Erlotinib Hydrochloride Recent Synthesis High Yield State of Art
Adv Pharm Balderdash. 2012; 2(1): 119–122.
Modified Synthesis of Erlotinib Hydrochloride
Leila Barghi
ane Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
ii Educatee Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
Ayuob Aghanejad
3 Inquiry Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran.
4 Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Hadi Valizadeh
1 Kinesthesia of Pharmacy, Tabriz Academy of Medical Sciences, Tabriz, Iran.
5 Drug Applied Research Center, Tabriz Academy of Medical Sciences, Tabriz, Iran.
Jaleh Barar
ane Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
three Enquiry Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Islamic republic of iran.
Davoud Asgari
1 Faculty of Pharmacy, Tabriz Academy of Medical Sciences, Tabriz, Iran.
3 Research Centre for Pharmaceutical Nanotechnology, Tabriz Academy of Medical Sciences, Tabriz, Iran.
Received 2012 Apr 10; Accepted 2012 April 29.
Abstract
Purpose: An improved and economic method has been described for the synthesis of erlotinib hydrochloride, as a useful drug in treatment of non-minor-cell lung cancer. Method: Erlotinib hydrochloride was synthesized in 7 steps starting from 3, 4-dihydroxy benzoic acid. In this study, nosotros were able to alter 1 of the central steps which involved the reduction of the 6-nitrobenzoic acid derivative to half-dozen-aminobenzoic acid derivative. An inexpensive reagent such as ammonium formate was used as an in situ hydrogen donor in the presence of palladium/charcoal (Pd/C) instead of hydrogen gas at loftier pressure level. Issue: This proposed method proceeded with 92% yield at room temperature. Synthesis of erlotinib was completed in 7 steps with overall yield of 44%. Conclusion: From the results obtained it tin can be concluded that the modified method eliminated the potential danger associated with the use of hydrogen gas in the presence of flammable catalysts. It should be mentioned that the goad was recovered subsequently the reaction and could be used again.
Keywords: Tyrosine kinase, Erlotinib, Palladium/Charcoal (Pd/C)
Introduction
Although there are wide range of cytotoxic drugs with different mechanismsof action, most of them could non distinguish between cancerous and normal jail cell types. Growth factor signaling pathways take major part in regulating fundamental cellular functions including cellproliferation,differentiation, metastasis and survival. An important mediator of growth gene signaling pathways is the human epidermal receptors (HERs).one Tyrosine kinase receptors, which belong to (HER) family unit, are over expressed in various types of solid tumors, including not-small-scale-cell lung cancer (NSCLC).These receptors are cell membrane bound proteins that consist of iii regions: an extracellular ligand binding site; an intracellular domain with tyrosine kinase action and regulatory functions; and a region that binds the receptor to the cell membrane.2-4 Phosphorylation of tyrosine residues on HERs is an of import stage in signal transduction, leading to cell proliferation for major human carcinomas. Therefore, interruption of this growth indicate is a potential target for anticancer treatment.v Erlotinib, a iv-anilinoquinazoline, is a potent inhibitor of tyrosine kinase. It reversibly and selectively binds to the adenosine triphosphate (ATP) binding site of the tyrosine kinase domain associated with HERs. Consequently phosphorylation of the tyrosine kinase is inhibited and thereby information technology tin interfere with cell communication, signal transduction and ultimately cellular growth.6 The mutual method for preparation of 4-anilinoquinazolines such as erlotinib involves the structure of suitable four-chloroquinazoline intermediate and then reacting of this intermediate with suitable substituted aniline in acidic media. The 4-chloroquinazolines are cardinal intermediates and their preparation involve a series of reaction and the utilise of highly flammable gas such as hydrogen at high pressure, and costly reagents such platinum oxide.7 Erlotinib hydrochloride was synthesized in seven steps starting from 3, 4-dihydroxy benzoic acid. In this study, nosotros were able to change one of the primal steps which involved the reduction of the 6-nitrobenzoic acrid derivative to 6-aminobenzoic acid derivative. An inexpensive reagent such every bit ammonium formate was used as an in situ hydrogen donor in the presence of palladium/charcoal (Pd/C) instead of hydrogen gas at high pressure. This modified method eliminated the potential danger associated with the use of hydrogen gas in the presence of flammable catalysts. Furthermore catalyst could be recovered and used again.
Materials and Methods
Etynyl aniline was purchased from Sigma-Aldrich. Other chemicals were purchased from Merck Chemical Visitor (Darmstadt, Frg). Melting points were adamant by a Gallenkamp capillary apparatus. H NMR spectra were obtained with a Bruken-Spectrospin 400 MHz spectrometer (Varian, Switzerland).
3,4-bis(two-methoxyethoxy)-benzoic acid (three)
A suspension of three,four-dihydroxy benzoic acid (23 g), potassium carbonate (82.5 thousand) and tetrabutyl ammonium iodide (5.51 g) in DMF (120 ml) was stirred for 1 h at 100 °C. The reaction mixture was cooled to 50 °C, and then i-chloro-2-methoxyethane (54.18 ml) was added and the reaction mixture was heated to 85 °C and stirred for xx h at this temperature. The reaction mixture was filtered and the solid material was washed with ethyl acetate (300 ml). The combined filtrates were evaporated under reduced pressure level to afford a xanthous rest (ii). Without any further isolation and purification, the ester residue was dissolved in a solution of ethanol (200 ml), h2o (70 ml) and potassium hydroxide (33.5g) and stirred for 4 h at room temperature. Ethanol was removed under reduced pressure, and the pH of the solution was adjusted to ~3 past adding a solution HCl (2 N) at 0 °C. A solid was precipitated which was filtered, washed with cold water, and dried (Na2soiv) to beget carboxylic acid (3: 40 grand, 99.27%) as a white solid; Rf (20% n-hexane/ethyl acetate) 0.25; Mp: 101-103 °C, 1H-NMR (CDCl3): 0.95-0.99 (t, 3H, CHthreeCH2, 3J= 7.ten Hz), three.43 (d, 6H, 2x OCHthree), three.78-3.81 (m, 4H, 2x CHiiO), 4.xviii-4.27 (q, 2H, CHii, 3J=7.10 Hz), 6.90-6.92 (d, 1H, HAr, 3J=8.41 Hz), 7.lx (d, 1H, HAr), vii.62-7.71 (dd, 1H, HAr,iiiJ=viii.41 Hz, 4J=1.96 Hz).
Ethyl 3,4-bis(2-methoxyethoxy)-benzoate (four)
To 3,4-bis(2-methoxyethoxy)-benzoic acrid (40 g) in ethanol (300 ml) was added sulfuric acid (three ml). The mixture was stirred nether N2 at reflux for 24 hours. The solvent was removed in vacuo and the residue was extracted with ethyl acetate. Then the organic stage was washed with sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford ethyl 3,four-bis(2-methoxyethoxy)-benzoate (31.65 thousand, 71.63%); Mp: 56.five-57.5°C, 1H-NMR (CDCl3): 1.xxx-1.33 (t, 3H, CH3CH2, 3J= 7.ten Hz), iii.44 (due south, 6H, 2x OCH3), 3.76-3.73 (m, 4H, 2x CH2O), iv.16-4.21 (thousand, 4H, ii x CH2O), 4.31-4.36 (q, 2H, CH2, 3J=7.10 Hz), half-dozen.89-half dozen.92 (d, 1H, HAr, 3J=viii.41 Hz), 7.50-7.52 (d, 1H, HAr,ivJ=ane.96 Hz), vii.60-7.62 (dd, 1H, HAr,3J=viii.41 Hz, 4J=1.96 Hz).
Ethyl four,five-bis(2-methoxyethoxy)-2-nitro-benzoate (five)
The product of previous step (30g) in acetic acid (90 ml)was treated drop wise with conc. HNO3 (25ml) at v °C, and the solution was stirred 24 hours before pouring in to the water ice. The solvent was removed in vacuo and the residue was extracted with ethyl acetate. Then the organic phase was washed with sodium bicarbonate solution and brine and concentrated in vacuo to beget Ethyl 4,5-bis(2-methoxyethoxy)-two-nitro-benzoate (32 1000, 92.75%); 1H-NMR (CDClthree): 1.32-1.36 (t,3H, CH3CHii, iiiJ= 7.xx Hz), 3.44 (s, 6H, 2x OCH3), three.71-iii.81(1000, 4H, 2x CHiiO), 4.23-iv.27 (m, 4H, 2x CH2O), four.34-4.36 (q, 2H, CHtwo, iiiJ=7.20 Hz),7.13 (s, 1H, HAr,), 7.50 (s, 1H, HAr).
ii-amino-4,v-bis (2-methoxyethoxy)-benzoate (vi)
2-Propanol (350 ml) was added to a flask containing Pd/C (9.32 m). Ammonium formate (55.xiv yard) in water (35 mL) was transferred to the same flask. The reaction mixture was stirred for ane min to actuate Pd/C. Next, Ethyl 4,5-bis(2-methoxyethoxy)-2-nitro-benzoate (30 thousand) were added, and the reaction mixture was stirred at room temperature (xx min). The reaction mixture was filtered and the solid cloth was washed with ethyl acetate and 2-propanol. The filtrate was evaporated under reduced force per unit area and the residue was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-amino-four,five-bis (2-methoxyethoxy)-benzoate (25.270 g, 92.33%); 1H-NMR (CDCliii):1.34-1.37 (t, 3H, CH3CH2, 3J= 7.10 Hz), three.43 (s, 6H, 2x OCH3), 3.71-3.77 (m, 4H, 2x CHtwoO), 4.06-4.x (m, 4H, 2x CH2O), 4.26-4.31 (q, 2H, CHtwo, 3J=7.10 Hz), 5.65 (br, 2H, NHtwo), vi.14 (s, 1H, HAr,),7.41 (s, 1H, HAr).
vi,7- bis (two-methoxy-ethoxy) quinazolone (7)
two-amino-iv,5-bis (2-methoxyethoxy)-benzoate(25g) and ammonium formate(5g) were dissolved in formamide(38ml) and the stirred mixture was heated to 160-165 °C under an temper of N;2 ;for two hours. Cold H2O was added and precipitated product was recovered by filtration, washed with cold H2O and dried in oven. The filtrate was extracted with CHCl3 and the organic extracts were washed with brine, stale over sodium sulfate and concentrated in vacuo. The residue and quinazolone precipitate were combined, treated with ether and filtered to afford six,7- bis (2-methoxy-ethoxy) quinazolone (20.45, 87.i%); Mp: 190-191°C, iHNMR (CDCl3): 3.48 (southward, 6H, OCHthree), 3.81-3.87 (thou, 4H, 2x OCHii), 4.27-iv.29(m, 4H, 2x OCHii), seven.15(s, 1H, HAr), 7.59 (southward, 1H, HAr), 8.04 (s, 1H, HAr).
iv-chloro-half-dozen,7-bis- (two-methoxy-ethoxy)- quinazoline (8)
To 6,vii- bis (2-methoxy-ethoxy) quinazolone (18.5g) in CHCl3 (470 ml) containing ii.5 ml DMF was added oxalylchloride (nineteen ml) in four portions over 20 minutes. Once foaming ceased the solution was refluxed 2 hours. The solvent was evaporated under reduced force per unit area and the residue was dissolved in dichloromethane and done with brine, sodium bicarbonate and h2o. The organic phase was dried over sodium sulfate and concentrated in vacuo to give four-chloro-6,7-bis- (2-methoxy-ethoxy)- quinazoline (19.5g, 99.1%); Mp: 107-108 °C, 1H-NMR (CDCl3): 3.49 (s, 3H, OCHiii), iii.fifty (s, 3H, OCHiii), 3.88-3.90 (thou, 4H, 2x OCH2), 4.32-4.39 (yard, 4H, 2x OCH2), seven.36 (southward, 1H, HAr),7.44 (s, 1H, HAr), 8.88 (s, 1H, HAr)
Erlotinib hydrochloride (nine)
4-chloro-half dozen,vii-bis- (2-methoxy-ethoxy)- quinazoline (xix.5 thousand ) was suspended in 300 ml water and 3-ethynylaniline (eight.4 one thousand )and 37% hydrochloric acrid (five.2 ml ) was added at 25-thirty °C. The reaction mixture was heated at 40 °C and stirred for 1.5 hours. After cooling, obtained solid material was filtered and washed with h2o and ethylacetate:n-hexane (l:50) and was stale in oven at 40 °C to beget erlotinib hydrochloride(22.26g, 83%); Mp: 225-227 °C, iH NMR (DMSO-d6) δ xi.xiii (due south, 1H, NH), 8.70 (s, 1H, H-Ar), eight.fourteen (s,1H, H-Ar), 7.70-vii.81 (m, 2H, H-Ar), 7.28-7.51 (m, 3H, HAr),iv.31-4.32 (1000, 4H, ii CH2O), three.74-three.77 (g, 4H, 2 CH2O), 3.67 (s, 1H, ethynyl), 3.33-three.34 (d, 6H, ii OCH3).
Results and Discussions
The synthesis of erlotinib (Figure one) was started from 3,iv-dihydroxy benzoic acrid. O-alkylation of iii,four-dihydroxy benzoic acid with 4.0 equivalent of one-chloro-2-methoxyethane in hot DMF afforded intermediate methoxyethoxy-3,four-bis(two-methoxyethoxy)-benzoate in quantitative yield. DMF was and so removed and basic hydrolysis of the ester was performed in the aforementioned batch to afford the three,4-bis(2-methoxyethoxy)-benzoic acrid in 99.27% overall yield. No further purification was performed in this step. Esterification of carboxylic acid in acidic ethanol gave ethyl 3,iv-bis (ii-methoxy-ethoxy)benzoate. Nitration of ethyl iii,4-bis(2-methoxyethoxy)-benzoate in nitric acrid and glacial acerb acid at 0 °C afforded the unmarried nitro product in 92.75% yield. No purification was performed in this stride.eight In that location accept been reports on the reduction of nitro compounds to their respective derivatives using ammonium formate as in situ hydrogen donor.9So, the reduction of the nitro grouping of ethyl 3,4-bis(2-methoxyethoxy)-2-nitro-benzoate, by using ammonium formate and Pd/C goad in aqueous alcoholic solvent at room temperature gave 2-amino-4,v-bis (2-methoxyethoxy)-benzoate. The cyclization of this product and construction of 6,7- bis (2-methoxy-ethoxy) quinazoloneby using formamide and ammonium formate was the side by side pace. So chlorination of quinazolone carried out past using oxalylchloride. The reaction mixture was refluxed 1.five hours and iv-chloro-6,seven-bis- (ii-methoxy-ethoxy)- quinazoline was formed. Finally erlotinib hydrochloride was prepared in aqueous medium by using iii-ethynylaniline under acidic status. The proposed method for reduction of six-nitrobenzoic acrid derivative proceeded with 92.33% yield at room temperature. Synthesis of erlotinib was completed in 7 steps with overall yield of 44%.
a) Thousand2CO3, ClCH2CH2OCH3, TBAI, DMF, 85 °C, 20h; b) KOH, CH3CH2OH, H2O, 4h; C) CH3CH2OH,Htwoso4,90°C; d) HNO3, glacial acerb acid, 0 °C, 2h; e)ammonium formate, Pd/C,ii-propanol,25°C,xx min; f)ammonium formate, formamide, 160°C, 2h; chiliad)CHCl3, DMF, oxalylchloride,80°C, 1.5h; h)HiiO,3-ethynylaniline, HCl, 25°C, 1.5h.
Determination
An improved and economical method has been described for the synthesis of erlotinib hydrochloride, which is used equally a second- and third-line handling of advanced or metastatic NSCLC. One of the key steps of erlotinib formation which involved the reduction of the 6-nitrobenzoic acrid derivative to 6-aminobenzoic acid derivative was modified. An inexpensive reagent such as ammonium formate was used equally an in situ hydrogen donor in the presence of Pd/C instead of hydrogen gas at high pressure. This modified method eliminated the potential danger associated with the use of hydrogen gas in the presence of flammable catalysts. Furthermore catalyst could be recovered and used again.
Acknowledgement
The authors would like to thank research center for pharmaceutical nanotechnology. This article was a part of a thesis submitted for PhD degree (No.51) in Kinesthesia of Pharmacy, Tabriz Academy of Medical Sciences, Tabriz, Iran.
Disharmonize of interest
The authors report no conflicts of interest.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3846011/
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