CC BY-ND-NC 4.0 · Synlett 2019; 30(04): 471-476
DOI: 10.1055/s-0037-1610375
letter
Copyright with the author

A New Synthesis of Gefitinib

Taber S. Maskrey
,
Tyler Kristufek
,
Matthew G. LaPorte
,
Prasanth R. Nyalapatla
,
Peter Wipf*
This work was partially supported by Sterling, Perugia, Italy.
Further Information

Publication History

Received: 08 September 2018

Accepted: 15 October 2018

Publication Date:
14 November 2018 (eFirst)

  

Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Abstract

A four-step synthesis of the FDA-approved anticancer agent gefitinib was developed starting from 2,4-dichloro-6,7-dimethoxyquinazoline. Reaction temperatures were highly practical (0–55 °C), and chromatographic purifications were avoided. The ionic liquid trimethylammonium heptachlorodialuminate was used to monodemethylate the dimethoxyquinazoline core. In the final step, a selective dehalogenation was employed to provide gefitinib in 14% overall yield on a gram scale.

Supporting Information

 
  • References and Notes

  • 1 Gridelli C, De Marinis F, Di Maio M, Cortinovis D, Cappuzzo F, Mok T. Lung Cancer 2011; 72: 249
  • 2 Siegel RL, Miller KD, Jemal A. CA-Cancer J. Clin. 2007; 67: 7
  • 3 da Cunha Santos G, Shepherd FA, Tsao MS. Annu. Rev. Pathol.: Mech. Dis. 2011; 6: 49
  • 4 Bogdanowicz BS, Hoch MA, Hartranft ME. J. Oncol. Pharm. Pract. 2017; 23: 203
  • 5 Knesl P, Röseling D, Jordis U. Molecules 2006; 11: 286
  • 6 Zheng Y, Li M, Zhang S, Ji M. J. Chem. Res. 2009; 388
  • 7 Chandregowda V, Rao GV, Reddy GC. Synth. Commun. 2007; 37: 3409
  • 8 Chandrasekhar M, Srinivasulu D, Seshaiah K, Kumar N. Pharm. Chem. J. 2014; 48: 520
  • 9 Li F, Feng Y, Meng Q, Li W, Li Z, Wang Q, Tao F. ARKIVOC 2007; (i): 40
  • 10 Gibson KH. US 5770599, 1998
  • 11 Bretherick L. 3rd ed. Hazards in the Chemical Laboratory . Royal Society of Chemistry; London: 1981: 503
  • 12 Chandregowda V, Rao GV, Reddy GC. Org. Process Res. Dev. 2007; 11: 813
  • 13 Kang SK, Lee SW, Woo D, Sim J, Suh Y.-G. Synth. Commun. 2017; 47: 1990
  • 14 Anon, Dangerous Prop. Ind. Mater. Rep. 1995; 15: 354
  • 15 Wipf P, George KM. Synlett 2010; 644
  • 16 Hao C, Zhao F, Song H, Guo J, Li X, Jiang X, Huan R, Song S, Zhang Q, Wang R, Wang K, Pang Y, Liu T, Lu T, Huang W, Wang J, Lin B, He Z, Li H, Li F, Zhao D, Cheng M. J. Med. Chem. 2018; 61: 265
  • 17 Iwaki T, Nakamura Y, Tanaka T, Ogawa Y, Iwamoto O, Okamura Y, Kawase Y, Furuya M, Oyama Y, Nagayama T. Bioorg. Med. Chem. Lett. 2017; 27: 4904
  • 18 Park H, Jung H.-Y, Mah S, Hong S. Angew. Chem. Int. Ed. 2017; 56: 7634
  • 19 Kemperman GJ, Roeters TA, Hilberink PW. Eur. J. Org. Chem. 2003; 1681
  • 20 Kemperman GJ, Ter Horst B, Van de Goor D, Roeters T, Bergwerff J, Van der Eem R, Basten J. Eur. J. Org. Chem. 2006; 3169
  • 21 Anon; Q3C — Tables and List Guidance for Industry: Revision 4; U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER): Silver Springs, 2018; https://www.fda.gov/downloads/ drugs/guidances/ucm073395.pdf
  • 22 Chelucci G, Figus S. J. Mol. Catal. A: Chem. 2014; 393: 191
  • 23 Röver S, Andjelkovic M, Bénardeau A, Chaput E, Guba W, Hebeisen P, Mohr S, Nettekoven M, Obst U, Richter WF, Ullmer C, Waldmeier P, Wright MB. J. Med. Chem. 2013; 56: 9874
  • 24 Yee NK, Farina V, Houpis IN, Haddad N, Frutos RP, Gallou F, Wang X.-J, Wei X, Simpson RD, Feng X, Fuchs V, Xu Y, Tan J, Zhang L, Xu J, Smith-Keenan LL, Vitous J, Ridges MD, Spinelli EM, Johnson M, Donsbach K, Nicola T, Brenner M, Winter E, Kreye P, Samstag W. J. Org. Chem. 2006; 71: 7133
  • 25 2-Chloro-N-(3-chloro-4-fluorophenyl)-6,7-dimethoxyquinazolin-4-amine (2)A vigorously stirred, pale-pink, homogeneous solution of 3-chloro-4-fluoroaniline (3.37 g, 23.2 mmol) in AcOH (22.5 mL, 394 mmol) was treated at 45 °C with neat 2,4-dichloro-6,7-dimethoxyquinazoline (1; 5.00 g, 19.3 mmol) in a single batch. The temperature was monitored with an internal thermometer. After the addition was complete (1 min), the resulting mixture was warmed to 55 °C for a total of 2 h. The pink solution turned viscous and then solidified after about 30 min, after which the magnetic stirring was stopped. TLC analysis after 2 h showed that the aniline was consumed, some quinazoline starting material remained, and the product had formed [5% MeOH–­CH2Cl2; quinazoline: Rf  = 0.85, aniline: Rf  = 0.7; product 2: Rf  = 0.2; byproduct (<5%; aniline dimer addition product): Rf  = 0.1]. The solid pink mixture was cooled to 40 °C then dissolved in warm EtOAc (0.50 L, 40 °C) and 2 M aq NaOH (275 mL) with vigorous agitation. The solution was transferred to a separatory funnel and vigorously shaken. The layers were separated and the aqueous layer (~pH 10) was back-extracted with EtOAc (2 × 100 mL). The combined organic layers were extracted with 0.5 M aq NaOH (2 × 100 mL), dried (Na2SO4, ~40 g), filtered, and concentrated (75 mL). The precipitate was collected by filtration and washed with EtOAc (40 mL) to yield a white powder that was dried in vacuo (0.5 Torr, 20 °C) to yield a first batch of product (yield: 3.99 g). The original organic filtrate was then further concentrated to 37.5 mL, and the precipitate was collected by filtration and washed with additional EtOAc (~20 mL) to afford a second batch of product (0.60 g). After 1H and 19F NMR analysis, the two batches were combined to give a colorless solid; yield: 4.59 g (12.5 mmol, 65%); mp 273.0–275.8 °C; TLC: Rf  = 0.2 (5% MeOH–CH2Cl2); IR (ATR, neat): 3387, 2980, 1980, 1623, 1573, 1500, 1457, 1342, 1217, 1147, 997, 963, 846, 795 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 9.92 (s, 1 H), 8.00 (dd, J = 6.8, 2.8 Hz, 1 H), 7.84 (s, 1 H), 7.76–7.72 (m, 1 H), 7.50 (app t, J = 9.2 Hz, 1 H), 7.20 (s, 1 H), 3.95 (s, 3 H), 3.93 (s, 3 H). 13C NMR (100 MHz, DMSO-d 6): δ = 158.2, 155.6, 154.4, 153.1, 149.6, 148.7, 136.3, 124.7, 123.5, 119.6, 117.4, 107.6, 107.2, 102.5, 56.8, 56.5. 19F NMR (376 MHz, DMSO-d 6): δ = –121.9; HRMS (LC/MS, ESI+): m/z [M + H]+ calcd for C16H13Cl2FN3O2: 368.0363; found: 368.0361.[TMAH][Al2Cl7]A suspension of AlCl3 (9.00 g, 67.5 mmol) in CH2Cl2 (67.5 mL) was cooled in an ice bath and treated by portionwise addition of Me3NH+ Cl (3.23 g, 33.7 mmol). After addition was complete, the reaction mixture was warmed to r.t. and stirred for 2 h. This mixture (12.2 g in 67.5 mL CH2Cl2) was used in the subsequent reaction without further purification or concentration.2-Chloro-4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-ol (3)A suspension of quinazolinamine 2 (4.11 g, 11.2 mmol) in CH2Cl2 (11 mL) was added in two portions to a freshly prepared solution of [TMAH][Al2Cl7] (12.2 g, 33.5 mmol) in CH2Cl2 (67.5 mL). The first batch (7.0 mL) was added at a rate of 1 mL/min, and the second batch, along with a rinse of CH2Cl2 (4.0 mL), was added at a rate of 2 mL/min. The reaction mixture was then magnetically stirred and heated for 2 h at reflux, while the external temperature was maintained at ~50 °C. After 1 h, a light-brown suspension formed. TLC analysis (5% MeOH–CH2Cl2) after 2 h showed that the starting material had been consumed and a product spot corresponding to the mixture of phenol regioisomers had formed (Rf  = 0.4). The suspension was cooled to 0 °C, and 2 M aq HCl (~200 mL) was added dropwise from an addition funnel at a rate of 4.0 mL/min over 50 min while the rapidly forming suspension was stirred vigorously. The internal temperature of the solution was maintained below 20 °C to avoid solvent evaporation. After complete addition of the 2 M aq HCl, the resulting mixture (pH = 0) was filtered through a fritted glass funnel (~200 mL of filtrate was collected). The collected filter cake was washed with H2O (2 × 40 mL) and briefly dried by vacuum filtration to give ~50 g of a viscous residue that was transferred into a round-bottomed flask and concentrated by rotary evaporation under vacuum until a slurry (about 15–16 g) was obtained. This residue was suspended in hot MeOH (100 mL), heated to reflux for 10 min, and then allowed to cool and precipitate for 6 h while stirring was maintained. The solid was collected by filtration, washed with MeOH (10 mL) and dried in vacuo (0.5 Torr, 20 °C) to give as a white solid consisting of a 97:3 mixture of regioisomers; yield: 1.26 g (3.56 mmol, 32%).Major Regioisomer 3Mp 335.4–336.7 °C; TLC: Rf  = 0.4 (5% MeOH–CH2Cl2); IR (ATR, neat): 3392, 2555, 1620, 1571, 1517, 1498, 1421, 1350, 1283, 1216, 1157, 1010, 973, 844, 802, 735 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 9.86 (s, 1 H), 9.83 (s, 1 H), 8.09 (dd, J = 6.8, 2.8 Hz, 1 H), 7.80–7.76 (m, 2 H), 7.46 (app t, J = 9.2 Hz, 1 H), 7.20 (s, 1 H), 3.97 (s, 3 H). 13C NMR (100 MHz, DMSO-d 6): δ = 157.5, 154.7, 153.2, 152.3, 147.3, 147.0, 136.2, 123.6, 122.5, 118.8, 116.5, 107.9, 106.7, 105.7, 56.1.19F NMR (376 MHz, DMSO-d 6): δ = –122.4; HRMS (LC/MS, ESI+): m/z [M + H]+ calcd for C15H11Cl2FN3O2: 354.0207; found: 354.0208.Characteristic Signals for Minor Regioisomer: 2-Chloro-4-[(3-chloro-4-fluorophenyl)amino]-6-methoxyquinazolin-7-ol (6) 1H NMR (400 MHz, DMSO-d 6): δ = 10.67 (s, 1 H). 19F NMR (376 MHz, DMSO-d 6): δ = –122.0.2-Chloro-N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine (4)A solution of quinazolinol 3 (1.25 g, 3.53 mmol), 4-(3-chloropropyl)morpholine (0.59 mL, 3.9 mmol), and Cs2CO3 (2.30 g, 7.06 mmol) in degassed DMSO (10.0 mL) was stirred at 40 °C under N2, while the reaction was monitored by TLC (5% MeOH–CH2Cl2; starting material: Rf  = 0.4; product 3: Rf  = 0.3). After 2.5 h, the mixture was cooled to r.t., diluted with EtOAc (100 mL), and extracted. The organic layer was washed sequentially with sat. aq NaHCO3 (2 × 25 mL), 1 M aq LiCl (7.5 mL), and 2 M aq NaOH (7.5 mL). The aqueous layer (pH >12) was then back-extracted with EtOAc (2 × 50 mL), and the combined organic layers were dried (Na2SO4, 12 g), filtered, rinsed with EtOAc (15 mL), and concentrated. The crude residue (2.02 g) was heated at reflux in MeOH (20 mL) for 10 min, and then allowed to precipitate overnight at r.t. The solids were collected by filtration, washed with MeOH (10 mL), and dried in vacuo (0.5 Torr, 20 °C) to afford a colorless solid; yield: 1.36 g, 2.82 mmol (80%); mp 213.7–217.3 °C; TLC: Rf  = 0.3 (5% MeOH–CH2Cl2); IR (ATR, neat): 3329, 2813, 1945, 1623, 1578, 1499, 1430, 1290, 1221, 1149, 1110, 1013, 960, 852, 735 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 9.92 (s, 1 H), 8.00 (dd, J = 6.8, 2.8 Hz, 1 H), 7.83 (s, 1 H), 7.76–7.73 (m, 1 H), 7.50 (app t, J = 9.2 Hz, 1 H), 7.19 (s, 1 H), 4.17 (t, J = 6.4 Hz, 2 H), 3.93 (s, 3 H), 3.58 (app t, J = 4.4 Hz, 4 H), 2.49–2.45 (m, 2 H), 2.38 (br s, 4 H), 2.01–1.98 (m, 2 H). 13C NMR (100 MHz, DMSO-d 6): δ = 158.2, 155.7, 154.4, 153.0, 149.0, 148.6, 136.3, 124.8, 123.6, 119.5, 119.4, 117.3, 117.1, 107.6, 107.2, 103.3, 67.7, 66.6, 56.6, 55.4, 53.9, 26.3. 19F NMR (376 MHz, DMSO-d 6): δ = –121.8; HRMS (LC/MS, ESI+): m/z [M + H]+ calcd for C22H24Cl2FN4O3: 481.1204; found: 481.1203. N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (5; Gefitinib, Iressa)AcOH (2.68 mL, 48.2 mmol) and quinazolinamine 4 (1.16 g, 2.41 mmol) were added sequentially in dropwise manner to a suspension of Zn dust (0.236 g, 36.1 mmol) and TMEDA (3.61 mL, 24.1 mmol) in MeOH (58.0 mL) at 0 °C. The mixture was then heated to 40–45 °C for 24 h, cooled to r.t., and diluted with MeOH (60.0 mL). 2-Mercaptonicotinic acid (5.61 g, 36.1 mmol) was added, and the suspension was vigorously stirred at r.t. for 30 min, diluted with MTBE (100 mL), and washed with 2 M aq NaOH (2 × 100 mL). The combined aqueous layers were back-extracted with MTBE (100 mL), and the combined organic layers were washed with sat. aq NaHCO3 (100 mL) then dried (Na2SO4), filtered, and concentrated to give a yellow solid residue (0.97 g). This solid was dissolved in hot MeOH (30 mL) and allowed to crystallize for 3 h at r.t. The colorless needles were collected by filtration, washed with MTBE (10 mL), and dried in vacuo (0.5 Torr, 20 °C) to provide a first batch of the crystalline product (0.84 g). The mother liquor was then concentrated (~15 mL) and allowed to crystallize overnight at r.t. The resulting crystals were collected by filtration and dried in vacuo (0.5 Torr, 20 °C) to provide a second batch of product (0.090 g; mp 188.5–190.6 °C), containing residual MeOH (~4% by 1H NMR), which was combined with the first batch. The product was further dried in vacuo (0.5 Torr, 80 °C) for 24 h to provide a colorless solid; yield: 0.930 g (2.08 mmol, 82%); mp 195.7–197.5 °C; TLC: Rf  = 0.2 (EtOH–EtOAc–hexanes); IR (ATR, neat): 3365, 3160, 1873, 2816, 1622, 1578, 1530, 1497, 1472, 1426, 1393, 1353, 1280, 1217, 1112, 1044, 993, 957, 850, 772 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 9.57 (s, 1 H), 8.50 (s, 1 H), 8.11 (dd, J = 6.8, 2.8 Hz, 1 H), 7.81 (s, 1 H), 7.80–7.77 (m, 1 H), 7.45 (app t, J = 9.2 Hz, 1 H), 7.21 (s, 1 H), 4.18 (t, J = 6.0 Hz, 2 H), 3.94 (s, 3 H), 3.58 (app t, J = 4.4 Hz, 4 H), 2.48–2.46 (m, 2 H), 2.39 (br s, 4 H), 2.03–1.96 (m, 2 H). 13C NMR (100 MHz, DMSO-d 6): δ = 156.0, 154.5, 152.6, 151.9, 148.3, 147.0, 136.8, 123.5, 122.4, 118.8, 118.7, 116.6, 116.4, 108.8, 107.3, 102.5, 67.1, 66.2, 55.9, 55.0, 53.4, 25.9. 19F NMR (376 MHz, DMSO-d 6): δ = –123.3; HRMS (LC/MS, ESI+): m/z [M + H]+ calcd for C22H25ClFN4O3: 447.1594; found: 447.1593.