Improved Synthesis of the Antitubercular Agent SQ109

Abstract

We present here an improved procedure for the preparation of the promising antitubercular drug SQ109 that is currently in phase Ib/III of clinical trials against Mycobacterium tuberculosis. We investigated and tested the literature synthetic procedure that enables the development of structure–activity relationships and report the observed inconsistencies as well as presenting improvements or novelties for the more efficient preparation of SQ109. Most significantly we applied a novel reduction step of the aminoamide precursor using Me₃SiCl­/LiAlH₄ under mild conditions. These findings are important for research groups investigating the efficacy of this drug and analogues in academia and industry.

Key words

SQ109 - tuberculosis - synthesis - reduction - trimethylsilyl chloride - geranylamine - lithium aluminum hydride

Publication History

Received: 10 August 2021

Accepted after revision: 27 September 2021

Accepted Manuscript online:
27 September 2021

Article published online:
14 December 2021

• References and Notes

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• 30 1-Bromo-3,7-dimethylocta-2,6-diene (1-geranyl bromide, 2)A mixture of geraniol (1, 500 mg, 3.24 mmol) and PBr₃ (351 mg, 1.30 mmol) in anhydrous diethyl ether was stirred at –5 ° for 3 h. The resulting solution was extracted with NaHCO₃ 5% w/v and brine. The organic extract was dried over Na₂SO₄ and evaporated in vacuo to give a yellow oil; yield 700 mg (99.5%). ¹H NMR (CDCl₃, 400 MHz): δ = 1.60 (s, 3 H, 8-H), 1.68 (s, 3 H, 7-CH₃), 1.73 (s, 3 H, 3-CH₃), 2.08 (m, 4 H, 4-H, 5-H), 4.03 (d, J = 8.4 Hz, 2 H, 1-H), 5.07 (m, 1 H, 6-H), 5.53 (t, J = 8.5 Hz, 1 H, 2-H) ppm.1-Phthalimido-3,7-dimethylocta-2,6-diene (1-geranyl phthal­imide, 3) A solution of geranyl bromide (520 mg, 2.40 mmol), phthalimide (353 mg, 2.40 mmol), and K₂CO₃ (994 mg, 7.2 mmol) in anhydrous THF (10 mL) was heated to reflux overnight. The solvent was then evaporated in vacuo, water was added, and the mixture was extracted twice with diethyl ether. The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated in vacuo. The crude product was purified by column chromatography using n-hexane/EtOAc (15:1) as eluent to afford geranyl phthalimide as a pale-yellow oil; yield 600 mg (88%). 1-Amino-3,7-dimethylocta-2,6-diene (1-geranylamine, 4) Procedure AA solution of geranyl phthalimide (600 mg, 2.12 mmol) and hydrazine monohydrate (0.160 mL, 3.18 mmol, 1.5 equiv) in absolute EtOH (10 mL) was heated to reflux for 6 h. The solvent was evaporated in vacuo, 15% aq. NaOH was added, and the mixture extracted twice with DCM. The combined organic phases were washed with water, dried over Na₂SO₄, filtered, and concentrated in vacuo. After column chromatography 81% of geranylamine 4 was obtained.Procedure BA mixture of azide 5 (240 mg, 1.34 mmol) and PPh₃ (386 mg, 1.47 mmol) in THF/water (10:1, 7 mL) was stirred at room temperature for 12 h. The solvent was evaporated under vacuum, and equal quantities of water (20 mL) and DCM (20 mL) were added for extraction. The organic solution was then washed with HCl 6% v/v, the aqueous extract was made alkaline with solid Na₂CO₃ and extracted with DCM. After solvent evaporation in vacuo the crude amine product was obtained (90 mg). Anhydrous diethyl ether (15 mL) was added, and the organic solution was treated with a saturated solution of ethanol with hydrogen chloride at 0 ℃ to afford the hydrochloride salt as a white precipitate. After overnight cooling at 5 ℃ and suction filtration, geranylamine 4 hydrochloride was obtained as a white solid (87 mg, 34% yield). Procedure CTo a suspension of LiAlH₄ (152 mg, 4.0 mmol) in anhydrous diethyl ether (8 mL), a solution of azide 5 (480 mg, 2.68 mmol) in anhydrous diethyl ether (5 mL) was added dropwise at 0 °. The mixture was left stirring at room temperature overnight and was quenched with water (2 mL), 15% w/v NaOH (2 mL), and then water (6 mL) at 0 °. The resulting inorganic precipitate was filtered off and washed thoroughly with diethyl ether. The filtrate was extracted twice with HCl 6 % v/v, and the aqueous phase was made alkaline with solid Na₂CO₃ and extracted twice with DCM. The combined organic extracts were washed with water and dried over solid Na₂SO₄. After filtration, the solvent was evaporated in vacuo to afford geranylamine 4 as a pale-yellow oil (98 mg, 24% yield). Hydrochloride salt: ¹H NMR (CDCl₃, 400 MHz): δ = 1.60 (s, 3 H, 8-H), 1.63 (s, 3 H, 7-CH₃), 1.68 (s, 3 H, 3-CH₃), 1.97–2.07 (m, 4 H, 4-H, 5-H), 3.30 (d, J = 7.4 Hz, 2 H, 1-H), 5.07–5.11 (m, 1 H, 6-H), 5.26 (t, J = 7.5 Hz, 1 H, 2-H) ppm. ¹³C NMR (CDCl₃, 150 MHz): δ = 16.5 (3-CH₃), 18.0 (7-CH₃), 26.0 (8-C), 26.8 (5-C), 39.7 (4-C), 39.9 (1-C), 124.4 (2-C), 125.1 (6-C), 131.9 (7-C), 137.5 (3-C) ppm.1-Azido-3,7-dimethylocta-2,6-diene (1-geranylazide, 5)A mixture of bromide 2 (500 mg, 2.30 mmol) and NaN₃ (299 mg, 4.60 mmol) in ethanol (7 mL) was heated to reflux for 5 h, the mixture was concentrated under reduced pressure, and water (15 mL) was added. The resulting solution was extracted with DCM (2 × 20 mL) and the combined organic extracts were washed with brine, dried over Na₂SO₄, filtered, and evaporated in vacuo to afford a yellow oil; yield 380 mg (92%). ¹H NMR (CDCl₃, 400 MHz): δ = 1.61 (s, 3 H, 8-H), 1.69 (s, 3 H, 7-CH₃), 1.71 (s, 3 H, 3-CH₃), 2.10 (m, 4 H, 4-H, 5-H), 3.76 (t, J = 7.4 Hz, 2 H, 1-H), 5.09 (m, 1 H, 6-H), 5.33 (t, J = 7.5 Hz, 1 H, 2-H) ppm.2-Adamantanamine (6)A solution of 2-adamantanone (3.0 g, 20 mmol) in ethanol (35 mL) was heated at 70 ℃. To this solution an aqueous solution (20 mL) of HCl·H₂NOH (2.08 g, 30.0 mmol) with solid Na₂CO₃ (3.82 g, 36.0 mmol) was added portion-wise at 70 ℃. The mixture was stirred at the same temperature for 10 min, and the ethanol was evaporated under reduced pressure. The aqueous suspension was allowed to cool at room temperature, and the white solid of 2-adamantanone oxime was filtered off; yield 2.86 g (86%). ¹H NMR (CDCl₃, 400 MHz): δ = 1.81–1.99 (m, 14 H, 1,3,4,5,6,7,8,9,10-adamantane Η) ppm.Το a suspension of LiAlH₄ (1.97 g, 51.9 mmol) in anhydrous THF (35 mL) a solution of 2-adamantanone oxime (2.86 g, 17 mmol) in anhydrous THF (40 mL) was added dropwise at 0 ℃, and the suspension was then heated to reflux and left overnight under stirring. The mixture was allowed to return to room temperature, then cooled at 0 ℃, and then water (2 mL), NaOH 15% w/v (2 mL), and water (6 mL) were added. The resulting inorganic precipitate was filtered off and washed thoroughly with diethyl ether. The filtrate was extracted twice with HCl 6 % w/v, the aqueous phase was made alkaline with solid Na₂CO₃ and extracted with DCM. The combined organic extracts were washed with water and dried over Na₂SO₄. After filtration, the DCM was evaporated in vacuo to afford a pale oil of 2-adamantanamine (6, 1.45 g, 56% yield). ¹H NMR (CDCl₃, 400 MHz): δ = 1.53 (d, J = 12 Hz, 2 H, 4eq,9eq-adamantane H), 1.70–1.85 (m, 10 Η, 1,3,5,7,6,8,10-adamantane Η), 1.99 (d, J = 12 Hz, 2 H, 4ax,9ax-adamantane H), 2.22 (br s, 2 H, NH₂), 3.02 (s, 1 H, 2-adamantane Η) ppm. ¹³C NMR (CDCl₃, 50 MHz): δ = 27.1 (7-adamantane C), 28.0 (5-adamantane C), 31.1 (4,9-adamantane C), 35.1 (8,10-adamantane C), 38.0 (1,3-adamantane C), 38.3 (6-adamantane C), 55.9 (2-adamantane C) ppm. N-(2-Adamantanyl)-2-bromoacetamide (7)Bromoacetyl chloride (801 mg, 5.09 mmol) in DCM (13 mL) was added dropwise at 0 °C to a vigorously stirred suspension of 2-adamantanamine (6, 700 mg, 4.63 mmol) in DCM (23 mL) and K₂CO₃ (806 mg) and water (8 mL). The mixture was stirred for 24 h, and then the aqueous phase was extracted twice with DCM. The combined organic extracts were evaporated in vacuo, and the crude product was dissolved in diethyl ether. The solution was washed sequentially with NaHCO₃ 10% w/v, water, HCl 3% v/v, water, and brine. The solvent was then evaporated in vacuo, and the product was filtered through silica gel using n-hexane/EtOAc (3:1) as eluent to afford a white solid (1.05g, 83% yield). ¹H NMR (CDCl₃, 400 MHz): δ = 1.67 (d, J = 12 Hz, 2 H, 4eq,9eq-adamantane H), 1.75–1.93 (m, 10 Η, 1,3,5,7,6,8,10-adamantane­ Η), 2.04 (s, 2 H, 4ax,9ax-adamantane H), 3.91 (s, 2 H, COCH₂Br), 4.02–4.04 (s, J = 8.4 Hz, 1 H, 2-adamantane Η) ppm. N-(2-Adamantanyl)-2-[(3,7-dimethylocta-2,6-dien-1-yl)amino]acetamide (8)Bromoacetamide 7 (1.05 g, 3.86 mmol) in dry THF (20 mL) was added dropwise at 0 °C to a stirred solution of geranylamine 4 (590 mg, 3.86 mmol) and triethylamine (390 mg, 3.86 mmol) in dry THF (30 mL). The stirring continued for 48 h at room temperature. Then the aqueous phase was extracted twice with DCM, the combined organic extracts were evaporated in vacuo, and the crude product was purified through column chromatography using a) diethyl ether/n-hexane (1:1), b) CHCl₃/MeOH (9:1) as solvent systems. The acetamide 8 was obtained as a pale-yellow oil; yield 1.14 g (86%). ¹H NMR (CDCl₃, 400 MHz): δ = 1.59 (s, 3 H, 8-H), 1.62 (s, 3 H, 7-CH₃), 1.67 (s, 3 H, 3-CH₃), 1.65–1.90 (m, 14 Η, 1,3,4,5,6,7,8,9,10-adamantane H), 2.02–2.07 (m, 4 H, 4-H, 5-H), 3.17 (s, 2 H, COCH₂ NH), 3.31 (d, J = 7.4 Hz, 2 H, 1-H), 3.18 (s, 1 H, 2-adamantane Η), 4.01 (s, 1 H, NH-adamantane), 5.05 (m, 1 H, 6-H), 5.25 (t, J = 7.4 Hz, 1 H, 2-H), 7.04 (s, 1 H, NH-geranyl) ppm. Hydrochloride salt: ¹³C NMR (CD₃OD, 100 MHz): δ = 17.9 (3-CH₃), 18.7 (8-C), 26.7 (7-CH₃), 28.0 (5-C), 29.5 (5,7-adamantane C), 33.4 (4,9-adamantane C), 34.1 (1,3-adamantane C), 39.1 (8,10-adamantane C), 39.4 (6-adamantane C), 41.7 (4-C), 55.7 (1-C), 56.2 (COCH₂NH), 56.9 (2-adamantane C), 114.1 (2-C), 125.3 (6-C), 134.1 (7-C), 151.9 (3-C), 166.0 (C=O) ppm. HRMS (ESI-TOF (+)): m/z [M + H]⁺ calcd for [C₂₂H₃₇N₂O]⁺: 345.2906; found: 345.2888.2-Bromo-N-(3,7-dimethylocta-2,6-dien-1-yl)acetamide (11)Bromoacetyl chloride (1.13 g, 7.18 mmol) in DCM (17 mL) was added dropwise at 0 °C to a vigorously stirred solution of geranylamine 4 (1 g, 6.53 mmol) in DCM (30 mL) and aqueous K₂CO₃ (1.14 g, 10 mL H₂O). The mixture was stirred for 24 h, and then the aqueous was extracted twice with DCM. The combined organic extracts were concentrated in vacuo, and the crude product was dissolved in diethyl ether. The solution was washed with NaHCO₃ 10% w/v, H₂O, HCl 3% v/v, H₂O, and brine. The solvent was then evaporated in vacuo, and the product was filtered through silica gel using n-hexane/EtOAc (3:1) as eluent to afford 1.64 g of bromoacetamide (11) as a yellow solid (91% yield). ¹H NMR (CDCl₃, 400 MHz): δ = 1.60 (s, 3 H, 8-H), 1.68 (s, 6 H, 7-CH₃, 3-CH₃), 2.00–2.12 (m, 4 H, 4-H, 5-H), 3.88 (s, 2 H, COCH₂Br), 5.06 (t, J = 7.0 Hz, 1 H, 6-H), 5.19 (t, J = 7.0 Hz, 1 H, 2-H) ppm.2-[(2-Αdamantyl)amino]-N-(3,7-dimethylocta-2,6-dien-1-yl)acetamide (12)Bromoacetamide 11 (960 mg, 3.50 mmol) in dry THF (20 mL) was added dropwise at 0 ℃ to a stirred solution of 2-adamantanamine (6)²⁶ (530 mg, 3.50 mmol) and triethylamine (354 mg, 3.50 mmol) in anhydrous THF (30 mL), and stirring was continued for 48 h at room temperature. The aqueous phase was extracted twice with DCM, the combined organic extracts were evaporated in vacuo, and the crude product was purified by column chromatography, eluting with a) diethyl ether/n-hexane (1:1), b) CHCl₃/MeOH (9:1). Acetamide 12 was obtained as a yellow oil (870 mg, 72% yield). ¹H NMR (CDCl₃, 400 MHz): δ = 1.56–1.59 (m, 5 H, 8-H, 4eq,9eq-adamantane H), 1.67 (s, 6 H, 7-CH₃, 3-CΗ₃), 1.67–1.71 (m, 4 H, 1,3,6-adamantane H), 1.81–1.92 (m, 6 H, 4ax,5,7,8ax,9ax,10ax-adamantane H), 1.98–2.10 (m, 4 H, 4,5-H), 2.77 (s, 1 H, 2-adamantane Η), 3.27 (s, 1 H, NHCH₂ CO), 3.43 (s, 1 H, NHCH₂ CO), 3.84–3.89 (m, 2 H, 1-H), 5.07 (m, 1 H, 6-H), 5.19 (m, 1 H, 2-H) ppm. ¹³C NMR (CD₃OD, 100 MHz): δ = 17.2 (3-CH₃), 18.6 (8-C), 26.7 (7-CH₃), 28.3 (5-C), 28.9 (5-adamantane C), 29.2 (7-adamantane C), 31.6 (4,9-adamantane C), 32.1 (1,3-adamantane C), 38.7 (8,10-adamantane C), 38.8 (6-adamantane C), 39.3 (4-C), 41.4 (1-C), 48.0 (NHCH₂CO), 65.8 (2-adamantane C), 121.5 (2-C), 125.8 (6-C), 133.4 (7-C), 141.9 (3-C), 166.6 (C=O) ppm. HRMS (ESI-TOF (+)): m/z [M + H]⁺ calcd for [C₂₂H₃₇N₂O]⁺: 345.2906; found: 345.2897. N-(2-Adamantanyl)-N′-(3,7-dimethylocta-2,6-dien-1-yl)ethane-1,2-diamine (SQ109, 10)Acetamide 8 (870 mg, 2.52 mmol) in dry DCM (11 mL) was stirred at 0–5 °C for 15 min under an argon atmosphere. Freshly distilled trimethylsilyl chloride (328 μL, 3.02 mmol) was then added at the same temperature, and the mixture was stirred for another 15 min. A suspension of LiAlH₄ (134 mg, 3.53 mmol) in a small quantity of anhydrous THF was added between –10 °C and 0 °C, and the stirring was continued for 2.5 h at the same temperature. The mixture was then treated with NaOH 10%, the resulting inorganic precipitate was filtered off, the organic phase was separated, and the aqueous phase was extracted twice with DCM. The combined organic extracts were evaporated in vacuo, and the crude product was dissolved in DCM and washed with brine. After separation and evaporation of the solvent, the crude product was purified by column chromatography using either CHCl₃/MeOH (9:1) or CHCl₃/MeOH/ΝΗ₃ (88:10:2), eluents, to afford diamine 10 as a pale-yellow oil; yield 260 mg (31%). Acetamide 12 (290 mg, 0.84 mmol) in dry DCM (4 mL) was stirred at 0–5 °C for 15 min under an argon atmosphere. Freshly distilled trimethylsilyl chloride (110 μL, 1.01 mmol) was then added at the same temperature, and the mixture was stirred for a further 15 min. A suspension of LiAlH₄ (45 mg, 1.18 mmol) in a small quantity of THF was added at –10 °C to 0 °C, and stirring was continued for 2.5 h at the same temperature. The mixture was then treated with 10% aqueous NaOH, the resulting inorganic precipitate was filtered off, the organic phase was separated, and the aqueous phase was extracted twice with DCM. The combined organic extracts were evaporated in vacuo, and the crude product was dissolved in DCM and washed with brine. After separation and evaporation of the solvent, the crude product was purified by column chromatography using either CHCl₃/MeOH (9:1) or CHCl₃/MeOH/ΝΗ₃ (88:10:2) as eluents to afford diamine 10 as a pale-yellow oil (111 mg, 38% yield). ¹H NMR (CDCl₃, 400 MHz): δ = 1.47 (d, J = 12 Hz, 2H, 4eq,9eq-adamantane H), 1.59 (s, 3 H, 8-H), 1.64 (s, 3 H, 7-CH₃), 1.67 (s, 3 H, 3-CH₃), 1.70–1.85 (m, 10 Η, 1,3,5,6,7,8,10-adamantane H), 1.95 (d, J = 12 Hz, 2H, 4ax,9ax-adamantane H), 1.98–2.02 (m, 2 H, 5-H), 2.06–2.11 (m, 2 H, 4-H), 2.71 (s, 1 H, 2-Η), 2.74 (s, 4 H, NHCH₂ CH₂ NH), 3.25 (d, J = 7.0 Hz, 2 H, 1-H), 5.09 (m, 1 H, 6-H), 5.26 (m, 1 H, 2-H) ppm. ¹³C NMR (CDCl₃, 100 MHz): δ = 16.5 (CH₃-3), 18.0 (8-C), 26.0 (7-CH₃), 26.8 (5-C), 27.9 (5-adamantane C), 28.1 (7-adamantane C), 31.7 (4,9-adamantane C), 32.5 (1,3-adamantane C), 37.9 (8,10-adamantane C), 38.3 (6-adamantane C), 40.2 (4-C), 46.8 (1-C), 47.4 (NHCH₂ CH₂NH-geranyl), 49.8 (NHCH₂CH₂NH-geranyl), 62.3 (2-adamantane C), 121.9 (2-C), 123.3 (6-C), 131.9 (7-C), 137.9 (3-C) ppm. HRMS (ESI-TOF (+)): m/z [M + H]⁺ calcd for [C₂₂H₃₉N₂]⁺: 331.3108; found: 331.3101.