Synthesis of TAK-218 using (R)-2-methylglycidyl tosylate as a chiral building block

Article abstract of DOI:10.1016/S0957-4166(99)00138-X

We performed an asymmetric synthesis of (S)-2,3-dihydro-2,4,6,7- tetramethyl-2-[(4-phenyl-1-piperidinyl)-methyl]-5-benzofuranamine dihydrochloride (TAK-218, 1), a compound used for the treatment of traumatic and ischemic central nervous system injuries. O

Full text of DOI:10.1016/S0957-4166(99)00138-X

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1521–1526
Synthesis of TAK-218 using (R)-2-methylglycidyl tosylate as a
chiral building block
Kohji Fukatsu,∗ Nobuhiro Fujii and Shigenori Ohkawa
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd, 17–85 Jusohonmachi 2-chome, Yodogawa-ku,
Osaka 532-8686, Japan
Received 16 March 1999; accepted 2 April 1999
Abstract
We performed an asymmetric synthesis of (S)-2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl)-
methyl]-5-benzofuranamine dihydrochloride (TAK-218, 1), a compound used for the treatment of traumatic and
ischemic central nervous system injuries. Oxirane 6, which was synthesized from (R)-2-methylglycidyl tosylate,
was treated with aqueous trifluoroacetic acid to afford benzofuranmethanol 7 with inversion of stereochemistry
at the stereogenic center. Compound 7 was converted into 1 with high enantiomeric excess in four steps. © 1999
Elsevier Science Ltd. All rights reserved.
1. Introduction
Oxygen radicals and monoamines are possible secondary factors involved in delayed neuronal
cell death. In a previous paper,1 we demonstrated that a 2,3-dihydrobenzofuran (coumaran) de-
rivative, (S)-2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl)methyl]-5-benzofuranamine di-
hydrochloride 1 has potent inhibitory activities on lipid peroxidation and dopamine release. These
activities inhibited functional deficits in a brain injury model and improved the survival rate in a central
ischemia model.
Coumaran derivatives having amino groups at position 5 are used as insecticides,2 diuretics,3 and
analgesics,4 however, the enantiomerically pure compounds have not been synthesized. Recently, Ha-
yashi et al. accomplished a high enantioselective coumaran ring construction using a Wacker-type
reaction of 2-allylphenols.5 Harada et al. also reported the asymmetric synthesis of coumarans that have
one substituent at position 2, using glycidyl phenyl sulfide as a chiral synthon.6 Herein we report the
asymmetric synthesis of 1, employing (R)-2-methylglycidyl tosylate 27 as a chiral building block.
∗
Corresponding author. Fax: +81 6 6300 6306; e-mail: fukatsu_kohji@takeda.co.jp
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00138-X

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2. Results and discussion
The methoxymethyl ether 4, prepared from bromophenol 3, was lithiated, and then condensed with
chiral oxirane 27 (94% ee; evaluated by NMR shift analysis) in the presence of boron trifluoride etherate8
to give tertiary alcohol 5 in 97% yield (Scheme 1). Treatment of the tertiary alcohol 5 with K2CO3 caused
oxirane ring formation to provide 6 in 93% yield. Coumaran ring construction was achieved with aqueous
trifluoroacetic acid to afford 7 in 82% yield with 93% ee. The enantiomeric excess was determined by
chiral HPLC analysis using rac-7, prepared from rac-2,9 as a racemic standard. Although the absolute
configuration at position 2 could not be determined at this stage, chiral HPLC analysis indicated almost
no change in enantiomeric excess after coumaran ring construction.
Scheme 1. Reagents: (a) MOMCl, NaH; (b) n-BuLi; (c) K2CO3; (d) aq. TFA; (e) MsCl, Et3N; (f) 4-phenylpiperidine, K2CO3;
(g) HCl; (h) 4-nitrobenzenediazonium chloride; (i) H2/Raney-nickel
Introduction of the piperidine moiety was accomplished by methanesulfonylation of the alcohol 7 in
quantitative yield, followed by condensation with 4-phenylpiperidine in the presence of K2CO3 in N,N-
dimethylacetamide at 180°C. The free base of 9 thus obtained was crystallized as its hydrochloride, and
recrystallization of 9 from ethanol/diethyl ether resulted in enrichment of enantiomeric purity (>99% ee)
with a yield of 72% from 8.†
Incorporation of an amino group into position 5 of 9 was accomplished using a two-step sequence;
diazo coupling reaction with 4-nitrobenzenediazonium chloride,10 followed by reductive cleavage of
†
The chiral HPLC analysis of rac-9 did not separate the enantiomers. We estimated the enantiomeric excess of 9 in relation to
that of the free base of 1 prior to crystallization of its dihydrochloride. See Experimental.

K. Fukatsu et al. / Tetrahedron: Asymmetry 10 (1999) 1521–1526
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the nitrogen–nitrogen bond using Raney-nickel as the catalyst. The product was crystallized as its
dihydrochloride in 70% overall yield from 9. Comparison of the specific rotation for the synthetic product
1, [α]D +27.5 (c 0.99, methanol), with the known compound,1 [α]D +27.8 (c 1.05, methanol), established
its absolute stereochemistry as S indicating that oxirane 6 was converted to benzofuranmethanol 7 with
inversion of stereochemistry at the stereogenic center. In conclusion, we have accomplished the efficient
and stereospecific synthesis of enantiomerically pure 1 using the intramolecular cyclization reaction of
chiral oxirane 6 as a key step.
3. Experimental
3.1. General methods
Melting points were determined on a Yanagimoto micro melting point apparatus and are uncorrected.
1
Infrared (IR) absorption spectra were recorded with a Shimadzu FTIR-8200PC spectrometer. H NMR
spectra were recorded on a Varian Gemini-200 spectrometer (200 MHz) and 13C NMR spectra were
recorded on a Bruker DRX500 spectrometer (500 MHz), with tetramethylsilane as the internal standard.
Optical rotations were determined with a JASCO DIP-370 digital polarimeter. Mass spectra were
measured on a JEOL JMS-AX505W (EI) or a Hitachi M-2000 (SIMS) mass spectrometer. TLC analyses
were carried out on Merck Kieselgel 60 F254 plates. Elemental analyses were carried out by Takeda
Analytical Research Laboratories, Ltd. Tetrahydrofuran (THF) was distilled over calcium hydride prior to
use, and other solvents and reagents were used without purification. Raney-nickel used was commercially
available as NDHT-90 (Kawaken Finechemical Co. Ltd), and was washed with distilled water (three
times) and ethanol (once) prior to use. Solutions in organic solvents were dried over anhydrous MgSO4,
and concentration of the organic solution was carried out under reduced pressure. Chromatographic
purification was carried out on silica gel columns (Merck Kieselgel 60, 0.063–0.200 mm).
3.2. 2-Bromo-3-(methoxymethoxy)-1,4,5-trimethylbenzene 4
To a solution of tert-butylamine (54 mL, 0.73 mol) in toluene (1.0 L) was added dropwise bromine (59
g, 0.37 mol) at −25°C. After the addition was complete, the mixture was cooled to −78°C. To the mixture
was added a solution of 2,3,5-trimethylphenol (50 g, 0.37 mol) in CH2Cl2 (250 mL) and the mixture
was allowed to warm to room temperature. The reaction mixture was diluted with EtOAc, washed with
aqueous Na2S2O4 and brine, dried and concentrated to afford crude 2-bromo-3,5,6-trimethylphenol 3. To
a solution of crude 3 in N,N-dimethylformamide (100 mL) was added 66% NaH (8.2 g, 0.22 mol, disper-
sed in mineral oil) under a nitrogen current with cooling in an ice-water bath, and the mixture was stirred
for 15 min. Then chloromethyl methyl ether (17 mL, 0.22 mol) was added and the mixture was stirred
for an additional 30 min. The reaction mixture was poured into ice water and the mixture was extracted
with hexane. The extract was washed with brine, dried and concentrated. The residue was distilled to give
31 g (32% yield, from 2,3,5-trimethylphenol) of 4 as a colorless oil: bp 94–96°C/0.2 mmHg; 1H NMR
(CDCl3) δ 2.20 (3H, s), 2.24 (3H, s), 2.34 (3H, s), 3.66 (3H, s), 5.04 (2H, s), 6.85 (1H, s).

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K. Fukatsu et al. / Tetrahedron: Asymmetry 10 (1999) 1521–1526
3.3. (R)-2-Hydroxy-3-[2-(methoxymethoxy)-3,4,6-trimethylphenyl]-2-methylpropyl 4-methylbenzene-
sulfonate 5
Under an argon atmosphere, to a solution of 4 (9.6 g, 37 mmol) in THF (100 mL) at −78°C was added
dropwise 1.7 M n-BuLi hexane solution (22 mL, 37 mmol), and the mixture was stirred for 15 min.
Then a solution of (R)-2-methylglycidyl tosylate7 (3.0 g, 12 mmol, 94% ee; evaluated by NMR shift
analysis) in THF (5 mL) and boron trifluoride diethyl ether complex (4.7 mL, 37 mmol) were added,
and the mixture was stirred for an additional 20 min. To the reaction mixture was added water, and the
aqueous mixture was extracted with EtOAc. The extract was washed with brine, dried and concentrated.
The residue was purified by column chromatography (EtOAc:hexane=1:4, followed by 1:3) to give 5.1 g
(97% yield, based on (R)-2-methylglycidyl tosylate) of 5 as a colorless oil: [α]D20 +8.7 (c 1.01, ethanol);
IR (KBr): 3464, 2944, 1456, 1369, 1190, 1177, 984 cm−1; 1H NMR (CDCl3) δ 1.05 (3H, s), 2.13 (3H,
s), 2.20 (3H, s), 2.24 (3H, s), 2.45 (3H, s), 2.83 (1H, d, J=14.2 Hz), 3.09 (1H, d, J=14.2 Hz), 3.59 (3H,
s), 3.85 (2H, s), 4.88 (1H, d, J=5.6 Hz), 4.93 (1H, d, J=5.6 Hz), 6.81 (1H, s), 7.34 (2H, d, J=8.2 Hz),
7.80 (2H, d, J=8.2 Hz); MS (SIMS) m/z: 422 (M+, 6), 391 (22), 361 (27), 189 (100), 149 (42).
3.4. (R)-2-[[2-(Methoxymethoxy)-3,4,6-trimethylphenyl]methyl]-2-methyloxirane 6
A mixture of 5 (5.1 g, 12 mmol) and K2CO3 (1.7 g, 12 mmol) in methanol (40 mL) was stirred at room
temperature for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The extract
was washed with brine, dried and concentrated. The residue was purified by column chromatography
20
(EtOAc:hexane=1:9) to yield 2.8 g (93% yield) of 6 as a colorless oil: [α]D −47.2 (c 1.02, ethanol);
1
IR (KBr): 2870, 1460, 1452, 1295, 1159, 1076, 1064, 1045, 981 cm−1; H NMR (CDCl3) δ 1.36 (3H,
s), 2.15 (3H, s), 2.20 (3H, s), 2.26 (3H, s), 2.45 (1H, d, J=5.2 Hz), 2.50 (1H, d, J=5.2 Hz), 3.03 (1H, d,
J=14.6 Hz), 3.11 (1H, d, J=14.6 Hz), 3.61 (3H, s), 4.91 (2H, s), 6.78 (1H, s); 13C NMR (CDCl3) δ 13.2,
20.0, 20.1, 22.3, 32.6, 53.0, 56.9, 57.4, 99.6, 126.1, 126.6, 127.8, 135.7, 136.3, 155.2; MS (EI) m/z: 250
(M+, 25), 205 (10), 187 (22), 175 (100), 133 (12).
3.5. (S)-2,3-Dihydro-2,4,6,7-tetramethyl-2-benzofuranmethanol 7
To a solution of 6 (2.8 g, 11 mmol) in THF (22 mL) cooled in an ice-water bath was added dropwise a
cold solution of trifluoroacetic acid (4 mL) in water (4 mL), and the mixture was stirred for 30 min. The
reaction mixture was poured into saturated aqueous NaHCO3, and the aqueous mixture was extracted
with EtOAc. The extract was washed with brine, dried and concentrated. The residue was purified
by column chromatography (EtOAc:hexane=1:4, followed by 1:3) to afford 1.9 g (82% yield) of 7 as
a colorless solid. The analytical sample was recrystallized from hexane. The enantiomeric excess of
7 was determined to be 93% by LC/MS (column, CHIRALCEL OD-R, 4.6×250 mm, 20°C; eluent,
MeCN−0.01 M AcONH4 (1:1); flow rate, 1.0 mL/min; tR of 7, 8.8 min; tR of enantiomer of 7, 7.7 min),
20
and did not improve after recrystallization from hexane: mp 54–57°C; [α]D +2.4 (c 1.01, ethanol); IR
1
(KBr): 3326, 2921, 1593, 1456, 1410, 1327, 1294, 1055 cm−1; H NMR (CDCl3) δ 1.43 (3H, s), 1.94
(1H, t, J=6.8 Hz), 2.08 (3H, s), 2.15 (3H, s), 2.19 (3H, s), 2.79 (1H, d, J=15.4 Hz), 3.13 (1H, d, J=15.4
Hz), 3.55–3.72 (2H, m), 6.51 (1H, s); 13C NMR (CDCl3) δ 11.6, 18.5, 19.3, 23.6, 37.3, 68.6, 88.0, 115.4,
122.5, 122.7, 131.3, 136.6, 157.1; MS (EI) m/z: 206 (M+, 40), 175 (100), 160 (9), 149 (14), 136 (9).
Anal. calcd for C13H18O2: C, 75.69; H, 8.80. Found: C, 75.45; H, 8.77.

K. Fukatsu et al. / Tetrahedron: Asymmetry 10 (1999) 1521–1526
1525
3.6. (S)-(2,3-Dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl methanesulfonate 8
To a solution of 7 (1.7 g, 8.3 mmol) and triethylamine (1.7 mL, 12 mmol) in THF (14 mL) cooled in an
ice-water bath was added dropwise methanesulfonyl chloride (0.71 mL, 9.1 mmol), and the mixture was
stirred for 15 min. The reaction mixture was diluted with water and extracted with EtOAc. The extract
was washed with brine, dried and concentrated to yield 2.3 g (98% yield) of 8 as a colorless solid: mp
70–71°C; [α]D +3.1 (c 1.00, ethanol); IR (KBr): 2940, 1460, 1366, 1175, 1001, 972, 828 cm−1; H
NMR (CDCl3) δ 1.51 (3H, s), 2.05 (3H, s), 2.15 (3H, s), 2.19 (3H, s), 2.88 (1H, d, J=15.6 Hz), 3.02 (3H,
s), 3.13 (1H, d, J=15.6 Hz), 4.26 (2H, s), 6.52 (1H, s); MS (EI) m/z: 284 (M+, 52), 187 (19), 175 (100),
159 (11), 147 (13). Anal. calcd for C14H20O2S: C, 59.13; H, 7.09; S, 11.28. Found: C, 58.86; H, 7.00; S,
11.26.
20
1
3.7. (S)-1-[(2,3-Dihydro-2,4,6,7-tetramethylbenzofuran-2-yl)methyl]-4-phenylpiperidine hydrochloride
9
A mixture of 8 (1.0 g, 3.5 mmol), 4-phenylpiperidine (1.1 g, 7.0 mmol), and K2CO3 (0.97 g, 7.0
mmol) in N,N-dimethylacetamide (5 mL) was stirred under an argon atmosphere at 180°C for 5 h.
After cooling, the reaction mixture was diluted with water and extracted with EtOAc. The extract
was washed with brine, dried and concentrated. The residue was purified by column chromatography
(EtOAc:hexane=1:19, followed by 1:9). The free base of 9 obtained (0.97 g) was dissolved in etha-
nol/EtOAc and 4 M HCl/EtOAc was added. The mixture was concentrated and the residue was re-
crystallized from ethanol/diethyl ether to yield 0.98 g (72% yield, from 8) of 9 as a colorless solid:
20
mp 178–182°C; [α]D +13.1 (c 1.00, ethanol); IR (KBr): 2934, 2483, 1456, 1429, 1406, 1283, 1073
cm−1; 1H NMR (DMSO-d6) δ 1.63 (3H, s), 1.85–2.42 (4H, m), 2.01 (3H, s), 2.13 (3H, s), 2.14 (3H, s),
2.73–3.01 (2H, m), 3.17–3.68 (6H, m), 3.82–3.91 (1H, m), 6.53 (1H, s), 7.22–7.36 (5H, m), 10.53 (1H, br
s); MS (SIMS) m/z: 350 (MH+ of free base, 97), 174 (100), 91 (9), 70 (13). Anal. calcd for C24H32ClNO:
C, 74.68; H, 8.36; Cl, 9.19; N, 3.63. Found: C, 74.46; H, 8.37; Cl, 9.18; N, 3.91.
3.8. (S)-1-[[2,3-Dihydro-2,4,6,7-tetramethyl-5-[(4-nitrophenyl)azo]benzofuran-2-yl]methyl]-4-
phenylpiperidine 10
4-Nitroaniline (0.16 g, 1.1 mmol) was dissolved in 2 N HCl (3 mL) by heating, and the resulting
solution was cooled in an ice-water bath. Then a solution of sodium nitrite (79 mg, 1.1 mmol) in water
(0.5 mL) was added dropwise and the mixture was stirred for 15 min. The diazonium chloride solution
obtained was added to a solution of 9 (0.40 g, 1.0 mmol) in acetic acid (3 mL), and the mixture was
stirred at room temperature for 15 h. The reaction mixture was poured into saturated aqueous NaHCO3,
and the aqueous mixture was extracted with EtOAc. The extract was washed with water and brine, dried
and concentrated. The residue (0.55 g) was used in the next step without further purification.
3.9. (S)-2,3-Dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl)methyl]-5-benzofuranamine
dihydrochloride 1
A mixture of 10 (0.55 g, crude) and Raney-nickel (0.6 g) in ethanol (30 mL) was stirred under a
hydrogen atmosphere (5 kgf/cm2) at room temperature for 2 h. The reaction mixture was filtered and
the filtrate was concentrated. The residue was purified by column chromatography (EtOAc:hexane=3:7,
followed by 1:1) to afford 0.30 g of the free base of 1. The enantiomeric excess of this compound

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K. Fukatsu et al. / Tetrahedron: Asymmetry 10 (1999) 1521–1526
was determined as 99.4% by LC/MS (column, CHIRALCEL OD-R, 4.6×250 mm, 20°C; eluent,
MeCN–phosphate buffer (pH 7) (1:1); flow rate, 1.0 mL/min; tR of 1, 21.6 min; tR of enantiomer of
1, 23.4 min). The free base was dissolved in ethanol and 4 M HCl/EtOAc was added to the solution. The
acidic solution was concentrated, and the residue was recrystallized from ethanol/diethyl ether to yield
0.32 g (70% yield, from 9) of 1 as a colorless crystal. The enantiomeric excess of 1 was determined as
99.8% by LC/MS (analytical condition was the same as used for the free base): mp 226–230°C (lit.1,
226°C); [α]D +27.5 (c 0.99, methanol) (lit.1, [α]D +27.8 (c 1.05, methanol)); IR (KBr): 2946, 2789,
20
1524, 1454, 1422, 1258, 1080 cm−1; 1H NMR (DMSO-d6) δ 1.63 (3H, s), 1.82–2.43 (4H, m), 2.07 (3H,
s), 2.23 (3H, s), 2.25 (3H, s), 2.74–2.86 (1H, m), 3.01–3.60 (7H, m), 3.78–3.86 (1H, m), 7.20–7.39 (5H,
m), 9.93 (3H, br s), 10.62 (1H, br s); 13C NMR (DMSO-d6) δ 12.0, 14.2, 14.9, 25.6, 29.1, 29.4, 53.5,
54.3, 62.7, 85.5, 116.2, 122.0, 123.0, 125.8, 126.4, 126.5, 128.4, 130.6, 144.4, 154.5; MS (SIMS) m/z:
365 (MH+ of the free base, 96), 174 (46). Anal. calcd for C24H34Cl2N2O: C, 65.90; H, 7.83; Cl, 16.21;
N, 6.40. Found: C, 65.72; H, 7.85; Cl, 15.95; N, 6.31.
Acknowledgements
We thank Mr. Norio Tada for chiral HPLC analyses.
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