A synthesis of RG-12525 has been published: The reaction of 2-methylquinoline (I) with chlorine gas gives 2-(chloromethyl)quinoline (II), which is condensed with an excess of hydroquinone (III) yielding 4-(quinolin-2-ylmethoxy)phenol (IV). The reaction of (IV) with an excess of alpha,alpha'-dichloro-o-xylene (V) affords the monoaddition compound (VI), which is treated with sodium cyanide giving the phenylacetonitrile derivative (VII). Finally, this compound is submitted to cyclization with sodium azide.

The condensation of 2-(chloromethyl)quinoline (I) with hydroquinone monobenzoate (II) by means of K2CO3 in refluxing acetone/DMF gives 4-(2-quinolylmethoxy)phenyl benzoate (III), which is treated with sodium ethoxide in ethanol to yield 4-(2-quinolylmethoxy)phenol (IV). The condensation of (IV) with alpha,alpha'-dichloro-o-xylene (V) by means of NaH in THF affords the benzyl chloride derivative (VI), which is treated with NaCN in toluene/water with a phase-transfer catalyst to provide the benzyl cyanide derivative (VII). Finally, this compound is cyclized with sodium azide in hot DMF to afford the target tetrazole derivative.

The condensation of 2-(chloromethyl)quinoline (I) with hydroquinone monobenzoate (II) by means of K2CO3 in refluxing acetone/DMF gives 4-(2-quinolylmethoxy)phenyl benzoate (III), which is treated with sodium ethoxide in ethanol to yield 4-(2-quinolylmethoxy)phenol (IV). The condensation of (IV) with alpha,alpha'-dichloro-o-xylene (V) by means of NaH in THF affords the benzyl chloride derivative (VI), which is treated with NaCN in toluene/water with a phase-transfer catalyst to provide the benzyl cyanide derivative (VII). Finally, this compound is cyclized with sodium azide in hot DMF to afford the target tetrazole derivative.

The condensation of 2-(chloromethyl)quinoline (I) with hydroquinone monobenzoate (II) by means of K2CO3 in refluxing acetone/DMF gives 4-(2-quinolylmethoxy)phenyl benzoate (III), which is treated with sodium ethoxide in ethanol to yield 4-(2-quinolylmethoxy)phenol (IV). The condensation of (IV) with alpha,alpha'-dichloro-o-xylene (V) by means of NaH in THF affords the benzyl chloride derivative (VI), which is treated with NaCN in toluene/water with a phase-transfer catalyst to provide the benzyl cyanide derivative (VII). Finally, this compound is cyclized with sodium azide in hot DMF to afford the target tetrazole derivative.

A synthesis of RG-12525 has been published: The reaction of 2-methylquinoline (I) with chlorine gas gives 2-(chloromethyl)quinoline (II), which is condensed with an excess of hydroquinone (III) yielding 4-(quinolin-2-ylmethoxy)phenol (IV). The reaction of (IV) with an excess of alpha,alpha'-dichloro-o-xylene (V) affords the monoaddition compound (VI), which is treated with sodium cyanide giving the phenylacetonitrile derivative (VII). Finally, this compound is submitted to cyclization with sodium azide.

A synthesis of RG-12525 has been published: The reaction of 2-methylquinoline (I) with chlorine gas gives 2-(chloromethyl)quinoline (II), which is condensed with an excess of hydroquinone (III) yielding 4-(quinolin-2-ylmethoxy)phenol (IV). The reaction of (IV) with an excess of alpha,alpha'-dichloro-o-xylene (V) affords the monoaddition compound (VI), which is treated with sodium cyanide giving the phenylacetonitrile derivative (VII). Finally, this compound is submitted to cyclization with sodium azide.

Synthesis of intermediate 4-(2-quinolinylmethoxy)phenol (V): The oxidation of 2-methylquinoline with urea and H2O2 in dichloromethane gives the N-oxide (II), which is treated with TsCl and K2CO3 in acetonitrile to yield the tosylate (III). Finally this compound is condensed with an excess of hydroquinone by means of NaOH in methanol/acetonitrile to afford the target intermediate (V).

Synthesis of intermediate 5-[2-(bromomethyl)benzyl]-2-(triphenylmethyl)-2H-tetrazole (X): The reduction of 2-(cyanomethyl)benzoic acid (VI) with I2 and NaBH4 in THF gives 2-(cyanomethyl)benzyl alcohol (VII), which is cyclized with NaN3 and TEA in hot N-methylpyrrolidinone to yield 2-(1H-tetrazol-5-ylmethyl)benzyl alcohol (VIII). The reaction of (VIII) with trityl chloride and pyridine in dichloromethane affords the trityl protected compound (IX), which is finally brominated to the target intermediate (X) with NBS and Me2S in dichloromethane. Synthesis of intermediate 5-[2-(bromomethyl)benzyl]-2-(tetrahydropyran-2-yl)-2H-tetrazole (XII): The reaction of 2-(1H-tetrazol-5-ylmethyl)benzyl alcohol (VIII) with NBS and PPh3 in THF gives the 2-(1H-tetrazol-5-ylmethyl)benzyl bromide (XI), which is finally treated with dihydropyran (DHP) and pyridinium p-toluenesulfonate (PPTS) to yield the tetrahydropyranyl protected target intermediate (XII).

Synthesis of the target compound 147690: This compound has been obtained by two similar ways: 1. The condensation of intermediate 4-(2-quinolinylmethoxy)phenol (V) with intermediate 5-[2-(bromomethyl)benzyl]-2-(triphenylmethyl)-2H-tetrazole (X) by means of KF/alumina in acetonitrile gives the adduct (XIII), which is finally deprotected to the target compound by means of HCl in methanol/THF. 2. The condensation of intermediate 4-(2-quinolinylmethoxy)phenol (V) with intermediate 5-[2-(bromomethyl)benzyl]-2-(tetrahydropyran-2-yl)-2H-tetrazole (XII) by means of KF/alumina in acetonitrile gives the adduct (XIV), which is finally deprotected to the target compound by means of HCl in methanol/THF.