合成路线1

This compound has been obtained by two related ways: 1) The reaction of phenol (I) with formaldehyde gives 4-(hydroxymethyl)phenol (II), which is treated with NaCN in hot DMF to yield 2-(4-hydroxyphenyl)acetonitrile (III). The hydrolysis of (III) in refluxing ethanol/water, catalyzed by a Pt catalyst affords the corresponding acetamide (IV), which is condensed with an excess of hot epichlorohydrin (V) by means of piperidine gives 2-[4-(2-oxiranylmethoxy)phenyl]acetamide (VI). Finally, the oxirane ring of (VI) is opened with isopropylamine in methanol. 2)The condensation of acetonitrile (III) with epichlorohydrin (V) as before gives the 2-[4-(2-oxiranylmethoxy)phenyl]acetonitrile (VIII), which is treated with isopropylamine (VII) in methanol yielding 2-[4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]acetonitrile (IX). Finally, this compound is hydrolyzed with refluxing ethanol/water catalyzed by a Pt catalyst as before to afford the target acetamide.

合成路线2

In this scheme various methods are shown for the synthesis of (S)-atenolol: 1. Treatment of (R)-glycidyl 4-nitrobenzenesulfonate (I) with HCl (either concentrated or with dichloromethane) provides 3-chloropropyl derivative (II), which is then coupled with isopropylamine (III) in dichloromethane to afford 3-chloropropylisopropylamine (IV). Finally, condensation of (IV) with 2-(4-hydroxyphenyl)acetamide (V) by means of KOH in MeOH gives the desired product. Alternatively, derivative (IV) can be converted into (S)-atenolol by its condensation with 2-(4-hydroxy-phenyl)acetonitrile (VI) by means of KOH to yield compound (VII), followed by hydrolysis with HCl at 40 C. 2. Condensation of (R)-glycidyl 3-nitrobenzenesulfonate (VIII) with isopropylamine (III) followed by coupling with acetamide (V) by means of potassium tert-butylate in DMSO provides the desired product. 3. Treatment of (VIII) with HCl affords 2(S)-hydroxy-3-chloropropyl-3-nitrobenzenesulfonate (IX), which is first coupled with isopropylamine (III) to give (IV) and finally condensed with amide (V). 4. Coupling of chloro derivative (IX) with benzyl-protected isopropylamine (X) provides protected derivative (XI), which is then condensed with acetamide (V) by means of KOH in MeOH to give (XII). Finally, compound (XII) is hydrogenated over Pd/C in MeOH for removal of the benzyl group.

合成路线3