*3.1.2.3 Case study 3: synthesis of Buparlisib [NVP-BKM120; BKM120; 1,202,777: 78-3, 5- (2,6-Dimorpholinopyrimidin-4-Yl)-4-(trifluoromethyl)pyridin-2-amine (115)]*

Buparlisib (BKM120, NVP-BKM120), belongs to a family of 2-morpholino, 4 substituted, 6-heterocyclic pyrimidine derivatives, that was developed by Novartis as a pan-PI3K inhibitor [85]. Recent studies indicated that it also targets tubulin [86] and it is a brain penetrable [87].

Burger *et al*. reported the synthesis of Buparlisib (BKM120; NVP-BKM120, 115) as a pan-class I PI3K inhibitor [88]. The synthesis was accomplished in a four-step process starting from 2,4,6-trichloropyrimidine (109). The first step encompasses a nucleophilic substitution reactions to form two C-N bonds of morpholine substituents with the pyrimidine core [4,6-dimorpholino-2-chloropyrimidine (110) and 2,4 dimorpholino-6-chloropyrimidine or 4,4<sup>0</sup> -(6-chloropyrimidine-2,4-diyl) dimorpholine (111), **Figure 18**]. Reacting (109) with 2.5 equivalent of morpholine ended in producing the 2,4-disubtituted intermediate 4,4<sup>0</sup> -(6-chloropyrimidine-2,4 diyl) dimorpholine (111) in a 80% yield. The reaction was highly regioselective, however, a minor amount (8%) of the 4,6-regioiomer (110) was also detected. In parallel, 2-amino-4-trifluoromethyl pyrimidine (112) was converted to 5-bromo-4- (trifluoromethyl)-2-pyrimidylamine (113) using N-bromosuccinimide (NBS) via an oxidative radical electrophilic brominating reaction [89]. The functionalized 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine (114) was prepared by reacting 5-bromo-4-(trifluoromethyl)-2-pyridylamine (113) with bis (pinacolato) diboron under conventional conditions (potassium acetate, bis (pinacolato) diboron and bis (diphenylphosphino) ferrocene palladium (II) chloride) in a 5:1 mixture with the starting material. The dioxaborolanated intermediate (114) was introduced to the pyrimidine core via palladium-mediated C-C cross-coupling

#### **Figure 18.**

*Synthesis of Buparlisib (BKM120; NVP-BKM120) (115). Reagents and conditions: a) morpholine, DIEA, EtOH, 80%; b) NBS, CH2Cl2, 80%; c) bispiacolatodoron (1,1'-Bis(diphenylphosphino) ferrocene palladium (II) chloride, Pd(dppd)2CleDCM), DME, 2 N Na2CO3, 95°C, 15 h, 48%; d) bispiacolatodoron, Pd (dppd)2CleDCM, DME, KOAc, (potassium acetate, bis(pinacolato) diboron (Bis(diphenylphosphino) ferrocene palladium (II) chloride), 95°C, 15 h, 95%.*

(step d in **Figure 18**) applying Suzuki reaction conditions affording the final product (115) in 95% yield [88].

The synthesis of Buparlisib (115) was also disclosed by Xu et al. employing similar conditions. A high yield and purity cross-coupling was reported (yield >94% and HPLC purity: >99%) [90].

### *3.1.3 Synthetic methods in preparing 2,4,6-Trisubstituted pyrimidines*

Step-wise replacement of chloride groups employing nucleophilic substitution conditions, Suzuki coupling, Ulman coupling or Grignard reaction was reported to afford di-, tri- and tetra-substituted derivatives of pyrimidine (114) (**Figure 19**). The conditions used depend in many cases on the order and type of the linkage emerging between the substituents and the heterocyclic pyrimidine. It has also to consider the physicochemical properties of the substituent.

The final 2,4,6-trisubstituted product (115) can vary according to the type of linkage with the core heterocyclic pyrimidine. There are various versions of linkages (see **Figure 20**, for possible combination of linking moieties with the pyrimidine heterocyclic core) (**Figure 21**).
