*3.1.2 Synthesis of 4,5,6-Trisubstituted pyrimidines*

*3.1.2.1 Case study 1: synthesis of Remibrutinib [LOU064, N-[3-[6-amino-5-[2-[methyl (prop-2-enoyl)amino]ethoxy]pyrimidin-4-yl]-5-fluoro-2-methylphenyl]-4 cyclopropyl-2-fluorobenzamide, (31)]*

Remibrutinib (LOU064, (31)), a highly selective and potent oral BTK inhibitor, with best-in-class profile, under investigation for a number of immune-mediated conditions [66, 68, 82]. Novartis reported rapid and effective disease activity control of Remibrutinib (31) that resulted in significant improvement in quality of life in patients with chronic spontaneous urticaria that were treated with the drug [83].

Structurally, Remibrutinib (31) belongs to a group of 4-N-5-O-6-C pyrimidine derivatives. Synthetically, the process was divided into two main parts".

i. Synthesizing the substrates (substituents) to be introduced.

ii. Step-wise substitution of the pyrimidine heterocycle core.

Three substituents are required for the construction of Remibrutinib (31): Ammonia (NH3, **Figure 13**, violet part), N-methyl-N-(2-hydroxyethyl) acrylamide (**Figure 13**, black and brow parts), and 5-fluoro-2-methylphenyl]-4-cyclopropyl-2 fluorobenzamide (**Figure 13**, blue and cyan parts). The three should be prepared with the proper functionalization site and reactivity for the successive substitution to work.

Starting from, 4,6-dichloro-5-methoxypyrimidine (79), the synthesis reported used the commercially available ammonium hydroxide (NH4OH) for performing the first amination in heated 2-propanol, 70°C for 48 h. This produced the 4-amino-5 methoxy-6-chloropyrimidine (80) in high yield of 94%. Following the cleavage of 5 methoxy group the 4-amino-5-hydroxy-6-chloropyrimidine (81) was produced in 59% using conventional conditions of (BBr3, DCM, 40°C, 3 h). The attachment of the derivatizable N-Boc-N-methyl-2- hydroxyethylamine (82) was attached to the pyrimidine core at 5-hydroxy using Mitsunobu reaction conditions (DIAD, Smopex-301, THF, 60°C, 2 hr) which afforded the intermediate (83) in 53% yield. Prior to

#### **Figure 13.**

*Structure of Remibrutinib (LOU064, (31)) and the possible disconnections: Pyrimidine core and three different substituents.*

coupling to the central pyrimidine at C6, the third substituent boronic ester intermediate (89) ought to be synthesized following the procedure depicted in the **Figure 14**.

2-Bromo-4-fluoro-6-nitrotoluene (84) was activated under Miyaura borylation reaction conditions (cross-coupling of bis (pinacolato) diboron (B2pin2) with aryl halides and vinyl halides using BISPIN, Pd(dppf)Cl2DCM, KOAc, dioxane, 100°C, 3.5 h) to afford 2-(5-fluoro-2-methyl-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2 dioxaborolane (85) in 92%, which was subjected to reduction using hydrogen gas over Pd-C catalyst to produce the amino derivative (86) in 93%. In parallel, 3-fluoro-4 bromobenzoate ester (87) was coupled to cyclopropyl moiety through Suzuki reaction. The sodium bis(trimethylsilyl) amide mediated coupling with 2-(5-fluoro-2-methyl-3 minophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (86) afforded the desired boronate intermediate (89). Having the 4-cyclopropyl-2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) benzamide intermediate (89) in hand paved the road to the third substitution at the pyrimidine core in sequence.

To synthesize the desired intermediate *tert*-butyl N-[2-[4-amino-6-[3-[(4 cyclopropyl-2-fluorobenzoyl)amino]-5-fluoro-2-methylphenyl]pyrimidin-5-yl] oxyethyl]-N-methylcarbamate (93) (**Figure 15**), the previously synthesized 4 cyclopropyl-2-fluoro-N-(5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)phenyl) benzamide (89, **Figure 14**) was coupled under Suzuki conditions to the BOC-protected *tert*-butyl-N-[2-(4-amino-6-chloropyrimidin-5-yl) oxyethyl]-N-methylcarbamate (83) that was prepared utilizing Mitsunobu reaction (step c in **Figure 15**). The reaction proceeded under microwave and catalyst assisted (PdCl2(PPh3)2, aq Na2CO3, DME, water, microwave, 110°C, 25 min) in 74% yield. The last two steps of de-BOCylation and coupling to acrylic acid undergone in feasible conditions. Worth noting the exploitation of Mitsunobu reaction (DIPEA, T3P (50% in DMF), DMF, RT, 2 h, 45% over 2 steps).

#### *3.1.2.2 Case study 2: synthesis of 2,4-Diamino-6-alkyl- (or 6-aryl-) pyrimidine derivatives*

Wang and colleagues reported the synthesis of 2,4-diamino-6-alkyl- or 6-aryl-Pyrimidine Derivatives [84]. In attempt to develop a general method, two approaches

#### **Figure 14.**

*Synthesis of Boronic Ester building block (89). Reagents and conditions: a) BISPIN, Pd(dppf)Cl2DCM, KOAc, dioxane, 100°C, 3.5 h, 92%; b) H2, Pd/C, MeOH, RT, 7 h, 93%; c) cyclopropylboronic acid, Pd(OAc)2, tricyclohexylphosphine, K3PO4, water, toluene, 100°C, overnight, 99%; d) (86), NaHMDS (1 M in THF),THF, RT, 4 h, 76%; e) cyclopropylboronic acid, Pd(PPh3)4, K3PO4, water, toluene, 110°C, 30 h, 96%.*

*Synthetic Approaches for Pharmacologically Active Decorated Six-Membered Diazines DOI: http://dx.doi.org/10.5772/intechopen.109103*

#### **Figure 15.**

*Synthesis of Remibrutinib (LOU064,)31(). Reagents and conditions: a) NH4OH, 2-propanol, 70°C, 48 h, 94%; b) BBr3, DCM, 40°C, 3 h, 59%; c) N-Boc-N-methyl-2-hydroxyethylamine, DIAD, Smopex-301,THF, 60°C, 2 h, 53%; d) (89), PdCl2(PPh3)2, aq Na2CO3, DME, water, microwave, 110°C, 25 min, 74%; e) TFA, DCM, RT, 12 h; f) acrylic acid, DIPEA,T3P (50% in DMF), DMF, RT, 2 h, 45% over 2 steps.*

were tried. First approach, the predetermined substituents were incorporated while constructing the heterocyclic pyrimidine core. This was achieved by condensing proper derivatives of 1,3-dicarbonyl with amidine or guanidine derivatives (see **Figure 16**).

The method depicted in **Figure 16** above incorporated 2-amino group (R1-NH-C2) and the 6-phenyl (R2-C6) during the assembling of the heterocyclic core. The 2 amino-6-phenylpyrimidine (101) was readily amminated at site-4 of the pyrimidine basic conditions. Relatively, mild conditions where needed for the step-wise introduction of the three substituents (**Figure 17**).

The researchers also reported the synthesis of 2,4,6-trisbustituted pyrimidines (108) using the commercially available 4,6-dichloro-2-methylthiopyrimidine (104) as a starting material for the sequential substitution under Suzuki conditions (phenylboronic acid in the presence of triphenylphosphine and palladium acetate) afforded the desired 4-chloro-2-methylthio-6-phenylpyrimidine (106a or 106b) in high yield [84] compared to the case when 2,4,6-trichloropyrimidine (109) was used

#### **Figure 16.**

*Synthesis of trisubstituted pyrimidine (103) via construction of the heterocyclic core. Reagents and conditions: a) CH3I, acetone, reflux; b) NH3, EtOH, 100°C; c) R2COCH2COOEt (100), DMF, 100°C, 48 hr.; d) POCl3; e) R3NH2, 110°C.*

#### **Figure 17.**

*Synthesis of 2,4,6-trisubstituted pyrimidines using the commercially available 4,6-dichloro-2 methylthiopyrimidine (104). Reagents and conditions: a) C6H5B(OH)2, Pd(Oac)2II,TPP, Na2CO3, Glyme, reflux, 18 hr.; b) R1NH2, 1-butanol, reflux, 6 hr.; c) 30%H2O2, NaWO4, EtOAc/toluene (1,1 v/v) 0°C for 30 min then RT for 2 hr.; d) R2NH2, neat, 140°C. DCP = 3,4-dichlorophenyl, IP = isopropyl, R1 = IP, R2 = DCP, R1 = DCP, R2 = IP.*

as a starting material. Though the first substitution under Suzuki conditions afforded the 2,4-dichloro-6-phenylpyrimidine (106a or 106b) in high yield. Underlying the difference in the reactivity between 2-, 4- or 6-chloro groups toward amination

*Synthetic Approaches for Pharmacologically Active Decorated Six-Membered Diazines DOI: http://dx.doi.org/10.5772/intechopen.109103*

reactions the following amination proved to be challenging with almost equal amounts of 2-amino- and 4-aminopyrimidine derivatives due to reduced selectivity. Using 4,6 dichloro-2-methylthiopyrimidine (104) as a starting material proved to be efficient in facilitating the first amination while the second amination was not accomplished in high yield.
