A Practical Synthesis of Differentially Protected 4,4′-Dipiperidinyl Ethers: Novel Ligands of Pharmaceutical Interest

Abstract

An efficient four-step synthesis (requiring no purification) of Boc-protected 4,4′-dipiperidinyl ethers is described.

Key words

ethers - hydrogenations - piperidines - pyridines - histamine

References and Notes

• 1 Bailey JM, Bruton G, Huxley A, Milner PH, and Orlek BS. inventors; WO  2005014571. 
• 2a Fromm E. Ber. Dtsch. Chem. Ges.  1909,  41:  3644 
• 2b Gadamer J. Arch. Pharm.  1921,  259:  234 
• 2c Arai H, Matsumura T, Ishida H, Yamaura Y, Aratake S, Ohshima E, Yanagawa K, Miyama M, Suzuki K, Kawabe A, Nakanishi S, Kobayashi K, Sato T, Miki I, Ueno K, Fujii S, and Iwase M. inventors; WO 2003104230, 2003; JP  2002-166504. 
• 3a Ye XM, Garofalo AW, Lawler RD, Fukuda JY, Konradi AW, Holcomb R, Rossiter KI, Wone DWG, and Wu J. inventors; WO  2006113140. 
• 3b Botez I, David-Basei C, Gourlaoueen N, Nicolaie E, Balavoine F, Valette G, and Serradeil-Le Gal C. inventors; WO  2006108965. 
• 4a Chao J. Israiel M. Zheng J. Aki C. Tetrahedron Lett.  2007,  48:  791 
• 4b

  The authors have reported similar findings in their two-step synthesis of 10, which proceeds in 37-40% yield and requires chromatography after both steps.

• 10a Kappe OC. Chimia  2006,  60:  308 
• 10b Kappe OC. Dallinger D. Nat. Rev. Drug Discovery  2006,  5:  51 
• 11a Jiang L. Buchwald SL. In Metal-Catalysed Cross-Coupling Reactions   2nd ed., Vol. 2:  de Meijere A. Diederich F. Wiley-VCH; Weinheim: 2004.  Chap. 13. p.699 
• 11b Buchwald SL. Muci AR. Top. Curr. Chem.  2002,  219:  131 
• 12 Recently advances in catalysis have shown that palladium-catalyzed C-N arylation is possible in the presence of heteroaromatic halides and NH carboxamides. See, for example: Anderson KW. Tundel RE. Ikawa T. Altman RA. Buchwald SL. Angew. Chem. Int. Ed.  2006,  45:  652 

5

All products gave satisfactory MS and ^¹H NMR (400 MHz) spectra.

6

For example, on a 50 gram scale, extended reaction times resulted in the deprotected amine reacting with excess ammonium formate in the reaction mixture to give N-formyl piperidines.

7

This latter procedure was chosen to mimic the contact with the Pd/C catalyst experienced during hydrogenolysis experiments, which in some cases would drive the reduction over time.

8

More vigorous conditions were avoided due to our previous observation that the phenyl methyl group in 10 was labile to reduction (see Table  [¹] , footnote b).

9

Synthesis of Compounds 6, 10, and 11
Sodium hydride (20.88 g) was suspended in DMSO (600 mL) under argon and 4-chloropyridine hydrochloride (31.0 g), suspended in DMSO (150 mL), was added slowly over 45 min. The reaction was then stirred for 10 min, and 5 (35 g), dissolved in DMSO (150 mL), was added over 15 min. The reaction was stirred at r.t. overnight. Saturated NaHCO₃ solution (150 mL) was then added slowly and the reaction stirred for 20 min. The mixture was evaporated to a minimum, redissolved in EtOAc (600 mL), and washed with sat. NaHCO₃ (150 mL) and H₂O (150 mL), followed by H₂O (5 × 250 mL). The organic layer was then dried (MgSO₄). The solution was filtered and evaporated to give a yellow solid, which was triturated with hexane and then dried at 50 ˚C overnight to give 6 as a pale yellow solid (38.0 g). MS (ES+): m/z = 279 [MH⁺]. ^¹H NMR (400 MHz, CDCl₃): δ = 8.43 (2 H, d, J = 4.8 Hz), 6.87 (2 H, d, J = 4.8 Hz), 4.57 (1 H, m), 3.68 (2 H, m), 3.37 (2 H, m), 1.90 (2 H, m), 1.78 (2 H, m), 1.47 (9 H, s).
Compound 6 (37.5g) was dissolved in CH₂Cl₂ (400 mL). Benzyl bromide (32.26 mL) was added, and the reaction was stirred at r.t. for 4 h. The solvent was removed in vacuo, and the crude residue was redissolved in a minimum quantity of CH₂Cl₂. Diethyl ether was added to the stirred CH₂Cl₂ solution until the product precipitated. The pale pink solid was isolated by filtration and dried at 50 ˚C under high vacuum overnight to give 10 (60.0 g) as a pink solid. MS (ES+): m/z = 369 [M⁺]. ^¹H NMR (400 MHz, CDCl₃): δ = 9.20 (2 H, d, J = 7.5 Hz), 7.58 (2 H, m), 7.50 (2 H, d, J = 7.5 Hz), 7.41 (3 H, m), 6.04 (2 H, s), 5.00 (1 H, m), 3.71 (2 H, m), 3.38 (2 H, m), 2.03 (2 H, m), 1.74 (2 H, m), 1.47 (9 H, s).
Compound 10 (55.2 g) was stirred in MeOH (300 mL) under argon at 0 ˚C and NaBH₄ (pellets, 9.3 g) was added portionwise over 1 h. The reaction was allowed to warm to r.t. for a further 90 min, and then acetone (50 mL) was added. The reaction was stirred for 1 h. The solvent was evaporated and residue partitioned between sat. aq NaHCO₃ solution and EtOAc (200 mL of each). The aqueous phase was separated and re-extracted with EtOAc (3 × 100 mL). The combined organics were dried over MgSO₄ with activated charcoal added, filtered, and evaporated to give the enol ether as a yellow-to-pink oil (40.6 g).
The crude oil (59.2 g) was dissolved in MeOH (900 mL) and ammonium formate (100.2 g) was added followed by 10% Pd/C (paste, 30 g). The reaction was heated to 60 ˚C (bath temperature, when internal temperature achieved 30 ˚C effervescence was observed), maintained at 55 ˚C for 1.5 h. The reaction was filtered and concentrated. The residue was re-dissolved in EtOAc (1 L) and washed with sat. K₂CO₃ solution (3 × 400 mL), dried (MgSO₄), and evaporated to give an oil which crystallized on standing to give 11 as a white solid (39.0 g). MS (ES+): m/z = 285 [MH⁺]. ^¹H NMR (400 MHz, CDCl₃): δ = 3.79 (2 H, m), 3.65-3.38 (2 H, m), 3.06 (4 H, m), 2.60 (2 H, m), 1.91-1.67 (4 H, m), 1.59-1.31 (13 H, m).