Novel Synthetic Industrial Approach for Efficient Synthesis of Baclofen through C–C Bond Formation

Abstract

Baclofen is an active pharmaceutical ingredient used for the treatment of muscle spasticity. We describe our efforts to develop a novel synthetic approach through C–C bond formation and a cost-effective route to baclofen. The synthesis involved a two-step approach through C–C bond formation using the extensively and commercially available starting material 4-chlorobenzyl cyanide with chloroacetic acid as a reagent in an aprotic solvent, followed by reduction of the nitrile functional group. The synthetic route to baclofen has been demonstrated to be commercially viable, cost-effective, and environmentally friendly. Execution of the developed process led to the isolation of (+)-baclofen in an overall yield of 60% at a multikilogram scale with >99.5% HPLC purity. This article also discusses the cost-effectiveness of the process, the impurity profiling, and the product quality.

Key words

baclofen - C-alkylation - medicinal chemistry - green chemistry

• References and Notes

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• 17 3-(4-Chlorophenyl)-3-cyanopropanoic Acid (27); Large-Scale Synthesis K₂CO₃ (110 kg, 3.98 mol) was added to DMSO (385 kg) at r.t., and the mixture was cooled to 10–15 °C. Chloroacetic acid (28; 58.8 kg, 3.13 mol) and 2-(4-chlorophenyl)acetonitrile (24; 100 kg, 3.29 mol) were then added, followed by portionwise addition of KOH (64.6 kg, 5.77 mol) at 10–15 °C. The mixture was then stirred for 90 min at 10–15 °C. The reaction was quenched with H₂O (500 kg), and toluene (867 kg) was added. The biphasic solution was stirred for 20 min and then the layers were separated. The aqueous layer was acidified to pH 3.5 with concd HCl (132 kg), and the product was extracted with toluene (346.8 kg). The product was back-extracted from the aqueous layer with toluene (173.4 kg). Additional product was extracted from the organic layers with aq NH₃ (176 kg) The aqueous layer was acidified with concd HCl and the product was collected by filtration. The wet material was stirred for 15–30 minutes in MeOH (198 kg) then H₂O (900 kg) was added. The suspension was stirred for 2–2.5 h, then filtered. The resulting product was dried at 30°C under vacuum to give a White solid; yield: 114.4 kg (82%; HPLC purity: 97.0%). IR (KBr pellet): 2265, 1700 cm^–1. ¹H NMR (400 MHz, DMSO): δ = 12.71 (br s, 1 H, -COOH), 7.45–7.5 (m, 4 H, Ar-H), 4.48–4.52 (m, 1 H, CN–CH–CH₂), 3.01–3.08 (dd, J = 16.4, 1 H, –CO–CH₂–), 2.86–2.92 (dd, J = 17.2, 1 H, –CO–CH₂–). ¹³C NMR (100 MHz, DMSO-d₆ ): δ = 31.5, 38.1, 120.7, 128.9, 129.6, 132.8, 134.4, 170.8. MS: m/z = 209 [M⁺].
• 18 Baclofen [4-Amino-3-(4-chlorophenyl)butanoic Acid] (1) 25% aq NH₃ (528 kg) and Raney nickel (10 kg) were added sequentially to a solution of acid 27 (100 kg, 0.48 mol), and the mixture was treated with H₂ at a pressure of 8–10 kg at 25–30 °C for 5 h and then at 60–65 °C for 3 h. The solids were collected by filtration and washed with wateH₂O (200 kg). The reaction mass was then distilled to remove excess ammonia. CH₂Cl₂ (66.25 kg) was added and the resultant mixture was stirred for 30–45 min. The organic layer was separated and recovered for recycling. The aqueous layer was treated with disodium EDTA dihydrate (5 kg, 0.028 mol) to reduce the nickel concentration to below 5 ppm, and the reaction mass was filtered. i-PrOH (157.2 kg) was added to the filtrate, and the pH was adjusted to 6.5–7 with HCl (58.8 kg). The product was precipitated, collected by filtration, and washed with H₂O at r.t. The wet product was again treated with H₂O (800 kg) at 70–75 °C to reduce the inorganic content to below 0.1%, cooled to r.t., and filtered. The residue was dried at 60–65 °C for 12 h to give a White solid; yield: 72 kg (72%; HPLC purity: 99.8%). IR (KBr pellet): 2907, 1627.79 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.77 (br s, 3 H, –COOH, –NH₂), 7.39–7.41 (d, J = 8.4, 2 H, Ar-H), 7.33–7.35 (d, J = 9, 2 H, Ar-H), 3.28–3.33 (m, 1 H, –CH₂–CH–CH₂–NH₂), 2.97–3.16 (m, 2 H, –CH₂–NH₂), 2.79–2.81 (d, J = 5.6, 1 H, –CO–CH₂–), 2.75–2.76 (d, J = 6, 1 H, –CO–CH₂–). ¹³C NMR (100 MHz, DMSO-d₆ ): δ = 172.5, 139.2, 132.1, 130.0, 128.7, 43.3, 39.4, 37.9. MS: m/z = 214.3 [M⁺]. (19) HPLC Achiral Analysis of 3-(4-Chlorophenyl)-3-cyanopropanoic Acid (27) Column: Waters Spherisorb ODS2, C18, 5 μm, 250 × 4.6 mm (Part no. PSS831915). Flow rate: 1.0 mL/min. Mobile phase A: Buffer (6.8 g KH₂PO₄ in 1000 mL water adjusted to pH 3 with H₃PO₄)–MeCN (85:15); Mobile phase B: Buffer–MeCN (25:75). The sample was prepared at a 500 ppm concentration in mobile phase A. Retention time: 27, t _R = 16.2 min; imide impurity, t _R = 21.0 min; 4-ClC₆H₄CHO (2), t _R = 27.0 min. HPLC Achiral Analysis of Baclofen (1) Column: Waters Spherisorb ODS2, 10 μm, 250 × 4.0 mm. Flow rate: 2.0 mL/min. Mobile phase: H₂O–MeOH [1.822 g of sodium hexanesulfonate dissolved in 56:44 H₂O–MeOH (1000 ml) + 5 mL glacial AcOH (equilibrated for 5 min)]. The sample was prepared at a 2500 ppm concentration in the mobile phase. Retention times: amide impurity, t _R = 2.6 min; baclofen (1); t _R = 4.6 min; baclofen impurity A, t _R = 7.3.