CN106674080A - Synthesis method of panobinostat - Google Patents

Synthesis method of panobinostat Download PDF

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Publication number
CN106674080A
CN106674080A CN201510776391.0A CN201510776391A CN106674080A CN 106674080 A CN106674080 A CN 106674080A CN 201510776391 A CN201510776391 A CN 201510776391A CN 106674080 A CN106674080 A CN 106674080A
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methyl
indole
amino
phenyl
ethyl
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许永翔
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Nanjing Cavendish Bio Engineering Technology Co Ltd
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Nanjing Cavendish Bio Engineering Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)

Abstract

The invention discloses a synthesis method of panobinostat. The method comprises the following steps: by using 2-methylindole as a raw material, carrying out acylation reaction with chloracetyl chloride or bromoacetyl bromide, carrying out reduction reaction, and carrying out coupling reaction with methyl (E)-3-[4-(aminomethyl)phenyl]acrylate to obtain the panobinostat. The synthesis method avoids the influence of toxic raw materials on the safety of the panobinostat product, and is suitable for industrial production.

Description

A kind of synthetic method of LBH589
Technical field
The invention belongs to field of pharmaceutical chemistry technology, more particularly, it relates to a kind of synthetic method of LBH589.
Background technology
LBH589, chemical name is N- hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- bases)-ethyl]-amino] methyl] phenyl] -2E-2- acrylamides, and chemical constitution is
LBH589 is a kind of hydroxamic acid micromolecular histone deacetylase enzyme (HDAC) inhibitor, and for Huppert's disease, the treatment of early stage acute myeloid leukaemia, in the U.S., approval is listed within 2 months 2015.
Novartis Co., Ltd discloses LBH589 compound and preparation method thereof in international application for patent WO02/22577A2, and the preparation method adopts 2- methyl -3- indoles-oxamides for raw material, Jing LiAlH4Reduction obtains 2- methyltryptamines, and Jing obtains LBH589 with 4- formyls-methyl cinnamate reaction, rehydrated hydrazinolysis.Being unsuitable for industrialized production preparation method condition harshness, impurity more.
Liu Qian etc. (《Chinese Journal of Pharmaceuticals》2011,42 (10), p725-727 a kind of synthetic method of LBH589) is disclosed, 2- methyltryptamines are obtained using phenylhydrazine and the chloro- 2 pentanones of 5-, intramolecular cyclization and rearrangement reaction, then react with (the E) -4- methyl cinnamic acids methyl esters by bromination, obtain (E) -3- [4- [[2- (2- Methyl-1H-indole -3- bases) ethylamino-] methyl] phenyl] methyl acrylate hydrochloride, obtain LBH589 with azanol reaction again, reaction scheme is as follows：
The reaction employs the big raw material of toxicity, so as to affect the security of final product.
Novartis Co., Ltd discloses a kind of synthetic method of LBH589 in international application for patent WO2007/146718A2, the method adopts phenylhydrazine for raw material, the chloro- 2 pentanone reactions of Jing and 5- obtain 2- methyltryptamines, and with 4- formyls-methyl cinnamate reaction, rehydrated hydrazinolysis LBH589 is obtained.The problems such as synthetic method equally there is also material toxicity.
The content of the invention
The present inventor have developed a kind of synthetic method of LBH589, overcome above-mentioned deficiency present in prior art.
It is an object of the invention to provide a kind of synthetic method of LBH589.
In embodiments of the invention, the invention provides a kind of synthetic method of LBH589, comprises the following steps：
(1) with 2 methyl indole as raw material, with chloracetyl chloride reaction, the chloro- 1- of 2- (2- Methyl-1H-indole -3- bases) ethyl ketone is obtained；
(2) the chloro- 1- of 2- (2- Methyl-1H-indole -3- bases) ethyl ketone issues raw reduction reaction in triethyl silicane/BFEE reduction system system, obtains 3- (2- chloroethyls) -2- Methyl-1H-indoles；
(3) 3- (2- chloroethyls) -2- Methyl-1H-indoles react with (E) -3- [4- (amino methyl) phenyl] methyl acrylate, react with HCl again, obtain (E) -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] methyl acrylate hydrochloride；
(4) (E) -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] methyl acrylate hydrochloride in the presence of an inorganic base with azanol reaction, obtain (E)-N- hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] acrylamide.
In embodiments of the invention, the invention provides a kind of synthetic method of LBH589, comprises the following steps：
(1) with 2 methyl indole as raw material, with bromoacetyl bromide reaction, the bromo- 1- of 2- (2- Methyl-1H-indole -3- bases) ethyl ketone is obtained；
(2) the bromo- 1- of 2- (2- Methyl-1H-indole -3- bases) ethyl ketone issues raw reduction reaction in triethyl silicane/BFEE reduction system system, obtains 3- (2- bromoethyls) -2- Methyl-1H-indoles；
(3) 3- (2- bromoethyls) -2- Methyl-1H-indoles react with (E) -3- [4- (amino methyl) phenyl] methyl acrylate, react with HCl again, obtain (E) -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] methyl acrylate hydrochloride；
(4) (E) -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] methyl acrylate hydrochloride in the presence of an inorganic base with azanol reaction, obtain (E)-N- hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] acrylamide.
In embodiments of the invention, the present invention's further includes (E)-N- hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] acrylamide) react with DL-LACTIC ACID, obtain (E)-N- hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] acrylamide DL-LACTIC ACID salt i.e. LBH589 DL-LACTIC ACID salt.
In embodiments of the invention, the LBH589 synthetic method that the present invention is provided, wherein, step (1) is with 2 methyl indole as raw material, polar non-solute (such as dichloromethane, tetrahydrofuran, acetone, methyl ethyl ketone, dimethylformamide, dimethyl acetamide, 1-METHYLPYRROLIDONE, formamide, acetonitrile, dimethyl sulfoxide (DMSO), propionitrile, Ethyl formate, methyl acetate, ethyl acetate, dioxane, preferably acetonitrile) it is solvent, and 2, in the presence of 6- lutidines, 25-35 DEG C of temperature control, chloracetyl chloride or bromoacetyl bromide is added dropwise, after the completion of reaction, water is added dropwise and is sufficiently stirred for, it is filtrated to get the chloro- 1- of 2- (2- Methyl-1H-indole -3- bases) ethyl ketones or the bromo- 1- of 2- (2- Methyl-1H-indole -3- bases) ethyl ketone.
In embodiments of the invention, the LBH589 synthetic method that the present invention is provided, wherein, step (2) is that the chloro- 1- of 2- (2- Methyl-1H-indole -3- bases) ethyl ketones or the bromo- 1- of 2- (2- Methyl-1H-indole -3- bases) ethyl ketones are mixed with triethyl silicane, acetonitrile, temperature control is added dropwise BFEE at 20-30 DEG C, reacted to obtain 3- (2- chloroethyls) -2- Methyl-1H-indoles or 3- (2- bromoethyls) -2- Methyl-1H-indoles.
In embodiments of the invention, the LBH589 synthetic method that the present invention is provided, wherein, step (3) is：3- (2- chloroethyls) -2- Methyl-1H-indoles or 3- (2- bromoethyls) -2- Methyl-1H-indoles are in polar non-solute (such as dichloromethane, tetrahydrofuran, acetone, methyl ethyl ketone, dimethylformamide, dimethyl acetamide, 1-METHYLPYRROLIDONE, formamide, acetonitrile, dimethyl sulfoxide (DMSO), propionitrile, Ethyl formate, methyl acetate, ethyl acetate, dioxane, preferably dimethylformamide) in, in organic base (preferred N, N- diisopropylethylamine) in the presence of with (E) -3- [4- (amino methyl) phenyl] methyl acrylate reaction；Jing reacts with hydrogen chloride solution (preferred ether solution of hydrogen chloride), obtains (E) -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] methyl acrylate hydrochloride.
In embodiments of the invention, the LBH589 synthetic method that the present invention is provided, wherein, step (4) is (E) -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] methyl acrylate hydrochlorides after sodium hydrate methanol solution is added dropwise, with azanol reaction, (E)-N- hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] acrylamide is obtained.
In embodiments of the invention, the LBH589 synthetic method that the present invention is provided, wherein, (E) -3- [4- (amino methyl) phenyl] methyl acrylate of step (3) is prepared as follows：
A., as raw material, adopt (BOC) with to chlorobenzylamine2O protects its amino, obtains 4- chlorobenzylamino t-butyl formates；
B.4- chlorobenzylamino t-butyl formate reacts with methyl acrylate, reuses acid removing amino protecting group, obtains (E) -3- [4- (amino methyl) phenyl] methyl acrylate.
In a kind of preferred embodiment of the present invention, the LBH589 synthetic method that the present invention is provided, wherein, (E) -3- [4- (amino methyl) phenyl] methyl acrylate of step (3) is prepared as follows：
A., as raw material, adopt (BOC) with to bretylium tosylate2O protects its amino, obtains 4- chlorobenzylamino t-butyl formates；
B.4- bromobenzyl carbamate reacts with methyl acrylate, reuses acid removing amino protecting group, obtains (E) -3- [4- (amino methyl) phenyl] methyl acrylate.
Compared with prior art, LBH589 synthetic method of the invention, it is to avoid impacts of the toxic starting materials to LBH589 Product Safety, while, there is provided it is suitable to the synthetic method of industrialized production.
The reaction scheme of the present invention; avoid the use for synthesizing phenylhydrazine poison auxiliary material in 2- methyltryptamine methods in prior art; synthesized using cheap raw material 2 methyl indole; other auxiliary materials used are also the wide reagent for using; and (E) -3- (4- formyl-phenyls) methyl acrylate is expensive used in prior art, improves synthesis cost；Using to bretylium tosylate (or to chlorobenzylamine) as initiation material, synthetic intermediate side chain, (E) -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] methyl acrylate hydrochloride important intermediate is prepared again, not only react simple and safe, the danger of sodium borohydride reaction hydrogen and the complexity of dosing operation are evaded very well, yield is improved, and reduces the way of production of impurity, and purification operations are simple.
Specific embodiment
Embodiment of the present invention is further discussed below below by specific example.For those of ordinary skills, under the teachings of the present invention, following Examples can be modified according to prior art, but still belongs to the scope that the present invention is claimed.
Embodiment 1
It is prepared by the chloro- 1- of 2- (2- Methyl-1H-indole -3- bases) ethyl ketone
2 methyl indole 25g (0.19mol) is added in 500ml four-hole bottles, acetonitrile 250ml, 2,6- lutidines 40.9g (0.381mol), 20-30 DEG C of stirring is molten clear, and 25-35 DEG C of temperature control is added dropwise chloracetyl chloride 32.3g (0.286mol), completion of dropping, continue to stir 1 hour, point plate detection raw material fundamental reaction completely, is added dropwise water 250ml, after being sufficiently stirred for, suction filtration, with acetonitrile/water=150ml/150ml drip washing filter cakes, 50 DEG C dry to constant weight, obtain light gray-white solid 31.56g, yield 79.7%.Mass：m/z 208.03[M+H]+, mp：217.3℃.
Embodiment 2
It is prepared by 3- (2- chloroethyls) -2- Methyl-1H-indoles
In 500ml, chloro- 1- (2- Methyl-1H-indole -3- bases) ethyl ketones solid 30g (0.144mol) of 2- are added in four-hole bottle, triethyl silicane 50.4g (0.433mol), acetonitrile 120ml, stirring, temperature control is added dropwise BFEE 28.89g (0.217mol) at 20-30 DEG C, completion of dropping, stirring 1 hour, start TLC detections, raw material fundamental reaction is complete, water 60ml is added dropwise, after being sufficiently stirred for, stand a point liquid, lower floor separates, extracted 2 times with ethyl acetate 50ml, merge upper organic phase, washed with saturated aqueous common salt 20ml, anhydrous sodium sulfate drying, concentration, system is husky, column chromatography, lost shape with ethyl acetate petroleum ether system 1: 20, obtain product grease, add n-hexane 90ml, 0-5 DEG C of stirring and crystallizing of temperature control 1 hour, suction filtration, 20-25 DEG C of vacuum drying, obtain light cyan solid 24.26g, yield 87%.Mass：m/z 194.09[M+H]+, mp：45.5℃-50.6℃.
Embodiment 3
4- bromobenzyl carbamates
Add in 100ml four-hole bottles to bretylium tosylate 13.2g (0.071mol), triethylamine 7.9g (0.078mol), dichloromethane 50ml, 0-5 DEG C of temperature control is added dropwise BOC2The dichloromethane solution 10ml of O 17.02g (0.078mol), drips stirring 30min, warms naturally to normal temperature, TLC detection reactions are complete, after adding water 60ml, extraction to wash, divide liquid, water mutually to be extracted 2 times with dichloromethane 30ml, merge organic phase, washed with saturated aqueous common salt 50ml, anhydrous sodium sulfate drying, suction filtration, concentration, obtain solid 15.4g, yield 90%.Mass：m/z 287.22[M+H]+, mp：72.7℃-75.2℃.
Embodiment 4
(E) -3- [4- (amino methyl) phenyl] methyl acrylate
Palladium 0.01g is added in 100ml four-hole bottles, triphenylphosphine 0.48g (1.8mmol), DMF50ml, 4- bromobenzyls carbamate solid 11.7g (0.041mol), methyl acrylate 4.5g (0.045mol), potassium carbonate 5.67g (0.041mol), heats up 100 DEG C and stirs 2 hours, TLC detections, raw material fundamental reaction is complete, it is cooled to 20-30 DEG C, suction filtration, filtrate added drop-wise water 100ml, separate out solid, 50 degree of drying, obtain light yellow solid 9.25g, yield 78%.Solid is added in 50ml dichloromethane, add trifluoroacetic acid 22ml, stir 1 hour at 25-30 DEG C, direct concentration of reaction solution, ethyl acetate 100ml extractions are added in concentrate, saturated sodium bicarbonate solution 50ml extractions are washed, liquid, organic phase saturated aqueous common salt 50ml extractions is divided to wash, anhydrous sodium sulfate drying, it is concentrated in vacuo to obtain yellow oil 5.87g, yield 96%.Mass：m/z 192.15[M+H]+
Embodiment 5
(E) -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] methyl acrylate hydrochloride
(E) -3- [4- (amino methyl) phenyl] methyl acrylate (10g is added in 250ml four-hole bottles, 0.052mol) with dry DMF (70ml), stirring is molten clear, add N, N- diisopropylethylamine 20.16g (DIPEA, 0.156mol), 20-30 DEG C of stirring 15min, 3- (2- chloroethyls) -2- Methyl-1H-indole (11.14g are added dropwise, DMF lysate 30ml 0.057mol), completion of dropping, continue to stir 4 hours, reactant liquor is poured into 200ml water, extracted with ethyl acetate (100ml*2), merge organic phase, water 100ml is used respectively, saturated aqueous common salt 100ml is washed, anhydrous sodium sulfate drying, filter, filtrate adds 1.0mol/L ether solution of hydrogen chloride (about 50ml), crystallization 1 hour, filter, filter cake is with cold ethyl acetate 40ml drip washing, it is dried, obtain yellow solid 15.67g, yield 78.3%.Mass：m/z349.23[M+H]+, mp：245.9℃.
Embodiment 6
(E)-N- hydroxyls -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] acrylamide
(E) -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] methyl acrylate hydrochloride (15g is added in 250ml four-hole bottles, 0.039mol), methyl alcohol (75ml), -10 DEG C～-15 DEG C stirrings of cooling, fast drop NaOH (4.68g, methanol solution 0.117mol), drop finishes, stirring 10min, hydroxylamine solution (50% aqueous solution correspondence hydroxylamine hydrochloride 16.26g of 32.52g is added dropwise, 0.234mol), completion of dropping is stirred 2 hours in -10 DEG C～-15 DEG C temperatures.Reactant mixture is warming into 0 DEG C, 0-5 DEG C of stirring 30min of insulation, 20 DEG C are warming to again, 20-25 DEG C of insulation is stirred 1 hour, is added dropwise to water 38ml, stirs 10min, suction filtration, with water 38ml drip washing, gained filtrate adjusts the pH value of solution to 10 with aqueous hydrochloric acid solution (aqueous solution of the 2mol/L of about 18.5g).The stirring and crystallizing at 20-25 DEG C, aqueous hydrochloric acid solution's (aqueous solution of the 2mol/L of about 15.5g) is used again, continue the pH value for adjusting solution to 8-9, stir 1 hour at a temperature of 20-25 DEG C, filter solid is crossed, with methyl alcohol water mixed liquid (v/v=1: 1) the drip washing filter cake of 50ml, is dried to constant weight in 50 degree of hot-air ovens, obtain solid 12.89g, yield 94.6%.Mass：m/z 350.26[M+H]+, mp：109.4℃-115.3℃.
Embodiment 7
(E)-N- hydroxyls -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] acrylamide DL-LACTIC ACID salt
DL-LACTIC ACID (4.0g, 85% aqueous solution, corresponding to the pure DL-LACTIC ACIDs of 3.4g, 0.0378mol) is diluted with water 27.2g, and solution is heated to more than 90 DEG C of 4 hours, cooling down is standby to room temperature.
(E)-N- hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] acrylamide (10.0g is added in 250ml four-hole bottles, 0.0286mol), add water 110ml, it is warmed up to 60-70 DEG C of stirred suspension, above-mentioned DL-LACTIC ACID solution is added dropwise at such a temperature, suspension is dissolved into solution, 30min is incubated at 60-70 DEG C, cool to 40-50 DEG C, crystallization 1 hour, 30-35 DEG C of insulated and stirred is cooled to again 1 hour, after again suspension is warmed up into 60-70 DEG C, it is slow cooling to 30-35 DEG C, after insulation 1 hour, 0-5 DEG C is slow cooling to again, insulation 2 hours.Suction filtration, with cold water 30ml drip washing filter cakes, filter cake is dried under vacuum to constant weight in 45 DEG C, obtains crystalline product, 11.44g, yield 91%.mp：180.2℃-182.7℃.

Claims (10)

1. a kind of synthetic method of LBH589, comprises the following steps：
(1) with 2 methyl indole as raw material, with chloracetyl chloride reaction, 2- chloro- 1- (2- methyl is obtained - 1H- indol-3-yls) ethyl ketone；
(2) the chloro- 1- of 2- (2- Methyl-1H-indole -3- bases) ethyl ketone is in triethyl silicane/boron trifluoride second Ether reduction system system issues raw reduction reaction, obtains 3- (2- chloroethyls) -2- Methyl-1H-indoles；
(3) 3- (2- chloroethyls) -2- Methyl-1H-indoles and (E) -3- [4- (amino methyl) phenyl] propylene Sour methyl esters reaction, then react with HCl, obtain (E) -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] Amino] methyl] phenyl] methyl acrylate hydrochloride；
(4) (E) -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] acrylic acid Methyl ester hydrochloride in the presence of an inorganic base with azanol reaction, obtain (E)-N- hydroxyl -3- [4- [[[2- (2- methyl - 1H- indol-3-yls) ethyl] amino] methyl] phenyl] acrylamide.
2. a kind of synthetic method of LBH589, comprises the following steps：
(1) with 2 methyl indole as raw material, with bromoacetyl bromide reaction, 2- bromo- 1- (2- methyl is obtained - 1H- indol-3-yls) ethyl ketone；
(2) the bromo- 1- of 2- (2- Methyl-1H-indole -3- bases) ethyl ketone is in triethyl silicane/boron trifluoride second Ether reduction system system issues raw reduction reaction, obtains 3- (2- bromoethyls) -2- Methyl-1H-indoles；
(3) 3- (2- bromoethyls) -2- Methyl-1H-indoles and (E) -3- [4- (amino methyl) phenyl] propylene Sour methyl esters reaction, then react with HCl, obtain (E) -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] Amino] methyl] phenyl] methyl acrylate hydrochloride；
(4) (E) -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] acrylic acid Methyl ester hydrochloride in the presence of an inorganic base with azanol reaction, obtain (E)-N- hydroxyl -3- [4- [[[2- (2- methyl - 1H- indol-3-yls) ethyl] amino] methyl] phenyl] acrylamide.
3. synthetic method as claimed in claim 1 or 2, optionally, further includes (E)-N- Hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] acrylamides and DL- Lactic acid reacts, and obtains (E)-N- hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] Phenyl] acrylamide DL-LACTIC ACID salt is LBH589 DL-LACTIC ACID salt.
4. synthetic method as claimed in claim 1 or 2, wherein, step (1) is with 2- methyl Yin Diindyl is raw material, and polar non-solute is solvent, and in the presence of 2,6- lutidines, temperature control 25-35 DEG C, chloracetyl chloride or bromoacetyl bromide are added dropwise, after the completion of reaction, water are added dropwise and are sufficiently stirred for, mistake Filter obtains the chloro- 1- of 2- (2- Methyl-1H-indole -3- bases) ethyl ketones or the bromo- 1- of 2- (2- Methyl-1H-indole -3- Base) ethyl ketone.
5. synthetic method as claimed in claim 1 or 2, wherein, step (2) is the chloro- 1- (2- of 2- Methyl-1H-indole -3- bases) ethyl ketone or the bromo- 1- of 2- (2- Methyl-1H-indole -3- bases) ethyl ketones and triethyl group Silane, acetonitrile are mixed, and temperature control is added dropwise BFEE at 20-30 DEG C, reacted to obtain 3- (2- Chloroethyl) -2- Methyl-1H-indoles or 3- (2- bromoethyls) -2- Methyl-1H-indoles.
6. synthetic method as claimed in claim 1 or 2, wherein, step (3) is：3- (2- chlorine Ethyl) -2- Methyl-1H-indoles or 3- (2- bromoethyls) -2- Methyl-1H-indoles be in polar non-solute In, with (E) -3- [4- (amino methyl) in the presence of organic base (preferred DIPEA) Phenyl] methyl acrylate reaction；Jing reacts with hydrogen chloride solution (preferred ether solution of hydrogen chloride), obtains To (E) -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] methyl acrylate salt Hydrochlorate.
7. synthetic method as claimed in claim 6, wherein, the non-matter of polarity described in step (3) Sub- solvent is preferably dimethylformamide.
8. synthetic method as claimed in claim 6, wherein, organic base is excellent described in step (3) Selection of land is DIPEA.
9. synthetic method as claimed in claim 1 or 2, wherein, step (4) is (E) -3- [4- [[[2- (2- Methyl-1H-indole -3- bases) ethyl] amino] methyl] phenyl] and methyl acrylate hydrochloride be added dropwise hydroxide After sodium methanol solution, (E)-N- hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- with azanol reaction, are obtained Base) ethyl] amino] methyl] phenyl] acrylamide.
10. synthetic method as claimed in claim 1 or 2, wherein, (E) -3- [4- of step (3) (amino methyl) phenyl] methyl acrylate prepared as follows：
A. to bretylium tosylate or to chlorobenzylamine as raw material, to adopt (BOC)2O protects its amino, obtains To 4- bromobenzyls carbamate or 4- chlorobenzylamino t-butyl formates；
B.4- bromobenzyl carbamate or 4- chlorobenzylaminos t-butyl formate and methyl acrylate Reaction, reuses acid removing amino protecting group, obtains (E) -3- [4- (amino methyl) phenyl] acrylic acid Methyl esters.
CN201510776391.0A 2015-11-10 2015-11-10 Synthesis method of panobinostat Pending CN106674080A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106866491A (en) * 2015-12-10 2017-06-20 江苏豪森药业集团有限公司 LBH589 lactate crystal formation I and its production and use
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Publication number Priority date Publication date Assignee Title
CN106866491A (en) * 2015-12-10 2017-06-20 江苏豪森药业集团有限公司 LBH589 lactate crystal formation I and its production and use
CN106866492A (en) * 2015-12-10 2017-06-20 江苏豪森药业集团有限公司 LBH589 lactate crystal formation II and its production and use
CN106866492B (en) * 2015-12-10 2021-11-26 江苏豪森药业集团有限公司 Panobinostat lactate crystal form II and preparation method and application thereof
CN106866491B (en) * 2015-12-10 2021-12-10 江苏豪森药业集团有限公司 Panobinostat lactate crystal form I and preparation method and application thereof
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WO2021170719A1 (en) * 2020-02-27 2021-09-02 Flamma Spa Process for the preparation of panobinostat

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