A Convenient Protocol for the Synthesis of Fatty Acid Amides

Abstract

Several classes of biologically occurring fatty acid amides have been reported from mammalian and plant sources. Many amides conjugated with fatty acids of mammalian origin exhibit specific activation of individual receptors. Their potential as pharmacological tools or as lead compounds towards the development of novel therapeutics is of great interest. Hence, access to such amides by a practical, high-yielding and scalable protocol without affecting the geometry or position of sensitive functionalities is needed. A protocol that meets all these requirements involves activation of the corresponding acid with carbonyl diimidazole (CDI) followed by reaction with the desired amine or its hydrochloride. More than fifty compounds have been prepared in generally high yields.

Key words

fatty acid amides - CDI - AM404 - ethanolamide - N-acylethanolamines (NAEs) - N-acyl dopamines (NAPs) - N-acyl amino acids (NAAs) - anandamide

• References and Notes

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• 21 General Procedure for Amide CouplingTo a stirred solution of the fatty acid (1.0 mmol, 1.0 equiv.) in CH₂Cl₂ (5 mL) was added CDI (0.178 g, 1.1 mmol, 1.1 equiv.). After 30 min at room temperature, the amine (1.1 mmol, 1.1 equiv.) was added. After 12 h, CH₂Cl₂ (25 mL) was added, followed by saturated aqueous NH₄Cl. The mixture was acidified to pH 2 by addition of HCl, the organic phase was separated, and the aqueous layer was further extracted with CH₂Cl₂ (3 × 10 mL). The organic phases were combined, dried over Na₂SO₄, filtered, and concentrated in vacuo, to give the amide.Example 1: (5Z,8Z,11Z,14Z,17Z)-N-[(R)-1-phenylethyl]icosa-5,8,11,14,17-pentaenamide (R-28)Starting with EPA (0.302 g, 1.0 mmol, 1.0 equiv.) and (R)-α-methylbenzylamine (0.133 g, 0.14 mL, 1.1 mmol, 1.1 equiv.). Yield 0.376 g, 93%; TLC (hexane/EtOAc 75:25, visualized by UV and KMnO₄ stain): R_f = 0.20; [α]_D ²⁰ +5.2 (c = 0.2, MeOH). ¹H NMR (400 MHz, CDCl₃): δ = 7.49–7.06 (m, 5 H), 5.65 (d, J = 8.2 Hz, 1 H), 5.47–5.27 (m, 10 H), 5.15 (p, J = 7.1 Hz, 1 H), 2.91–2.73 (m, 8 H), 2.18 (dd, J = 8.3, 6.6 Hz, 2 H), 2.15–2.02 (m, 4 H), 1.79–1.67 (m, 2 H), 1.50 (d, J = 6.9 Hz, 3 H), 0.98 (t, J = 7.5 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.7, 143.2, 132.0, 129.1, 128.7 (2 × CH), 128.6, 128.5, 128.2, 128.2, 128.1, 128.0, 127.8, 127.3, 126.9, 126.1(2 × CH), 48.6, 36.1, 26.6, 25.6, 25.5, 25.4, 21.6, 20.5, 14.2. IR(ATR): ν_max = 3300, 3014, 2964, 1644, 1544 cm^–1. HRMS (EI⁺): exact mass calcd for C₂₈H₃₉NO [M]⁺ m/z = 405.3032; found: 405.3051.Antipodal S-28Yield 0.403 g, >96%; [α]_D ²⁰ –5.4 (c = 0.3, MeOH).Example 2: (4Z,7Z,10Z,13Z,16Z,19Z)-N-[(R)-1-phenylethyl]-docosa-4,7,10,13,16,19-hexaenamide (R-14)Starting with DHA (0.328 g, 1.0 mmol, 1.0 equiv.) and (R)-α-methylbenzylamine (0.133 g, 0.14 mL, 1.1 mmol, 1.1 equiv.). Yield 0.417 g, >96%; TLC (hexane/EtOAc 75:25, visualized by UV and KMnO₄ stain): R_f = 0.23; [α]_D ²⁰ +6.5 (c = 0.2, MeOH). ¹H NMR (400 MHz, CDCl₃): δ = 7.39–7.21 (m, 5 H), 5.68 (d, J = 7.9 Hz, 1 H), 5.47–5.26 (m, 12 H), 5.15 (p, J = 7.0 Hz, 1 H), 2.91–2.77 (m, 10 H), 2.46–2.38 (m, 2 H), 2.27–2.21 (m, 2 H), 2.13–2.03 (m, 2 H), 1.49 (d, J = 7.0 Hz, 3 H), 0.98 (t, J = 7.5 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.2, 143.1, 132.0, 129.3, 128.6 (2 × CH), 128.5, 128.2 (2 × CH), 128.2 (2 × CH), 128.1, 128.0, 128.0, 127.8, 127.3, 127.0, 126.2 (2 × CH), 48.6, 36.5, 25.6, 25.6, 25.6, 25.5, 23.4, 21.7, 20.5, 14.2. IR(ATR): ν_max = 3294, 3014, 2964, 1644, 1544 cm^–1. HRMS (EI⁺): exact mass calcd for C₃₀H₄₁NO [M]⁺ m/z = 431.3188; found: 431.3164.Antipodal S-14Yield 0.430 g, >96%; [α]_D ²⁰ –6.2 (c = 0.2, MeOH).Example 3: (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen morpholide (12)Starting with EPA (0.302 g, 1.0 mmol, 1.0 equiv.) and morpholine (0.096 g, 0.095 mL, 1.1 mmol, 1.1 equiv.). Yield 0.417 g, >96%; TLC (hexane/EtOAc 40:60, visualized by UV and KMnO₄ stain): R_f = 0.32. ¹H NMR (400 MHz, CDCl₃): δ = 5.45–5.25 (m, 10 H), 3.66 (dd, J = 5.7, 3.9 Hz, 4 H), 3.62 (d, J = 4.9 Hz, 2 H), 3.45 (d, J = 4.9 Hz, 2 H), 2.90–2.75 (m, 8 H), 2.34–2.28 (m, 2 H), 2.18–2.02 (m, 4 H), 1.72 (p, J = 7.5 Hz, 2 H), 0.98 (t, J = 7.5 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.5, 132.0, 129.2, 128.7, 128.5, 128.2, 128.2, 128.1, 128.0, 127.8, 126.9, 66.9, 66.6, 45.9, 41.8, 32.3, 26.7, 25.6, 25.6, 25.5, 24.9, 20.5, 14.2. IR (ATR): ν_max = 3009, 2964, 2931, 2863, 1656, 1432 cm^–1. HRMS (EI⁺): exact mass calcd for C₂₄H₃₇NO₂ [M]⁺ m/z = 371.2824; found: 371.2833.
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