Highly flexible and efficient synthesis of the GABA B enhancer 4-(2-hexylsulfanyl-6-methyl-pyrimidin-4-ylmethyl)-morpholine Julien Verron, Paricher Malherbe, Eric Prinssen, Andrew W. Thomas, Nadine Nock and Raffaello Masciadri * F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Discovery Chemistry, CH-4070 Basel, Switzerland Received 6 October 2006; revised 10 November 2006; accepted 14 November 2006 Available online 4 December 2006 Abstract—In the course of establishing a flexible synthesis of 2,4,6-substituted pyrimidines, we discovered that 2-hexyl-isothiourea hydrobromide reacts at ambient temperature and in a mildly exothermic fashion with 5,5-diethoxy-pent-3-yn-2-one upon treatment with 2 equiv of triethylamine in tetrahydrofuran to afford 4-diethoxymethyl-2-hexylsulfanyl-6-methyl-pyrimidine in 80% isolated yield. The methodology was developed in the search for an improved synthesis of the GABA B enhancer 4-(2-hexylsulfanyl-6- methyl-pyrimidin-4-ylmethyl)-morpholine. Ó 2006 Elsevier Ltd. All rights reserved. The non-fused pyrimidine ring is an important scaffold in medicinal chemistry. According to the Derwent World Drug Index Ò close to 100 drugs with a non-fused pyrim- idine ring have been launched in the pharmaceutical market and several of these drugs have reached block- buster status including trimethoprim, buspirone, bosen- tan, and imatinib. The vitamin thiamine belongs to the same structural class. The chemistry of the non-fused pyrimidines has been exhaustively reviewed in monographs. 1,2 Many publica- tions of more recent solution 3–6 and solid phase synthe- ses 7 have appeared in the literature. In the course of a medicinal chemistry program aimed at the discovery of novel GABA B receptor enhancers, 8 we were in need of a flexible synthesis of 2,4,6-substituted pyrimidines. We opted for a previously reported method 9 which uses the condensation of a alkynone with a thiuronium salt. In order to resynthesize our lead compound 5, we first chose the pathway shown in Scheme 1. Morpholine was readily alkylated with propargyl bromide and potassium carbonate in methanol to afford the propar- gyl amine 1, 10 which was purified on large scale directly by distillation. Propargyl amine 1 was treated with iso- propyl magnesium chloride at low temperature which led to the formation of the corresponding acetylenic Grignard reagent under the liberation of propane. The Grignard reagent was cannulated slowly into a cold solution of the commercial Weinreb amide 2. 11 The purification of the resulting acetylenic ketone 3 proved to be difficult and unreacted starting material could not 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.11.090 Keywords: 2,4,6-Substituted pyrimidines; 2-Hexyl-isothiourea hydro- bromide; 5,5-Diethoxy-pent-3-yn-2-one; Modular pyrimidine synthe- sis; GABA B enhancer. * Corresponding author. Tel.: +41 61 688 7504; fax: +41 61 688 6459; e-mail: raffaello.masciadri@roche.com N N N S O Br O N O NH 2 NH S N H O N O O N O HBr 75% 55% 30% a b c 1 2 3 5 4 Scheme 1. Reagents and conditions: (a) K 2 CO 3 , MeOH, 0–20 °C; (b) (i) i-PrMgCl (1 equiv), THF, À20 °C, (ii) AcNMeOMe, THF, À10 °C (inverse addition); (c) DIPEA (4 equiv), DMF, 24 h, 20 °C. Tetrahedron Letters 48 (2007) 377–380