CN105968103B - The synthetic method of anti-tumor drug Afatinib - Google Patents
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Abstract
The invention discloses a kind of synthetic methods of anti-tumor drug Afatinib, belong to field of pharmaceutical chemistry technology.This method chemically reacts to obtain Afatinib using 2- nitro -5- bromophenol as raw material by five steps.The synthetic route is raw materials used to be easy to get, and process route shortens, easy to operate, and product yield is high, easy to industrialized production.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, are related to a kind of synthetic method of anti-tumor drug Afatinib.
Background technique
Afatinib is by a kind of multiple target point small-molecule drug of the Boehringer Ingelheim company research and development of Germany.Belong to epidermis
The irreversible inhibitor of growth factor receptors (EGFR) and people's epidermal receptor (HER2) tyrosine kinase and first it is used for epidermis
Lung cancer therapy drug after growth factor receptor inhibitor treatment failure.It can be clinically used for advanced Non-small cell lung and advanced stage
The treatment of breast cancer, intestinal cancer.The medicine is logical by the quick examination & approval of Food and Drug Adminstration of the US (FDA) on 2 15th, 2008
Road, trade name Tovok.
Afatinib (Afatinib, I), entitled 4- [(the chloro- 4- fluorophenyl of 3-) amino] -6- { [4- (N, the N- diformazan of chemistry
Base amino)-1- oxo-2- butene-1-yl] amino }-7- [(S)-(tetrahydrofuran-3- base) oxygroup] quinazoline.
The Afatinib synthetic route reported at present has following several situations：
1) the world patent WO0250043A1 and WO03094921A2 that the original of Boehringer Ingelheim company is ground report Ah method
For the preparation method of Buddhist nun：With parent nucleus 4- [(the chloro- 4- fluorophenyl of 3-) amino] -6- nitro -7- Fluquinconazole quinoline (A) for starting material,
The substitution reaction that halogens fluorine occurs with (S) -3- dihydroxy-tetrahydro furans under the catalysis of basic catalyst potassium tert-butoxide, generates 4-
[(the chloro- 4- fluorophenyl of 3-) amino] -6- nitro -7- [(S)-(tetrahydrofuran -3- base) oxygroup] quinazoline (B)；Intermediate (B) warp
The nitro reduction for crossing 6-, obtains corresponding amino-compound (C)；Amide occurs for the compound (C) and bromo crotons isoxazolecarboxylic acid
Change reaction and obtain intermediate (D), which obtains Afatinib by the aminating reaction with dimethylamine.
The key of Afatinib technology of preparing is the structure design and the selection on cyclic opportunity of quinazoline parent nucleus.Ah method at present
For the preparation method of Buddhist nun, be the quinazoline parent nucleus (IV) of 4- function dough is first obtained by various distinct methods, then successively into
The modified with functional group that row is 7- and 6-.For this method since reaction step is more, total recovery is relatively low, thus is not suitable for industrialization
It is required that.
2) patent CN201310181150.2 and patent CN201310180796.9 is with 3,4-AHBA
(2) it is starting material, obtains 2,5- diamino -4- hydroxy benzenes through zinc nitrate and trichloro-triazine (TCT) nitrification, palladium carbon catalytic hydrogenation
Formic acid (3), 3 with formamide cyclic condensation, obtain 6- amino -7- hydroxyl -3,4- dihydroquinazoline -4- ketone (4).4 triphenyl phasphine,
Mitsunobu occurs with (S) -3- hydroxyl tetrahydrofuran (5) in the presence of diisopropyl azo-2-carboxylic acid (DIAD) and reacts to obtain 6- ammonia
Base -7- [(S)-(tetrahydrofuran -3- base)-oxygroup] -3,4- dihydroquinazoline -4- ketone (6), 6 in the presence of triethylamine with 4- (N,
TMSDMA N dimethylamine base)-2- alkene-butyl chloride (7) occurs acylation reaction and obtains 6- [[4- (N, TMSDMA N dimethylamine base)-1- oxo-2- butene-1-
Base] amino] -7- [(S)-(tetrahydrofuran -3- base) oxygroup] -3,4- dihydroquinazoline -4- ketone (8), 8 in benzotriazole -1- base
In the presence of oxygroup three (dimethylamino) phosphorus father-in-law hexafluorophosphate (BOP),-ten one -7- alkene (DBU) of 1,8- diaza-bicyclo [5.4.0],
1 is generated with chloro- 4- fluoroaniline (9) condensation of 3-.
The route is improvements over the prior art, and overall synthetic route shorten to the reaction of five steps, but total recovery is not still high.
Summary of the invention
It is an object of that present invention to provide a kind of new sides that Afatinib is prepared using 2- nitro -5- bromophenol as starting material
Method, the preparation method raw material are easy to get, and process route is simple, and total recovery improves, and are suitble to industrialized production.
The synthetic method of anti-tumor drug Afatinib provided by the invention is realized by following steps：
(a) starting material 2- nitro -5- bromophenol, with formamidine acetate under catalyst, ligand and alkaline condition the system of reacting
Obtain compound III；
(b) compound III is reacted under cesium carbonate, catalysts conditions with the chloro- 4- fluorobenzene isonitrile (X) of 3- is made compounds Ⅳ；
(c) compounds Ⅳ is reacted with S-3- hydroxyl tetrahydrofuran (V) is made compound VI；
(d) compound VII is made through restoring in compound VI；
(e) compound VII reacts under trimethyl aluminium effect with 4- dimethylamine ethyl crotonate is made Afatinib (I)；Its
Synthetic route is as follows：
Preferably, reaction dissolvent is selected from methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, isobutyl in step (a)
Alcohol, sec-butyl alcohol or the tert-butyl alcohol；The catalyst be tris(dibenzylideneacetone) dipalladium, the ligand be 2- di-t-butyl phosphine -2 ',
4 ', 6 '--1,1 '-biphenyl of triisopropyl -3,6- dimethoxy or 2- (dicyclohexylphosphontetrafluoroborate) -3,6- dimethoxy -2 ', 4 ', 6 ' -
1,1 '-biphenyl of triisopropyl -, preferably 2- di-t-butyl phosphine -2 ', 4 ', 6 '-triisopropyl -3,6- dimethoxy -1,1 '-biphenyl；
The alkali is selected from cesium carbonate；2- nitro -5- bromophenol, formamidine acetate, catalyst, ligand and cesium carbonate molar ratio are 1:1~
1.1:1~3:2~6:1~2.2.
Preferably, reaction dissolvent is selected from toluene or methylene chloride in step (b)；Catalyst is selected from palladium acetate；Chemical combination
The chloro- 4- fluorobenzene isonitrile of object III, 3-, palladium acetate and cesium carbonate molar ratio are 1:1~3:2~5:1~1.5.
Preferably, restoring method used is metal reduction of iron in the presence of hydrochloric acid or acetic acid, chemical combination in step (d)
The molar ratio of object VI and reducing metal is 1:1~9, preferably 1:5~9.
Preferably, step (e) reaction dissolvent be toluene, chloroform or methylene chloride, 10 DEG C~60 DEG C of reaction temperature, instead
3~5h between seasonable；The molar ratio of compound VII, 4- dimethylamine ethyl crotonate and trimethyl aluminium is 1:1:1~3.
Preferably, the chloro- 4- fluorobenzene isonitrile (X) of 3- is synthesized by following steps：
(1) the chloro- 4- fluoroaniline of 3- and formic acid react 3.5 hours preparation N- (the chloro- 4- fluorophenyl of 3-) first under the conditions of 80 DEG C
Amide (Ⅸ)；
(2) N- (the chloro- 4- fluorophenyl of 3-) formamide (Ⅸ) organic solvent be methylene chloride, catalyst be triphenylphosphine and
Elemental iodine, alkali prepare the chloro- 4- fluorobenzene isonitrile (X) of 3- for reaction 1h under the conditions of triethanolamine, is stirred at room temperature.
Compared with the prior art, the beneficial effects of the present invention are：
1) present invention chemically reacts to obtain Afatinib using 2- nitro -5- bromophenol as raw material by five steps, compared to existing
Technology simplifies process route, and reaction condition is mild, easy to operate, and every step yield has reached 85% or more, improves product
Total recovery.
2) 4- dimethylamine ethyl crotonate cheap and easy to get is used (to prepare referring to CN200480007723.9) for raw material, with
Compound VII carries out amidation under the conditions of trimethyl aluminium, not only has condition adaptability stronger, all kinds of esters can cracking ammonia
Solution, there are also high incomes, react the advantages that mild.
Specific embodiment
Summary of the invention of the invention is described in further detail below by specific embodiment, but is not therefore limited
Determine the contents of the present invention.
Embodiment 1
The preparation of compound III
Compound ii 21.8g, formamidine acetate 10.4g, tris(dibenzylideneacetone) dipalladium are sequentially added in reaction flask
91.6g, 2- di-t-butyl phosphine -2 ', 4 ', 6 '-triisopropyl -3,6- dimethoxy -1,1 '-biphenyl 96.94g, cesium carbonate
32.6g, n-butanol 2L react 2h under the conditions of 85 DEG C of temperature, and TLC monitors raw material fully reacting, is down to room temperature naturally, filter,
Pillar layer separation obtains compound III 16.4g, molar yield 90%, and HPLC purity is 99.2%.
Embodiment 2
The preparation of compound III
Compound ii 21.8g, formamidine acetate 11.5g, tris(dibenzylideneacetone) dipalladium are sequentially added in reaction flask
374.7g, 2- di-t-butyl phosphine -2 ', 4 ', 6 '-triisopropyl -3,6- dimethoxy -1,1 '-biphenyl 290.8g, cesium carbonate
71.7g, methanol 2L react 2h under the conditions of 85 DEG C of temperature, and TLC monitors raw material fully reacting, is down to room temperature naturally, filter, column
Chromatographic isolation obtains compound III 17.1g, molar yield 94%, and HPLC purity is 99.5%.
Embodiment 3
The preparation of compound III
Compound ii 21.8g, formamidine acetate 11.5g, tris(dibenzylideneacetone) dipalladium are sequentially added in reaction flask
374.7g, 2- (dicyclohexylphosphontetrafluoroborate) -3,6- dimethoxy -2 ', 4 ', 6 '-triisopropyl -1,1 '-biphenyl 322.1g, cesium carbonate
71.7g, n-butanol 2L react 2h under the conditions of 85 DEG C of temperature, and TLC monitors raw material fully reacting, is down to room temperature naturally, filter,
Pillar layer separation obtains compound III 16.2g, molar yield 88%, and HPLC purity is 98.5%.
Embodiment 4
The preparation of compounds Ⅳ
Step a：The preparation of the chloro- 4- fluorobenzene isonitrile of 3-
Chloro- 4- fluoroaniline 72.8g and 180ml (26.6mol/L) formic acid of 3- is added in reaction flask, is warming up to 80 under stirring
℃.Reaction 3.5 hours in cooling a moment, reaction solution is poured into the beaker equipped with 250mL water, is stood to room temperature, abundant to solid
It is precipitated.Suction filtration obtains product N- (the chloro- 4- fluorophenyl of 3-) formamide (84.8g, 97.7%).
1LCH is sequentially added into above-mentioned solid2Cl2, 500mmol triphenylphosphine, elemental iodine 127g add after mixing evenly
Enter 1mol triethanolamine.After 1h is stirred at room temperature, end of reaction is added ice water 1L, uses CH2C12(3 × 1L) extraction, merges organic
Phase, with saturated common salt water washing, anhydrous sodium sulfate is dry, column chromatography for separation (PE) obtain the chloro- 4- fluorobenzene isonitrile of 3- (69.9g,
92%).
Step b：In O2In environment, the chloro- 4- fluorobenzene isonitrile 37.3g of compound III 14.7g, 3-, vinegar are added in reaction flask
Sour palladium 35.9g, cesium carbonate 26.1g, toluene 1L mixture are stirred and are heated to reflux, reaction time 3.5h, and reaction system is cooling
To room temperature, water 1L is added, continues stirring 1 hour, there are a large amount of solids to be precipitated.Filtering, solid are eluted with water, are dried to obtain compound
IV 26.0g, molar yield 97%, HPLC purity 99.8%.
Embodiment 5
The preparation of compounds Ⅳ
Step a：The chloro- 4- fluorobenzene isonitrile of 3- is prepared according to preparation method in above-described embodiment 4.
Step b：In O2In environment, the chloro- 4- fluorobenzene isonitrile 37.3g of compound III 14.7g, 3-, vinegar are added in reaction flask
Sour palladium 35.9g, cesium carbonate 26.1g, methylene chloride 1L mixture are stirred and are heated to reflux, reaction time 3.5h, reaction system
It is cooled to room temperature, water 1L is added, continue stirring 1 hour, there are a large amount of solids to be precipitated.Filtering, solid are eluted with water, being dried to obtain
Close IV 25.0g of object, molar yield 93%, HPLC purity 99.6%.
Embodiment 6
The preparation of compounds Ⅳ
Step a：The chloro- 4- fluorobenzene isonitrile of 3- is prepared according to preparation method in above-described embodiment 4.
Step b：In O2In environment, the chloro- 4- fluorobenzene isonitrile 12.4g of compound III 14.7g, 3-, vinegar are added in reaction flask
Sour palladium 35.9g, cesium carbonate 39.1g, toluene 1L mixture are stirred and are heated to reflux, reaction time 3.5h, and reaction system is cooling
To room temperature, water 1L is added, continues stirring 1 hour, there are a large amount of solids to be precipitated.Filtering, solid are eluted with water, are dried to obtain compound
IV 24.54g, molar yield 91%, HPLC purity 99.3%.
Embodiment 7
The preparation of compound VI
By compounds Ⅳ 24.5g, S-3- hydroxyl tetrahydrofuran (V) 6.4g, triphenylphosphine 19.1g, 1800ml tetrahydrofuran
It is added in reaction flask, stirring and dissolving is placed in ice-water bath, is kept for 10 DEG C or less be slowly added dropwise containing diethyl azodiformate
The tetrahydrofuran solution 500ml of 25.4g, is added dropwise, and insulation reaction 30min, is then warmed to room temperature at 10 DEG C, until TLC is shown
Raw material disappears, and reaction solution precipitation is spin-dried for, residue silica gel column chromatography obtains solid 26.6g, molar yield 89%, HPLC purity
98.8%.
Embodiment 8
The preparation of compound VI
By compounds Ⅳ 24.5g (73mmol), S-3- hydroxyl tetrahydrofuran (V) 6.4g, triphenylphosphine, 1800ml tetrahydro
Furans is added in reaction flask, and stirring and dissolving is placed in ice-water bath, is kept for 10 DEG C or less be slowly added dropwise containing azoformic acid two
The tetrahydrofuran solution 500ml of ethyl ester 20.3g, is added dropwise, and insulation reaction 30min, is then warmed to room temperature at 10 DEG C, until TLC
It shows that raw material disappears, reaction solution precipitation is spin-dried for, residue silica gel column chromatography obtains solid 25.5g, molar yield 85%, HPLC
Purity 98.4%.
Embodiment 9
The preparation of compound VII
Water 900mL is added into reaction flask, is heated to 40 DEG C, iron powder 17.4g is added and adjusts pH with concentrated hydrochloric acid, after of continuing rising
Temperature is added portionwise VI 25.5g of compound, finishes, 10h is reacted at 60~80 DEG C to 60 DEG C, and 10% hydroxide is then added
Sodium solution adjusts pH to 8~9, stirs 30min.It filters, filtrate is acidified to pH to 4~5 with concentrated hydrochloric acid, there is solid precipitation, collects
Solid, obtains VII solid 21.9g of compound, molar yield 93.9% after vacuum drying, HPLC purity is 99.3%.
Embodiment 10
The preparation of compound VII
Water 900mL is added into reaction flask, is heated to 40 DEG C, iron powder 3.5g is added and adjusts pH with concentrated hydrochloric acid, after of continuing rising
Temperature is added portionwise VI 25.5g of compound, finishes, 10h is reacted at 60~80 DEG C to 60 DEG C, and 10% hydroxide is then added
Sodium solution adjusts pH to 8~9, stirs 30min.It filters, filtrate is acidified to pH to 4~5 with concentrated hydrochloric acid, there is solid precipitation, collects
Solid, obtains VII solid 20.4g of compound, molar yield 87% after vacuum drying, HPLC purity is 98.9%.
Embodiment 11
The preparation of compound VII
Water 900mL is added into reaction flask, is heated to 40 DEG C, iron powder 31.2g is added and adjusts pH with concentrated hydrochloric acid, after of continuing rising
Temperature is added portionwise VI 25.5g of compound, finishes, 10h is reacted at 60~80 DEG C to 60 DEG C, and 10% hydroxide is then added
Sodium solution adjusts pH to 8~9, stirs 30min.It filters, filtrate is acidified to pH to 4~5 with concentrated hydrochloric acid, there is solid precipitation, collects
Solid, obtains VII solid 22.3g of compound, molar yield 95.9% after vacuum drying, HPLC purity is 99.8%.
Embodiment 12
The preparation of Afatinib (I)
At 5 DEG C, the trimethyl aluminium hexane solution of compound concentration 2M, spare；Methylene chloride is sequentially added in reaction flask
1800mL, 22.4g compound VII is added the hexane solution 90mL for the trimethyl aluminium that concentration is 2M, is stirred at room temperature 2 hours,
4- dimethylamino ethyl crotonate 7.9g is added, is heated to 60 DEG C, reacts 5h, TLC monitoring reaction is completed, is cooled to room temperature,
Add water quenching reaction, be extracted with ethyl acetate, merges organic layer, with anhydrous MgSO4It dries, filters, is concentrated under reduced pressure, get A Fa is replaced
Buddhist nun 28.6g, molar yield 98%, HPLC purity are 99.8%.
Embodiment 13
The preparation of Afatinib (I)
At 5 DEG C, the trimethyl aluminium hexane solution of compound concentration 2M, spare；Methylene chloride is sequentially added in reaction flask
1800mL, 22.4g compound VII is added the hexane solution 90mL for the trimethyl aluminium that concentration is 2M, is stirred at room temperature 2 hours,
4- dimethylamino ethyl crotonate 7.9g is added, is heated to 60 DEG C, reacts 3h, TLC monitoring reaction is completed, is cooled to room temperature,
Add water quenching reaction, be extracted with ethyl acetate, merges organic layer, with anhydrous MgSO4It dries, filters, is concentrated under reduced pressure, get A Fa is replaced
Buddhist nun 28.1g, molar yield 96%, HPLC purity are 99.6%.
Embodiment 14
The preparation of Afatinib (I)
At 5 DEG C, the trimethyl aluminium hexane solution of compound concentration 2M, spare；Toluene is sequentially added in reaction flask
1800mL, 22.4g compound VII is added the hexane solution 30mL for the trimethyl aluminium that concentration is 2M, is stirred at room temperature 2 hours,
4- dimethylamino ethyl crotonate 7.9g is added, control temperature reacts 5h to 10 DEG C, and TLC monitoring reaction is completed, and is cooled to room
Temperature adds water quenching reaction, is extracted with ethyl acetate, and merges organic layer, with anhydrous MgSO4Dry, filter, be concentrated under reduced pressure, obtain Ah
Method replaces Buddhist nun 26.5g, molar yield 90%, and HPLC purity is 99.1%.
Claims (9)
1. a kind of synthetic method of anti-tumor drug Afatinib, which is characterized in that this method includes the following steps：
(a) starting material 2- nitro -5- bromophenol reacts obtainedization under catalyst, ligand and alkaline condition with formamidine acetate
Close object III；The catalyst be tris(dibenzylideneacetone) dipalladium, the ligand be 2- di-t-butyl phosphine -2 ', 4 ', 6 '-three is different
Propyl -3,6- dimethoxy -1,1 '-biphenyl or 2- (dicyclohexylphosphontetrafluoroborate) -3,6- dimethoxy -2 ', 4 ', 6 '-triisopropyl -1,
1 '-biphenyl；
(b) compound III is reacted under cesium carbonate, catalysts conditions with the chloro- 4- fluorobenzene isonitrile (X) of 3- is made compounds Ⅳ；It is described
Catalyst is selected from palladium acetate；
(c) compounds Ⅳ is reacted with S-3- hydroxyl tetrahydrofuran (V) is made compound VI；
(d) compound VII is made through restoring in compound VI；
(e) compound VII reacts under trimethyl aluminium effect with 4- dimethylamine ethyl crotonate is made Afatinib (I)；It is synthesized
Route is as follows：
2. the synthetic method of Afatinib as described in claim 1, which is characterized in that step (a) reaction dissolvent be selected from methanol,
Ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, sec-butyl alcohol or the tert-butyl alcohol.
3. the synthetic method of Afatinib as described in claim 1, which is characterized in that alkali described in step (a) is selected from carbon
Sour caesium；2- nitro -5- bromophenol, formamidine acetate, catalyst, ligand and cesium carbonate molar ratio are 1:1~1.1:1~3:2~6:1
~2.2.
4. the synthetic method of Afatinib as described in claim 1, which is characterized in that step (b) reaction dissolvent is selected from toluene
Or methylene chloride.
5. the synthetic method of Afatinib as described in claim 1, which is characterized in that the chloro- 4- of step (b) compound III, 3-
Fluorobenzene isonitrile, palladium acetate and cesium carbonate molar ratio are 1:1~3:2~5:1~1.5.
6. the synthetic method of Afatinib as described in claim 1, which is characterized in that restoring method used in step (d) is iron
The molar ratio of metal reduction in the presence of hydrochloric acid or acetic acid, compound VI and reducing metal is 1:1~9.
7. the synthetic method of Afatinib as described in claim 1, which is characterized in that step (e) reaction dissolvent is toluene, chlorine
Imitative or methylene chloride, 10 DEG C~60 DEG C of reaction temperature, 3~5h of reaction time.
8. the synthetic method of Afatinib as described in claim 1, which is characterized in that in step (e), compound VII, 4- bis-
The molar ratio of methylamine ethyl crotonate and trimethyl aluminium is 1:1:1~3.
9. the synthetic method of Afatinib as described in claim 1, which is characterized in that the chloro- 4- fluorobenzene isonitrile (X) of 3- is by following
Step synthesis：
(1) the chloro- 4- fluoroaniline of 3- and formic acid react 3.5 hours preparation N- (the chloro- 4- fluorophenyl of 3-) formamides under the conditions of 80 DEG C
(Ⅸ)；
(2) N- (the chloro- 4- fluorophenyl of 3-) formamide (Ⅸ) is organic solvent is methylene chloride, catalyst is triphenylphosphine and iodine list
Matter, alkali prepare the chloro- 4- fluorobenzene isonitrile (X) of 3- for reaction 1h under the conditions of triethanolamine, is stirred at room temperature.
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