Organic Process Research & Development
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with TBME (0.5 L). The filtrate was concentrated to dryness to
obtain 320 g of a crude oil. The product was purified by a
filtration over silica (1.6 kg) using EtOAc/heptane 1:4 (v:v) as
eluent to get an orange oil (200 g) which was crystallized from
heptane (1.5 L). The product was dried at 50 °C and reduced
pressure to obtain 13 as a yellow solid. Yield: 156 g (83%).
Purity (LC−MS): 100% a/a, Rt 1.837 min, [M + 1]+ = 423; er
(HPLC method 2): (S):(R) = 98.6:1.4, Rt 5.801 min (S-
98.4:1.6, Rt 12.3 min (S-isomer), 10.0 min (R-isomer); H
NMR (D6 DMSO): δ 7.78 (s, 2H), 7.69 (m, 1H), 7.05 (s, 1H),
6.97 (s, 1H), 5.56 (t, J = 5.5 Hz, 1H), 5.31 (d, J = 5.0 Hz, 1H),
4.01 (m, 1H), 3.84 (d, J = 5.4 Hz, 2H), 3.75 (m, 2H), 3.57 (q, J
= 6.7 Hz, 4H), 3.45 (m, 1H), 3.24 (m, 1H), 2.73 (q, J = 7.3 Hz,
2H), 2.42 (s, 3H), 2.34 (s, 3H), 1.22 (t, J = 7.4 Hz, 3H), 1.15
(t, J = 6.8 Hz, 6H); 13C NMR (CDCl3): δ 175.4, 173.2, 168.7,
158.6, 157.7, 157.2, 137.6, 132.3, 131.5, 128.4, 126.7, 122.8,
107.5, 100.3, 74.1, 70.2, 62.2, 42.4, 42.3, 24.8, 22.9, 16.5, 14.8,
12.9.
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isomer), 5.499 min (R-isomer); H NMR (D6 DMSO): δ 7.77
(s, 2H), 7.03 (s, 1H), 6.96 (s, 1H), 4.19 (d, J = 11.2 Hz, 1H),
3.68 (dd, J1 = 11.1 Hz, J2 = 6.8 Hz, 1H), 3.56 (q, J = 6.7 Hz,
4H), 3.38 (s, 1H), 2.85 (t, J = 4.5 Hz, 1H), 2.73 (m, 3H), 2.41
(s, 3H), 2.34 (s, 3H), 1.22 (t, J = 7.4 Hz, 3H), 1.15 (t, J = 6.8
Hz, 6H).
Via (R)-Epichlorohydrin. A mixture of phenol 12 (10 g,
0.027 mol, 1.0 equiv), (R)-epichlorohydrin (25 g, 10 equiv,
99% ee by CoA), and Me4NCl (1 g, 0.33 equiv) was stirred at
25 °C for 2 d. MeOH (40 mL) and 32% NaOH (5.8 mL, 1.7
equiv) were added to the suspension at 0 °C. The suspension
was stirred at 20 °C for 60 min. The suspension was filtered
and washed with MeOH (10 mL) to obtain 13 as a yellow solid
after drying at 50 °C and reduced pressure. Yield: 11.25 g
(98%). Purity (LC−MS): 100% a/a, Rt 1.837 min, [M + 1]+ =
423; er (HPLC method 2): (S):(R) = 97.8:2.2, Rt 5.801 min (S-
isomer), 5.499 min (R-isomer).
ASSOCIATED CONTENT
* Supporting Information
■
S
Analytical methods and characterization data of 1 and
intermediates. This material is available free of charge via the
AUTHOR INFORMATION
Corresponding Author
■
565 80 28.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(S)-N-(3-(4-(5-(2-(Diethylamino)-6-methylpyridin-4-
yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)-2-
hydroxypropyl)-2-hydroxyacetamide (1). 1M LiHMDS in
THF (213 mL, 2 equiv) was added to a solution of epoxide 13
(45 g, 0.107 mol, 1.0 equiv) in THF (0.5 L) at 22 °C. The
solution was stirred at 22 °C for 1 d. The reaction mixture was
added to sat. aq NH4Cl solution (0.75 L). The mixture was
stirred for 1 h, and TBME (200 mL) was added. The aqueous
layer was separated, and the organic layer was washed with
brine (2 × 250 mL). After concentration to dryness,
aminopropanol 14 was obtained as a brown oil which was
used in the next step without purification. Yield: 54 g (115%).
We thank Daniel Leuenberger, Patric Dorrwachter, and Marco
̈
̈
Tschanz for their skillful experimental work, and Dr. Thomas
Weller for the most fruitful and seamless collaboration with
Medicinal Chemistry. We acknowledge the contribution of Dr.
Antonio Soi and Dr. Silke Erbeck from Carbogen-Amcis for the
́
scale-up of 1 to 12 kg. We are grateful to Aurelien Henriou for
analytical support.
REFERENCES
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(1) Bolli, M. H.; Mathys, B.; Mueller, C.; Nayler, O.; Steiner, B.;
Velker, J. WO/2008/114157, 2008.
(2) For recent reviews on sphingosine 1-phosphate (S1P) receptor
modulation, see: (a) Bolli, M. H.; Lescop, C.; Nayler, O. Curr. Top.
Med. Chem. 2011, 11, 726−757. (b) Hla, T; Brinkmann, V. Neurology
2011, 76, S3−S8.
1
Purity (LC−MS): 92% a/a, Rt 1.339 min, [M + 1]+ = 440; H
NMR (D6 DMSO): δ 7.78 (m, 2H), 7.06 (s, 1H), 6.98 (s, 1H),
3.77 (m, 3H), 3.58 (q, J = 6.9 Hz, 4H), 3.18 (d, J = 2.9 Hz,
2H), 2.74 (m, 3H), 2.42 (s, 3H), 2.35 (s, 3H), 1.32 (s, 1H),
1.23 (m, 3H), 1.16 (t, J = 7.0 Hz, 6H). EDC·HCl (22.6 g, 1.1
equiv) was added in portions to a solution of 14, glycolic acid
(8.95 g, 1.1 equiv), HOBt·H2O (15.9 g, 1.1 equiv), and THF
(500 mL) at 22 °C. The mixture was stirred at 20 °C for 3 h.
Glycolic acid (1.6 g, 0.2 equiv), HOBt·H2O (2.2 g, 0.15 equiv),
and EDC·HCl (3.1 g, 0.15 equiv) were added, and stirring was
continued for 15 h. THF was removed at 50 °C and reduced
pressure. To the residue was added EtOAc (0.5 L). The
solution was washed with water (0.5 L), half-sat. aq NaHCO3
solution (2 × 0.5 L) and water (0.25 L). The organic layer was
concentrated to dryness to obtain 1 as a yellow solid. Yield: 50
g (94%). Purity (HPLC method 1): 89% a/a. Purification: The
crude material (50 g), MeOH (0.5 L), and 1 N NaOH (25 mL)
were stirred for 45 min at 60 °C. MeOH was removed at 50 °C
and reduced pressure. EtOAc (0.5 L) was added to the residue
at 20 °C, and the resulting solution was extracted with water (2
× 250 mL). The organic layer was concentrated to dryness at
50 °C and reduced pressure. The crude solid was dissolved in
EtOAc (0.5 L) at 70 °C, the solution was cooled to 20 °C, and
the resulting suspension was filtered and dried to obtain 1 as a
yellow solid. Yield: 26 g (49%). Purity (HPLC method 1):
98.6% a/a, Rt 7.6 min, er (HPLC method 2): (S):(R) =
(3) Widmer, U. Synthesis 1983, 135−136.
(4) Dimethyl zinc, 2 M, in toluene from Aldrich catalogue: CHF
3400/500 mL.
(5) Smith, W. E. J. Org. Chem. 1972, 37, 3972−3973.
(6) Best offers for first kilogram of phenol 7: 2 months delivery time,
CHF 8’000 for 1 kg.
(7) (a) Baron, H.; Remfry, F. G. P; Thorpe, J. F. J. Chem. Soc. 1904,
85, 1726−1761. (b) Guareschi, I. Gazz. Chim. Ital. 1919, 49, 124−133.
(8) For alternative syntheses of amino isonicotinic acids, see:
́
(a) Alajarin, M.; Cabrera, J.; Pastor, A.; Sanchez-Andrada, P.; Bautista,
D. J. Org. Chem. 2006, 71, 5328−5339. (b) Yin, J.; Xiang, B; Huffman,
M. A.; Raab, C. E.; Davies, I. W. J. Org. Chem. 2007, 72, 4554−4557.
(9) (a) Ali, M. H.; Buchwald, S. L. J. Org. Chem. 2001, 66, 2560−
2565. (b) Hartwig, J. F.; Kawatsutra, S. H.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575−5580.
(10) (a) Bardhan, J. C. J. Chem. Soc. 1929, 2223−2232.
(b) Libermann, D.; Rist, N.; Grumbach, F.; Cals, S.; Moyeux, M.;
Rouaix, A. Bull. Soc. Chim. Fr. 1958, 687−694. (c) Blackwood, R. K.;
Hess, G. B.; Larrabee, C. E.; Pilgrim, F. J. J. Am. Chem. Soc. 1958, 80,
6244−6249. (d) Ichiba, A.; Emoto, S. Sci. Pap. Inst. Phys. Chem. Res.
(Tokyo) 1941, 38, 347. (e) Pieper, P. A.; Yang, D.; Zhou, H.; Liu, H. J.
Am. Chem. Soc. 1997, 119, 1809−1817. (f) Tracy, A. H.; Elderfield, R.
C. J. Org. Chem. 1941, 70−76.
(11) Murata, T.; Shimada, M.; Sakakibara, S.; Yoshino, T.; Kadono,
H.; Masuda, T.; Shimazaki, M.; Shintani, T.; Fuchikami, K.; Sakai, K.;
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dx.doi.org/10.1021/op200326s | Org. Process Res. Dev. 2012, 16, 595−604