Synthesis and crystal structure of 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[ b ][1,4]thiazepin-4(5 H )-one

Abstract

7-Bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one is prepared from 6-methoxybenzo[d]thiazol-2-amine and 2-(bromomethyl)-2-butylhexanoic acid as the key starting materials via five simple steps including hydrolysis, substitution, condensation, bromination, and aromatic amidation under microwave conditions. This new route has reduced the reaction time and increased the overall yield to 43%. Moreover, the structure of the target product is also confirmed by X-ray crystal analysis, and further studies indicate that the existence of an intramolecular C–H···Cg1 non-classical hydrogen bond is effective in stabilization of the crystal structure.

Introduction

Constipation is a common digestive disease having a prevalence rate of about 20% in China. It occurs more frequently in women than in men, and the prevalence rate is higher in older people. ¹ Prucalopride succinate is now on the market for the treatment of constipation in women.^2,3 In addition, stool softeners increase water absorption by the faeces by lowering the surface tension of the feces, a representative example being docusate. ⁴ However, these stimulant laxatives and stool softeners only provide temporary effects.

Recent medical research has demonstrated that the transfer of bile acids is one of the leading causes of constipation. Benzothiazepine derivatives inhibit bile acid transport that regulates bile acid reabsorption,^5–7 thus increasing bile acid flow to the colon, thereby promoting the intestinal tract to secrete more water and facilitate defecation, so as to naturally improve natural defecation in patients. On 19 April 2018, EA Pharma and Mochida launched the World’s first bile acid transport inhibitor in Japan. Its generic name is Elobixibat hydrate. ⁸

7-Bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one is a key intermediate of Elobixibat hydrate and is the main bioactive group. However, there are only a few studies reported that discuss the synthesis of the title compound in the literature.^9,10 Herein, we report an efficient route to prepare the title compound. Compared with the original research patent, we have shortened the reaction time of the last step (from 17 h to 30 min) and reduced the reaction temperature (from 190 °C to 130 °C). In the aromatic amidation step,^11–13 we have reduced the amount of amine ligand, which is more conducive to large-scale production (Scheme 1). This synthetic route afforded a 43% overall yield. Furthermore, a single crystal of the title compound was obtained and the molecular structure was determined by X-ray diffraction.

Scheme 1.

The synthetic route toward 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one.

Results and discussion

In order to prepare the target product, we first investigated the original research patent. ⁹ When compounds 2 and 3 were synthesized with ethylene glycol as the solvent and without protection in N₂ atmosphere, the yield of compound 3 reached 92%. However, the original patent did not use the protection of the NH₂ group and the yield was only 51%. Compound 3 was converted into compound 4 by reaction with 2-(7-azabenzotriazol-1-yl)-N, N, N′, N′-tetramethyluronium hexafluorophosphate (HATU) and N, N-diisopropylethylamine (DIPEA) in dichloromethane at 25 °C for 2 h. As a brominating reagent, N-bromosuccinimide (NBS) was reacted with compound 4 to afford bromide 5 at 25 °C in high yield. Finally, the title compound 6 was obtained by the metal-catalyzed cross-coupling reaction of 5 with iodobenzene in dimethylsulfoxide (DMSO) at 130 °C for 30 min under microwave conditions and with CuI as the catalyst. In the original route, tris[2-(2-methoxyethoxy)ethyl]amine was added as the amine ligand and the mixture was heated at reflux at 190 °C for 17 h. After experimenting, we found that this metal-catalyzed cross-coupling reaction did not require an amine ligand (like ethylenediamine, cyclohexanediamine, or 1,10-phenanthroline). Thus, we optimized the reaction conditions for this step (Table 1). As can be seen from Table 1, the presence of amine ligands had no effect on the yield of the product. The reaction time was shortened from 17 h to 30 min under microwave irradiation, and the reaction temperature was reduced from 190 °C to 130 °C. In addition, we found that the reaction time and microwave power have little effect on the yield, with a yield of 79% being obtained.

Table 1.

Optimization of the reaction conditions (ligand, temperature, mode of heating, and duration of reaction) for the preparation of the title compound.

Entry	Ligand	Temperature (°C)	Time	Yield (%)
1	None (MWI: 400 W)	130	30 min	78
2	None (MWI: 300 W)	130	30 min	75
3	None (MWI: 400 W)	130	40 min	79
4	Cyclohexanediamine (MWI: 400 W)	130	30 min	77
5	None	130	12 h	62
6	Cyclohexanediamine	130	12 h	67
7	Tris[2-(2-methoxyethoxy)ethyl]amine	190	18 h	64
8	1,10-phenanthroline	140	12 h	63

MWI: microwave irradiation.

Meanwhile, we successfully grew a single crystal of product 6 from n-hexane, and the structure was confirmed by the X-ray crystal analysis (Figure 1, CCDC 1960860).

Figure 1.

ORTEP diagram of compound 6 with 50% ellipsoid probability (a axis, b axis, c axis).

Compound 6 crystallizes in the P-1 space group and its molecular structure consists of two benzene rings. Furthermore, the dihedral angle between the two benzene rings (Cg1 (C1–C2–C3–C4–C5–C6) and Cg2 (C18–C19–C20–C21–C22–C23)) is 83.0(2)°, indicating that these rings are not coplanar. The crystal structure was formed though a C10–H10B···Cg1 non-classical hydrogen bonds. The distance between C10–H10B and the benzene ring centroid of Cg1(x, y, z) was 3.509(4). Classical hydrogen bonds and π–π stacking interactions were not found in the structure.

Conclusion

In summary, using 6-methoxybenzo[d]thiazol-2-amine as a starting material, 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one was synthesized. By optimizing the original research route, the overall yield of this five-step sequence was 43%. At the same time, the reaction efficiency was greatly improved by using a microwave, and thus the use of expensive ligands was reduced and production costs were saved. A study of the crystal structure of the title compound may contribute evidence for further studies on drug designs and mechanisms.

Experimental

General information

Unless noted otherwise, all the reagents were commercially available and were used without further purification. The reactions were monitored by thin-layer chromatography (TLC). Microwave irradiation was performed in a MAS-1 microwave reactor apparatus (Shanghai Sineo Microwave Chemistry Technology Co., Ltd). Melting points were measured with an X4-A microscopic melting point apparatus. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker BioSpin 400 MHz spectrometer with chemical shifts reported in ppm (in dimethyl sulfoxide-d₆ (DMSO-d₆), with tetramethylsilane (TMS) as the internal standard). High-resolution mass spectrometry (HRMS) was performed using a 6540 Ultra High Definition (UHD) Accurate-Mass Quadrupole Time-of-Flight (Q-TOF) liquid chromatography/mass spectrometry (LC/MS) instrument. X-ray single-crystal diffraction data were recorded on a XtaLAB Synergy, Dualflex, HyPix four-circle diffractometer.

Preparation of 2-{[(2-amino-5-methoxyphenyl)thio]methyl}-2-butylhexanoic acid (3)

Under a nitrogen atmosphere, 6-methoxybenzo[d]thiazol-2-amine (1) (9.00 g, 0.05 mol) was suspended in ethylene glycol (12 mL). To the suspension was added 50% potassium hydroxide 50 mL and the mixture heated to 120 °C for 18 h. The reaction was monitored by TLC to confirm the formation of 2-amino-5-methoxybenzenethiol (2). After cooling to 25 °C, 2-bromomethyl-2-butylhexanoate (15.9 g, 0.06 mol) was added and the mixture stirred at 25 °C for 8 h. The resulting solution was washed with 3 N HCl and the pH was adjusted to 6.0 with 3 N HCl. Saturated sodium chloride solution and ethyl acetate were added, and the mixture was stirred for 30 min and then the ethyl acetate layer was separated. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated compound was washed with n-hexane and then concentrated again. Compound 3 was obtained as a yellow oily liquid (15.6 g), yield 92%. ¹H NMR (400 MHz, DMSO-d₆): δ 6.86 (d, J = 2.0 Hz, 1H), 6.72–6.64 (m, 2H), 3.64 (s, 3H), 2.98 (s, 2H), 1.64–1.46 (m, 4H), 1.21–1.10 (m, 4H), 1.09–0.90 (m, 4H), 0.79 (t, J = 7.2 Hz, 6H). HRMS (ES⁺): m/z calcd for C₁₈H₃₀NO₃S [M + H]⁺: 340.1868, found: 340.2108.

Preparation of 3,3-dibutyl-8-methoxy-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one (4)

Compound 3 (13.0 g, 0.038 mol) in dichloromethane (100 mL) was stirred at 25 °C, HATU (17.4 g, 0.046 mol) was added dropwise under stirring, and the mixture was then stirred for 10 min. DIPEA (5.95 g, 0.046 mol) was added slowly dropwise under stirring. The reaction progress was monitored by TLC with starting material 3 having disappeared after stirring at room temperature for 2 h. The reaction mixture was washed with water and the dichloromethane layer separated. The dichloromethane layer was dried over anhydrous sodium sulfate, filtered, and concentrated to afford a brown liquid. Hexane was added with stirring to afford, after isolation, an off-white crystalline solid (9.75 g), yield 81%. m.p.: 70.2–72.2 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 9.52 (s, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 2.5 Hz, 1H), 6.86 (dd, J = 8.8, 2.6 Hz, 1H), 3.73 (s, 3H), 2.98 (s, 2H), 1.66–1.55 (m, 2H), 1.54–1.40 (m, 2H), 1.25–1.09 (m, 8H), 0.82 (t, J = 6.7 Hz, 6H). HRMS (ES⁺): m/z calcd for C₁₈H₂₈NO₂S [M + H]⁺: 322.1762, found: 322.1565.

Preparation of 7-bromo-3,3-dibutyl-8-methoxy-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one (5)

A mixture of compound 4 (4.47 g, 0.014 mol) and NBS (2.67 g, 0.015 mol) in dichloromethane 50 mL was stirred in a dark reaction vessel at 25 °C for 2 h. Next, saturated ammonium chloride solution was added and the dichloromethane layer was separated. The dichloromethane layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was charged with 100 mL of a mixture of hexane and ethyl acetate (hexane/ethyl acetate = 30/1), and the resulting solid was filtered to afford compound 5 as a yellow solid (4.1 g), yield 74%. m.p.: 120–122 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 9.60 (s, 1H), 7.33 (s, 1H), 7.11 (s, 1H), 3.83 (s, 3H), 3.00 (s, 2H), 1.70–1.56 (m, 2H), 1.54–1.41 (m, 2H), 1.27–1.10 (m, 8H), 0.83 (t, J = 6.8 Hz, 6H). HRMS (ES⁺): m/z calcd for C₁₈H₂₆BrNO₂S [M + H]⁺: 400.0868, found: 400.1197.

Preparation of 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one (6)

Compound 5 (2.0 g, 0.005 mol) in DMSO (30 mL) was charged with iodobenzene (1.2 g, 0.006 mol), copper iodide (0.19 g, 0.001 mol) and potassium carbonate (1.38 g, 0.01 mol). The mixture was stirred at 25 °C for about 5 min and then heated in a microwave reactor (400 W) at 130 °C for 30 min. The resulting mixture was cooled to room temperature, was washed with water, and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated compound was recrystallized from n-hexane to afford compound 6 (1.85 g), yield 78%. m.p.: 96.8–97.8 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 7.43–7.35 (m, 3H), 7.29–7.24 (m, 1H), 7.12–7.05 (m, 3H), 3.88 (s, 3H), 3.16 (s, 2H), 1.44 (m, 4H), 1.19 (m, 8H), 0.81 (t, J = 6.0 Hz, 6H). HRMS (ES⁺): m/z calcd for C₂₄H₃₁BrNO₂S [M + H]⁺: 476.1181, found: 476.1265.

X-Ray structure determination

A colorless block-like crystal of compound 6 was grown in n-hexane with dimensions of 0.20 mm × 0.20 mm × 0.20 mm and was used for structural determination. Single crystals suitable for X-ray diffraction were selected, glued on fiberglass, and mounted on a Rigaku XtaLAB Synergy, Dualflex, HyPix four-circle diffractometer equipped with a mirror-monochromatic Cu–Kα radiation source at 293 K (λ = 1.54184 Å). Data collection and reduction were performed using the CrysAlisPro software suite. ¹⁴ Empirical absorption corrections were carried out using SCALE3. ¹⁵ The structure was solved by direct methods and expanded by difference Fourier techniques. The non-hydrogen atoms were refined anisotropically and the hydrogen atoms were added according to the theoretical models with Uiso(H) = 1.2 (1.5 for methyl) Ueq(C). The structure was refined by the full-matrix least-squares method on F² with SHELXL-2015. ¹⁶ The crystallographic data for the compound 6 (CCDC, 1960860) are summarized in Table 2.

Table 2.

Crystallographic data for compound 6.

Formula	C24H30BrNO2S
Formula weight	476.46
Temperature (K)	293
Wavelength (Å)	1.54184
Crystal system	Triclinic
Space group	P-1
a (Å)	9.8322(4)
b (Å)	11.2888(3)
c (Å)	11.5601(6)
Volume (Å)	1196.55(9)
Z	2
Absorption coefficient (mm−1)	3.298
F(000)	496
Crystal size (mm3)	0.2 × 0.2 × 0.2
Goodness-of-fit on F2	1.076
θ range for data collection	3.9–75.7°
Reflections collected/unique	12,371/4763
Collection range	−12 ⩽ h ⩽ 12
	−13 ⩽ k ⩽ 13
	−14 ⩽ l ⩽ 14
R int	0.047
Data/restraints/parameters	4763/0/265
R1, wRR2 (I > 2σ(I))	0.0712, 0.1852
R1, wRR2 (all data)	0.0761, 0.1907
Δρmax/Δρmin (e·Å3)	0.56, −1.29

Supplemental Material

Data – Supplemental material for Synthesis and crystal structure of 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one

Supplemental material, Data for Synthesis and crystal structure of 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3-dihydrobenzo[b][1,4]thiazepin-4(5H)-one by Damin Du and Haijian Wu in Journal of Chemical Research