ChemicalBook CAS DataBase List Alectinib Hydrochloride

Alectinib Hydrochloride synthesis

5synthesis methods

Product Name:Alectinib Hydrochloride
CAS Number:1256589-74-8
Molecular formula:C30H35ClN4O2
Molecular Weight:519.09

The synthetic route to alectinib as reported by Chugai begins with 7-methoxy-2-tetralone (1). Bis-methylation with tetrabutylammonium hydrogen sulfide (TBAHS)/aq KOH/MeI followed by bromination with N-bromosuccinimide (NBS) provided the bromo-tetralone 2 in 67% yield over the two steps. Further reaction of 2 with 3-hydrazinobenzonitrile/trifluoroacetic acid (TFA) led to formation of the desired Fischer indole product, albeit as a 1:1 mixture of regioisomers (3/4), which were carried forward as a mixture to oxidation with 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone (DDQ). It is important to note that although representative procedures are published describing the conversion of 2 to alectinib (I), no yields were provided for these transformations. Following oxidation, the desired product 5 could be isolated as a single isomer via precipitation from the crude reaction mixture. Installation of the 4-morpholino-piperidine moiety took place in three transformations from 5, beginning with 1-dodecanethiol/ N-methyl-2-pyrrolidone (NMP)/NaOMe-facilitated methyl cleavage. The corresponding phenol was then readily converted to the triflate intermediate and displaced with 4-(piperidin-4-yl)morpholine (6) at elevated temperature, providing intermediate 7. Crosscoupling of the bromide 7 with ethynyl triisopropylsilane under Pd-catalyzed cross-coupling conditions (Pd(CH3CN)2Cl2/2-dicyclohexylphosphino- 20,40,60-triisopropylbiphenyl (XPhos), reflux) followed by cleavage of the resulting alkylsilane with tetrabutylammonium fluoride (TBAF) yielded the ethynyl precursor to alectinib. Hydrogenation of this unsaturated system under standard conditions (H2, Pd/C) followed by HCl salt formation furnished the final drug target alectinib hydrochloride (I).

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Yield:-

Reaction Conditions:

with hydrogenchloride;acetic acid in water;butanone at 60; for 0.5 h;

Steps:

30 Compound F6-20

Hydrochloride Salt
9-Ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile was dissolved in a mixture of 10 v/w of methyl ethyl ketone, 4 v/w of water, and 3 v/w of acetic acid at 60° C.
To the dissolved solution, 1 v/w of hydrochloric acid (2 N) was added dropwise.
After stirring at 60° C. for 30 minutes, 25 v/w of ethanol was added dropwise.
The precipitated solid was filtered and dried to give 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile monohydrochloride salt.
9-Ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile monohydrochloride salt obtained was pulverized by using a jet mill.
¹H-NMR (400 MHz, DMSO-D₆) δ: 12.78 (1H, s), 10.57 (1H, br.s), 8.30 (1H, J=8.4 Hz), 8.05 (1H, s), 7.99 (1H, s), 7.59 (1H, d, J=7.9 Hz), 7.36 (1H, s), 4.02-3.99 (2H, m), 3.84-3.78 (2H, m), 3.51-3.48 (2H, m), 3.15-3.13 (1H, s), 2.83-2.73 (2H, s), 2.71-2.67 (2H, s), 2.23-2.20 (2H, m), 1.94-1.83 (2H, m), 1.75 (6H, s), 1.27 (3H, t, J=7.5 Hz)
FABMS: m/z 483 [M+H]⁺

References:

US2013/143877,2013,A1 Location in patent:Paragraph 0683; 0684; 0685