Chemical Synthesis of the ODM-201’s Diastereomers through an Efficient Intramolecular 1,3-Dipolar Cycloaddition

Abstract

An efficient synthesis of ODM-201’s diastereomers has been developed from (R)-methyl 3-hydroxybutanoate or (S)-methyl 3-hydroxybutanoate, respectively, with high overall yield and excellent diastereomeric purity. The key step in this synthesis is the preparation of the key intermediate (R)-5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-carboxylic acid or (S)-5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-carboxylic acid through intramolecular 1,3-dipolar cycloaddition of the vinyl diazo carbonyl compounds.

ODM-201 (1) is a novel androgen receptor (AR) inhibitor that showed significant antitumor activity and a favorable safety profile in phase 1/2 studies in men with castration-resistant prostate cancer (CRPC).^1,2) ODM-201 (Fig. 1) is structurally distinct from any known antiandrogens including the second-generation antiandrogens enzalutamide and ARN-509. In contrast to other antiandrogens, ODM-201 displays negligible brain penetrance and does not increase serum testosterone levels in mice.³⁾

Fig. 1. Chemical Structures of ODM-201 (1) and Its Diastereomers 1a, b

As demonstrated in Fig. 1, ODM-201 is a synthetic compound comprising a mixture (1 : 1) of diastereomers, namely 1a and b. Although both compounds 1a and b are claimed to be pharmacologically active,⁴⁾ the specific data was not disclosed. We believe that more bioactivity studies are necessary to clarify the action mechanism, which requires substantial supply of diastereomerically pure 1a and b. There are two methods have been reported for the synthesis of 1a and b.⁵⁾ In the first method, special enzymes (KREDs) were used for the selective reduction which limited the extensive application. The second one only gave a very low yield (0.025%) in the synthesis of (R)-ethyl-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxylate or (S)-ethyl-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxylate, which is hard for practical production.

As well known, 1,3-dipolar cycloaddition has been widely employed in construction of 5-membered heterocyclic systems.⁶⁾ In the present work, we devoted to developing an efficient synthetic route for the synthesis of ODM-201’s diastereomers through intramolecular 1,3-dipolar cycloaddition.

Results and Discussion

As displayed in Figs. 2 and 3, we initiated our synthesis from commercially available enantiopure (R)-methyl 3-hydroxybutanoate (2a) and (S)-methyl 3-hydroxybutanoate (2b). We firstly tried to protect the 3-OH in 2a and b with trimethyl silyl (TMS) group, the following transformation, however, only resulted in poor yield. Considering that tert-butyldimethylsilyl (TBS) is more stable than TMS in most cases, we thereof prepared TBS protected intermediates (R)-methyl 3-((tert-butyldimethylsilyl)oxy)butanoate (3a) and (S)-methyl 3-((tert-butyldimethylsilyl)oxy)butanoate (3b) in 94–97% yield. Following diisobutylaluminium hydride (DIBAL)-H reduction of 3a and b gave aldehydes 4a and b correspondingly in 88–92% yield.

Fig. 2. Synthetic Route to 1a

Fig. 3. Synthetic Route to 1b

With aldehydes 4a and b available, we explored the conditions for preparation of 5a and b through condensation with ethyl diazoacetate. We found that when strong bases such as lithium diisopropylamide (LDA) or lithium hexamethyldisilazide (LiHMDS) were employed, target compounds 5a and b were prepared in 73–75% yield.^7,8) The yield of this method is acceptable, but low temperature of −78°C and absolutely anhydrous conditions are required, which limited its application. Further optimization revealed that when ethyl diazoacetate treated with milder base tetrabutylammonium hydroxide (TBAOH) using dimethyl sulfoxide (DMSO) as solvent at room temperature, the desired products (5a, b) were obtained in 73–76% yield.⁹⁾

The following dehydration of β-hydroxy diazo carbonyl compounds (5a, b) was quite challenging considering the relative labile character of diazo group. We systematically screened several conditions including the common dehydration condition i.e., excessive phosphorus oxychloride in pyridine,¹⁰⁾ which failed to provide a desirable yield. Finally, we found that when the combination of (CF₃CO)₂O and Et₃N in CH₂Cl₂ was employed, the vinyl diazo carbonyl compounds (6a, b) were obtained in 84–90% yield.¹¹⁾

With compounds 6a and b in hand, we started to construct the key intermediates 7a and b via an intramolecular 1,3-dipolar cycloaddition. 6a or b were dispensed in n-octane and heated to 110°C for one hour, giving rise to intermediate (R)-ethyl 5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-carboxylate and (S)-ethyl 5-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-carboxylate, respectively. The resulting crude material was directly hydrolyzed with 10% NaOH in tetrahydrofuran (THF) and the products (7a, b) were obtained in 79–82% yield.

Following the reported procedure, the coupling between 7a or b and 8 with existence of N-hydroxybenzotriazole (HOBt) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) proceeded smoothly to give the corresponding products 9a and b in 81–89% isolated yields.¹²⁾ Further tetrabutylammonium fluoride (TBAF) promoted deprotection of TBS group in 9a and b finished the synthesis of target compounds (1a, b) in 85–92% yield.

In conclusion, we developed a new and efficient route to synthesize ODM-201 diastereomers 1a and b from commercially available (R)-methyl 3-hydroxybutanoate and (S)-methyl 3-hydroxybutanoate. The present synthesis was concise and easy to perform. The overall yield was excellent with both ODM-201 diastereomers’ chiral purity above 99%.

Experimental

Materials

(R)-Methyl 3-hydroxybutanoate (2a) and (S)-methyl 3-hydroxybutanoate (2b) were obtained from Energy Chemical, Ltd. (China). All other chemicals and solvents are analytical reagent grade and available from commercial sources. All compounds were dried and distilled per standard procedures.

Instruments

¹H- and ¹³C-NMR spectra were obtained on Bruker AV-400(400 MHz). Electrospray ionization (ESI)-MS and high resolution (HR)-ESI-MS were carried out on a Q-Tof micro YA019 spectrometer. Melting points (mps) were determined by TAQ 2000. HPLC analysis were recorded in Dionex Ultimate 3000 chromatograph and chiral HPLC analysis were recorded in Agilent 1260 Series spectrometer.

Normal-phase TLC was performed on Silica gel plates using a mixture of EtOAc–hexane (1 : 5, v/v), methanol–dichlorometnane (1 : 10, v/v) as the developing solvent.

(R)-Methyl 3-((tert-Butyldimethylsilyl)oxy)butanoate (3a)

To a suspension of (R)-methyl 3-hydroxybutanoate (2a) (20 g, 0.17 mol) and imidazole (23 g, 0.34 mol) in dichloromethane (DCM) (350 mL), TBSCl (30.5 g, 0.2 mol) was added at −5 to 0°C. After this addition, the reaction mixture was stirred for 3 h at room temperature. TLC showed the complete consumption of 2a. Then, ice water (300 mL) was added and the mixture was stirred for 5 min and then separated. The organic phase was washed with brine, dried over Na₂SO₄, and filtered and concentrated to obtain the crude product as colorless oil. Yield 38 g (96.7%).

(S)-Methyl 3-((tert-Butyldimethylsilyl)oxy)butanoate (3b)

(S)-Methyl 3-hydroxybutanoate (2b) was reacted in a manner identical to synthesis of 3a above, to provide 3b in 94.0% yield.

(R)-3-((tert-Butyldimethylsilyl)oxy)butanal (4a)

To a solution of 3a (15 g, 64 mmol) in DCM (375 mL) at −78°C was added DIBAL-H (67 mL, 1 M in hexane, 67 mmol) dropwise. The mixture was stirred at −78°C for 1h. TLC showed the complete consumption of 3a. Then the reaction was quenched by the addition of methanol (15 mL). The reaction mixture was poured onto a saturated aqueous solution of Rochelle’s salts (350 mL) and diluted with Et₂O (300 mL). This mixture was vigorously stirred for 2 h until having two clear phases. The phases were separated and the aqueous phase was extracted with Et₂O (300 mL, twice). The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄ and filtered and concentrated to obtain the crude product as colorless oil. Yield 12 g (91.6%).

(S)-3-((tert-Butyldimethylsilyl)oxy)butanal (4b)

(S)-Methyl 3-((tert-butyldimethyl-silyl)oxy)butanoate (3b) was reacted in a manner identical to synthesis of 4a above, to provide 4b in 88.5% yield.

(5R)-Ethyl 5-((tert-Butyldimethylsilyl)oxy)-2-diazo-3-hydroxyhexanoate (5a)

To a solution of TBAOH (8.5 mL, 1.0 M solution in water, 8.5 mmol) in DMSO (60 mL) was added ethyl diazoacetate (3.2 g, 28.0 mmol) at room temperature. Then, the aldehyde (4a) (6 g, 29.6 mmol) was added over 15 min to the reaction mixture, which was stirred at room temperature for 6 h. TLC showed the complete consumption of 4a. To the reaction mixture, saturated ammonium chloride solution (15 mL) was added and the mixture was extracted with EtOAc (30 mL, twice). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, concentrated. The residue was filtered through silica gel, gaving the products as yellow oil. Yield 6.7 g (75.3%).

(5S)-Ethyl 5-((tert-Butyldimethylsilyl)oxy)-2-diazo-3-hydroxyhexanoate (5b)

(S)-3-((tert-Butyldimethylsilyl)oxy)butanal (4b) was reacted in a manner identical to synthesis of 5a above, to provide 5b in 73.2% yield.

(R,E)-Ethyl 5-((tert-Butyldimethylsilyl)oxy)-2-diazohex-3-enoate (6a)

To a solution of (5R)-ethyl 5-((tert-butyldimethylsilyl)oxy)-2-diazo-3-hydroxyhexanoate (5a) (5 g, 15.8 mmol) and triethylamine (4.0 g, 39.6 mmol) in dry DCM (60 mL), trifluoroacetic anhydride (6.6 g, 31.6 mmol) was added dropwise at −10°C. After this addition, the reaction mixture was stirred for 6 h at 10°C. TLC showed the complete consumption of 5a. Then, ice water (300 mL) was added and the mixture was stirred for 5 min and then separated. The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated and further purification by flash chromatography with petrol ether–ethyl acetate (10 : 1) to give 6a as brown red oil. Yield 4.0 g (84.7%). ¹H-NMR (400 MHz, DMSO-d₆) δ: 5.93 (dd, J=15.8, 1.5 Hz, 1H), 5.51 (dd, J=15.8, 5.1 Hz, 1H), 4.49–4.43 (m, 1H), 4.20 (q, J=6.8 Hz, 2H), 1.22 (t, J=7.1 Hz, 3H), 1.17 (d, J=6.3 Hz, 3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H). ¹³C-NMR (100 MHz, CDCl₃) δ: 164.35, 129.00, 110.48, 68.22, 60.83, 26.31, 25.64, 24.53, 17.77, 14.16, −4.83, −4.87; HR-ESI-MS (ES⁺) m/z: [M+Na]⁺ Calcd for C₁₄H₂₆N₂O₃NaSi, 321.1610. Found, 321.1612.

(S,E)-Ethyl 5-((tert-Butyldimethylsilyl)oxy)-2-diazohex-3-enoate (6b)

(5S)-Ethyl 5-((tert-butyldimethylsilyl)oxy)-2-diazo-3-hydroxyhexanoate (5b) was reacted in a manner identical to synthesis of 6a above, to provide 6b in 89.4% yield. ¹H-NMR (400 MHz, DMSO-d₆) δ: 5.92 (dd, J=15.8, 1.4 Hz, 1H), 5.51 (dd, J=15.8, 5.1 Hz, 1H), 4.50–4.40 (m, 1H), 4.19 (q, J=7.1 Hz, 2H), 1.21 (t, J=7.1 Hz, 3H), 1.17 (d, J=6.3 Hz, 3H), 0.87 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H). ¹³C-NMR (100 MHz, CDCl₃) δ: 164.41, 129.05, 110.48, 68.24, 60.88, 26.32, 25.68, 24.56, 17.80, 14.19, −4.78, −4.83. MS (ES⁺) m/z: 321 [M+Na]⁺.

(R)-5-(1-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-carboxylic Acid (7a)

6a (3.5 g, 11.7 mmol) was added into n-octane (25 mL) at room temperature. The reaction mixture was heated to 110°C for 1 h. TLC showed the complete consumption of 6a. Then THF (35 mL) and 10% aqueous NaOH (1.0 g, 25.0 mmol) were added at room temperature. After this addition, the reaction mixture was stirred at 65°C for 1.5 h. Solvent was evaporated to dryness and the residue dissolved in H₂O (35 mL). After treatment with 2 M HCl until pH≈3, the product was precipitated and got 7a as an off-white solid. Yield 2.6 g (82%). ¹H-NMR (400 MHz, DMSO-d₆) δ: 13.12 (br s, 2H), 6.57 (s, 1H), 4.95 (q, J=6.4 Hz, 1H), 1.40 (d, J=6.4 Hz, 3H), 0.84 (s, 9H), 0.05 (s, 3H), −0.03 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ: 161.78, 152.95, 138.89, 104.75, 64.10, 25.69, 24.60, 17.80, −4.95, −4.86; HR-ESI-MS (ES⁺) m/z: [M+Na]⁺ Calcd for C₁₂H₂₂N₂O₃NaSi, 293.1297. Found, 293.1288.

(S)-5-(1-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-carboxylic Acid (7b)

(S,E)-Ethyl 5-((tert-butyldimethylsilyl)oxy)-2-diazohex-3-enoate (6b) was reacted in a manner identical to synthesis of 7a above, to provide 7b in 78.9% yield. ¹H-NMR (400 MHz, DMSO-d₆) δ: 13.13 (br s, 2H), 6.57 (s, 1H), 4.95 (q, J=6.4 Hz, 1H), 1.40 (d, J=6.4 Hz, 3H), 0.84 (s, 9H), 0.05 (s, 3H), −0.03 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ: 162.01, 152.98, 138.89, 104.78, 64.12, 25.70, 24.63, 17.82, −4.85, −4.93. MS (ES⁻) m/z: 269 [M−H]⁻.

5-((R)-1-((tert-Butyldimethylsilyl)oxy)ethyl)-N-((S)-1-(3-(3-chloro-4-cyanopheny-l)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide (9a)

7a (2.4 g, 8.8 mmol) and N,N-diisopropylethylamine (DIPEA) (1.2 g, 9.2 mmol) were dissolved in dry DCM (28 mL). HOBt (1.2 g, 8.8 mmol) and EDCI (1.7 g, 8.9 mmol) were added at room temperature. (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (8) (2.0 g, 7.67 mmol) was added and the reaction was stirred for overnight at room temperature. TLC showed the complete consumption of 8. Solvent was evaporated to dryness and the residue dissolved in H₂O (50 mL) and EtOAc (100 mL). The phases were separated and the aqueous phase was extracted with EtOAc (50 mL, twice). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered and concentrated to obtain the crude product. The crude product was crystallized from isopropanol–water (6 : 1) to get pure 9a as an off-white solid. Yield 3.2 g (81.2%). ¹H-NMR (400 MHz, DMSO-d₆): Major tautomer (ca. 75%) δ: 13.05 (s, 1H), 8.19 (d, J=8.5 Hz, 1H), 8.07 (s, 1H), 7.96–7.94 (m, 2H), 7.81 (d, J=2.3 Hz, 1H), 6.92 (d, J=2.3 Hz, 1H), 6.42 (d, J=1.7 Hz, 1H), 4.98 (q, J=6.4 Hz, 1H), 4.49–4.35 (m, 2H), 4.30–4.25 (m, 1H), 1.41 (d, J=6.4 Hz, 3H), 1.12 (d, J=6.5 Hz, 3H), 0.82 (s, 9H), 0.04 (s, 3H), −0.05 (s, 3H). Minor tautomer (ca. 25%) δ: 13.16 (s, 1H), 8.31 (d, J=8.5 Hz, 1H), 8.05 (s, 1H), 7.92–7.88 (m, 2H), 7.80 (s, 1H), 6.92 (d, J=2.3 Hz, 1H), 6.75 (d, J=2.3 Hz, 1H), 4.89 (q, J=6.4 Hz, 1H), 4.49–4.35 (m, 2H), 4.30–4.25 (m, 1H), 1.37 (d, J=6.4 Hz, 3H), 1.17 (d, J=6.5 Hz, 3H), 0.83 (s, 9H), 0.04 (s, 3H), −0.05 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ: 161.24, 148.58, 147.28, 146.28, 139.56, 135.73, 134.83, 133.09, 125.59, 124.08, 116.05, 109.81, 104.16, 102.05, 62.91, 55.67, 44.73, 25.62, 24.70, 17.94, 17.75, −4.97, −5.05. HR-ESI-MS (ES⁺) m/z: [M+Na]⁺ Calcd for C₂₅H₃₃N₆O₂NaSiCl, 535.2021. Found, 535.2017.

5-((S)-1-((tert-Butyldimethylsilyl)oxy)ethyl)-N-((S)-1-(3-(3-chloro-4-cyanopheny-l)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide (9b)

(S)-5-(1-((tert-Butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-carboxylic acid (7b) was reacted in a manner identical to synthesis of 9a above, to provide 9b in 88.8% yield. ¹H-NMR (400 MHz, DMSO-d₆): Major tautomer (ca. 75%) δ: 13.04 (s, 1H), 8.19 (d, J=8.2 Hz, 1H), 8.07 (s, 1H), 7.97 (s, 2H), 7.81 (s, 1H), 6.92 (s, 1H), 6.42 (s, 1H), 4.98 (d, J=6.2 Hz, 1H), 4.45–4.34 (m, 2H), 4.30–4.25 (m, 1H), 1.41 (d, J=6.1 Hz, 3H), 1.15 (d, J=6.5 Hz, 3H), 0.83 (s, 9H), 0.04 (s, 3H), −0.04 (s, 3H). Minor tautomer (ca. 25%) δ: 13.16 (s, 1H), 8.31 (d, J=8.2 Hz, 1H), 8.07 (s, 1H), 7.94–7.91 (m, 2H), 7.81 (s, 1H), 6.92 (s, 1H), 6.75 (s, 1H), 4.88 (d, J=4.8 Hz, 1H), 4.45–4.34 (m, 2H), 4.30–4.25 (m, 1H), 1.39 (d, J=6.4 Hz, 3H), 1.12 (d, J=6.5 Hz, 3H), 0.83 (s, 9H), 0.04 (s, 3H), −0.04 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ: 161.25, 148.63, 147.29, 146.38, 139.57, 135.85, 134.92, 133.11, 125.67, 124.09, 116.18, 109.89, 104.17, 102.02, 62.91, 55.67, 44.74, 25.64, 24.73, 17.93, 17.77, −4.96, −5.03. MS (ES⁺) m/z: 535[M+Na]⁺.

N-((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((R)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide (1a)

9a (3.0 g, 5.8 mmol) was dissolved in dry THF (48 mL). Anhydrous TBAF (11 mL, 1.0 M solution in THF, 11 mmol) was added dropwise at 0°C. The reaction was stirred for overnight at room temperature. TLC showed the complete consumption of 9a. EtOAc (100 mL) and H₂O (50 mL) were added. The phases were separated and the aqueous phase was extracted with EtOAc (50 mL, twice). The combined organic phases were concentrated to obtain the crude product. The crude product was crystallized from EtOH–water (5 : 1) to get pure 1a as a white solid. Yield 2.1 g (91.3%) (mp (DSC)=175.31°C); chiral purity (HPLC): 99.2%; ¹H-NMR (400 MHz, DMSO-d₆) Major tautomer (ca. 85%) δ: 13.04 (s, 1H), 8.20 (d, J=8.4 Hz, 1H), 8.09 (s, 1H), 8.00 (s, 2H), 7.82 (d, J=2.3 Hz, 1H), 6.94 (d, J=2.3 Hz, 1H), 6.42 (s, 1H), 5.42 (d, J=5.0 Hz, 1H), 4.84–4.78 (m, 1H), 4.50–4.35 (m, 2H), 4.31–4.26 (m, 1H), 1.40 (d, J=6.5 Hz, 3H), 1.12 (d, J=6.5 Hz, 3H). Minor tautomer (ca. 15%) δ: 13.12 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.07 (s, 1H), 7.94–7.90 (m, 2H), 7.82 (d, J=2.3 Hz, 1H), 6.80 (s, 1H), 6.51 (s, 1H), 5.08 (d, J=5.0 Hz, 1H), 4.73–4.71 (m, 1H), 4.50–4.35 (m, 2H), 4.31–4.26 (m, 1H), 1.36 (d, J=6.5 Hz, 3H), 1.17 (d, J=6.5 Hz, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ: 161.28, 149.54, 147.32, 146.36, 139.49, 135.79, 134.92, 133.07, 125.62, 124.04, 116.15, 109.82, 104.07, 101.59, 60.85, 55.61, 44.58, 23.65, 17.90.

N-((S)-1-(3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-((S)-1-hydroxyethyl)-1H-pyrazole-3-carboxamide (1b)

5-((S)-1-((tert-Butyldimethylsilyl)oxy)ethyl)-N-((S)-1-(3-(3-chloro-4-cyanopheny-l)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-3-carboxamide (9b) was reacted in a manner identical to synthesis of 1a above, to provide 1b in 85.8% yield. (mp (DSC)=192.36°C); chiral purity (HPLC): 99.54%; ¹H-NMR (400 MHz, DMSO-d₆) Major tautomer (ca. 85%) δ: 13.04 (s, 1H), 8.20 (d, J=8.4 Hz, 1H), 8.08 (s, 1H), 7.99 (s, 2H), 7.82 (d, J=2.3 Hz, 1H), 6.94 (d, J=2.3 Hz, 1H), 6.42 (s, 1H), 5.42 (d, J=5.0 Hz, 1H), 4.82–4.79 (m, 1H), 4.49–4.35 (m, 2H), 4.31–4.26 (m, 1H), 1.39 (d, J=6.5 Hz, 3H), 1.12 (d, J=6.5 Hz, 3H). Minor tautomer (ca. 15%) δ: 13.11 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.08 (s, 1H), 7.95–7.92 (m, 2H), 7.82 (d, J=2.3 Hz, 1H), 6.94 (s, 1H), 6.81 (s, 1H), 5.09 (s, 1H), 4.72 (m, 1H), 4.49–4.35 (m, 2H), 4.31–4.26 (m, 1H), 1.36 (d, J=6.5 Hz, 3H), 1.16 (d, J=6.5 Hz, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ: 161.28, 149.47, 147.24, 146.30, 139.49, 135.78, 134.91, 133.06, 125.60, 124.02, 116.15, 109.81, 104.07, 101.57, 60.84, 55.60, 44.58, 23.64, 17.89. MS (ES⁺) m/z: 421 [M+Na]⁺.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

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