Synthesis of Danusertib

M.Wt: 474.55
Formula: C₂₆H₃₀N₆O₃
CAS No.: 827318-97-8

PHA-739358 (Danusertib) is a pyrrolopyrazole and small molecule Aurora kinases and Bcr-Abl kinase inhibitor with IC50 of 13, 79, and 61 nM for Aurora A, B, and C, respectively.
High activity was also observed against kinases known to be mutated or over expressed in different cancers such as Ret, Trk-A, and Abl (∼2-fold higher IC50 compared with Aurora A). Cross-reactivity with FGFR-1 was seen at a 4-fold higher IC50 compared with Aurora A. However, in another study, its specificity was tested in vitro against a broad panel of kinases representative of different kinase families. It was shown to be a potent inhibitor of all three Aurora kinases with IC50s of 27, 135, and 120 nM for Aurora A, B, and C, respectively.

Cortes-Franco J, Dombret H, Schafhausen P, et al. Danusertib hydrochloride (PHA-739358), a multi-kinase aurora inhibitior, elicits clinical benefit in advanced chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia. Blood. 2009,114, 356.

Synthesis of Dasatinib

J. Med. Chem. 2004, 47, 6658-6661

Синтез дазатиниба (спрайсел, БРИСТОЛ-МАЙЕРС СКВИББ)

ARKIVOC 2010 (vi) 32-38

"A new and efficient preparation of 2-aminothiazole-5-carbamides: applications to the synthesis of the anti-cancer drug dasatinib"

Bang-Chi Chen, Rulin Zhao, Bei Wang, Roberto Droghini, Jean Lajeunesse,Pierre Sirard, Masaki Endo, Balu Balasubramanian, and Joel C. Barrisha

Synthesis of Lapatinib

Guntrip S.B., Lackey K.E., Cockerill G.S., Carter M.C., Smith K.J. Bicyclic heteroaromatic compounpds as protein tyrosine kinase inhibitors. EP 1047694; WO 9935146 .

Quinazoline ditosylate salt compounds  (US7157466)

A NOVEL PROCESS FOR THE PREPARATION OF LAPATINIB AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS (WO 2010061400)

Synthesis of Sorafenib

.

Bankston, D.; Dumas, J.; Natero, R.; Riedl, B.; Monahan, M.-K.; Sibley, R.
Org.Pro. Res. Deve. 2002, 6, 777-781 

Other article

Sorbera, L.A., Castañer, J., Bozzo, J., Leeson, P.A. BAY-43-9006. Drugs Fut 2002, 27, 12, 1141.

Synthesis of Cediranib

Synthesis of Erlotinib

Synthesis of tert-butyl (1H-benzo[d]imidazol-2-yl)methylcarbamate.

tert-Butyl (1H-benzo[d]imidazol-2-yl)methylcarbamate.

Benzene-1, 2-diamine (1.05 g, 9.72 mmol) and N-(tert-butoxycarbonyl)glycine (1.71 g, 9.72 mmol) were dissolved in 30 ml of THF and cooled to 0 °C. Into the above solution was added N, N'-dicyclohexylcarbodiimide (2.41 g, 11.7 mmol ) in batches and the mixture was stirred at 0 °C for half an hour and then at room temperature overnight. The reaction mixture was filtrated and evaporated to afford a brown oil, which was purified by a silica-gel column chromatography (dichloromethane / methanol, 25:1 by volume) to get a yellow solid (2.24 g). The solid was dissolved in 20 ml of acetic acid and the solution was stirred at 72 °C for 8 h. The acetic acid was removed under reduced pressure and the crude compound was purified by a silica-gel column chromatography (dichloromethane / methanol, 25:1 by volume) to afford a white solid. Yield: 82%. m.p. 181-183 °C. IR (KBr) cm-1: 3343 (-NH-), 3058, 2980, 2940 (CH, aliphatic), 1686 (>C=O), 1529 (-C=C-), 736 (-Ar-); 1H NMR (300 MHz, CDCl3, δ ppm): 1.45 (s, 9H, CH3), 4.53-4.55 (d, 2H, J = 6.3 Hz, CH2), 6.12 (brs, 1H, NH), 7.22-7.25 (m, 2H, Ar-H), 7.54-7.60 (m, 2H, Ar-H); HRMS (ESI): [M + H]+ calcd m/z 248.1400, found 248.1397.δ ppm): 1.45 (s, 9H, CH3), 4.53-4.55 (d, 2H, J = 6.3 Hz, CH2), 6.12 (brs, 1H, NH), 7.22-7.25 (m, 2H, Ar-H), 7.54-7.60 (m, 2H, Ar-H); HRMS (ESI): [M + H]+ calcd m/z 248.1400, found 248.1397.

Synthesis of Gefitinib from Methyl 3-Hydroxy-4-methoxybenzoate

Статья описывает все существующие варианты синтеза Gefinitib и предлагает новый.
Report describes all existing variants of synthesis Gefinitib and offers the new method.
http://www.mdpi.org/molecules/papers/12030673.pdf

Synthesis of Imatinib

(a) Zimmermann, J. EP Patent 564,409, 1993.

(b) Zimmermann, J. U.S. Patent 5,521,184, 1996.

(c) Zimmermann, J.; Buchdunger, E.;Mett, H.; Meyer, T.; Lydon, N. B.; Traxler, P. Bioorg. Med. Chem.Lett. 1996, 11, 1221.

Loiseleur, O.; Kaufmann, D.; Abel, S.; Buerger, H. M.; Meisenbach, M.; Schmitz, B.; Sedelmeier, G. W.O.Patent 03/066,613, 2003.

Organic Process Research & Development  2008, 12, 490–495 

United States Patent 7674901

Process for preparation of imatinib base

An improved process for the preparation of imatinib base and its pharmaceutically acceptable acid addition salts by (a) reacting 2-methyl-5-nitroaniline with cyanamide in the presence of hydrochloric acid to obtain 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride; (b) converting 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride to 1-(2-methyl-5-nitrophenyl)guanidine nitrate; (c) condensing 3-acetylpyridine with N,N-dimethylformamide dimethyl acetal to obtain 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one; (d) reacting 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one with 1-(2-methyl-5-nitrophenyl)guanidine nitrate to obtain N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine; (e) reducing N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine using hydrazine in the presence of Raney nickel to obtain N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine; (f) condensing N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine with 4-chloromethylbenzoyl chloride in the presence of an inorganic base to obtain 4-(chloromethyl)-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide; and (g) condensing 4-(chloromethyl)-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide with an excess of N-methylpiperazine to obtain imatinib base; and adding water or a mixture of water and an organic solvent; and isolating said imatinib base. The process allows for using simple starting materials, while simultaneously avoiding a laborious isolation and purification of intermediates and the final product, thereby facilitating scale-up.

The synthesis of Bcr-Abl inhibiting anticancer
pharmaceutical agents imatinib, nilotinib and dasatinib
Benjamin J. Deadman,a Mark D. Hopkin,a Ian R. Baxendaleb and Steven V. Ley*a
 

Org. Biomol. Chem., 2013, Advance Article