Full Papers
doi.org/10.1002/ejoc.202100058
raphy (heptane:EtOAc 4:1) to provide compound 15 (108 mg,
0.23 mmol) as a white solid (yield 60%). H NMR (400 MHz, CDCl3,):
J=2.2, 1H), 8.38 (dd, =8.9, 2.2, 1H), 7.96 (dd, J=7.6, 1.1, 1H), 7.60
(tt, J =7.6, 0.8, 1H), 7.16 (d, J=9.0, 1H), 4.88–4.79 (m, 1H), 3.61–3.55
(m, 2H), 2.86–2.80 (m, 2H), 1.51 (d, J=6.1,6H) ppm..[28] MS (ESI) 382
(M+Na)+
1
2
3
4
5
6
7
8
9
1
δ 8.28 (s, 1H), 8.22 (d, J=8.0, 1H), 7.96 (d, J=8.0, 1H), 7.41 (d, J=
7.6, 1H), 7.28 (t, J=7.6, 1H), 7.03 (d, J=9.2, 1H), 5.16 (d, J=7.2, 1H),
4.85 (t, J=6.4, 1H), 4.75–4.69 (m, 1H), 3.38–3.32 (m, 1H), 3.10–3.01
(m, 1H), 2.58–2.56 (m, 1H), 1.82–1.73 (m, 1H), 1.43–1.39 (m, 15H)
ppm. 13C NMR (400 MHz, CDCl3): δ 172.9, 168.8, 162.7, 155.7, 145.3,
142.9, 134.0, 133.8, 128.2, 127.2, 126.8, 123.1, 116.8, 115.2, 113.6,
103.9, 72.7, 55.7, 33.8, 31.5, 28.4, 28.2, 21.7 ppm. HRMS (ESI) calcd
for C26H28N4NaO4 (M+Na)+ 483.2008; found 483.20082.
Ozanimod (1) through hydrogen transfer reduction of imine 18.
To a dispersion of ketone 19 (500 mg, 1.39 mmol) in a 4:1 (V/V)
mixture of toluene and ethanol (60 mL), PTSA (4.7 mg,
0.0247 mmol) and 2-aminoethanol (340 mg, 5.54 mmol) were
added. The mixture was maintained under reflux conditions and
the formed water distilled out using a Dean-Stark condenser
containing activated 4 A molecular sieves. The formation of a
precipitate was observed during the course of the reaction. After
complete conversion (about 12 hours), the mixture was cooled to
5’,5’-Dimethyl-2,3-dihydrospiro[indene-1,2’-[1,3]dioxane]-4-car-
bonitrile 22. To a solution of ketone 3 (30 g, 0.19 mol) in toluene
(200 mL), neopentyl glycol (19.6 g, 0.19 mol) and PTSA (0.72 g,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
°
°
°
0.0038 mol) were added under stirring at 25 C. Trimethyl orthofor-
mate (26.4 g, 0.24 mol) was added and the mixture was maintained
20 C and the solid filtered, washed with toluene and dried at 40 C
under reduced pressure, thus yielding 540 mg of the crude imine
18, yield: 96%; ES/MS 403 (M+H)+, 827, (2 M+Na)+. An aliquot of
50 mg of 18 (0.12 mmol), dispersed in 2,2,2-trifluoroethanol (1 mL),
was mixed with C3-[(S,S)-teth-MtsDPEN RuCl] (1.6 mg,
0.0024 mmol), 2-aminoethanol (7.6 mg, 0.12 mmol) and formic acid
triethylamine complex 5:2 (53.7 mg, 0.62 mmol), under stirring at
°
under stirring at 20–25 C until complete conversion (about
°
12 hours). The reaction was cooled to 5 C, then a 10% aqueous
solution of Na2CO3 (150 mL) and toluene (100 mL) were added. The
resulting phases were separated, and the aqueous layer was
extracted with toluene (80 mL). The collected organic phases were
evaporated under reduced pressure up to obtain a residue which
was triturated in 2-PrOH (130 mL) for 1 hour. The resulting solid
was filtered, washed with 2-propanol and dried at 40 C under
reduced pressure yielding 28.6 g of the title compound (yield:
°
°
25 C. The mixture was maintained under stirring at 50 C until
°
complete conversion (about 24 hours), then it was cooled to 20 C
°
and diluted with methanol. An aliquot of the mixture was analysed
by HPLC according to the method described in literature[10] showing
an enantiomeric excess (ee)=99%. To this methanolic solution a
10% (w/w) solution of hydrogen chloride in methanol (0.13 g,
1
62%). H NMR (300 MHz, DMSO-d6): δ 7.78 (dd, J=25.6, 7.6, 2H),
7.47 (t, J=7.7, 1H), 3.73 (d, J =11.2, 2H), 3.49 (d, J =11.2, 2H), 3.04
(t, J=6.9, 2H), 2.46 (d, J=6.9, 2H), 1.25 (s, 3H), 0.80 (s, 3H) ppm. MS
(ESI) 266 (M+Na)+ C15H17NO2 (243.30): calcd C 74.05, H 7.04, N 5.76;
found C 74.06, H 7.07, N 5.78.
°
0.36 mmol) was added. The mixture was gently heated to 45 C and
maintained under stirring for 2 hours. After cooling, the resulting
solid was filtered, washed with methanol and dried under reduced
pressure to provide 46.5 mg of Ozanimod.HCl (yield 96%) with
chiral HPLC and spectral data in accordance with those reported in
literature.[10]
N’-Hydroxy-5,5-dimethylspiro[1,3-dioxane-2,1’-2,3-dihydroin-
dene]-4’-carboximidamide 23. To a dispersion of hydroxylamine
hydrochloride (20.3 g, 292.2 mmol) in ethanol (490 mL), triethyl-
amine (31.5 g, 311.7 mmol) was added. The mixture was maintained
under stirring at 25 C for 1 hour, then acetal 22 (23.7 g, 97.4 mmol)
was added. The reaction was maintained under stirring at the same
temperature until complete conversion (about 48 hours). The
Ozanimod (1) via reductive amination of ketone 19. To a
dispersion of compound 19 (50 mg, 0.14 mmol) in 2,2,2-trifluoroe-
thanol (1 mL), C3-[(S,S)-teth-TrisDPEN RuCl] (2.0 mg, 0.0028 mmol),
heated to 50 C, 2-aminoethanol (17.0 mg, 0.28 mmol) and formic
acid triethylamine complex 5:2 (60.2 mg, 0.70 mmol) were slowly
added under stirring. The mixture was maintained under stirring at
°
°
°
resulting solid was filtered, washed with ethanol and dried at 40 C
under reduced pressure, yielding 20 g of the title compound
(quantitative yield). An analytical sample was prepared through
recrystallisation with EtOAc. 1H NMR (500 MHz, DMSO-d6): δ 9.55 (s,
1H), 7.47 (dd, J=7.6, 1.2, 1H), 7.41(dd, J=7.6, 1.2, 1H), 7.28 (dd, J=
8.0, 7.3, 1H), 5.72 (s, 2H), 3.71 (d, J=11.1, 2H), 3.47 (dt,J=11.3, 1.1,
2H), 3.02 (t, J=6.9, 2H), 2.34 (dd, J=7.4, 6.5, 2H), 1.26 (s, 3H), 0.78
(s, 3H) ppm. MS (ESI) 275 (MÀ H)À C15H20N2O3 (276.33): calcd C 65.20,
H 7.30, N 10.14; found C 65.17, H 7.29, N 10.12.
°
50 C until complete conversion (about 24 hours), then it was
°
cooled to 20 C and diluted with methanol. An aliquot of the
mixture was analysed by HPLC according to the method described
literature showing an enantiomeric excess (ee)=99%. Purification
through a shorth path of silica with EtOAc/heptane 5 :1, followed
by evaporation of the solvent gave a pure sample of amine 1
1
(45 mg, 90% yield). H NMR (500 MHz, CDCl3) δ=8.44 (s, 1H), 8.36
(dd, J=8.9, 2.2, 1H), 8.10 (d, J=6.7, 1H), 7.57 (d, J=6.4, 1H), 7.41 (t,
J=7.6, 1H), 7.14 (d, J=9.1, 1H), 4.82 (p, J=6.2, 1H), 4.38 (t, J=6.8,
1H), 3.80–3.66 (m, 2H), 3.54–3.42 (m, 1H), 3.28–3.16 (m, 1H), 3.02–
2.89 (m, 2H), 2.61–2.51 (m, 1H), 2.26 (s, 2H), 2.01–1.90 (m, 1H), 1.50
(d, J=6.1, 6H). 13C NMR (126 MHz, CDCl3) δ=173.04, 169.04,
162.76, 146.40, 143.59, 134.15, 133.89, 128.18, 126.99, 123.23,
116.93, 115.31, 113.57, 103.98, 72.76, 62.82, 61.24, 48.44, 33.25,
31.83, 21.76. MS (ESI) 405 (M+H)+
2-Isopropoxy-5-(3-(1-oxo-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadia-
zol-5-yl)benzonitrile 19. To a dispersion of 3-cyano-4-isopropox-
ybenzoic acid 12 (17 g, 82.8 mmol) in cyclopentyl methyl ether
°
(300 mL) heated to 55 C, 1,1’-carbonyldiimidazole (20.8 g,
128.3 mmol) was added portionwise. The mixture was maintained
under stirring at the same temperature until complete conversion
(about 1 hour), then amidoxime 23 (22.9 g, 82.8 mmol) was added.
The reaction was heated to 80 C and maintained under stirring at
the same temperature until complete conversion (about 12 hours).
After cooling to 60 C, cyclopentyl methyl ether (200 mL) and a
0.5 M aqueous solution of sodium hydroxide (200 mL) were added.
The resulting phases were separated at 50 C and the organic layer
was washed with water (200 mL) at the same temperature. The
organic phase was evaporated under reduced pressure to obtain a
solid which was dispersed in acetone (400 ml) containing PTSA
(1.28 g, 6.73 mmol). The mixture was maintained under stirring at
25 C until complete conversion (about 2 hours), then the resulting
solid was filtered, washed with acetone and dried at 45 C under
°
°
Acknowledgements
°
Support from MIUR (Rome) through the grant Dipartimento di
Eccellenza 2018–2022 is gratefully acknowledged.
°
°
reduced pressure, thus yielding 22.6 g of the title compound (yield:
93%). 1H NMR (500 MHz, CDCl3): δ 8.50 (dd, J=7.6, 1.2, 1H), 8.47 (d,
Eur. J. Org. Chem. 2021, 1924–1930
1929
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