A Scaleable Synthesis of 3-Hydroxy-1,5-naphthyridine-4-carbaldehyde

Abstract

A scaleable synthesis of 3-hydroxy-1,5-naphthyridine-4-carbaldehyde is described. 3-Amino-5-methoxy-4-methyl-pyridine underwent the Skraup reaction to give the corresponding 1,5-naphthyridine which, upon treatment with DMF-DMA in the presence of catalytic amount of LiOH, provided the N,N-dimethyl enamine intermediate. Oxidative cleavage, followed by removal of the methyl ether afforded the titled product.

Key words

naphthyridine - Skraup reaction - pyridine - enamine - DMF-DMA - oxidation

References and Notes

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6

We were unsuccessful in identifying a functionalized methyl group at the C-4 that survived the Skraup reaction conditions. Attempts to formylate 3-methoxy-1,5-napthyridine at the C-4 position also met with failure.

15

Solubility <0.3 mg/mL in DMSO, MeOH, or H₂O, and <0.1 mg/mL in THF, CH₂Cl₂, MeCN, PhMe, and acetone.

18

3-Methoxy-4-methyl-1,5-naphthyridine (2)
To a 200 L glass-lined reactor, charged concd H₂SO₄ (49 kg) and sodium 3-nitrobenzene sulfonate (20.9 kg, 95.5 mol) in portions. FeSO₄˙7H₂O (1.66 kg, 5.98 mol) and boric acid (2.86 kg, 46.2 mol) were added, respectively, in one portion below 40 ˚C. Water (13.3 kg) was then added slowly below 40 ˚C, followed by addition of 3 (10 kg, 57.3 mol). The reaction mixture was heated to 135-140 ˚C. Glycerol (14.7 kg, 16.0 mol) was added at the rate of 50 ± 10 mL/min while keeping the reaction at 135-145 ˚C. The reaction was heated for 6 h, then cooled to 80-90 ˚C. The reaction mixture was transferred into a vessel containing H₂O (30 kg) and ice (100 kg), then adjusted pH to 8-9 with 20% aq NaOH. Additional H₂O (220 kg) was added to dissolve the inorganic salts. The mixture was then extracted with EtOAc (3 × 200 kg). The combined organic phase was stirred with Na₂SO₄ (5 kg) and active carbon (1 kg) for 4 h. After filtration, the filtrate was concentrated under reduced pressure until black solid appeared as precipitate. CH₂Cl₂ (54 kg) was added, the resulting mixture was stirred into complete solution with heat (40 ˚C), then cooled and washed with 10% aq NaOH (3 × 15 kg), followed by H₂O (15 kg). The organic phase was filterer to remove any insoluble material and concentrated to dryness to give the desired product as a yellow solid (6.79 kg, 39.0 mol, 68%); mp 100-101 ˚C (MeCN). LC-MS:
m/z = 175.1 [M + 1]. ^¹H NMR (300 MHz, CDCl₃): δ = 2.71 (s, 3 H), 4.11 (s, 3 H), 7.50 (dd, J = 4.1, 8.5 Hz, 1 H), 8.32 (dd, J = 1.8, 8.5 Hz, 1 H), 8.81 (s, 1 H), 8.95 (dd, J = 1.8, 4.1 Hz, 1 H).

19

3-Methoxy-1,5-naphthyridine-4-carbaldehyde (10) To a 200 L glass-lined reactor was charged DMF (113 kg) and 2 (12 kg, 68.9 mol). After stirring into a complete solution, LiOH (0.33 kg, 13.8 mol) and DMF-DMA (16.4 kg, 137.6 mol) were added sequentially. The reaction was heated to 120-130^˚C for 24 h, then cooled to r.t. The reaction mixture was filtered, and the filtrate concentrated under reduced pressure until 105 ± 5 kg of distillate was collected. The resulting residue was cooled to r.t., and MeOH (115 kg) was added. The resulting enamine solution in MeOH was split into 4 identical batches for the sodium periodate oxidation. Thus, to one fourth of the batch, was added H₂O (4.4 kg), followed by NaIO₄ (7.45 kg, 34.8 mol) in portions while keeping the reaction temperature at 30-40 ˚C. The reaction mixture was stirred at 30-40 ˚C for 16 h. NaHCO₃ (1.45 kg, 17.3 mol) was added to adjust the pH to 7-8. The reaction mixture was filtered, and the filter cake rinsed with MeOH. The filtrate was concentrated until the residue volume was 31-47 L. 47.2 kg H₂O was added, and vacuum concentration was continued until the residue was 31-47 L. 31 kg of H₂O was added, and the resulting mixture was stirred for 1 h at r.t. The mixture was filtered, and the filter cake rinsed with H₂O. The filter cake was dried at 50 ˚C under vacuum to give the product as the first crop. The mother liquor was extracted with CH₂Cl₂ (3 × 50 L), the combined organic phase was concentrated to a minimum stir volume. The mixture was then filtered. The filter cake was dried to give the product as the second crop. Both crops from all four batches were combined to give 10 as a yellow solid (10.2 kg, 54.2 mol, 79%); mp 170-172 ˚C (MeCN). ^¹H NMR (400 MHz, CDCl₃): δ = 11.35 (1 H, s), 9.09 (1 H, s), 9.05 (1 H, dd, J = 4.36, 1.86 Hz), 8.425 (1 H, dd, J = 8.41, 1.55 Hz), 7.61 (1 H, dd, J = 8.41, 4.05 Hz), 4.246 (3 H, s). ^¹³C NMR (100 MHz, CDCl₃): δ = 16.0, 57.9, 122.6, 137.4, 141.4, 152.6, 191.9.

20

3-Hydroxy-1,5-naphthyridine-4-carbaldehyde (1) LiCl (6.38 kg, 150 mol) was added to DMF (26.4 kg). The resulting mixture was heated to 110-120 ˚C. To a second reactor, was charged DMF (44.2 kg) and 10 (9.4 kg, 50 mol), and the mixture was heated to 110-120 ˚C. The LiCl in DMF prepared above was transferred to the second reactor. The mixture was stirred for 30 min at 110-120 ˚C, then cooled to 30-40 ˚C. The mixture was concentrated at 60-70 ˚C under vacuum until the residue was 20-30 L. The material was transferred to a rotary evaporator, and continued to concentrate to dryness at 60-70 ˚C under vacuum (6.7-13.3 mbar). MeOH (22.4 kg) was added, and the resulting mixture was transferred to a reactor, and cooled to 0-5 ˚C. After stirring for 5 h, the mixture was filtered using a centrifuge filter, the filter cake was rinsed with MeOH (7.4 Kg, pre-cooled to 0-5^˚C). The filter cake was dried at 40-50 ˚C under vacuum to obtain the lithium salt of 1. This was combined with water (140 kg) and active carbon (0.93 kg). The mixture was heated at 90-100 ˚C for 3 h. The mixture was filtered hot at 80-90 ˚C. To the filtrate was added 6 M HCl solution (5.31 kg) until pH 5-6. The reaction mixture was then stirred for 10 h at 0-5 ˚C and filtered. The filter cake was rinsed with H₂O, and dried at 40-50 ˚C under vacuum until KF £0.5%. This gave the product as a yellow solid (4.87 kg, 28.0 mol, 56%, 99.1% HPLC purity at 240 nm); mp 238-240 ˚C (MeOH). MS (ESI⁺): m/z = 175 [M + H]⁺. ^¹H NMR (400 MHz, D₂O): δ = 10.04 (1 H, s), 8.54-8.46 (1 H, m), 8.46-8.40 (1 H, m), 8.32 (1 H, s), 7.56-7.46 (1 H, m).