**2.3 Homochiral drugs**

*Translational Research in Cancer*

**2.2 Synthesis of tetrahydrobenzoxazepine 2,6-dichloropurine** *O,N***-acetals** 

The preparation of the *O*,*N*-acetals **1** and **2** was achieved by the microwaveassisted Vorbrüggen one-pot condensation of the cyclic acetals **3a** and **3b** [27] and the commercially available purine base 2,6-dichloropurine, using trimethylsilyl chloride (TMSCl), 1,1,1,3,3,3-hexamethyldisilazane (HMDS) and tin(IV) chloride as the Lewis acid in anhydrous acetonitrile. The reaction mixture was microwave-

Compounds **11** and **12** were obtained along with the cyclic 2,6-dichloropurine *O,N*-acetals (**1** and **2**, bozepinib) and the acyclic one **13** (when starting from **3b**) in the reaction of purines with **3a** and **3b**, respectively. The mechanism of the reaction of these compounds is important as none of them were previously isolated in the

*Reagents and conditions: (a) 3a (1 equiv), 2,6-dichloropurine (1.5 equiv), trimethylsilyl chloride (TMSCl, 1.5 equiv), 1,1,1,3,3,3-hexamethyldisilazane (HMDS, 1.5 equiv) and SnCl4 (1 M solution in CH2Cl2, 1.5 equiv), 140°C, microwave, 5 min; (b) 3b (1 equiv), 2,6-dichloropurine (2.5 equiv), TMSCl (4.0 equiv), HMDS (4.0* 

*equiv) and SnCl4 (1 M solution in CH2Cl2, 4.0 equiv), 140°C, microwave, 5 min.*

**with nitrosulfonyl groups on the nitrogen atom**

irradiated at a temperature of 140°C for 5 min (**Figure 6**).

**132**

**Figure 6.**

A better understanding of the molecular recognition of the therapeutic targets in many diseases highlights the issue of drug in the design and development of new drugs. The separation of racemates, chiral pool and asymmetric synthesis are the three most used methods for the production of a chiral drug. Since the 1980s there has been a significant increase in the development of chiral pharmaceutical drugs. When patents of racemic drugs expire, pharmaceutical companies can extend patents by developing the synthesis of enantiomers that exhibit the desired biological activity [29].

Compound **2** was resolved into its two enantiomers: [(*R*)-**2**: [α] 25 D = −43.6 (c = 0.22, THF) and (*S*)-**2**: [α] 25 D = +41.0 (c = 0.23, THF)]; using a semipreparative column CHIRALPAK® and a mixture of hexane/*t*-BuOMe/*i*PrOH as eluant [28]. From this moment on, the racemic **2** [(*RS*)-**2**] will be named only as bozepinib.
