HETEROCYCLES

Paper | Regular issue | Vol. 89, No. 7, 2014, pp. 1632-1643
Received, 23rd April, 2014, Accepted, 23rd May, 2014, Published online, 4th June, 2014.
DOI: 10.3987/COM-14-13012

■ A Practical Synthesis of (4-(Spiro[chromane-2,4'-piperidin]-6-yl)phenyl)methanol as a Key Intermediate of Novel GPR119 Agonist

Tomoaki Koshizawa, Hayato Hosoi, Gen Watanabe, Toshiharu Morimoto, Tadaaki Ohgiya, and Kimiyuki Shibuya*

Pharmaceutical Division, Tokyo New Drug Research Laboratories, Kowa Co., Ltd., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan

Abstract

Starting from commercially available 4'-hydroxy-[1,1'-biphenyl]-　4-carboxylic acid, a practical synthesis has been established in high yield for (4-(spiro[chromane-2,4'-piperidin]-6-yl)phenyl)methanol as a key intermediate for a novel GPR119 agonist.

INTRODUCTION
GPR119 is a G protein-coupled receptor predominantly expressed in pancreatic islet β-cells and incretin-releasing cells in the gastrointestinal tract. GPR119 agonists are reported to stimulate glucose-dependent insulin secretion in vitro and lower elevated blood-glucose levels in vivo.1 Therefore, these agents have emerged as a promising target for the treatment of type 2 diabetes and obesity by improving glucose homoeostasis.2
During the course of our drug discovery program, we identified (R)-1,1,1-trifluoropropan-2-yl 6- (4-(((pyridin-2-ylmethyl)sulfonyl)methyl)phenyl)spiro[chromane-2,4'-piperidine]-1'-carboxylate (1) as a highly potent GPR119 agonist (EC50 = 54 nM) with a hypoglycemic effect (3 mg/kg po. 30% decrease in OGTT/C57BL mice).3 We required a large amount of 1 to conduct a safety test.
In the initial production of 1, we performed a palladium-mediated coupling reaction between (4-(hydroxymethyl)phenyl)boronic acid (4) and tert-butyl 6-bromospiro[chromane-2,4'-piperidine]- 1'-carboxylate (5)4 to produce the key intermediate 3 leading to 2 as a precursor of 1 in moderate yield, as shown in Figure 1.

To date, the Suzuki-Miyaura coupling reaction has been widely demonstrated for industrial applications as a convenient and useful method for the construction of biaryl compounds.5 However, when applying it to the production of an active pharmaceutical ingredient (API), we encountered several potential drawbacks. a) The cost: the Pd catalyst and arylboronic acid are expensive. b) Genotoxicity concerns: arylboronic acids have been recently indicated as structure alerts for mutagenicity or carcinogenicity according to a structure-based assessment using the in silico tool DEREK (Deductive Estimation of Risk from Existing Knowledge).6,7 c) Residual-Pd issue: the content of Pd should be controlled to less than 10 ppm in orally administered drug substances according to API regulations.8,9 d) Process control: attention should be paid to the suitable selection of the Pd ligands and base, ligand-particle size, and moisture and oxygen content for the optimization of the reaction procedure when converting to large-scale production.10 To avoid these problems, we must develop an alternative synthetic method for the production of 2 without using a metal-catalyzed cross coupling reaction. Here, we report a facile and powerful synthetic route to the key intermediate 2 from readily available and affordable starting materials.

RESULTS AND DISCUSSION
In the retrosynthetic analysis (Scheme 1), our attention was focused on avoiding C-C bond formation of the biaryl compound by the unfavorable Suzuki-Miyaura coupling reaction and on constructing the requisite skeleton starting from a commercially available biphenyl material. The key intermediate 2 that possesses a 6-phenylspiro[chromane-2,4'-piperidine] skeleton would be dismantled into the biphenylethanone unit 6 and the 4-oxopiperidine unit 7 via spirocyclization. The required compound 6 could be prepared by a regioselective acylation of 4'-hydroxy-[1,1'-biphenyl]-4-carboxylic acid (8), which was chosen as an inexpensive starting material.11

At first, we attempted to transform 4'-acetoxy-[1,1'-biphenyl]-4-carboxylic acid (9a) into 10a via a Fries-rearrangement reaction with AlCl3 (Scheme 2), but we did not obtain a satisfactory result because of the difficult separation between the deacetylated compound 8 and the desired compound 10a in a simple workup.

Then, we followed a reported procedure12 to prepare methyl 4'-methoxy-[1,1'-biphenyl]-4-carboxylate (9b) and conducted a Friedel-Crafts reaction of 9b with acetyl chloride and AlCl3 in 1,2-dichloroethane. The regioselective acylation, subsequently followed by demethylation of methyl ether, proceeded smoothly to produce the desired compound 10b in 89% yield. Thus, the obtained compound 10b was treated with tert-butyl 4-oxopiperidine-1-carboxylate (7) and pyrrolidine13 in MeOH at reflux temperature to give the cyclized product 11 in 86% yield. The reduction of the spirochromanone-piperidine compound 11 with NaBH4 produced the spirochromanol-piperidine compound 12 in 93% yield.
To convert 11 or 12 into the desired spirochroman-piperidine 13, we investigated a variety of reaction conditions to identify a high-yield and efficient procedure (Scheme 3, Table 1).

Upon exposure of the spirochromanol-piperidine compound 12 to Et3SiH and CF3CO2H in CH2Cl2,4 deoxygenation occurred (entry 1). The desired product 13 was successfully obtained along with the deprotection of the N-Boc group in 89% yield. Having obtained a satisfactory yield, we next sought to avoid expensive and erosive solvent such as CF3CO2H. Similarly, the deprotection product 13 was obtained in 95% yield when conducting the hydrogenolysis of 12 in the presence of Pd-C in AcOH at 80 °C (entry 2). To avoid stepwise reduction, we investigated an alternative reaction, treating 11 with a combination of Et3SiH and InCl3 or InBr3,14 but these conditions resulted in no reaction (entries 3 and 4). The conversion of 11 into 13 by a conventional method such as the Clemmensen reduction could be performed in 68% yield, but it also resulted in a small amount of subproduct 14 (entry 5).

We additionally attempted this conversion with a combination of a reducing reagent and a Lewis acid such as Me2NH·BH3/TiCl4.15 Our initial attempt gave a mixture of 13 and the over-reduced compound 15 when performing the reaction at 0 °C (entry 6). Then, we optimized the reaction conditions for the quantity of reducing agent and the reaction temperature to minimize the over-reduction of 13, leading to the subproduct 15 by way of 2. Finally, we were able to control well the reduction of the ketone accompanied by the deprotection of the N-Boc in 11 to produce the intermediate 13 in 79% yield when treated with a small surplus amount (1.2 eq.) of reducing reagent in the temperature range from -20 °C to room temperature (entry 7). After workup, the remaining ester could be smoothly reduced by NaBH4 in pyridine at 100 °C in 75% yield.
In conclusion, we established a practical synthesis of a key intermediate 2 of a novel GPR119 agonist staring from 4'-hydroxy-[1,1'-biphenyl]-4-carboxylic acid (8) without troublesome intermediates or a tedious protocol. Furthermore, we developed a feasible, convenient reduction system to convert a ketone into a methylene and an ester into an alcohol with deprotection. Further process development and toxicological study are currently in progress.

EXPERIMENTAL
General. All reactions were performed under an argon atmosphere unless otherwise noted. The IR spectra were recorded on a Thermo Nicolet 370 FTIR spectrometer. The 1H-NMR spectra and 13C-NMR spectra were obtained on a JEOL JNM-AL 400 MHz spectrometer using the solvents CDCl3 or CD3OD with tetramethylsilane as an internal standard, unless otherwise noted. The mass spectra were obtained on a JEOL MS-BU20 mass spectrometer. The elemental analyses (C, H, and N) were performed by Yanaco MT-5. The melting points were determined in open glass capillaries on a Buchi B-545 melting point apparatus.

tert-Butyl 6-bromospiro[chromane-2,4'-piperidine]-1'-carboxylate (5)
The target compound 5 was prepared according to the patent literature.4

tert-Butyl 6-(4-(hydroxymethyl)phenyl)spiro[chroman-2,4'-piperidine]-1'-carboxylate (3)
Na2CO3 (55.0 g, 520 mmol) and Pd(PPh3)4 (2.40 g, 2.10 mmol) were added at room temperature under an argon atmosphere to a stirred solution of 4 (21.0 g, 140 mmol) and 5 (40.0 g, 100 mmol) in a mixture of DME (500 mL) and water (500 mL). The reaction mixture was stirred at 90 °C for 18 h and then allowed to cool to room temperature. The reaction mixture was extracted with AcOEt (3 x 300 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was crystallized from AcOEt to give 3 (31.0 g, 72%) as a colorless, crystalline powder.
mp 173 °C; IR (KBr): 3462, 2942, 1679, 1488, 1432, 1366, 1234, 1165, 1149, 819;
1H-NMR (400 MHz, CDCl3) δ: 1.47 (9H, s), 1.54-1.67 (2H, m), 1.79-1.87 (4H, m), 2.84 (2H, t, J = 6.8 Hz), 3.14-3.36 (2H, m), 3.75-4.02 (2H, m), 4.69-4.75 (2H, br), 6.90 (1H, d, J = 8.3 Hz), 7.29 (1H, d, J = 2.2 Hz), 7.34 (1H, dd, J = 8.3, 2.2 Hz), 7.40 (2H, d, J = 8.0 Hz), 7.53 (2H, d, J = 8.0 Hz); 13C-NMR (100 MHz, CDCl3) δ: 23.0, 29.9, 33.4, 35.8, 40.9, 66.3, 74.3, 81.0, 119.1, 122.9, 127.6, 128.2, 128.9, 129.5, 134.3, 140.8, 141.6, 154.3, 156.4; MS (EI) m/z 409 [M+]; Anal. Calcd for C25H31NO4: C, 73.32; H, 7.63; N, 3.42. Found: C, 73.46; H, 7.69; N, 3.48.

Methyl 4'-methoxy-[1,1'-biphenyl]-4-carboxylate (9b)
The target compound was prepared from 4’-hydroxy-[1,1’-biphenyl]-4-carboxylic acid (8) according to the patent literature.12

Methyl 3'-acetyl-4'-hydroxy-[1,1'-biphenyl]-4-carboxylate (10b)
Acetyl chloride (30.0 mL, 420 mmol) was added at 0 °C under an argon atmosphere to a suspension of AlCl3 (112 g, 839 mmol) in dry 1,2-dichloroethane (210 mL). After stirring for 10 min, 9b (50.8 g, 210 mmol) was added to this mixture dropwise. The resulting mixture was stirred at 70 °C for 1 h. After completing the reaction, the reaction mixture was poured onto ice (1000 g) and then diluted with AcOEt (1.7 L). The organic layer was washed with water (600 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was dissolved in CHCl3 (130 mL) and diluted with hexane (500 mL). The precipitate was filtered off and washed with hexane (200 mL) to give 10b (50.3 g, 89%) as a yellow solid.
A sample was crystallized from CHCl3 and hexane to give colorless prisms for analysis.
mp 150-152 °C; IR (KBr): 3017, 1709, 1641, 1606, 1520, 1433, 1304, 1288, 1216, 1109;
1H-NMR (400 MHz, CDCl3) δ: 2.74 (3H, s), 3.97 (3H, s), 7.11 (1H, d, J = 8.8 Hz), 7.63 (2H, d, J = 8.0 Hz), 7.77 (1H, dd, J = 8.8, 2.0 Hz), 7.98 (1H, d, J = 2.0 Hz), 8.14 (2H, d, J = 8.0 Hz), 12.36 (1H, s); 13C-NMR (100 MHz, CDCl3) δ: 26.7, 52.2, 119.2, 119.9, 126.9, 128.9, 129.2, 130.3, 131.1, 135.3, 144.3, 162.5, 166.8, 204.5; MS (EI) m/z 270 [M+]; Anal. Calcd for C16H14O4: C, 71.10; H, 5.22. Found: C, 71.12; H, 5.29.

tert-Butyl 6-(4-(methoxycarbonyl)phenyl)-4-oxospiro[chromane-2,4'-piperidine]-1'-carboxylate (11)
At room temperature, 10b (74.8 g, 277 mmol) was added to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (55.2 g, 277 mmol) and pyrrolidine (11.4 mL, 138 mmol) in MeOH (277 mL). The reaction mixture was stirred at reflux temperature for 12 h. After completing the reaction, the reaction mixture was cooled to 0 °C. The precipitate was filtered off and washed with cold MeOH to give 11 (107.8 g, 86%) as a yellow solid. A sample was crystallized from AcOEt and hexane to give yellow prisms for analysis.
mp 159-160 °C; IR (KBr): 1722, 1688, 1607, 1433, 1397, 1303, 1249, 1147, 1115, 770;
1H-NMR (400 MHz, CDCl3) δ: 1.49 (9H, s), 1.63-1.71 (2H, m), 2.04-2.12 (2H, br m), 2.79 (2H, s), 3.22-3.34 (2H, br m), 3.80-3.99 (2H, m), 3.96 (3H, s), 7.12 (1H, d, J = 8.8 Hz), 7.67 (2H, d, J = 8.0 Hz), 7.81 (1H, dd, J = 8.8, 2.0 Hz), 8.13 (2H, d, J = 8.0 Hz), 8.17 (1H, d, J = 2.0 Hz); 13C-NMR (100 MHz, CDCl3) δ: 28.3, 33.9, 39.1, 47.9, 52.0, 78.2, 79.8, 119.0, 120.1, 125.0, 126.4, 128.9, 130.1, 133.9, 134.9, 143.8, 154.6, 158.9, 166.7, 191.2; MS (EI) m/z 451 [M+]; Anal. Calcd for C26H29NO6: C, 69.16; H, 6.47; N, 3.10. Found: C, 69.24; H, 6.53; N, 3.06.

tert-Butyl 4-hydroxy-6-(4-(methoxycarbonyl)phenyl)spiro[chromane-2,4'-piperidine]-1'-carboxylate (12)
NaBH4 (4.40 g, 116 mmol) was added portionwise at 0 °C to a solution of 11 (52.6 g, 116 mmol) in a mixture of MeOH (50 mL) and THF (200 mL). The reaction mixture was stirred at room temperature for 1 h. After completing the reaction, the solvent was removed under reduced pressure. The residue was dissolved in AcOEt (300 mL) and quenched with a saturated aqueous solution of NH4Cl (100 mL). The aqueous layer was extracted with AcOEt (100 mL). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was dissolved in AcOEt (50 mL) and diluted with hexane (150 mL). The precipitate was filtered off and washed with hexane to give 12 (48.9 g, 93%) as a white solid. A sample was crystallized from AcOEt and hexane to give colorless prisms for analysis.
mp 168-170 °C; IR (KBr): 3476, 2957, 1713, 1674, 1607, 1488, 1427, 1284, 1236, 1170;
1H-NMR (400 MHz, CDCl3) δ: 1.47 (9H, s), 1.63-2.00 (5H, m), 2.20 (1H, dd, J = 13.4, 6.1 Hz), 3.12-3.34 (2H, br m), 3.86-3.94 (2H, m), 3.94 (3H, s), 4.99-4.92 (1H, br m), 6.96 (1H, d, J = 8.4 Hz), 7.50 (1H, dd, J = 8.4, 2.0 Hz), 7.63 (2H, d, J = 8.3 Hz), 7.74 (1H, d, J = 2.0 Hz), 8.08 (2H, d, J = 8.3 Hz); 13C-NMR (100 MHz, CDCl3) δ: 28.4, 33.7, 35.9, 41.8, 52.1, 62.8, 74.2, 79.6, 117.9, 125.1, 126.4, 126.9, 128.2, 128.3, 130.1, 132.5, 145.1, 152.8, 154.8, 167.1; MS (EI) m/z 453 [M+]; Anal. Calcd for C26H31NO6: C, 68.86; H, 6.89; N, 3.09. Found: C, 68.91; H, 6.94; N, 3.07.

Methyl 4-(spiro[chromane-2,4'-piperidin]-6-yl)benzoate (13) (Entry 1)
CF3CO2H (441 mL) and subsequently Et3SiH (75.0 mL, 470 mmol) were added at 0 °C to a stirred solution of 12 (20.0 g, 44.1 mmol) in CH2Cl2 (66 mL). The reaction mixture was stirred at room temperature for 12 h. After completing the reaction, the reaction mixture was concentrated in vacuo. The residue was dissolved in AcOEt (50 mL) and diluted with hexane (50 mL). The precipitate was filtered off to give the CF3CO2H salt of 13 (19.3 g) as a white solid. A saturated aqueous solution of NaHCO3 (300 mL) was added to a stirred suspension of the CF3CO2H salt in MeOH (200 mL). The reaction mixture was stirred at room temperature for 30 min. MeOH was evaporated from the reaction solvent under reduced pressure. The precipitate was filtered off and washed with THF (60 mL) and hexane (60 mL) to give 13 (14.4 g, 96%) as a white solid.
A sample was recrystallized from CHCl3 and hexane to give a colorless, crystalline powder for analysis.
mp 148-149 °C; IR (KBr): 3340, 2934, 1711, 1605, 1486, 1436, 1284, 1245, 1184, 1110;
1H-NMR (400 MHz, CDCl3) δ: 1.52-1.62 (2H, br m), 1.78-1.87 (4H, br m), 2.93-2.78 (4H, br m), 3.06 (2H, t, J = 10.5 Hz), 3.92 (3H, s), 6.92 (1H, d, J = 8.3 Hz), 7.33 (1H, s), 7.37 (1H, d, J = 8.3 Hz), 7.59 (2H, d, J = 8.3 Hz), 8.05 (2H, d, J = 8.3 Hz); 13C-NMR (100 MHz, CDCl3) δ: 21.1, 31.7, 35.3, 41.6, 51.6, 73.1, 117.5, 121.4, 125.8, 125.9, 127.6, 127.9, 129.6, 131.1, 145.0, 153.5, 166.7; MS (EI) m/z 337 [M+]; Anal. Calcd for C21H23NO3: C, 74.75; H, 6.87; N, 4.15. Found: C, 74.77; H, 6.92; N, 4.19.

Hydrogenolysis of 12 (Entry 2)
Under an argon atmosphere, 5% Pd-C (60 mg) was added to a solution of 12 (200 mg, 0.442 mmol) in AcOH (3 mL). The reaction mixture was stirred at room temperature for 4 h and heated at 60 °C for 15 h and at 80 °C for 9 h under a hydrogen atmosphere. After completing the reaction, 4N HCl/AcOEt (9 mL) was added to the reaction mixture. The resulting mixture was stirred overnight at room temperature. MeOH (10 mL) was added to this mixture to dissolve the precipitate that appeared. The insoluble material (Pd-C) from the reaction mixture was filtered off. The filtrate was concentrated in vacuo and diluted with AcOEt (30 mL). The organic solution was washed with a saturated aqueous solution of NaHCO3 (30 mL) and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20% sat. NH3/MeOH in CHCl3) to give 13 (141 mg, 95%) as a white solid.

Clemmensen reduction (Entry 5)
Zinc powder (3.60 g, 552 mmol) was added at room temperature to a stirred solution of 11 (1.00 g, 22.1 mmol) in AcOH (10 mL). The reaction mixture was stirred at 100 °C for 5 h. After completing the reaction, the insoluble material was filtered off and washed with a mixed solvent of THF and MeOH (40 mL/10 mL). To cleave the N-Boc group, 4N HCl/AcOEt (20 mL) was added at room temperature to the filtrate. The resulting mixture was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in CHCl3 (100 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 (30 mL) and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20% sat. NH3/MeOH-CHCl3) to give an inseparable mixture of 13 and 14 (517 mg) as a white solid. The yield of 13 and 14 were calculated on the basis of 1H-NMR analysis to show 64% and 4%, respectively.

Methyl 4-(spiro[chromene-2,4'-piperidin]-6-yl)benzoate (14)
The authentic sample 14 was synthesized after mesylation of 12 and elimination under basic conditions.
mp 144-145 °C; IR (KBr): 3351, 2940, 2809, 1705, 1604, 1488, 1429, 1292, 1180, 1106;
1H-NMR (400 MHz, CDCl3) δ: 1.55-1.68 (2H, m), 1.90-2.03 (2H, m), 2.78-2.87 (2H, m), 3.04-3.14 (2H, m), 3.90 (3H, s), 5.65 (1H, d, J = 9.6 Hz), 6.39 (1H, d, J = 9.6 Hz), 6.90 (1H, d, J = 8.0 Hz), 7.22 (1H, d, J = 2.0 Hz), 7.36 (1H, dd, J = 8.0, 2.0 Hz), 7.56 (2H, d, J = 8.0 Hz), 8.04 (2H, d, J = 8.0 Hz); 13C-NMR (100 MHz, CDCl3) δ: 36.3, 41.5, 51.8, 75.5, 116.7, 122.0, 122.7, 124.9, 126.1, 127.7, 128.0, 129.8, 130.2, 132.4, 144.8, 152.7, 166.7; MS (EI) m/z 309 [M+]; Anal. Calcd for C21H21NO3: C, 75.20; H, 6.31; N, 4.18. Found: C, 75.16; H, 6.38; N, 4.05.

Reduction of 11 by Me2NH·BH3 and TiCl4 (Entry 6)
A solution of 11 (10.0 g, 22.1 mmol) in dry CH2Cl2 (70 mL) was added dropwise at 0 °C under an argon atmosphere to a stirred solution of TiCl4 in dry CH2Cl2 (1.0 M solution, 26.5 mL) and Me2NH·BH3 (1.60 g, 26.5 mmol) in dry CH2Cl2 (30 mL). After stirring at this temperature for 30 min, the reaction mixture was allowed to warm to room temperature and was stirred for 3 h. After completing the reaction, the reaction mixture was quenched with H2O (100 mL) at 0 °C. The resulting mixture was stirred overnight at room temperature. The precipitate was filtered off to give a mixture of 13 and 15 as hydrochloride salts (7.54 g). The yield of 13 and 15 were calculated on the basis of 1H-NMR analysis (CD3OD) to show 83% and 8%, respectively.

Reduction of 11 by Me2NH·BH3 and TiCl4 (Entry 7)
This procedure was the same as that in Entry 6 except for the reaction temperature at -20 °C. The ratio of each compound of hydrochloride salts (13:15 = 50:1) was determined by 1H-NMR analysis (CD3OD). A mixture of products was crystallized from MeOH to give the hydrochloride salt of 13 (6.54 g, 79%).

(4-(Spiro[chromane-2,4'-piperidin]-6-yl)phenyl)methanol (2)
NaBH4 (1.52 g, 40.0 mmol) at 0 °C under an argon atmosphere was added to a stirred solution of 13·HCl (6.00 g, 16.0 mmol) in dry pyridine (100 mL). The stirring reaction mixture was allowed to warm to room temperature and heated at 100 °C for 14 h. After completing the reaction, the reaction mixture was quenched with MeOH (50 mL) at 0 °C and concentrated in vacuo. The residue was dissolved in CHCl3 (200 mL) and H2O (200 mL). The aqueous layer was extracted with CHCl3 (200 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (20 mL) and AcOEt (80 mL). At 0 °C, 4N HCl/AcOEt (20 mL) was added to this solution. The resulting mixture was stirred at 0 °C for 30 min and concentrated in vacuo. The residue was dissolved in CHCl3 (200 mL). The organic layer was washed with 1N NaOH (30 mL), and the aqueous layer was extracted with CHCl3 (200 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The solid product was crystallized from THF (100 mL) and hexane (50 mL) to give 2 (2.88 g, 58%) as a colorless, crystalline powder. The mother liquid was concentrated in vacuo and crystallized from THF (40 mL) and hexane (15 mL) to give 2 (0.83 g, 17%) as a colorless, crystalline powder.
A sample was recrystallized from THF to give a colorless needle for analysis.
mp 190-191 °C; IR (KBr): 3260, 3066, 2924, 1490, 1250, 1160, 1142, 1036, 972, 841;
1H-NMR (400 MHz, CDCl3) δ: 1.61-1.72 (2H, m), 1.81-1.90 (4H, m), 2.71-2.96 (4H, m), 3.08 (2H, t, J = 11.7 Hz), 4.62 (2H, s), 6.82-6.88 (1H, m), 7.32-7.39 (4H, m), 7.53 (2H, d, J = 8.3 Hz); 13C-NMR (100 MHz, CDCl3) δ: 20.9, 31.8, 34.4, 40.9, 63.6, 72.8, 117.2, 121.6, 125.4, 126.0, 127.1, 127.5, 132.7, 139.4, 139.9, 152.8; MS (EI) m/z 309 [M+]; Anal. Calcd for C20H23NO2: C, 77.64; H, 7.49; N, 4.53. Found: C, 77.46; H, 7.55; N, 4.54.

ACKNOWLEDGEMENTS
We thank Dr. S. Tanabe, Director, for his encouragement and support at Tokyo New Drug Research Laboratories, Kowa Co., Ltd.

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