Methyl 5-ethyl-1,3-thiazole-4-carboxylate synthesis

Yield: 78%

Reaction Conditions:

Stage #1:methyl 2-amino-5-ethyl-1,3-thiazole-4-carboxylate with hypophosphorous acid;sodium nitrite in water at 0 - 20; for 3 h;
Stage #2: with sodium hydroxide in water at 0;

Steps:

173.a
The following diazotization step was adapted from Barton, A. et al, J. C.S. Perkin Trans I, 159-164 (1982): A solution of NaN0₂ (150 mg, 2.17 mmol) in water (1.0 mL) was added dropwise to a stirred, cold (0 °C) solution of methyl 2-amino-5-ethyl-l,3- thiazole-4-carboxylate (186 mg, 1.0 mmol) in 50% H3PO2 (3.2 mL). The mixture was stirred at 0 °C for 1 h and allowed to warm up to room temperature where it stirred further for 2h. After recooling to 0 °C, the mixture was treated slowly with a solution of NaOH (85 mg) in water (10 mL). The mixture was then diluted with saturated NaHCC solution and extracted twice with ether. The organic layers were combined, dried over MgS0₄ and concentrated to give methyl 5-ethylthiazole-4-carboxylate (i.e., Cap-173, step a) (134 mg, 78%) as an orange oil (85% pure) which was used directly in the next reaction. R_t = 1.58 min (Cond.-MDl); LC/MS: Anal. Calcd. for [M+H]⁺ C₇H₁₀NO₂S: 172.05; found: 172.05.

References:

BRISTOL-MYERS SQUIBB COMPANY;PACK, Shawn, K.;TYMONKO, Steven;PATEL, Bharat, P.;NATALIE, JR., Kenneth, J.;BELEMA, Makonen WO2011/59850, 2011, A1 Location in patent:Page/Page column 127-128