The preparation method of afatinib compoundTechnical field
The present invention is field of medicinal chemistry, more particularly to afatinib compound and one kind of maleic acid AfatinibNew preparation process.
Background technique
Maleic acid Afatinib (Afatinib dimaleate) is a kind of tyrosine kinase inhibitor.In July, 2013 byU.S. FDA approval listing, trade name GILOTRIF, as first-line treatment drug for treating EGF-R ELISA(EGFR) Metastatic Nsclc (NSCLC) patient of the missing of exons 19 or exon 21 (L858R) substitution mutation.
Afatinib compound (1 compound of embodiment (10)) is disclosed in CN1481370A.
A kind of method preparing maleic acid Afatinib is disclosed in CN1867564A, by N4(the chloro- 4- fluoro-phenyl of 3-) -7-The aryl amide that ((S)-tetrahydrofuran -3- base oxygen) quinazoline -4,6- diamines is obtained with the reaction of diethyl phosphine ethyl acetoacetic acid, then same 2-Aminoacetaldehyde (or its acetal) occur Wittig-Horner-Emmons reaction generate Afatinib, then again with maleic acid atSalt.The raw materials used dimethylamino acetaldehyde of the technique, dimethylamino acetal higher cost and it is easy to oxidative degradation, it is difficult toIt stores for a long time, is unfavorable for industrialized production, and the technique also needs to provide ar gas environment in process of production.The technique simultaneouslyTrans double bond is constructed by Wittig-Horner-Emmons reaction, due to stereoselective difference, there are still a small amount of in productCis-isomer impurity.
Summary of the invention
The present invention provides a kind of new methods of preparation afatinib compound, and the Afatinib obtained by this methodFurther maleic acid Afatinib obtained, the pharmaceutical composition containing the maleic acid Afatinib.Additionally provide the systemNew intermediate compound used in standby maleic acid afatinib compound new method.
The new method of preparation afatinib compound provided by the invention, can be realized by following scheme:
(1) Formula IV compound reacts to obtain V compound with Formula VII compound,
(2) Formula V compound reacts in the presence of n-BuLi with formula IV compound obtains formula III compound,
(3) formula III compound passes through NaBH4Reduction obtains Formula II compound,
(4) Formula II compound is restored by NaH and obtains compound of formula I,
Reaction condition is one or more in following conditions in step (1) of the present invention: Formula IV compound and Formula VII chemical combinationThe reaction dissolvent of object synthesis Formula V compound is preferably chosen from methylene chloride, 1,2- dichloroethanes, chloroform, bis- neoprene of 1,2-One of alkane is a variety of；More preferably methylene chloride.Reaction temperature is preferably room temperature.Reaction time is preferably 1~20 hours.The molar ratio of Formula IV compound and Formula VII compound is preferably 1:(0.85~1.15).Room temperature is 10 in the present invention~30 DEG C, more preferably 15~25 DEG C.
Reaction condition is one or more in following conditions in step (2) of the present invention: Formula V compound and formula IV compoundThe reaction dissolvent for closing compound of Formula III is preferably chosen from tetrahydrofuran and/or 2- methyltetrahydrofuran；More preferably tetrahydroFurans.Reaction temperature is preferably room temperature.Reaction time is preferably 0.5~4 hour.Formula V compound and formula IV compoundMolar ratio is preferably 1:(0.85~1.15).The molar ratio of Formula V compound and n-BuLi is preferably 1:(0.8~1.2).
Reaction condition is one or more in following conditions in step (3) of the present invention: formula III compound is reduced to Formula IIThe reaction dissolvent of compound is preferably chosen from one of methanol, ethyl alcohol, normal propyl alcohol, isopropanol or a variety of；More preferably firstAlcohol and/or ethyl alcohol.Reaction temperature is preferably 55~75 DEG C.Reaction time is preferably 0.5~6 hour.Formula III compound withNaBH4Molar ratio be preferably 1:(1.5~0.5).
Reaction condition is one or more in following conditions in step (4) of the present invention: Formula II compound is reduced to Formulas IClose object reaction dissolvent be preferably chosen from one of N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide orIt is a variety of；More preferably N,N-dimethylformamide.Reaction temperature is preferably 10~30 DEG C.Reaction time is preferably 0.5~6 hours, more preferably 1~6 hour.The molar ratio of Formula II compound and NaH are preferably 1:(1.5~4), more preferablyFor 1:(2~3).
The present invention also provides obtaining new intermediate compound in the preparation Afatinib new method, Formula II compound orIts salt,
The present invention also provides obtain new intermediate compound, formula III compound in the preparation Afatinib new methodOr its salt,
The present invention also provides obtaining new intermediate compound in the preparation Afatinib new method, Formula V compound orIts salt,
The Afatinib prepared by the method for the invention can also further be prepared into pharmaceutically acceptable salt, preferably2-maleate is made in ground, can be realized by the technical solution recorded in prior art CN1867564A.It is heretofore describedMaleic acid Afatinib refer to the 2-maleate of Afatinib.
Pharmaceutical composition can also be further made in maleic acid Afatinib provided by the invention；The system of the compositionDosage form formula can be oral solid formulation or parenteral formulations agent.In the present invention, the composition further includes pharmaceuticallyAcceptable carrier；Pharmaceutically acceptable carrier be usually those of ordinary skill in the art can according to specific form of medication andSpecific choice.It can be with it is well known that technology such as routine granulation, mixing, dissolution, formation capsule, freeze-drying technique manufacture this hairBright pharmaceutical composition.The present composition can be made to the form for being used for various administration routes, for example, oral administration, veinIt is interior etc..Preferably, maleic acid Afatinib provided by the invention can be according to technical solution in prior art CN102056589AThe pharmaceutical composition of solid dosage form is made.
(diphenylphosphino)acetic acid and N used in preparation Afatinib new method provided by the invention, N- dimethylamino acetic acidEthyl ester is to be commercialized obtainable chemicals raw material, and at low cost, chemical property is stablized, convenient for long-term storage.
Present invention process respectively walk it is easy to operate, without the special gas preservation condition such as argon gas, and reaction time mild condition,Technique is smooth, is suitble to industry amplification.
Method provided by the invention prepares the total recovery of maleic acid Afatinib up to 60% or more, has industrialized productionValue.
The salt of Afatinib or Afatinib that preparation Afatinib new method provided by the invention obtains is (including but unlimitedIn maleate) in cis-isomer content it is lower, using routine HPLC methods detect result be not detected.
Detailed description of the invention
The MS map for the Afatinib that Fig. 1 embodiment 5 obtains
The HPLC map for the maleic acid Afatinib that Fig. 2 embodiment 5 obtains
The HPLC map for the maleic acid Afatinib that Fig. 3 is obtained according to the Examples 1 to 3 of CN1867564A
The LC-MS map for the maleic acid Afatinib that Fig. 4 is obtained according to the Examples 1 to 3 of CN1867564A
Specific embodiment
It is further illustrated below by the mode of embodiment, but skilled in the art realises that, following embodiments are not pairThe limitation of the scope of the present invention.
The preparation of 1 Formula V compound of embodiment
Phosphorus trichloride (0.5g) is slowly instilled to (diphenylphosphino)acetic acid (2.37g) to be dissolved in 25mL dichloromethane solution, is controlled0 DEG C of reaction temperature processed.Drop finish 15 DEG C be stirred to react 2 hours after be cooled to 0 DEG C.By triethylamine (1.02g) and 4- [(the chloro- 4- fluorine of 3-Phenyl)-amino] -6- amino -7- ((S)-tetrahydrofuran -3- base oxygroup)-quinazoline (3.41g) is dissolved in bis- chloroethene of 25mL1,2-Above-mentioned solution is slowly instilled in alkane solution, drop finishes, and 25 DEG C are reacted 2 hours.20mL purified water is added after completion of the reaction for TLC monitoringExtracting and demixing, organic phase continue to purify water washing, anhydrous sodium sulfate dry, filtering, filtrate decompression with 20mL to be concentrated into grease,Tetrahydrofuran/isopropyl ether (1:1) 40mL is added and recrystallizes to obtain off-white powder (Formula V compound).
Phosphorus trichloride (0.5g) is slowly instilled to (diphenylphosphino)acetic acid (2.37g) to be dissolved in 25mL chloroform soln, is controlled0 DEG C of reaction temperature processed.Drop finish 25 DEG C be stirred to react 1.5 hours after be cooled to 0 DEG C.By triethylamine (1.02g) and 4- [(the chloro- 4- of 3-Fluorophenyl)-amino] -6- amino -7- ((S)-tetrahydrofuran -3- base oxygroup)-quinazoline (3.41g) is dissolved in 25mL1,2- dichloroAbove-mentioned solution is slowly instilled in butane solution, drop finishes, and 15 DEG C are reacted 8 hours.TLC monitoring after completion of the reaction adds 20mL purified waterEnter extracting and demixing, organic phase continues to purify dry water washing, anhydrous sodium sulfate, filtering, filtrate decompression with 20mL to be concentrated into oilyObject is added tetrahydrofuran/isopropyl ether (1:1) 40mL and recrystallizes to obtain off-white powder (Formula V compound).
Phosphorus trichloride (0.5g) is slowly instilled to (diphenylphosphino)acetic acid (2.37g) to be dissolved in 25mL dichloromethane solution, is controlled0 DEG C of reaction temperature processed.Drop finish 20 DEG C be stirred to react 2 hours after be cooled to 0 DEG C.By triethylamine (1.02g) and 4- [(the chloro- 4- fluorine of 3-Phenyl)-amino] to be dissolved in 25mL chloroform molten for -6- amino -7- ((S)-tetrahydrofuran -3- base oxygroup)-quinazoline (3.41g)Above-mentioned solution is slowly instilled in liquid, drop finishes, and 10 DEG C are reacted 16 hours.20mL purified water, which is added, after completion of the reaction for TLC monitoring extractsTake layering, organic phase continues to purify dry water washing, anhydrous sodium sulfate, filtering, filtrate decompression with 20mL to be concentrated into grease, addsEnter tetrahydrofuran/isopropyl ether (1:1) 40mL and recrystallizes to obtain off-white powder (Formula V compound).
The preparation of 2 formula III compound of embodiment
By slowly dropping type V compound (5g) is dissolved in 28mL dry four at 0 DEG C of temperature in n-BuLi (1.5M, 6ml) controlIn hydrogen tetrahydrofuran solution.Drop finishes, and is cooled to -10 DEG C；Dimethylamino ethyl acetate (1.05g) is instilled in above-mentioned solution, drop finishes, and risesTo being stirred at room temperature 0.5 hour, saturated ammonium chloride solution 12mL is added into reaction solution after monitoring end of reaction by TLC, is saturated chlorinationSodium solution 8mL, methylene chloride 12mL extracting and demixing, organic phase anhydrous magnesium sulfate is dry, filters, grease is concentrated under reduced pressure to obtain, and addsEnter tetrahydrofuran/isopropyl ether (1:2) 40mL and recrystallizes to obtain off-white powder (formula III compound).
By slowly dropping type V compound (5g) is dissolved in the dry 2- of 28mL at 0 DEG C of temperature in n-BuLi (1.5M, 6ml) controlIn methyltetrahydrofuran solution.Drop finishes, and is cooled to -10 DEG C；Dimethylamino ethyl acetate (1.05g) is instilled in above-mentioned solution,Drop finishes, and is warmed to room temperature stirring 4 hours, and saturated ammonium chloride solution 12mL, saturation are added into reaction solution after monitoring end of reaction by TLCSodium chloride solution 8mL, methylene chloride 12mL extracting and demixing, organic phase anhydrous magnesium sulfate is dry, filters, oily is concentrated under reduced pressure to obtainObject is added tetrahydrofuran/isopropyl ether (1:2) 40mL and recrystallizes to obtain off-white powder (formula III compound).
By slowly dropping type V compound (5g) is dissolved in 28mL dry four at 0 DEG C of temperature in n-BuLi (1.5M, 6ml) controlIn hydrogen tetrahydrofuran solution.Drop finishes, and is cooled to -10 DEG C；Dimethylamino ethyl acetate (1.05g) is instilled in above-mentioned solution, drop finishes, and risesTo being stirred at room temperature 2 hours, saturated ammonium chloride solution 12mL, saturated sodium-chloride are added into reaction solution after monitoring end of reaction by TLCSolution 8mL, methylene chloride 12mL extracting and demixing, organic phase anhydrous magnesium sulfate is dry, filters, grease is concentrated under reduced pressure to obtain, and is addedTetrahydrofuran/isopropyl ether (1:2) 40mL recrystallizes to obtain off-white powder (formula III compound).
The preparation of 3 Formula II compound of embodiment
Sodium borohydride (0.15g) addition formula III compound (5g) is dissolved in the solution of 50mL methanol, 75 DEG C of heating 0.5It is cooled to room temperature after hour, 50mL saturated ammonium chloride solution is added, vacuum distillation removes partial solvent, and 50mL is added and is saturated chlorinationSodium solution, 80mL methylene chloride extracting and demixing, organic phase anhydrous magnesium sulfate is dry, filtering, is concentrated under reduced pressure, and dichloro is added in residueMethane/normal heptane (1:3) 50mL stirring and crystallizing obtains faint yellow solid (Formula II compound).
Sodium borohydride (0.27g) addition formula III compound (5g) is dissolved in the solution of 50mL isopropanol, 65 DEG C are heated backStream is cooled to room temperature after 4 hours, and 50mL saturated ammonium chloride solution is added, and vacuum distillation removes partial solvent, and 50mL saturation is addedSodium chloride solution, 80mL methylene chloride extracting and demixing, organic phase anhydrous magnesium sulfate is dry, filtering, is concentrated under reduced pressure, and residue is addedMethylene chloride/normal heptane (1:3) 50mL stirring and crystallizing obtains faint yellow solid (Formula II compound).
Sodium borohydride (0.38g) addition formula III compound (5g) is dissolved in the solution of 50mL normal propyl alcohol, 55 DEG C of heating 6It is cooled to room temperature after hour, 50mL saturated ammonium chloride solution is added, vacuum distillation removes partial solvent, and 50mL is added and is saturated chlorinationSodium solution, 80mL methylene chloride extracting and demixing, organic phase anhydrous magnesium sulfate is dry, filtering, is concentrated under reduced pressure, and dichloro is added in residueMethane/normal heptane (1:3) 50mL stirring and crystallizing obtains faint yellow solid (Formula II compound).
4 compound of formula I of embodiment (Afatinib) preparation
The n,N-Dimethylformamide 30mL that the drying of Formula II compound (5g) is added in sodium hydride (80%, 0.42g) is moltenIn liquid, 10 DEG C of reaction solution are stirred to react 6 hours, purified water 85mL, saturated sodium chloride solution is added in TLC monitoring after completion of the reaction20mL, methylene chloride 50mL extract liquid separation, and gained organic phase is dry with anhydrous magnesium sulfate, are concentrated under reduced pressure, and acetic acid is added in residueEthyl ester/hexahydrotoluene (1:2) 60mL stirring and crystallizing obtains white powdery solids (compound of formula I).
The n,N-dimethylacetamide 30mL that the drying of Formula II compound (5g) is added in sodium hydride (80%, 0.42g) is moltenIn liquid, 30 DEG C of reaction solution are stirred to react 2 hours, purified water 85mL, saturated sodium chloride solution is added in TLC monitoring after completion of the reaction20mL, methylene chloride 50mL extract liquid separation, and gained organic phase is dry with anhydrous magnesium sulfate, are concentrated under reduced pressure, and acetic acid is added in residueEthyl ester/hexahydrotoluene (1:2) 60mL stirring and crystallizing obtains white powdery solids (compound of formula I).
Sodium hydride (80%, 0.42g) is added in the dimethyl sulfoxide 30mL solution of the drying of Formula II compound (5g), it will be anti-20 DEG C of liquid are answered to be stirred to react 4 hours, purified water 85mL, saturated sodium chloride solution 20mL, dichloro is added in TLC monitoring after completion of the reactionMethane 50mL extracts liquid separation, and gained organic phase is dry with anhydrous magnesium sulfate, is concentrated under reduced pressure, and ethyl acetate/methyl is added in residueHexamethylene (1:2) 60mL stirring and crystallizing obtains white powdery solids (compound of formula I).
The preparation of 5 maleic acid Afatinib of embodiment
Phosphorus trichloride (4.94g, 0.036mol) is slowly instilled to (diphenylphosphino)acetic acid (23.42g, 0.09mol) to be dissolved inIn 250mL anhydrous methylene chloride solution, 0 DEG C of reaction temperature is controlled.Drop finish 20 DEG C be stirred to react 1.5 hours after be cooled to 0 DEG C.It willTriethylamine (10.12g, 0.1mol) and 4- [(the chloro- 4- fluorophenyl of 3-)-amino] -6- amino -7- ((S)-tetrahydrofuran -3- base oxygenBase)-quinazoline (33.73g, 0.09mol) is dissolved in 250mL anhydrous methylene chloride solution and slowly instills above-mentioned solution, and drop finishes, and 20DEG C reaction 1.5 hours.After completion of the reaction extracting and demixing is added in 200mL purified water by TLC monitoring, and organic phase continues pure with 200mLChange water washing, anhydrous sodium sulfate are dry, filter, filtrate decompression is concentrated into grease, are added tetrahydrofuran/isopropyl ether (1:1)400mL recrystallizes to obtain off-white powder 52.75g, yield: 94.9%.
N-BuLi (1.5M, 62.5ml) is controlled slowly to instill at interior 0 DEG C of temperature and walks product (52.75g, 0.085mol)It is dissolved in 280mL dry tetrahydrofuran solution.Drop finishes, and is cooled to -10 DEG C；By dimethylamino ethyl acetate (11.15g,0.085mol) in the above-mentioned solution of instillation, drop finishes, and is warmed to room temperature stirring 1 hour, and TLC adds after monitoring end of reaction into reaction solutionEnter saturated ammonium chloride solution 120mL, saturated sodium chloride solution 80mL, methylene chloride 120mL extracting and demixing, organic phase anhydrous slufuric acidMagnesium is dry, filter, grease is concentrated under reduced pressure to obtain, and tetrahydrofuran/isopropyl ether (1:2) 420mL is added and recrystallizes to obtain off-white powder50.13g, yield: 83.4%.
Intermediate (50.13g, 0.071mol) being walked in sodium borohydride (1.52g, 0.04mol) addition, to be dissolved in 500mL anhydrousIt in the solution of ethyl alcohol, is cooled to room temperature after being heated to reflux 1 hour, 500mL saturated ammonium chloride solution is added, be evaporated under reduced pressure removing unitDivide solvent, 500mL saturated sodium chloride solution, 800mL methylene chloride extracting and demixing, the drying of organic phase anhydrous magnesium sulfate, mistake is addedFilter is concentrated under reduced pressure, and residue is added methylene chloride/normal heptane (1:3) 500mL stirring and crystallizing and obtains faint yellow solid 46.05g, receivesRate: 92.1%.
The N, N- of the drying of product (46.05g, 0.065mol) will be walked in sodium hydride (80%, 3.9g, 0.13mol) additionIn dimethylformamide 300mL solution, reaction 1 hour is stirred at room temperature in reaction solution, purified water is added in TLC monitoring after completion of the reaction800mL, saturated sodium chloride solution 200mL, methylene chloride 500mL extract liquid separation, and gained organic phase is dry with anhydrous magnesium sulfate, subtractsPressure concentration, residue are added ethyl acetate/hexahydrotoluene (1:2) 570mL stirring and crystallizing and obtain white powder Afatinib27.58g, yield: 87.3%.The MS testing result of white powder solid is [M+H]+=486.2 (map is shown in Fig. 1), moisture containsAmount measurement result is 0.8% (Karl_Fischer method, instrument KF870).
Afatinib (20g, 0.041mol) that upper step is obtained, ethyl alcohol 280mL are added in reaction flask, are warming up to 70 DEG C,Maleic acid (9.7g, the 0.084mol) solution & stir for being dissolved in 120mL ethyl alcohol is added.Mixture is cooled to 20 after precipitating crystalDEG C stirring 2 hours, then 0 DEG C stir 3 hours filter.Filter cake is rinsed with ethyl alcohol and is dried under reduced pressure to obtain 27.7g horse at 40 DEG CCome sour Afatinib, yield 94.1%.
Embodiment 6
HPLC detection is carried out to the maleic acid Afatinib that embodiment 5 obtains；HPLC map is shown in Fig. 2.FoundationExamples 1 to 3 carries out reference examples experiment in CN1867564A, carries out HPLC detection to the maleic acid Afatinib of acquisition；HPLCMap is shown in Fig. 3.
HPLC condition are as follows:
Chromatographic column: octadecylsilane chemically bonded silica (Inertsil ODS-SP, 150mm × 4.6mm, 5 μm)
Mobile phase: ammonium acetate buffer (take ammonium acetate 7.7g, water 1000ml is added to make to dissolve, shake up to get): acetonitrile (60:40)
Flow velocity: 1.0mL/min
Detection wavelength: 252nm
Column temperature: 30 DEG C
Sample volume: 5 μ L
As the result is shown: the chromatographic peak retention time of Afatinib is 10.663 minutes in Fig. 3, and peak area percent is99.496%；Retention time is that 9.467 minutes chromatographic peaks represent cis-isomer impurity, peak area percent 0.318%；The chromatographic peak that retention time is 1~2 minute is the chromatographic peak of maleic acid.The chromatographic peak retention time of Afatinib is in Fig. 210.679 minutes, peak area percent 99.879%；Cis-isomer impurity is not detected；The color that retention time is 1~2 minuteSpectral peak is the chromatographic peak of maleic acid.
Carry out reference examples experiment according to Examples 1 to 3 in CN1867564A, the maleic acid Afatinib of acquisition is carried outLC-MS detection；Map is shown in Fig. 4.Abscissa is retention time (min) in Fig. 4；The peak that retention time is 7.060min is cis- differentStructure body impurity, the peak that retention time is 8.620min are Afatinib.The MS figure of substance at 7.301min is also shown in Fig. 4Spectrum is cis-isomer impurity；It shows the MS map of substance at 9.312min, is Afatinib.