CN102718709A - Novel method for preparing amonafide - Google Patents
Novel method for preparing amonafide Download PDFInfo
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- CN102718709A CN102718709A CN2011100787155A CN201110078715A CN102718709A CN 102718709 A CN102718709 A CN 102718709A CN 2011100787155 A CN2011100787155 A CN 2011100787155A CN 201110078715 A CN201110078715 A CN 201110078715A CN 102718709 A CN102718709 A CN 102718709A
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- amonafide
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- 0 CN(C)CCN(C(c1c2c3cc([*+])cc2ccc1)=O)C3=O Chemical compound CN(C)CCN(C(c1c2c3cc([*+])cc2ccc1)=O)C3=O 0.000 description 2
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Abstract
The invention discloses a novel method for preparing a compound amonafide (I). According to the method, a compound (II) which used as a raw material, hydrazine or hydrazine hydrate which is used as a hydrogen source and a water-miscible organic solvent which is used as a medium undergo a reaction under the action of a catalyst to prepare the compound (I).
Description
Technical field
The present invention relates to a kind of preparation compound (
I)Novel method.
Background technology
Compound (
I)Be the L MALIC ACID salt of amonafide, chemistry 5-amino-2-(2-(dimethylamino)-ethyl) by name-1H-benzo [
DE] isoquinoline 99.9-1,3 (2
H)-diketone
L MALIC ACID (Amonafide
L-malate).
The L type malate of amonafide is that it can go between the base pair of DNA in intercalation by the compound that is used to treat cancer of Antisoma development, and the RNA's of inhibition DNA is synthetic, and suppresses topoisomerase
IIThereby, reach the purpose that suppresses growth of tumour cell.
Synthetic about amonafide and L type malate thereof, following two kinds of methods:
The compound method of patent US20040082788 is as follows:
This method adopts DMF and methyl alcohol to make solvent from patent US20040082788, uses ammonium formiate to make hydrogen source, and raw material Mitonafide reduces under the katalysis of palladium carbon and generates title product.Describe according to patent, this reaction drops into raw material 266 g, but obtains product 399 g, and yield reaches 160 %.To this situation, my company has carried out simulation to document and has reappeared.
We find in actual tests, and the solubleness of raw material Mitonafide in common solvent is relatively poor, has used the stronger DMF of dissolving power to make solvent in the patent.Yet the result who causes like this is, the DMF during reaction in the system is generated a large amount of n n dimetylaniline by catalyst reduction, causes the catalytic efficiency (of catalyzer to descend greatly, and causing feedstock conversion is that the speed of title product is slower.
Through the reductive product is the Amonafide free alkali; Need again further and the L MALIC ACID salify; Usually for salify fully need add excessive acid, because reduction back compound amino is more, the salify mode is various; Be difficult to control the preparation of monomolecular L-type malate, thereby cause the product can't quantitative Analysis and use.So this method still has certain defective on reaction principle.
Then mentioned other a kind of preparation method among the US6693198, reaction formula is following:
This reaction adopts the L MALIC ACID salt of Mitonafide to make raw material, and hydrogen is made hydrogen source, makes water as reaction solvent, synthesis under normal pressure 12h, and product is through decolouring, temperature control crystallization and recrystallization operation, and yield is 68%.See from operating procedure; This reaction uses the L MALIC ACID salt of Mitonafide to make starting raw material; Avoided Mitonafide to reduce salify then separately, possibly cause salify number situation more rambunctious, and solvability has been better behind the raw material Mitonafide salify; Be convenient to this reaction and use water as solvent, also comparatively environmental protection.Weak point is that this reaction uses hydrogen to make hydrogen source, and industrialization has certain restriction, and simultaneously, post-processing operation is comparatively loaded down with trivial details, causes efficient low, and cost is higher.
Summary of the invention
The object of the present invention is to provide a kind of method that comparatively simply prepares amonafide L type malate.This method is used source reagent and solvent comparatively widely, and is easy to operate.
The present invention avoids hydrogen as source of the gas, according to pertinent literature, adopts hydrazine or Hydrazine Hydrate 80 to make hydrogen source; Secondly, raw material is the nitro-compound of indissoluble comparatively, in order to reach the homogeneous phase of reaction, simultaneously for salifiable convenience, adopts first salify, and back reductive mode is carried out.This method is through the actually operating checking, and confirmation can be passed through highly effective reaction, prepares target compound.Concrete route is formula as follows:
The present invention need not separate with Mitonafide and L MALIC ACID first salify in the organic solution that can dissolve each other with water, directly in reaction system, adds Hydrazine Hydrate 80 or hydrazine, adds catalyzer then, and the one kettle way reaction obtains title product.Aftertreatment concentrated solvent, bullion use the ETHYLE ACETATE washing, use ethyl alcohol recrystallization then, can obtain the higher title product of purity.
Wherein used and the miscible organic solvent of water refer to one or more in methyl alcohol, ethanol, Virahol, propyl carbinol, the THF, wherein preferred alcohol.
Used catalyzer is nickel system or palladium series catalyst, preferred Raney nickel or 10% palladium Kohlenhydrate.
Temperature of reaction is controlled to be 0 ℃ of system reflux temperature extremely, preferred 45-55 ℃.
The practical implementation instance
Following embodiment is to specify the present invention, but should not be construed as limiting the invention.
Embodiment: 5-amino-2-(2-(dimethylamino)-ethyl)-1H-benzo [
DE] isoquinoline 99.9-1,3 (2
H)-diketone
Synthesizing of L MALIC ACID salt.
Embodiment one
In the 100mL there-necked flask, add 5.0 g Mitonafide, add 50mL ethanol, agitation condition adds 2.4 g L MALIC ACIDs down; Back flow reaction 30min, cooling adds 6 mL, 50% Hydrazine Hydrate 80 in reaction system; Add 0.2 g, 10% palladium Kohlenhydrate then, 50 ℃ of reaction 4h react completely.Stopped reaction, suction filtration, filtrating is revolved dried, obtains brown solid, and add a small amount of Virahol and stir, suction filtration, filter cake uses the alcohol-water recrystallization, obtains yellow crystal property solid, and filter cake obtains yellow solid 5.6 g, yield 84% in 55 ℃ of dry 4h of vacuum.mp.182.3-184.5℃。
1H?NMR?(D
2O,?ppm)?δ?2.83?(d,?2H,?malate-CH
2),?3.14
(s,?6H,?N,N-(CH
3)
2),?3.68～3.76?(m,?2H,?imido-N-CH
2),?4.56～4.67?(m,?3H,?amino-N-CH
2?and?malate-CH),?7.35～8.26?(m,?5H,?Ar-H)。LC-MS：418.4，[M+1]
+。
Embodiment two
In the 100mL there-necked flask, add 5.0 g Mitonafide, add 50mL ethanol and make solvent, agitation condition adds 2.4 g L MALIC ACIDs down; Back flow reaction 30min, cooling adds 6 mL, 50% Hydrazine Hydrate 80 in reaction system; Add 0.5 g Raney nickel then, back flow reaction 4h reacts completely.Stopped reaction, suction filtration, concentrated filtrate obtains the light brown solid, adds a small amount of Virahol agitator treating, suction filtration, filter cake uses the alcohol-water recrystallization, and suction filtration obtains yellow crystal property solid, and filter cake obtains product 5.3 g, yield 79% in 55 ℃ of dry 4h of vacuum.mp.184.1-185.9?℃。
1H?NMR?(D
2O,?ppm)?δ?2.85?(d,?2H,?malate-CH
2),?3.16?(s,?6H,?N,N-
(CH
3)
2),?3.65～3.76?(m,?2H,?imido-N-CH
2),?4.56～4.67?(m,?3H,?amino-N-CH
2?and?malate-CH),?7.33～8.25?(m,?5H,?Ar-H)。LC-MS：418.4，[M+1]
+。
Embodiment three
In the 100mL there-necked flask, add 5.0 g Mitonafide, add 50mL ethanol and make solvent, agitation condition adds 2.4 g L MALIC ACIDs down; Back flow reaction 30min; Cooling adds 6 mL, 50% Hydrazine Hydrate 80 in reaction system, add 0.2 g, 10% palladium Kohlenhydrate then; Room temperature reaction 10h, TLC show that the raw material primitive reaction is complete.Stopped reaction, suction filtration, filtrating is revolved dried, obtains brown solid; Add a small amount of Virahol making beating, suction filtration, filter cake uses the alcohol-water recrystallization, obtains yellow crystal property solid; Suction filtration, filter cake obtains safran solid product 5.0 g in 55 ℃ of dry 4h of vacuum, yield 75 %.mp.183.3-185.4?℃。
1H?NMR?(D
2O,?ppm)?δ?2.81?(d,?2H,?malate-CH
2),?3.17?(s,?6H,?N,N-(CH
3)
2),?3.65～3.74?(m,?2H,?imido-N-CH
2),?4.56～4.66?(m,?3H,?amino-N-CH
2?and?malate-CH),?7.31～8.25?(m,?5H,?Ar-H)。LC-MS：418.4，[M+1]
+。
Embodiment four
In the 100mL there-necked flask, add 5.0 g Mitonafide, add 50mL methyl alcohol and make solvent, agitation condition adds 2.4 g L MALIC ACIDs down; Back flow reaction 30min; Cooling adds 6 mL, 50% Hydrazine Hydrate 80 in reaction system, add 0.2 g, 10% palladium Kohlenhydrate then; Room temperature reaction 10h, TLC show that the raw material primitive reaction is complete.Stopped reaction, suction filtration, filtrating is revolved dried, obtains yellow solid, adds a small amount of Virahol making beating, suction filtration, filter cake uses the alcohol-water recrystallization, obtains crystalline solid, suction filtration, filter cake obtains light yellow solid 4.2 g in 55 ℃ of dry 4h of vacuum, yield 63 %.mp.179.2-182.7℃。
Claims (6)
- One kind prepare the compound amonafide ( I) novel method, it is characterized in that, with compound ( II) be raw material, be hydrogen source with hydrazine or Hydrazine Hydrate 80, being medium with the miscible organic solvent of water, preparation compound under the effect of catalyzer ( I)
。
- 2. preparation method according to claim 1 is characterized in that, described can be in methyl alcohol, ethanol, Virahol, propyl carbinol, the THF one or more with the miscible organic solvent of water.
- 3. preparation method according to claim 1 is characterized in that, described catalyzer is nickel catalyst or palladium series catalyst.
- 4. preparation method according to claim 2 is characterized in that, described organic solvent is an ethanol.
- 5. preparation method according to claim 3 is characterized in that, catalyzer is the palladium carbon of Raney nickel or 10%.
- 6. preparation method according to claim 1 is characterized in that, temperature of reaction is 45-55 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100787155A CN102718709A (en) | 2011-03-30 | 2011-03-30 | Novel method for preparing amonafide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100787155A CN102718709A (en) | 2011-03-30 | 2011-03-30 | Novel method for preparing amonafide |
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| Publication Number | Publication Date |
|---|---|
| CN102718709A true CN102718709A (en) | 2012-10-10 |
Family
ID=46944611
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011100787155A Pending CN102718709A (en) | 2011-03-30 | 2011-03-30 | Novel method for preparing amonafide |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030203932A1 (en) * | 2002-04-22 | 2003-10-30 | Xanthus Life Sciences, Inc. | Amonafide salts |
| US20040082788A1 (en) * | 2002-07-08 | 2004-04-29 | Chemgenex Therapeutics, Inc. | Naphthalimide synthesis including amonafide synthesis and pharmaceutical preparations thereof |
| US20050239816A1 (en) * | 2002-04-22 | 2005-10-27 | Xanthus Life Sciences, Inc. | Amonafide salts |
| CN101479247A (en) * | 2006-05-05 | 2009-07-08 | 尤尼拜欧斯克林股份公司 | 5-urea substituted naphthalimide derivatives, methods of production and pharmaceutical compositions for treating cancer |
-
2011
- 2011-03-30 CN CN2011100787155A patent/CN102718709A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030203932A1 (en) * | 2002-04-22 | 2003-10-30 | Xanthus Life Sciences, Inc. | Amonafide salts |
| US20050239816A1 (en) * | 2002-04-22 | 2005-10-27 | Xanthus Life Sciences, Inc. | Amonafide salts |
| US20040082788A1 (en) * | 2002-07-08 | 2004-04-29 | Chemgenex Therapeutics, Inc. | Naphthalimide synthesis including amonafide synthesis and pharmaceutical preparations thereof |
| CN101479247A (en) * | 2006-05-05 | 2009-07-08 | 尤尼拜欧斯克林股份公司 | 5-urea substituted naphthalimide derivatives, methods of production and pharmaceutical compositions for treating cancer |
Non-Patent Citations (1)
| Title |
|---|
| 吕荣文，等: "水合脐还原对硝基乙酰苯胺的研究", 《染料与染色》 * |
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Application publication date: 20121010 |