85.2mlml
Oxolane recrystallization, crosses filter solid in 0 DEG C, obtains the first intermediate that 16.8g is in light yellow solid powder, yield
67.7%, purity 98.4%.
Synthesize the second intermediate: by prepared 12.0g (0.05mol) first intermediate of upper step, 20g (0.125mol) uncle n-
Butoxy carbonyl ethylenediamine, 8.3g (0.06mol) potassium carbonate and 60ml n- methyl pyrrolidone add reaction bulb interior (in the middle of first
Body, n- tertbutyloxycarbonyl ethylenediamine, potassium carbonate mol ratio be 1:2.5:1.2), be heated to 65 DEG C reaction 6h, obtain second
Solution, the second solution is poured slowly in 276ml deionized water (weight of the first intermediate and deionized water than for 1:23), stirs
Mix separate out be in a large number royalblue the second solids, room temperature filters, and filter cake washes with water 3 times, then with 120ml methanol and dichloromethane
(v/v=1:1) mixed solvent recrystallization, filters in 0～5 DEG C, obtains the second intermediate, yield 79%, purity 99.4%.
Double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone 2-maleate of synthesis 6,9-: in nitrogen
Protection, second intermediate of the 10.6g (0.02mol) that upper step is obtained and 23.0g (0.2mol) trifluoracetic acid are added to
In 106ml dichloromethane, 13h is stirred at room temperature, adds 53ml ethanol, concentrating under reduced pressure at less than 60 DEG C, obtain navy blue residual
Excess, after adding 42.4ml deionized water dissolving, then adjusts ph value to 4.5 with 20% potassium hydroxide, obtains navy blue molten
Liquid, obtains the second filtrate after being removed by filtration a small amount of insoluble matter, add 20ml (0.06mol) 3m maleic acid molten in the second filtrate
Liquid, the potassium hydroxide solution regulation solution ph with 20% to 3.6, after 13h is stirred at room temperature, filtering must be solid in the navy blue 3rd
Body, carries out recrystallization with 53ml95% ethanol to the 3rd solid, obtains 6.7g maleic acid Pixantrone crystal, yield 57%, purity ＞
99.6%, wherein maleic content is 40.6%.
In sum, double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5 of 6,9- of the embodiment of the present invention, 10- bis-
The product purity that the synthesis technique of ketone 2-maleate is obtained is higher than literature value, purity be more than 99.5% it is known that single impurity and
Unknown single impurity content is respectively less than 0.1%, the important intermediate stable in properties involved by this synthesis technique, is easy to store, and
And the reaction condition of this synthesis technique is gentle, simple, low cost, the industrialized production of suitable maleic acid Pixantrone.In addition it is obtained
Maleic acid Pixantrone, can be made into freeze-dried powder injection, for treatment adult recurrence refractory, aggressive non-Hodgkin′ses lymph
Tumor.
Embodiments described above is a part of embodiment of the present invention, rather than whole embodiments.The reality of the present invention
The detailed description applying example is not intended to limit the scope of claimed invention, but is merely representative of the selected enforcement of the present invention
Example.Based on the embodiment in the present invention, those of ordinary skill in the art are obtained under the premise of not making creative work
Every other embodiment, broadly falls into the scope of protection of the invention.
Claims (10)
1. the synthesis work of double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone 2-maleate of a kind of 6,9-
Skill is it is characterised in that it comprises the following steps:
3,4- picolinic acid acid anhydride and hydroquinone are reacted in the presence of catalyst, obtains the first intermediate, described catalyst
The silica gel load phosphoric acid being 40%～50% for load capacity, described first intermediate is 6,9- dihydroxy benzo [g] isoquinolin -5,
10- diketone；
By described first intermediate and n- tertbutyloxycarbonyl reacting ethylenediamine, obtain the second intermediate, described second intermediate is
N, n- tertbutyloxycarbonyl pixantrone；
Deprotection is carried out to described second intermediate, becomes salt with maleic acid, obtain double [(2- amino-ethyl) amino] benzo of 6,9-
[g] isoquinolin -5,10- diketone 2-maleate.
2. double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone two horse of 6,9- according to claim 1
Carry out the synthesis technique of hydrochlorate it is characterised in that described 3,4- picolinic acid acid anhydride and described hydroquinone mol ratio be 1:0.8～
1.2；The weight of described 3,4- picolinic acid acid anhydride and described catalyst is than for 1:1～1.4.
3. double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone two horse of 6,9- according to claim 1
Carry out the synthesis technique of hydrochlorate it is characterised in that the concrete preparation process of described catalyst is:
The silica gel of 40-100 mesh is placed in dimethylbenzene, adds triethylamine and zinc acetate, described silica gel, described triethylamine and described
Than for 1:0.015～0.025:0.004～0.006, agitating heating, flow back to obtain the weight of zinc acetate the first solution；In 0.4h-
In 0.6h in described first solution Deca strong phosphoric acid, the weight of described silica gel and described strong phosphoric acid ratio for 1:0.8～1.2, returns
After flow point water 2h～3h, it is cooled to 8 DEG C～12 DEG C, sucking filtration, drying, obtain final product.
4. double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone two horse of 6,9- according to claim 1
Carry out the synthesis technique of hydrochlorate it is characterised in that the concrete synthesis technique of described first intermediate is:
Add described 3,4- pyridine anhydride, described hydroquinone and hexamethylene in a reservoir, add described catalyst, heat back
Flow point water 4h～6h, is cooled to temperature and is less than 10 DEG C, filter to obtain the first filtrate, washs described first filtrate and obtains organic faciess,
Decompression organic faciess, obtain grease；Add diisopropyl ether in described grease, stirring separates out the first solid, filters, recrystallization, that is,
?.
5. double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone two horse of 6,9- according to claim 4
Carry out the synthesis technique of hydrochlorate it is characterised in that recrystallization is carried out to described first solid after filtering using oxolane.
6. double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone two horse of 6,9- according to claim 1
Carry out the synthesis technique of hydrochlorate it is characterised in that the concrete synthesis technique of described second intermediate is:
Described first intermediate and n- tertbutyloxycarbonyl ethylenediamine are placed in n- methyl pyrrolidone, add potassium carbonate, described
The mol ratio of the first intermediate, described n- tertbutyloxycarbonyl ethylenediamine and described potassium carbonate is 1:1.5～2.5:0.8～1.2, plus
Heat, to 55 DEG C～65 DEG C, is reacted 4h～6h, cooling, is obtained the second solution, described second solution is added in deionized water, institute
State the weight of the first intermediate and described deionized water ratio for 1:17～23, stirring separates out the second solid, filters, recrystallization, that is,
?.
7. double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone two horse of 6,9- according to claim 6
Carry out the synthesis technique of hydrochlorate it is characterised in that be the methanol of 1:1 and dichloromethane using volume ratio mixed liquor to filtering after
Described second solid carries out recrystallization.
8. double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone two horse of 6,9- according to claim 1
Carry out the synthesis technique of hydrochlorate it is characterised in that double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5 of described 6,9-, 10- bis-
The concrete synthesis technique of ketone 2-maleate is:
Under nitrogen protection, described second intermediate and trifluoracetic acid are added in dichloromethane, 11h～13h are stirred at room temperature,
Add ethanol, concentrating under reduced pressure at less than 60 DEG C, add deionized water dissolving, adjust ph value be 4～4.5, filter second
Filtrate, adds 3m maleic acid solution in described second filtrate, and adjusting ph value is 3.2～3.6, stirs 11h～13h, filters
3rd solid, recrystallization, obtain final product.
9. double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5,10- diketone two horse of 6,9- according to claim 8
Carry out the synthesis technique of hydrochlorate it is characterised in that recrystallization is carried out to described 3rd solid using 95% ethanol.
10. one kind 6, double [(2- amino-ethyl) amino] benzo [g] isoquinolin -5 of 9-, 10- diketone 2-maleate, its feature exists
In: it is obtained using the synthesis technique as described in any one of claim 1 to 9.
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| US11530215B2 (en) | 2018-06-18 | 2022-12-20 | Elc Management Llc | Photostabilizing compounds, compositions, and methods |
| US11655215B2 (en) | 2018-06-18 | 2023-05-23 | Elc Management Llc | Photostabilizing compounds, compositions, and methods |
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| CN110873765B (en) * | 2018-09-04 | 2022-05-17 | 北京凯莱天成医药科技有限公司 | Detection method of pixantrone maleate related substance |
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