CN106008267B - A kind of preparation method of cancer therapy drug Vorinostat - Google Patents
A kind of preparation method of cancer therapy drug Vorinostat Download PDFInfo
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- CN106008267B CN106008267B CN201610486703.9A CN201610486703A CN106008267B CN 106008267 B CN106008267 B CN 106008267B CN 201610486703 A CN201610486703 A CN 201610486703A CN 106008267 B CN106008267 B CN 106008267B
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- suberic acid
- vorinostat
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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Abstract
The invention discloses a kind of preparation method of cancer therapy drug Vorinostat, this method comprises the following steps：1) hydrophilic substrate is contacted to progress self assembly with suberic acid and obtains suberic acid substrate self-assembled film；2) in the presence of 1,3 dicyclohexylcarbodiimide, suberic acid substrate self-assembled film is contacted in THF with hydroxylamine hydrochloride, reaction terminates, and adds 4M HCl solution stirring reactions, and dichloromethane extracts to obtain the carboxyl heptamide of N hydroxyls 7；3) in the presence of 1,3 dicyclohexylcarbodiimide and alkali, the carboxyl heptamide of N hydroxyls 7 obtains Vorinostat with aniline reaction.The preparation method of Vorinostat provided by the invention provides the new route of synthesis of Vorinostat.Good using the method provided by the invention for preparing Vorinostat, mild condition, selectivity, the time of reaction is particularly to be substantially reduced with the time of aniline Amideization reaction, while the yield of Vorinostat greatly improves.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, in particular it relates to a kind of preparation method of cancer therapy drug Vorinostat.
Background technology
Vorinostat (Vorinostat), in October, 2006 list in the U.S., are first suppression deacetylase protein base enzymes
New anticancer drug, it can by Cell differentiation inducing activity, block cell cycle, inducing cell regulation and control play a role.Specifically
Structural formula is as follows：
Synthetic method at present on Vorinostat is a lot, mostly using suberic anhydride or suberic acid and aniline open loop acid amides
Change obtains suberic acid monoanilide, and then resterification, hydroxylamine hydrochloride aminolysis obtain.But all exist in these methods yield it is low,
The problems such as reaction time is long, and reaction condition is quite harsh.Such as J.Med.Chem., 1995,38 (9):1411-1413 is reported
The method in road, first diacid reacts with aniline, KOH under 190 degree of high temperature is made suberic acid monoamides；Passing through ion exchange resin
22h is esterified, obtains suberic acid monoanilide methyl esters, is then obtained within 26 hours with hydroxylamine hydrochloride aminolysis, reaction again, total recovery only has
35% or so, and, it is apparent that severe reaction conditions (high temperature), the problems such as reaction time is long.
A kind of method for preparing Vorinostat is disclosed in CN102264694B, this method includes preparing Vorinostat
Two kinds of approach, one kind is first to make suberic acid and aniline or its reactant salt in the presence of coupling agent, to form octanoyl aniline acid
And the octanoyl aniline acid is set to obtain Vorinostat with azanol or its reactant salt；Another way is first under action of coupling agents
Suberic acid obtains suberic acid list acyl azanol with hydroxylamine hydrochloride, then obtains Vorinostat with aniline reaction again.Although this method is adopted
Certain selectivity is realized with the combination of special coupling agent, improves the yield of Vorinostat, but this method Vorinostat
Yield is still very low, the reaction time be particularly it is especially long with reaction time of aniline Amide, in addition, Vorinostat purity compared with
It is low, it is necessary to can be only achieved medicinal requirements by especially purifying.
Therefore, this area needs that a kind of reaction time is short, selectivity is good and the method for preparing Vorinostat of high income badly.
The content of the invention
It is an object of the invention to overcome reaction time length, poor selectivity, production in the existing method for preparing Vorinostat
The defects of product yield is low, there is provided a kind of suitable reaction time is short, selectivity is got well and the preparation method of the Vorinostat of high income.
Make it that yield is low without selectivity because suberic acid reacts two carboxyls in the preparation of Vorinostat, prior art
In, be all by adjusting reaction condition or being adjusted using special coupling agent so as to control the reaction of suberic acid mono carboxylic, and
, can be from solving the problems, such as reaction selectivity at all by the way that a carboxyl in suberic acid is modified.The invention of the present invention
People has found under study for action, the modification of single carboxyl can be realized by the way that suberic acid and hydrophilic substrate are carried out into self assembly, so as to control
System is reacted selective, and then improves the yield of Vorinostat.
To achieve these goals, the present invention provides a kind of method for preparing cancer therapy drug Vorinostat, and this method includes
Following steps：
1) hydrophilic substrate is contacted to progress self assembly with suberic acid and obtains suberic acid-substrate self-assembled film；
2) in the presence of 1,3- dicyclohexylcarbodiimides, by suberic acid-substrate self-assembled film and hydroxylamine hydrochloride in THF
Contact, reaction terminate, and add 4M HCl solution stirring reactions, and dichloromethane extracts to obtain N- hydroxyls -7- carboxyls-heptamide；
3) N- hydroxyls -7- carboxyls-heptamide is with reacting to obtain Vorinostat.
In the case of in the present invention, it is preferred to, the detailed process of self assembly includes：Hydrophilic substrate is added to the nothing of suberic acid
In the solution of water-toluene, 45~60 DEG C of insulation reactions 8~12 hours, then take out substrate, wash, produce suberic acid-substrate from
Assembling film.
It is in order that more regular derived from assembling, it is preferable that the solution concentration of the dry toluene of suberic acid is 1 × 10-2~1 ×
10-6mol/L；It is further preferred that the solution concentration of the dry toluene of suberic acid is 1 × 10-3mol/L。
In the present invention, in order that Atom economy must be improved, it is preferable that in step 2), per cm2Hydrophilic substrate, benzene
The dosage of amine is 2~4mmol, and the dosage of 1,3- dicyclohexylcarbodiimide is 1~2mmol.
In the present invention, the hydrophilic substrate is preferably the silicon chip, quartz plate or sheet glass of hydrophilic treated.
It is not particularly limited for hydrophilic treated, such as the process of the hydrophilic treated includes：By the base of well cutting
Piece (silicon chip, quartz plate or sheet glass) is placed in strong acid mixed solution (H2SO4/HNO3, volume ratio 1:1), 90 DEG C are boiled 1 hour, then
Stand to normal temperature and clean up simultaneously ultrasound 15 minutes with deionized water, be then stored in deionized water.
In the present invention, the preparation of step 3) Vorinostat is referred to the conventional method in this area, for example, by N- hydroxyls-
7- carboxyls-heptamide is dissolved in absolute ethyl alcohol, then add 1,3- dicyclohexylcarbodiimides (2~5eq), aniline (1~5eq),
Potassium hydroxide (2~8eq), 40~60 DEG C, insulated and stirred 30min are heated to, after completion of the reaction, reaction solution concentration, are poured into water,
Filtering, washing, is dried in vacuo to obtain Vorinostat Vorinostat.
In the present invention, the dry toluene used is referred to this area conventional technology and handled, and chooses new
The dry toluene of processing, such as the backflow of sodium silk can be added, benzophenone makees indicator, when solution becomes navy blue, steams i.e.
With.
In the present invention, the conventional method in this area can be used to be monitored tracking to reacting, such as TLC, LCMS,
GCMS etc., reaction finish refer to TLC monitor not excess raw material disappeared or LCMS, GCMS in not excess raw material residue be less than
2%.
The preparation method of Vorinostat provided by the invention provides the new route of synthesis of Vorinostat.Carried using the present invention
The method for preparing Vorinostat supplied, mild condition, selectivity is good, time of reaction be particularly with aniline Amideization reaction when
Between substantially reduce, while the yield of Vorinostat greatly improves.
For beneficial effect acquired by the present invention, inventor thinks that suberic acid interacts with hydrophilic substrate, carboxyl and base
Hydrophilic OH functional group reactionses form new interface on piece, promote the self assembly of suberic acid, so as to complete the present invention, on deeper
The mechanism of one step, during inventor just explores.
Other features and advantages of the present invention will be described in detail in subsequent specific embodiment part..
Embodiment
With reference to specific embodiment, the present invention is expanded on further.But these embodiments be only limitted to explanation the present invention without
It is the further restriction to protection scope of the present invention.
Embodiment 1
The preparation of suberic acid-substrate self-assembled film
The hydrophilic treated of quartz plate：The substrate (quartz plate, 10cm × 10cm) of well cutting is placed in strong acid mixed solution
(H2SO4/HNO3, volume ratio 1:1), 90 DEG C are boiled 1 hour, are then stood to normal temperature and are cleaned up simultaneously 15 points of ultrasound with deionized water
Clock, obtain hydrophilic substrate and be stored in deionized water, it is stand-by.
The detailed process of self assembly includes：Hydrophilic substrate is added in the solution of the dry toluene of suberic acid, 50 DEG C of guarantors
Temperature reaction 10 hours, then takes out substrate, washes, produces suberic acid-substrate self-assembled film.The solution of the dry toluene of suberic acid
Concentration is 1 × 10-3mol/L。
Embodiment 2
The preparation of suberic acid-substrate self-assembled film
The hydrophilic treated of quartz plate：The substrate (silicon chip, 10cm × 10cm) of well cutting is placed in strong acid mixed solution
(H2SO4/HNO3, volume ratio 1:1), 90 DEG C are boiled 1 hour, are then stood to normal temperature and are cleaned up simultaneously 15 points of ultrasound with deionized water
Clock, obtain hydrophilic substrate and be stored in deionized water, it is stand-by.
The detailed process of self assembly includes：Hydrophilic substrate is added in the solution of the dry toluene of suberic acid, 60 DEG C of guarantors
Temperature reaction 8 hours, then takes out substrate, washes, produces suberic acid-substrate self-assembled film.The solution of the dry toluene of suberic acid
Concentration is 1 × 10-4mol/L。
Embodiment 3
The preparation of suberic acid-substrate self-assembled film
The hydrophilic treated of quartz plate：The substrate (sheet glass, 10cm × 10cm) of well cutting is placed in strong acid mixed solution
(H2SO4/HNO3, volume ratio 1:1), 90 DEG C are boiled 1 hour, are then stood to normal temperature and are cleaned up simultaneously 15 points of ultrasound with deionized water
Clock, obtain hydrophilic substrate and be stored in deionized water, it is stand-by.
The detailed process of self assembly includes：Hydrophilic substrate is added in the solution of the dry toluene of suberic acid, 45 DEG C of guarantors
Temperature reaction 10 hours, then takes out substrate, washes, produces suberic acid-substrate self-assembled film.The solution of the dry toluene of suberic acid
Concentration is 1 × 10-3mol/L。
Embodiment 4
The preparation of N- hydroxyls -7- carboxyls-heptamide
The suberic acid that embodiment 1 is obtained-substrate self-assembled film, 1,3- dicyclohexylcarbodiimides 43.2g (210mmol)
And hydroxylamine hydrochloride 18.4g (265mmol) is added to haptoreaction in 100ml THF, reaction terminates, and adds 150ml 4M HCl
Solution stirring reaction, dichloromethane extraction, washing, dry N- hydroxyls -7- carboxyls-heptamide 18.3g, yield 92.3%,
Purity 99.70%；Yield calculates feeding intake for the suberic acid based on reaction, suberic acid input 34.8g, reclaims 16.5g.
Embodiment 5
The preparation of N- hydroxyls -7- carboxyls-heptamide
The suberic acid that embodiment 2 is obtained-substrate self-assembled film, 1,3- dicyclohexylcarbodiimides 21.6g (105mmol)
And hydroxylamine hydrochloride 14.3g (206mmol) is added to haptoreaction in 100ml THF, reaction terminates, and adds 150ml 4M HCl
Solution stirring reaction, dichloromethane extraction, washing, dry N- hydroxyls -7- carboxyls-heptamide 17.5g, yield 89.7%,
Purity 99.53%；Yield calculates feeding intake for the suberic acid based on reaction, suberic acid input 34.8g, reclaims 16.8g.
Embodiment 6
The preparation of N- hydroxyls -7- carboxyls-heptamide
The suberic acid that embodiment 3 is obtained-substrate self-assembled film, 1,3- dicyclohexylcarbodiimides 31.2g (151mmol)
And hydroxylamine hydrochloride 28.1g (405mmol) is added to haptoreaction in 100ml THF, reaction terminates, and adds 150ml 4M HCl
Solution stirring reaction, dichloromethane extraction, washing, dry N- hydroxyls -7- carboxyls-heptamide 17.4g, yield 90.9%,
Purity 99.49%；Yield calculates feeding intake for the suberic acid based on reaction, suberic acid input 34.8g, reclaims 17.2g.
Embodiment 7
The preparation of Vorinostat
N- hydroxyls -7- carboxyls-heptamide 3.8g (20mmol) is dissolved in 20ml absolute ethyl alcohols, then adds the hexamethylenes of 1,3- bis-
Base carbodiimide 16.5g (80mmol), aniline 6.5g (70mmol), potassium hydroxide 5.6g (100mmol), 50 DEG C are heated to, protected
Temperature stirring 30min, after completion of the reaction, reaction solution concentration, it is poured into water, filters, washing, be dried in vacuo to obtain Vorinostat Fu Linuo
He is 4.4g, yield 82.4%, purity 99.52%.
Comparative example 1
It is specific as follows such as the method for preparing Vorinostat of embodiment 1 in CN102264694B：
1st stage：Suberic acid is converted into octanoyl aniline acid
Stirred 1 hour in 25 DEG C of mixtures by the CDI (0.5eq) in THF (15vol) and DCC (0.8eq).Add THF
Suberic acid 17.8g (1eq) and aniline (1eq) in (1vol) are simultaneously stirred for mixture 18 hours.It is filtered to remove solid by-product
And it is concentrated in vacuo filtrate at 50 DEG C.With KOH (2eq) in water (10vol) solution processing obtain solid residue and
Stirred 30 minutes at 30 DEG C, be then filtered to remove any solid by-product to be formed.The filtrate obtained is heated at 60 DEG C 4 hours simultaneously
20 DEG C are cooled to before HCl/water solution (17.5%, 3vol) is added.Stir mixture 30 minutes and cross filter solid, use
Water (2 × 5vol) is washed and is dried in vacuo at 60 DEG C.Purity=99.42% that molar yield=54.6%, HPLC measures.
2nd stage：Octanoyl aniline acid changes into thick Vorinostat
The octanoyl aniline acid (leq) obtained in the 1st stage is dissolved in DMF (5vol) at 25 DEG C and adds CDI
(2eq), then it is incubated 30 minutes under agitation.Add hydroxylamine hydrochloride (4eq) and continue stirring 30 minutes.Then water is added
(25vol) and stir mixture 2 hours.The solid of precipitation is filtered, is washed with water (2 × 5vol), then vacuum is done at 50 DEG C
It is dry.Purity=98.75% that molar yield=71.2%, HPLC measures.
3rd stage：The purifying of thick Vorinostat
Ammoniacal liquor (2.5vol) is added into the thick Vorinostat (l eq) in acetonitrile (l5vol) at 30 DEG C.Then cold
But mixture is incubated 1 hour at 55 DEG C with before being stirred for 1 hour to 25 DEG C.Filter obtain solid, with acetonitrile (2 ×
0.5vol) wash, and be dried in vacuo 5 hours at 50 DEG C.Purity >=99.8% that molar yield=52.1%, HPLC measures.
Comparative example 2
Such as the preparation method of N- hydroxyls -7- carboxyls-heptamide in embodiment 4, except that, use 18.3g pungent two
Acid substitutes suberic acid-substrate self-assembled film, obtains N- hydroxyls -7- carboxyls-heptamide 8.2g, yield 41.5%, purity
97.80%.
The preferred embodiment of the present invention described in detail above, still, the present invention are not limited in above-mentioned embodiment
Detail, in the range of the technology design of the present invention, a variety of simple variants can be carried out to technical scheme, this
A little simple variants belong to protection scope of the present invention.
It is further to note that each particular technique feature described in above-mentioned embodiment, in not lance
In the case of shield, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention to it is various can
The combination of energy no longer separately illustrates.In addition, any group can also be carried out between a variety of embodiments of the present invention
Close, as long as it without prejudice to the thought of the present invention, it should equally be considered as content disclosed in this invention.
Claims (5)
1. a kind of preparation method of cancer therapy drug Vorinostat, it is characterised in that the preparation method comprises the following steps：
1）Hydrophilic substrate is contacted into progress self assembly with suberic acid and obtains suberic acid-substrate self-assembled film；
2）In the presence of 1,3- dicyclohexylcarbodiimides, suberic acid-substrate self-assembled film is connect in THF with hydroxylamine hydrochloride
Touch, reaction terminates, and adds 4M HCl solution stirring reactions, and dichloromethane extracts to obtain N- hydroxyls -7- carboxyls-heptamide；
3）In the presence of 1,3- dicyclohexylcarbodiimides and alkali, N- hydroxyls -7- carboxyls-heptamide and aniline reaction get Fu Li
Promise he；
In step 1）In, the detailed process of self assembly includes：Hydrophilic substrate is added in the solution of the dry toluene of suberic acid,
45 ~ 60 DEG C of insulation reactions 8 ~ 12 hours, then take out substrate, wash, produce suberic acid-substrate self-assembled film；The hydrophilic group
Piece is silicon chip, quartz plate or the sheet glass of hydrophilic treated；The process of the hydrophilic treated includes：By the silicon chip of well cutting, quartz
Piece or sheet glass are placed in volume ratio as 1:1 H2SO4/HNO3Strong acid mixed solution, 90 DEG C are boiled 1 hour, are then stood to normal temperature and are used
Deionized water cleans up simultaneously ultrasound 15 minutes, is then stored in deionized water.
2. preparation method according to claim 1, it is characterised in that the solution concentration of the dry toluene of suberic acid be 1 ×
10-2~1×10-6mol/L。
3. preparation method according to claim 2, it is characterised in that the solution concentration of the dry toluene of suberic acid be 1 ×
10-3mol/L。
4. preparation method according to claim 1, it is characterised in that in step 2）In, per cm2Hydrophilic substrate, hydroxylamine hydrochloride
Dosage be 2 ~ 4mmol, the dosage of 1,3- dicyclohexylcarbodiimide is 1 ~ 2mmol.
5. preparation method according to claim 1, it is characterised in that N- hydroxyls -7- carboxyls-heptamide and aniline, 1,3-
Dicyclohexylcarbodiimide, alkali dosage mol ratio be 1:1~5:2~5:2 ~ 8, the alkali is sodium hydroxide or potassium hydroxide.
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| CN201610486703.9A CN106008267B (en) | 2016-06-27 | 2016-06-27 | A kind of preparation method of cancer therapy drug Vorinostat |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| AU2009305214B2 (en) * | 2008-10-15 | 2015-06-25 | Generics [Uk] Limited | Process for the preparation of vorinostat |
| EP2531185A2 (en) * | 2010-02-02 | 2012-12-12 | Board Of Regents, The University Of Texas System | Combination therapy for treating cancer comprising an igf-1r inhibitor and an hdac inhibitor |
| CN104292133B (en) * | 2014-09-29 | 2016-06-01 | 烟台市华文欣欣医药科技有限公司 | The synthetic method of a kind of cancer therapy drug Vorinostat |
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