A New Synthesis of (R)-(-)-Sumanirole (PNU-95666E)

Abstract

A twelve-step synthesis of (R)-(-)-sumanirole hydrochloride, starting from quinoline, has been achieved. The key reaction features selective epoxidation of the C3-C4 double bond of a 1,2-dihydroquinoline bearing a chiral auxiliary at N-1.

Key words

quinoline - reduction-acylation - asymmetric epoxidation - (R)-(-)-sumanirole

References and Notes

• 1a Heier RF. Dolak LA. Duncan JN. Hyslop DK. Lipton MF. Martin IJ. Mauragis MA. Piercey MF. Nichols NF. Schreur PJKD. Smith MW. Moon MW. J. Med. Chem.  1997,  40:  639 
• 1b McCall RB. Lookingland KL. Bédard PJ. Huff RM. J. Pharmacol. Exp. Ther.  2005,  314:  1248 
• For a review of the synthetic routes to sumanirole, see:
• 2a Wuts PGM. Curr. Opin. Drug Discovery Dev.  1999,  2:  557 
• For more recent syntheses, see:
• 2b Wuts PGM. Gu RL. Northuis JM. Kwan TA. Beck DM. White MJ. Pure Appl. Chem.  2002,  74:  1359 
• 2c Gala D. Dahanukar VH. Eckert J. Lucas BS. Schumacher DP. Zavialov IA. Org. Process Res. Dev.  2004,  8:  754 
• 2d Jagdale AR. Reddy RS. Sudalai A. Org. Lett.  2009,  11:  803 
• 3 Minter DE. Stotter PL. J. Org. Chem.  1981,  46:  3965 
• 4 Pirkle WH. Simmons KA. J. Org. Chem.  1983,  48:  2520 
• 9 Moon MW. Morris JK. Heier RF. Chidester CG. Hoffmann WE. Piercey MF. Althaus JS. Von Voiglander PF. Evans DL. Figur LM. Lahti RA. J. Med. Chem.  1992,  35:  1076 
• 10 Pauvert M. Collet S. Bertrand M.-J. Guingant A. Evain M. Tetrahedron Lett.  2005,  46:  2983 
• 15 Burla MC. Caliandro R. Camalli M. Carrozzini B. Cascarano GL. De Caro L. Giacovazzo C. Polidori G. Spagna R. J. Appl. Crystallogr.  2005,  38:  381 
• 16 Petricek V. Dusek M. Palatinus L. Jana2006. The Crystallographic Computing System   Institute of Physics; Praha: 2006. 

5

Procedure for the Preparation of 7
To a solution of quinoline (1.6 mL, 13.6 mmol) in CH₂Cl₂ (20 mL), maintained at 0 ˚C under an argon atmosphere, was added a 1 M solution of DIBAL-H in hexane (13.6 mL, 13.6 mmol). After stirring at 0 ˚C for 1 h, the red solution was cannulated into a solution of carbamoyl chloride 9 (1.63 g, 6.8 mmol) in 2mL of CH₂Cl₂. The temperature was slowly raised to 20 ˚C, and stirring was continued for 5 h at this temperature. The reactive mixture was then cannulated into 150 mL of cold H₂O. The resulting emulsion was stirred for 30 min then aq 6 N HCl was added until the aqueous phase reached pH 4. After phase separation, the aqueous phase was extracted with CH₂Cl₂ (4 × 60 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was purified by silica gel chroma-tography (toluene-PE-Et₂O = 2:1:1, R _f  = 0.26) to afford 1,2-dihydroquinoline 7 as a slightly yellow oil (1.39 g, 61%, calculated based on carbamoyl chloride 9); [α]_D ^²0 +7.7 (c 0.5, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 7.12-7.40 (m, 9 H), 6.59 (dd, J = 9.6, 2.4 Hz, 1 H), 5.99-6.04 (m, 1 H), 4.73-4.78 (m, 1 H), 4.40 (dd, J = 17.0, 5.5 Hz, 1 H), 4.08-4.31 (m, 3 H), 2.92 and 3.26 (ABX system, J = 13.5, 8.7, 3.3 Hz, 2 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 153.3, 152.4, 136.0, 134.9, 129.5 (2 C), 129.2, 129.0 (2 C), 128.5, 128.3, 127.5, 126.7, 126.4, 125.5, 122.9, 67.0, 56.5, 45.9, 38.1. IR (KBr): 3060-3028, 3003, 2923-2853, 1722, 1685 cm^-¹. MS: m/z (%) = 334 (<1) [M⁺], 130 (100), 91 (19). HRMS (EI): m/z calcd for C₂₀H₁₈N₂O₃: 334.1317; found: 334.1313 [M]⁺.

6

Epoxide 11: recrystallization from CHCl₃-PE (1:1); mp 204-203 ˚C; [α]_D ^²0 +54.2 (c 0.5, CHCl₃).

7

Crystal Structure Data for C ₂₀ H ₁₈ N ₂ O ₄
Mw = 350.4, colorless block, 0.48 × 0.42 × 0.38 mm^³, orthorhombic, P2₁2₁2₁, a = 9.7121 (9)Å, b = 12.6679 (16) Å, c = 13.6030 (8) Å, V = 1673.6 (3) Å^³, Z = 4, D _x = 1.390 g cm^-³, µ = 0.10 mm^-¹. 33596 reflections were measured on a Nonius-Kappa CCD diffractometer (graphite monochro-mator, λ = 0.71073 Å) up to a resolution of (sin θ/λ)_max = 0.7 Å^-¹ at r.t.; 4820 reflections were unique (Rint = 0.038). The structure was solved by direct methods^¹5 and refined with JANA2006 program^¹6 against F ^² for all reflections. Nonhydrogen atoms were refined with aniso-tropic displacement parameters. All H atoms were introduced in geometrically optimized positions and refined with a riding model, except for two H atoms (attached to C3 and C4) which positions were refined under constrains. Altogether, 241 parameters were refined. R ₁/wR ₂ [I≥÷ 2σ(I)] = 0.0473/0.1072. R ₁/wR ₂ [all reflections] = 0.0682/0.1189, S = 1.74. Residual electron density is between 0.14 and -0.13 e Å^-³. CCDC 769777 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

8

Procedure for the Preparation of 13
Epoxidation
To a solution of 1,2-dihydroquinoline 7 (1.6g, 4.78 mmol) in CH₂Cl₂ (250 mL) were added NaHCO₃ (644 mg, 6.22 mmol) and 70-75% MCPBA (1.5g, 6.22 mmol). The mixture was stirred at 20 ˚C for 18 h under argon, then washed with a sat. NaHCO₃ solution (250 mL). After phase separation, the aqueous phase was extracted with CH₂Cl₂ (3 × 160 mL). The combined organic layers were dried over MgSO₄, filtered, and concentrated in vacuo. The crude product (white powder) was engaged in the reduction process without further purification.
Reduction
To a solution of the above crude epoxide product in a 1:1 mixture of CH₂Cl₂-EtOAc (80 mL) was added 10% Pd/C (668 mg, 9%mol). The mixture was stirred for 18 h at 20 ˚C under a hydrogen pressure of 8 bar then filtered through a pad of Celite. Celite was rinsed with a 1:1 mixture of CH₂Cl₂-EtOAc, then solvents were concentrated in vacuo. The residue was purified by silica gel chromatography (PE-EtOAc = 1:1, R _f  = 0.39) to afford alcohol 13 as a white powder (0.9 g, 54%); [α]_D ^²0 -191.0 (c 0.34, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 7.00-7.40 (m, 9 H), 4.80 (m, 1 H), 4.28 (m, 1 H), 4.11 and 4.24 (ABX system, J = 8.4, 8.4, 7.5 Hz, 2 H), 3.38 and 4.41 (ABX system, J = 12.6, <1, <1 Hz, 2 H), 2.99 and 3.15 (ABX system, J = 18.0, 5.4, <1 Hz, 2 H), 2.85 and 3.60 (ABX system, J = 12.9, 10.2, 3.6 Hz, 2 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 154.1, 152.9, 138.0, 133.9, 129.4 (2 C), 128.1 (2 C), 128.0, 126.5, 125.2, 124.2, 120.3, 67.2, 62.9, 55.2, 50.6, 37.0, 34.7. IR (film): 3452, 3050, 2932, 1772, 1683 cm^-¹. MS: m/z (%) = 323 (9) [M⁺ ], 132 (38), 130 (38), 118 (20), 117 (16), 91 (100). HRMS (EI): m/z calcd for C₂₀H₂₀N₂O₄: 352.1423; found: 352.1427 [M]⁺.

11

Azido compound 18 was isolated along with variable amounts of an elimination product (1,2-dihydroquinoline). Because mesylate 17 is stable in DMF at 80 ˚C, formation of the elimination byproduct is thus induced by NaN₃. Noteworthy also is the formation of the sole elimination product by treatment of alcohol 16 with DPPA under Mitsunobu conditions.

12

HPLC profiles showed that azide substitution took place without erosion of enantioselectivity. Mesylate 17: [α]_D ^²0 +34.0 (c 0.2, CHCl₃; 96% ee determined by chiral HPLC); azido compound 18: [α]_D ^²0 +58.4 (c 0.51, CHCl₃; 96% ee determined by chiral HPLC).

13

This two-step N-methylation protocol has already been reported for transforming sumanirole into its N,N-dimethyl analogue, see ref. 1a.

14

Hydrochloride of (R)-3: [α]_D ^²0 -29.1 (c 0.25, MeOH; 98% ee determined by chiral HPLC), lit.^¹a [α]_D ^²0 -30.3 (c 1, MeOH).