Synthesis of Bosutinib from 3-Methoxy-4-hydroxybenzoic Acid

Molecules 2010, 15, 4261-4266

Synthesis of Bosutinib from 3-Methoxy-4-hydroxybenzoic Acid

Dasatinib

Dasatinib is an oral multi- BCR/ABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It is being evaluated for use in numerous other cancers, including advanced prostate cancer.

Name:             N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide monohydrate

CAS No.:        302962-49-8

M.W.:             488.01

Formula:         C₂₂H₂₆ClN₇O₂S

Synonym:       BMS-354825, sprycel

URL:            http://www.sprycel.com/                        http://medi.ru/doc/047100.htm

Targets:          BCR/ABL and Src

Synthesis:       http://ak-tki.blogspot.com/2011/01/synthesis-of-dasatanib.html

Фармакологическое действие препарата Дазатиниб (Спрайсел)

Противоопухолевый препарат, мультикиназный ингибитор, наномолярных концентрациях ингибирует тирозинкиназы: BCR-ABL, семейство SRC (SRC, LCK, YES, FYN), c-KIT, EPHA2 и PDGFRβ. C помощью компьютерного моделирования установлено, что дазатиниб связывается со многими формами ABL киназы.

In vitro спрайсел показывает активность в различных лейкозных клеточных линиях, как чувствительных, так и резистентных к гливеку. Дазатиниб останавливает рост клеточных линий острого лимфобластного лейкоза и хронического миелолейкоза с гиперэкспрессией BCR-ABL. Дазатиниб показывает активность в случаях резистентность, связанную с мутациями BCR-ABL киназы, путем активацией альтернативных сигнальных путей, включающих киназы семейства SRC (LYN, НСК) и гиперэкспрессией гена лекарственной полирезистентности.

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