3-(1-Methanesulfonyl-piperidin-4-yl)-acrylic acid isopropyl ester synthesis

6synthesis methods

Product Name:3-(1-Methanesulfonyl-piperidin-4-yl)-acrylic acid isopropyl ester
CAS Number:937282-79-6
Molecular formula:C12H21NO4S
Molecular Weight:275.36

1-Methanesulfonyl-piperidine-4-carbaldehyde

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601-79-6 Synthesis

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3-(1-Methanesulfonyl-piperidin-4-yl)-acrylic acid isopropyl ester

937282-79-6
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Yield:937282-79-6 59%

Reaction Conditions:

Stage #1: 1-(methylsulfonyl)-4-piperidinecarboxaldehyde;isopropylmalonic acid;piperidine in toluene at 85 - 95;
Stage #2: with hydrogenchloride in water;toluene at 40 - 50; for 0.25 h;

Steps:

5

Preparation 5 Preparation of /so-propyl 3-(l-methanesulfonylpiperidin-4-yl)propenoate(l-Methanesulfonylpiperidin-4-yl)methanal (1 mol eq) was charged to a reaction vessel followed by a line wash of toluene (11 rel vol). Piperidine (0.1 mol eq) was charged to the vessel followed by a line wash of toluene (0.5 rel vol), and the reaction mixture heated to between 85 and 95⁰C. A solution of the wo-propyl malonic acid (1.25 mol eq) in toluene (prepared as described above) was added in 10 approximately equal portions over 6 to 8 hours and the reaction mixture was stirred at to between 85 and 95⁰C until it reached completion. The reaction mixture was then cooled to between 40 and 5O⁰C and HCl (0.5M, 3 rel vol) was added to the reaction maintaining the temperature between 40 and 50⁰C. After stirring for at least 15 minutes the phases were separated. Sodium bicarbonate (0.5M, 3 rel vol) was added to the organic phase, still maintaining the temperature between 40 and 5O⁰C. The 2-phase mixture was stirred for at least 15 minutes before separating the phases and washing the organic phase with water (3 rel vol). The organic phase was then concentrated to approximately 16 rel vols by vacuum distillation at between 40 and 50⁰C. Toluene (3.5 rel vol) was charged, the solution clarified at between 40 and 5O⁰C and then concentrated to approximately 7 rel vol by vacuum distillation. The mixture was then cooled to between 0 and 10⁰C and stirred for at least 60 minutes at this temperature before isolating the sub-titled compound by filtration and washing the residue with toluene (2 rel vol) at between 0 and 10⁰C. The solid was dried to leave the sub-titled compound in approximately 59% yield.¹H NMR (400 MHz₅ CDCl₃) δ 6.87 (dd, J= 15.8, 6.5 Hz, IH), 5.81 (dd, J= 15.8, 0.9 Hz, IH), 5.07 (quintet, J= 6.2 Hz, IH), 3.82 (d, J= 12.0 Hz, 2H), 2.79 (s, 3H), 2.74 (td, J= 12.0, 2.4 Hz, 2H), 2.36 - 2.17 (m, IH), 1.95 - 1.80 (m, 2H), 1.57 (ddd, J= 24.9, 11.7, 4.0 Hz, 2H), 1.27 (d, J= 6.4 Hz, 6H).