A Novel Synthesis of the Antidepressant Agomelatine

Abstract

Agomelatine was synthesized from (2-methoxynaphthalene-8-yl)oxoacetic acid in a four-step approach involving borane reduction, semipinacol rearrangement of the resulting diol, ald­oxime formation, and Ra-Ni hydrogenation/acetylation in 51% overall yield. The reaction sequence includes a novel one-pot conversion of an aldoxime into an N-acetylamine. The synthetic route could be useful as a new approach towards N-acetylarylethyl­amines.

Agomelatine is a newly approved melatonergic antidepressant derived from the neurohormone melatonin by a bioisosteric replacement of the indole ring with a naphthalene moiety (Figure  [¹] ). [¹]

It was first synthesized by Yous et al. in a multi-step route starting from the difficult-to-access (7-methoxynaphth-1-yl)acetic acid [²] in 1992. [³] Several modifications of the original procedure, mostly aiming at industrial scale synthesis, have been published later in the patent literature. [4] In 2010, chemists at Servier reported a simplified three-step synthesis of agomelatine using the naphthylglyoxylic acid 1 as the starting material. [5] The novel route involved amidation using ammonium chloride and N,N-diisopropylethylamine, then a borane and aluminum trichloride reduction of the resulting glyoxyamide 2 to give 2-(2-methoxynaphthalen-8-yl)ethanamine (3), and the final N-acetylation (Scheme  [¹] ). In the course of our studies on subtype-selective melatonergic ligands, we attempted to adopt the latter procedure for agomelatine synthesis. Surprisingly, the borane and aluminum trichloride reduction of the glyoxylic amide 2 provided α-hydroxyacetamide 4 in 79% yield, instead of the reported ethylamine 3. In this paper, we report an efficient alternative four-step route to agomelatine starting from the glyoxylic acid 1 yielding the target compound in 51% overall yield.

The known glyoxamic acid 1 was obtained in two steps from the commercially available 2-methoxynaphthalene (Scheme  [²] ). Staudinger et al. reported a double Friedel-Crafts acylation of 2-methoxynaphthalene using oxalic acid phenylimidochloride (prepared from oxalic acid chloride and aniline [6] ) to give 3-methoxyacenaphthenequinone (5). [7] Applying the same procedure in toluene instead of benzene afforded the desired diketone 5 in 80% yield. The second step involved the regioselective cleavage of 5 using potassium hydroxide and 18-crown-6 in dimethylsulfoxide as previously described by Gottlieb et al. [8] to give the desired glyoxamic acid 1 in 82% yield.

Our novel four-step approach towards agomelatine is displayed in Scheme  [²] . It commenced with the reduction of both carbonyl groups of glyoxamic acid 1 using borane in tetrahydrofuran to give the diol 6 in 87% yield. The second step involves semipinacol rearrangement of the diol 6 to give the acetaldehyde 7. In our first attempt, we applied the procedure of Naves [9] using 25% sulfuric acid as reagent, which resulted in a nonseparable mixture of decomposition products. However, we were pleased to observe that a strong acidic ion-exchange resin Dowex^® HCR-W2 proved to be successful in affording the desired aldehyde 7 in 75% yield.

In the next step, the aldehyde group was supposed to be converted into a primary amine by means of reductive amination. Since employing the classical conditions of reductive amination, such as sodium cyanoborohydride and ammonium acetate or sodium triacetoxyborohydride and ammonium acetate failed, we decided to examine an alternative route via the corresponding oxime. Thus, aldehyde 7 was converted into the aldoxime 8 using hydroxylamine hydrochloride in 79% yield. NMR spectra revealed that the recrystallized 8 exists as an E/Z mixture in a 1:1.4 ratio, respectively, as indicated by the integration of the corresponding CH=NOH resonance signals. The E/Z assignment was based on different chemical shifts of the nuclei around the carbonyl atom of the oxime group, namely the aldoxime protons and the α-carbons. [¹0] Both the aldoxime proton and the α-carbons were deshielded in the E-oxime (δ_H = 7.48, δ_C = 34.8) when compared to the corresponding signals of the Z-isomer (δ_H = 6.68, δ_C = 30.7).

In the next step, aldoxime 8 was supposed to be reduced to the corresponding primary amine which, in turn, should give the target compound in a final N-acetylation reaction. In order to minimize the number of reaction steps and to achieve the best possible overall yield, we have chosen a one-pot Ra-Ni hydrogenation/acetylation procedure previously reported for the reduction of nitriles to give directly the N-acetylated product. [¹¹] We were pleased to find that aldoxime 8 could be converted into agomelatine using Ra-Ni hydrogenation in the presence of acetic anhydride in an excellent 98% yield.

Our four-step approach provides agomelatine in 51% overall yield and is, to the best of our knowledge, the shortest and most efficient small-scale route reported up to date. Moreover, the reaction sequence is generally applicable as a novel route for the introduction of ethyl­amine side chains into activated aromatic rings as the glyoxamic acid starting material is supposed to be easily accessible via Friedel-Crafts acylation using oxalyl chloride or oxalyl chloride ethyl ester (ethyl 2-chloro-2-oxoacetate).

Melting points were determined using a capillary melting point apparatus (Gallenkamp, Sanyo) and are uncorrected. Column chromatography was carried out on silica gel 60 (0.063-0.200 mm) obtained from Merck. A Bruker AV-400 spectrometer was used to obtain ^¹H NMR (400 MHz) and ^¹³C NMR (100 MHz) spectra, respectively. ^¹H NMR chemical shifts are referred to CHCl₃ (7.24 ppm) and CD₃OD (3.31 ppm). ^¹³C NMR chemical shifts are referred to CDCl₃ (77.00 ppm) and CD₃OD (49.00 ppm). The NMR resonances were assigned by means of HH-COSY, HMQC, and HMBC experiments. EI mass spectra were determined on a Finnigan MAT 8200 and on an ESI-microTOF spectrometers. IR spectra, recorded as ATR, were obtained by using a Biorad PharmalyzIR FT-IR instrument. Elemental analyses were performed by the microanalytical section of the Institute of Inorganic Chemistry, University of Würzburg. All reactions were carried out in a Schlenk flask under an argon atmosphere. The hydrogenation reaction was performed in a stainless-steel autoclave (capacity 75 mL) under stirring using magnetic stirrer and heating on an oil bath.

Compound 5 was synthesized according to Ref. 7 using toluene as solvent (1.75 mL total volume/mmol 2-methoxynaphthalene). Compound 1 was synthesized according to Ref. 8. The crude product was purified by silica gel column chromatography using CHCl₃-MeOH-formic acid (10:1:0.1) to give 1 in 82%.

2-Hydroxy-2-(2-methoxynaphthalen-8-yl)acetamide (4)

To a solution of 2 [5] (140 mg, 0.611 mmol) in anhyd THF (5.8 mL) was added AlCl₃ (163 mg, 1.22 mmol). A 1 M solution of BH₃ in THF (3.66 mL, 3.66 mmol) was dropwise added under cooling (0-5 ˚C) and the reaction mixture was stirred at r.t. for 2.5 h. The cooled mixture was quenched with sat. aq Na₂CO₃ (10 mL) and extracted with MTBE (4 × 20 mL). The combined organic layers were dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CHCl₃-MeOH-aq 25% ammonia, 10:1:0.1) to yield 4 as white solid (111 mg, 0.480 mmol, 79%). Analytical sample was obtained by recrystallization from CH₂Cl₂; mp 173-174 ˚C; R _f  = 0.35 (CHCl₃-MeOH-aq 25% ammonia, 10:1:0.1).

IR (ATR): 3283, 2540, 2425, 2389, 1625, 1602, 1509, 1470, 1449, 1431, 1389, 1258, 1216, 1061, 1030, 826 cm^-¹.

^¹H NMR (400 MHz, CD₃OD): δ = 3.93 (s, 3 H, OCH₃), 5.61 (s, 1 H, CHOH), 7.14 (dd, J = 2.3, 9.0 Hz, 1 H, H-3), 7.31 (t, J = 7.7 Hz, 1 H, H-6), 7.53 (d, J = 7.1 Hz, 1 H, H-7), 7.66 (d, J = 2.3 Hz, 1 H, H-1), 7.74-7.80 (m, 2 H, H-4, H-5).

^¹³C NMR (100 MHz, CD₃OD): δ = 55.8, 77.3, 104.3, 119.4, 123.9, 128.0, 129.7 (2 C), 131.0, 134.0, 136.1, 159.3, 178.8.

MS (EI, 70 eV): m/z (%) = 232 (14, [M + H]⁺), 231 (30, [M⁺]), 188 (25), 187 (100), 159 (26), 144 (51), 128 (15), 127 (24), 116 (20), 115 (40).

Anal. Calcd for C₁₃H₁₃NO₃: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.12; H, 5.77; N, 5.94.

1-(2-Methoxynaphthalen-8-yl)ethane-1,2-diol (6)

A 1 M BH₃ in THF (25.4 mL, 25.4 mmol) was dropwise added to 1 (584 mg, 2.54 mmol) at 0 ˚C. After heating under reflux for 2.5 h, the cooled reaction mixture was poured onto ice-cooled 10% aq NH₃ in H₂O (40 mL) (evolution of gas). THF was removed under vacuum and the residual mixture was extracted with CHCl₃ (4 × 20 mL) and EtOAc (2 × 20 mL). The combined organic layers were dried (Na₂SO₄) and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CHCl₃-MeOH-aq 25% ammonia, 10:1:0.1) to yield 6 as a white solid (480 mg, 2.20 mmol, 87%). Analytical sample was obtained by recrystallization from THF-MTBE; mp 108-109 ˚C; R _f  = 0.56 (CHCl₃-MeOH-aq 25% ammonia, 10:1:0.1).

IR (ATR): 3320, 2926, 1744, 1623, 1604, 1508, 1465, 1445, 1431, 1351, 1252, 1211, 1179, 1095, 1061, 1030, 890, 829, 702 cm^-¹.

^¹H NMR (400 MHz, CD₃OD): δ = 3.66-3.77 (m, 1 H, CHOHCH _a-H_bOH), 3.82-3.89 (m, 1 H, CHOHCH_a H _bOH), 3.93 (s, 3 H, OCH₃), 5.44-5.48 (m, 1 H, CHOHCH₂OH), 7.13 (d, J = 7.8 Hz, 1 H, H-3), 7.32 (t, J = 7.3 Hz, 1 H, H-6), 7.45 (s, 1 H, H-1), 7.64 (d, J = 7.3 Hz, 1 H, H-7), 7.70 (d, J = 7.3 Hz, 1 H, H-5), 7.76 (d, J = 7.8 Hz, 1 H, H-4).

^¹³C NMR (100 MHz, CD₃OD): δ = 55.7, 68.1, 78.1, 102.8, 119.0, 124.1, 125.2, 128.7, 130.7, 131.3, 133.2, 137.3, 159.2.

MS (EI, 70 eV): m/z (%) = 219 (4, [M + H]⁺), 218 (30, [M⁺]), 188 (12), 187 (100), 159 (20), 144 (43), 128 (15), 127 (16), 116 (13), 115 (29).

Anal. Calcd for C₁₃H₁₄NO₃: C, 71.54; H, 6.47. Found: C, 71.45; H, 6.52.

2-(2-Methoxynaphthalen-8-yl)acetaldehyde (7)

A mixture of 6 (360 mg, 1.65 mmol) and Dowex^® HCR-W2 (3.60 g) in anhyd toluene (24 mL) was stirred under reflux for 1 h. The resin was filtered off through Celite^® and washed with THF (50 mL). The combined filtrates were concentrated in vacuo and the residue was purified by column chromatography on silica gel [EtOAc-petroleum ether (bp 40-60 ˚C), 1:1] to yield 7 as a yellow viscous oil (248 mg, 1.24 mmol, 75%); R _f  = 0.72 (EtOAc-petroleum ether, 1:1).

IR (ATR): 3055, 3002, 2933, 2833, 2722, 1720, 1626, 1600, 1510, 1470, 1449, 1434, 1388, 1250, 1212, 1176, 1135, 1030, 826, 750 cm^-¹.

^¹H NMR (400 MHz, CDCl₃): δ = 3.91 (s, 3 H, OCH₃), 4.03 (d, J = 2.6 Hz, 2 H, CH ₂CHO), 7.09 (d, J = 2.3 Hz, 1 H, H-1), 7.17 (dd, J = 2.3, 9.0 Hz, 1 H, H-3), 7.32 (t, J = 7.5 Hz, 1 H, H-6), 7.38 (d, J = 6.0 Hz, 1 H, H-5), 7.72-7.81 (m, 2 H, H-4, H-7), 9.73 (t, J = 2.6 Hz, 1 H, CH₂CHO).

^¹³C NMR (100 MHz, CDCl₃): δ = 48.8, 55.4, 102.2, 118.6, 123.1, 123.4, 128.2, 129.1, 129.4, 130.5, 133.6, 158.3, 199.7.

HRMS (ESI, neg): m/z [M - H]^- calcd for C₁₃H₁₂O₂: 199.07645; found: 199.07643.

2-(2-Methoxynaphthalen-8-yl)acetaldehyde Oxime (8)

Compound 7 (200 mg, 1.00 mmol), Et₃N (251 mg, 2.50 mmol, 0.4 mL), and hydroxylamine hydrochloride (139 mg, 2.00 mmol) were stirred under reflux in abs EtOH (3 mL) for 5 h. The solvent was removed in vacuo and the residue was partitioned between aq 2 M HCl (25 mL) and EtOAc (25 mL). After separation, the aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic layers were dried (Na₂SO₄) and evaporated in vacuo. The residue was purified by column chromatography on silica gel (CHCl₃-MeOH-formic acid, 10:1:0.1) to yield 8 as a yellow solid (170 mg, 0.790 mmol, 79%). The aldehyde 7 could be reisolated (15%). Analytical sample (colorless needles or cubic crystals) were obtained by recrystallization from CH₂Cl₂. The following data refer to the E/Z-mixture of 8 in respective 1:1.4 ratio as indicated by the integration of the CH=NOH NMR signals; mp 130-132 ˚C; R _f  = 0.57 (CHCl₃-MeOH-formic acid, 10:1:0.1).

IR (ATR): 3191, 3057, 2932, 2877, 1626, 1600, 1510, 1469, 1449, 1433, 1389, 1250, 1211, 1183, 1136, 1055, 1026, 824, 747, 702 cm^-¹.

^¹H NMR (400 MHz, CD₃OD): δ = 3.86-3.89 (m, 5 H, E-ArCH ₂, E-OCH₃), 3.91 (s, 3 H, Z-OCH₃), 4.07 (d, J = 5.6 Hz, 2 H, Z-ArCH ₂), 6.68 (t, J = 5.6 Hz, 1 H, Z-HC=NOH), 7.12 (d, J = 8.8 Hz, 2 H, E-H-3, Z-H-3), 7.25 (t, J = 7.6 Hz, 2 H, E-H-6, Z-H-6), 7.29-7.42 (m, 4 H, E-H-1, Z-H-1, E-H-7, Z-H-7), 7.48 (t, J = 6.4 Hz, 1 H, E-HC=NOH), 7.74 (d, J = 8.8 Hz, 2 H, E-H-4, Z-H-4), 7.68 (d, J = 8.1 Hz, 2 H, E-H-5, Z-H-5).

^¹³C NMR (100 MHz, CD₃OD): δ = 30.7, 34.8, 55.8 (2 C), 103.4, 103.5, 119.3, 119.5, 124.2, 124.3, 128.2, 128.3, 128.4, 128.7, 130.7, 130.8, 131.1, 131.2, 132.7, 133.3, 134.6, 134.7, 150.6, 150.8, 159.3, 159.4.

MS (EI, 70 eV): m/z (%) = 215 (100, [M⁺]), 199 (18), 198 (51), 197 (23), 183 (25), 182 (20), 172 (19), 171 (96), 167 (24), 166 (30), 158 (23), 128 (43), 127 (18).

Anal. Calcd for C₁₃H₁₃NO₂: C, 72.54; H, 6.09; N, 6.51. Found: C, 72.82; H, 6.02; N, 6.47.

N -[2-(2-Methoxynaphthalen-8-yl)ethyl]acetamide (Agomelatine)

A solution of 8 (46 mg, 0.214 mmol) in THF (1.3 mL) and Ac₂O (0.28 mL, 2.97 mmol) was hydrogenated over Raney Ni (0.3 mL, 50% suspension in H₂O) at 10 bar H₂ for 6 h at 50 ˚C. The catalyst was filtered off on Celite^®, washed with THF (20 mL), and the combined filtrates were concentrated in vacuo. The residue was purified by column chromatography on silica gel (CHCl₃-MeOH-aq 25% ammonia, 10:1:0.1) to yield agomelatine as a pale yellow solid (51 mg, 0.210 mmol, 98%). An analytical sample was obtained by recrystallization from toluene-hexane; mp 109-110 ˚C; R _f  = 0.57 (CHCl₃-MeOH-aq 25% ammonia, 10:1:0.1).

IR (ATR): 3252, 3079, 2937, 1625, 1598, 1561, 1509, 1446, 1435, 1252, 1213, 1182, 1031, 862, 831, 755, 734, 697 cm^-¹.

^¹H NMR (400 MHz, CDCl₃): δ = 1.89 (s, 3 H, COCH ₃), 3.21 (t, J = 7.2 Hz, 2 H, CH ₂CH₂NHAc), 3.58 (q, J = 6.8 Hz, 2 H, CH₂ CH ₂NHAc), 3.95 (s, 3 H, OCH₃), 5.70 (br s, 1 H, NHCO), 7.13 (dd, J = 2.4, 8.9 Hz, 1 H, H-3), 7.20-7.27 (m, 2 H, H-6, H-7), 7.44 (d, J = 2.4 Hz, 1 H, H-1), 7.64 (dd, J = 2.8, 6.5 Hz, 1 H, H-5), 7.72 (d, J = 8.9 Hz, 1 H, H-4).

^¹³C NMR (100 MHz, CDCl₃): δ = 23.2, 33.2, 40.1, 55.5, 102.4, 118.3, 123.1, 127.0, 127.1, 129.3, 130.2, 133.2, 133.6, 158.0, 170.4.

MS (EI, 70 eV): m/z (%) = 243 (24, [M⁺]), 202 (12), 185 (16), 184 (100), 172 (18), 171 (97), 169 (11), 153 (17), 128 (26).

Acknowledgment

The authors thank Prof. Ulrike Holzgrabe, University of Würzburg for financial support and Anna Kucharski, University of Würzburg for her skilful assistance in synthesizing some intermediates.

References

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References

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  CrossrefPubMedSearch in Google Scholar
• 2a Tang J.-D. Cen J.-D. Org. Prep. Proced. Int.  2009,  41:  164 
  Search in Google Scholar
• 2b Silverman IR. Daub GH. VanderJagt DL. J. Org. Chem.  1985,  50:  5550 
  Search in Google Scholar
• 3 Yous S. Andrieux J. Howell HE. Morgan PJ. Renard P. Pfeiffer B. Lesieur D. Guardiola-Lemaitre B. J. Med. Chem.  1992,  35:  1484 
  CrossrefSearch in Google Scholar
• 4a Zhou S, and Jian F. inventors; Faming Zhuanli Shenqing CN  101759591.  ; Chem. Abstr. 2010, 153, 174638
• 4b Hu W, Xu Q, and Yang L. inventors; Faming Zhuanli Shenqing CN  101792400.  ; Chem. Abstr. 2010, 153, 310977
• 4c Zhang Z, Li P, Xu J, Chen L, and Lu W. inventors; Faming Zhuanli Shenqing Gongkai Shuomingshu CN  101735091.  ; Chem. Abstr. 2010, 153, 87525
• 4d Hardouin C, Lecouve J.-P, and Bragnier N. inventors; PCT Int. Appl. WO  2010015745.  ; Chem. Abstr, 2010, 152, 238612
• 4e Bontempelli P, Jalenques X, Starck J.-B, and Sery J.-P. inventors; PCT Int. Appl. WO  2010015744.  ; Chem. Abstr, 2010, 152, 238611
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• 4g Dubuffet T, Lecouve J.-P, and Hermet J.-P. inventors; Fr. Demande FR  2919606.  ; Chem. Abstr. 2009, 150, 191168
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• 4i Souvie J.-C, Blanco IG, Thominot G, Chapuis G, Horvath St, and Damien G. inventors; Eur. Pat. Appl. EP  1564202.  ; Chem. Abstr. 2008, 143, 193816
• 4j Poissonnier-Durieux S. Ettaoussi M. Peres B. Boutin J.-A. Audinot V. Bennejean C. Delagrange P. Caignard D.-H. Renard P. Berthelot P. Lesieur D. Yous S. Bioorg. Med. Chem.  1998,  16:  8339 
  Search in Google Scholar
• 5 Hardouin C, and Lecouve J.-P. inventors; PCT Int. Appl. WO  2010015746.  ; Chem. Abstr. 2010, 152, 238613
• 6 Buehrdel G. Beckert R. Petrlikova E. Herzigova P. Klimesova V. Fleischhauer J. Goerls H. Synthesis  2010,  3071 
• 7 Staudinger H. Goldstein H. Schlenker E. Helv. Chim. Acta  1921,  6:  342 
  Search in Google Scholar
• 8 Gottlieb L. Kellner D. Loewenthal HJE. Synth. Commun.  1989,  19:  2987 
  CrossrefSearch in Google Scholar
• 9 Naves YR. Helv. Chim. Acta  1967,  50:  319 
  CrossrefSearch in Google Scholar
• 10 Gottlieb L. Hassner A. Gottlieb HE. Synth. Commun.  2000,  14:  2445 
  Search in Google Scholar
• 11 Spadoni G. Bedini A. Guidi T. Tarzia G. Lucini V. Pannacci M. Fraschini F. ChemMedChem  2006,  1:  1099 
  CrossrefSearch in Google Scholar