A practical synthesis of a chiral analogue of FTY720

Article abstract of DOI:10.1021/op800144h

A practical synthesis of 1 involving a catalytic enantioselective construction of the quaternary carbon from imine 10 (derived from 13 and 14) and alkyl iodide 5 using Maruoka's chiral catalyst 11 is described. This asymmetric alkylation followed by hydrolysis to amino acid 9 was accomplished in good yield with high chemical purity (>98%) and chiral purity (>96% ee). The improved synthesis enabled production of 1 in seven chemical steps (six isolations) in an overall yield of 22%.

Full text of DOI:10.1021/op800144h

Organic Process Research & Development 2008, 12, 1164–1169
A Practical Synthesis of a Chiral Analogue of FTY720
Xinglong Jiang, Baoqing Gong, Kapa Prasad,* and Oljan Repicˇ
Process Research & DeVelopment, NoVartis Pharmaceuticals Corporation, One Health Plaza, East HanoVer,
New Jersey 07936, U.S.A.
Abstract:
As our aim was to make 1 on multikilogram scale for further
A practical synthesis of 1 involving a catalytic enantioselective
construction of the quaternary carbon from imine 10 (derived from
13 and 14) and alkyl iodide 5 using Maruoka’s chiral catalyst 11
is described. This asymmetric alkylation followed by hydrolysis
to amino acid 9 was accomplished in good yield with high chemical
purity (>98%) and chiral purity (>96% ee). The improved
synthesis enabled production of 1 in seven chemical steps (six
isolations) in an overall yield of 22%.
study, we evaluated all possible options, trying to improve the
research route to 1. After brief evaluation, we settled on the
strategy shown in Scheme 2.
Since the introduction of the term phase transfer catalysis
by Starks4 in 1971, many phase transfer catalysts have been
developed and successfully used in organic synthesis to
construct many useful molecules for academia and industries.5
Of particular relevance to our work was the method reported
by Maruoka, in which a series of optically enriched disubstituted
R-amino acids were synthesized by alkylation of the alanine-
derived imines in the presence of chiral phase transfer catalyst
11. The enantiomeric excess of the products reported under these
conditions varied from 90 to 99%. The final synthesis of
compound 1 that we designed based on this approach is shown
in Scheme 3.
Introduction
FTY720 is a novel immunomodulator which acts via S1P-
receptor agonism and is highly effective in animal models of
organ transplantation and autoimmunity. Chiral derivatives of
FTY720 played an important role in the initial understanding
of FTY720’s mode of action.1 They are also invaluable tools
to clarify further the pharmacology of single S1P-receptors.
Compound 1 was selected as an interesting chiral analogue of
FTY720 for further development, and in this publication a
practical synthesis of 1 is described.
The previous method2 that had been used for making
compound 1 is shown in Scheme 1. The key reaction in this
sequence is the generation of the quaternary carbon in com-
pound 7 which is achieved from compound 5 using Val-Ala-
derived Scho¨lkopf auxiliary 6.3
The diastereoselectivity of the C-C bond-forming alkylation
step was 90-95%. Although this chemistry is elegant in the
academic sense, it is of less preparative value as one needs to
use stoichiometric amounts of Scho¨lkopf’s reagent, which is
expensive and not readily available. In addition, these alkylation
conditions needed low temperature (typically -70 °C) and
workup was cumbersome. In addition, elimination of HI from
5 occurred to a significant extent as the reaction utilized
n-butyllithium.
Synthesis of Iodo Intermediate 5. Although the synthesis
of 5 employed by research was straightforward, we modified
their route as ethylene oxide that was used for introducing the
hydroxylethyl chain is toxic and has low emission limits. The
details are as follows. For converting 2 to 3 in the finalized
procedure, acetone was used as the solvent, and alkylation was
conducted with 1-iodopropane using potassium carbonate as
the base. Product 3 (95% yield and 99% purity by HPLC) was
precipitated from the reaction mixture by water addition. The
modification involves a palladium-catalyzed C-C bond forma-
tion6 as shown in Scheme 4.
In this two-step process, the reaction mixture containing
3, ethyl acetoacetate, K3PO4 · H2O, Pd(OAc)2, and a
phosphino ligand in toluene was first heated to 85-90
°C to generate the intermediate shown in Scheme 4, which
was then deacylated by heating at 100-104 °C. To
minimize the formation of des-bromo byproduct, the first-
step reaction temperature should be kept strictly at 85-90
* Author for correspondence. E-mail: prasad.kapa@novartis.com.
(1) (a) Brinkmann, V. Yonsei Med. J. 2004, 45, 991–997. (b) Chiba, K.
Pharmacol. Ther. 2005, 108, 308–319. (c) Albert, R.; Hinterding, K.;
Brinkmann, V.; Guerini, D.; Mu¨ller-Hartwieg, C.; Knecht, H.; Simeon,
C.; Streiff, M.; Wagner, T.; Welzenbach, K.; Ze´cri, F.; Zollinger, M.;
Cooke, N.; Francotte, E. J. Med. Chem. 2005, 48, 5373–5377.
(2) (a) Hinterding, K.; Cottens, S.; Albert, R.; Zecri, F.; Buehlmayer, P.;
Spanka, C.; Brinkmann, V.; Nussbaumer, P.; Ettmayer, P.; Hoegenauer,
K.; Gray, N.; Pan, S. Synthesis 2003, 1667. (b) Buehlmayer, P.;
Hinterding, K.; Spanka, C.; Zecri, F., WO 2004/024673, CAN 140:
287164 AN 2004:252472, 2004.
(4) Starks, C. M. J. Am. Chem. Soc. 1971, 93, 195.
(5) Maruoka, K. Asymmetric Phase Transfer Catalysis; Wiley-VCH Verlag
Gmbh & Co., KGaA: Weinheim, 2008 and references therein.
(6) Zeevaart, J. G.; Parkinson, C. J.; de Koning, C. B. Tetrahedron Lett.
2004, 45, 4261.
(3) (a) Scho¨lkopf, U.; Groth, U.; Westphalen, K.-O.; Deng, C. Synthesis
1981, 12, 969. (b) Scho¨lkopf, U. Pure Appl. Chem. 1983, 55, 1799.
1164
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10.1021/op800144h CCC: $40.75
2008 American Chemical Society
Published on Web 09/26/2008

Scheme 1. Research synthesis
Scheme 2. Retrosynthesis
simplify the purification process, a modified procedure utilizing
Ph3P, I2, and imidazole was adopted.7 The imidazole hydrogen
iodide salt was easily removed by aqueous workup. The
majority of Ph3PO was removed as an insoluble solid by
slurrying the crude product in a 1:1 ratio of MTBE and
n-heptane followed by filtration. This simple treatment removed
more than 90% of Ph3PO. The rest was removed by a simple
silica gel pad filtration. Iodo intermediate 5 was obtained in
90.6% yield with 98.1% HPLC purity.
Main-Chain Chemistry. Aldimine 10 was prepared from
alanine tert-butyl ester hydrochloride 12 and 4-chlorobenzal-
dehyde 13 in the presence of MgSO4 in methanol. Product 10
was isolated in 95% yield and >98% purity by NMR, and it
was used as a toluene solution in the next step.
The key step in the present synthesis is the asymmetric
alkylation of 10 with 5 using a chiral phase transfer catalyst.
As mentioned earlier, our choice in this context was the C2-
symmetric chiral PTC 11 developed by Maruoka and co-
workers.8 Thus we first investigated the alkylation of 10 with
iodide 5 using PTC 11 and CsOH ·H2O as the base in toluene
at 0 °C. Gratifyingly, the result (Table 1, entry 1) was excellent
with >94% conversion and 96% ee. We next examined bases
such as Cs2CO3 and KOH. Alkylation in the presence of Cs2CO3
gave a similar result (entry 4) as in entry 1, while with a stronger
°C. The reaction temperature was then raised to 100-104
°C after HPLC analysis confirmed the complete consump-
tion of starting material 3. Premature heating of the
reaction mixture to 100-104 °C could generate up to 15%
of the des-bromo byproduct, which was difficult to remove
as 12 is an oil. With the two-staged temperature control
approach, the unwanted des-bromo byproduct was mini-
mized to <2%. When anhydrous K3PO4 was used as the
base, we found that it took more than 24 h to complete
the deacylation, whereas a small amount of water acceler-
ated this deacylation. Consequently, K3PO4 monohydrate
was used as the base, and the deacylation was usually
finished within 5 h. We observed light etching of the
glassware when using K3PO4 monohydrate, and the use
of metal reactors is recommended for this purpose.
The transformation of 12 to 4 was accomplished using LiBH4
in THF at 60 °C. The major byproduct was the olefin formed
from elimination. The chemical purity at this stage can be
increased to >98% by slurrying the crude product in a mixture
of isopropyl acetate and n-heptane, and 4 was isolated in 85%
yield. Research used NIS and Ph3P to convert 4 to 5. Silica gel
column purification was required, as both succinimide and
Ph3PO were generated as byproducts in large quantities. To
Table 1. Catalytic Asymmetric Phase Transfer Alkylation of
10
temp time
conversion
(%)
entry solvent
base
toluene CsOH
toluene CsOH
(°C)
(h)
R/S
1
2
3
4
5
6
7
8a
0
10
6
98/2
80/20
65/35
97/3
>94
>94
>94
>95
13
>92
>90
>95
5-10
20-22
0
toluene CsOH
toluene Cs2CO3
6
10
toluene 50% KOH 0-22 16
NA
CH2Cl2 CsOH
THF CsOH
TBME CsOH
0
0
0
5
6
6
52/48
51/49
53/47
a 1 mol % of catalyst 11 was used.
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Scheme 3. Current synthesis
Scheme 4
not soluble in toluene, we optimized these conditions further.
The final conditions chosen were 1.0 equiv of 10, 1.3 equiv of
5, and 5 equiv of cesium hydroxide monohydrate in 17:1 (v/v)
toluene/TBME at 0 °C for 10 h.
Since the crude 15 contained impurities, such as excess
of 5, the elimination byproduct of 5, PTC, and a small
amount of 10, the purification was tedious and not ideal
for scale-up. To address this challenging issue, crude 15
was treated with 2 N HCl in acetonitrile to form the
hydrochloride salt 9, during which both the imine and the
tert-butyl ester group hydrolyzed, in 70% yield (based on
10) with 96% ee. The enrichment of the chiral purity of
9 could easily be achieved by slurrying 9 in absolute
ethanol (200 proof) at 56 °C, followed by addition of
toluene and cooling. The optimal ratio was 1 g of 9 in
4.5 mL of ethanol and 50 mL of toluene. The undesired
enantiomer could be reduced from 2.5% to 0.3% under
these conditions, and the yield was 90%. About 2 kg of 9
were obtained in one batch with >99% ee.
base KOH (entry 5), decomposition of 5 to the corresponding
styrene became a serious problem. Since the best result was
obtained using cesium hydroxide (entry 1), two critical param-
eters, i.e., solvent and temperature, were varied (entries 2, 3, 6,
7, and 8). Solvents such as THF, dichloromethane and TBME
gave almost no enantioselectivity (Table 1, entries 6-8)
although the reaction time was dramatically reduced to 5-6 h.
The conditions mentioned in entry 1 were found to be best. As
cesium hydroxide monohydrate and the chiral catalyst 11 were
The carboxylic acid 9 was reduced to the corresponding
alcohol with lithium aluminum hydride in THF at 56 °C.
After quenching the reaction with the minimum amount
of water/NaOH, the heterogeneous mixture was filtered,
and the product was isolated by precipitation from ethyl
(7) Trost, B. M.; Shen, H. C.; Dong, Li; Surivet, J.-P.; Sylvain, C. J. Am.
Chem. Soc. 2004, 126, 11966.
(8) Maruoka, K.; Ooi, T. Chem. ReV. 2003, 103, 3013–3028.
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acetate and heptane. Under these conditions, 1.2 kg of 1
was obtained in 77% yield with almost 100% ee.
to 0 °C. Water (50 L) was added at such a rate as to maintain
an internal temperature of e10 °C. The resulting solution was
warmed to 20 °C and held for 1 h. The organic layer was
separated, washed twice with 5% aqueous sodium chloride
solution (25 kg per wash) and once with saturated aqueous
sodium chloride solution (25 kg). The organic layer was filtered
through Celite, the filter cake was washed with toluene (8 kg),
and the wash was combined with the filtrate. The solution was
concentrated under reduced pressure (maximum jacket tem-
perature ) 60 °C) to afford 12 [14.2 kg, 81.8% (corrected)] as
a brown oil, 95.2% pure by HPLC (excluding solvent). The
product contained 13% toluene as determined by 1H NMR. 1H
NMR (CDCl3) δ 7.78 (d, J ) 3 Hz, 1 H), 7.76 (d, J ) 2 Hz,
1H), 7.73 (s, 1 H), 7.46 (dd, J ) 9 Hz, 2 Hz, 1 H), 7.34 (m, 1
H), 7.19 (d, J ) 3 Hz, 1 H), 4.25 (q, J ) 7 Hz, 2 H), 4.11 (t,
J ) 7 Hz, 2 H), 3.82 (s, 2 H), 1.96 (m, 2 H), 1.34 (t, J ) 7 Hz,
3 H), 1.16 (t, J ) 7 Hz, 3 H).
6-Propoxy-2-naphthalene Ethanol (4). A stirred solution
of 6-propoxy-2-naphthalene acetic acid ethyl ester 12 (12.8
kg as a concentrate, 47 mol) in dry tetrahydrofuran (47
L) was treated at -15 °C with lithium borohydride (2.0
N solution in tetrahydrofuran, 18.8 L, 37.6 mol) over 1 h
at such a rate as to maintain an internal temperature e0
°C. The reaction mixture was heated to reflux (65 °C)
and held for 4 h. The reaction mixture was cooled to -15
°C and carefully quenched with 2 N hydrochloric acid
solution (0 °C, 18.8 L) at such a rate as to maintain an
internal temperature e0 °C. The resulting solution was
warmed to 30 °C and concentrated under reduced pressure
(maximum jacket temperature ) 30 °C). The concentrate
was diluted with water (4.7 L) and isopropyl acetate (75
L), and the reaction mixture was stirred at room temper-
ature for 30 min. The aqueous layer was separated. The
organic layer was washed four times with 5% aqueous
sodium chloride solution (8 kg per wash) and twice with
saturated aqueous sodium chloride solution (8 kg per
wash). The organic phase was filtered through Celite, the
filter cake was washed with isopropyl acetate (8 L), and
the wash was combined with the filtrate. The resulting
solution was concentrated under reduced pressure (maxi-
mum jacket temperature ) 50 °C). The resulting brown
solid was slurried in isopropyl acetate (5 L) at 40 °C,
stirred 15 min and diluted with n-heptane (treated with
antistatic agent, 65 L). The mixture was cooled to room
temperature and held for 16 h. The slurry was cooled to
10 °C, held 30 min, and filtered. The filter cake was
washed with a cold (10 °C) mixture of n-heptane (7.6 L)
and isopropyl acetate (0.5 L) and dried in vacuo at 50 °C
for 16 h to afford 4 [8.6 kg, 80.2% (corrected)] as a tan,
crystalline solid, 96% pure by HPLC; mp 100-101 °C;
1H NMR (DMSO-d6) δ 7.72 (m, 2 H), 7.62 (s, 1 H), 7.33
(d, J ) 8 Hz, 1 H), 7.24, (d, J ) 2 Hz, 1 H), 7.12 (dd, J
) 9 Hz, 3 Hz, 1 H), 4.70 (t, J ) 5 Hz, 1 H), 4.00 (t, J )
7 Hz, 2 H), 3.69 (m, 2 H), 2.85 (t, J ) 7 Hz, 2 H), 1.77
(m, 2 H), 1.00 (t, J ) 7 Hz, 3 H); 13C NMR (DMSO-d6)
δ 156.12, 134.61, 132.86, 128.76, 128.52, 128.19, 126.72,
126.47, 118.64, 106.38, 68.93, 62.26, 39.05, 22.09, 10.48.
Conclusions
In summary, an improved synthesis of 1 was developed. The
new synthetic route featured a practical asymmetric alkylation
using the C2-symmetric chiral catalyst 11 of Maruoka. This
particular step combined with hydrolysis to 9 achieved an 80%
yield and >96% ee. Finally, we demonstrated that the enan-
tiopurity of 9 could be enhanced to >98% ee through crystal-
lization, and the drug substance itself was isolated in >99% ee
in an overall yield of 22% based on 2.
Experimental Section
General. Melting points were measured on a MEL-
TEMP 3.0 melting point apparatus and were uncorrected.
1H and 13C NMR spectra were recorded on Bruker
AVANCE 400 or Bruker AVANCE 500 instruments.
Chemical shifts are given on a δ (ppm) scale. Enantiomeric
purity of compounds was determined by area % using
chiral HPLC. For compound 9, a Chiralpak WH 4.6 mm
× 250 mm column was used. The mobile phase A was
0.25 mM CuSO4, and B was acetonitrile. The chiral
method conditions were isocratic for 60 min, column
temperature 50 °C, flow rate 2.0 mL/min, wavelength 230
nm. For compound 1, a Chiralpak AS-H 4.6 mm × 250
mm column was used. The mobile phase was hexanes/2-
propanol/diethylamine (83:17:0.1). The chiral method
conditions were isocratic for 30 min, column temperature
20 ( 5 °C, flow rate 0.7 mL/min, wavelength 230 nm.
2-Bromo-6-propoxynaphthalene (3). A stirred suspension
of 6-bromo-2-naphthol, 2, (10 kg, 44.8 mol) and potassium
carbonate (9.3 kg, 67.2 mol) in acetone (50 L) was treated at
room temperature with 1-iodopropane (9.1 kg, 53.8 mol). The
reaction mixture was heated to reflux (59 °C) and held for 48 h.
Water (75 L) was added at such a rate as to maintain an internal
temperature of g50 °C. The resulting mixture was cooled to
32 °C, seeded with 3, and held for 3 h. The resulting suspension
was cooled to 25 °C, held for 16 h, further cooled to 0 °C, and
held for 1 h. The solids were filtered, washed with cold (0 °C)
2:1 (v/v) water/acetone solution (18.75 L), and dried in vacuo
at 45 °C for 16 h to afford 3 [11.0 kg, 95.4% (corrected)] as a
white crystalline solid, 99.1% pure by HPLC; mp 59-60 °C;
1H NMR (DMSO-d6) δ 8.07 (s, 1 H), 7.80 (d, J ) 9 Hz, 1 H),
7.74 (d, J ) 9 Hz, 1 H), 7.53 (dd, J ) 9 Hz, 2 Hz, 1 H), 7.31
(s, 1 H), 7.19 (dd, J ) 9 Hz, 2 Hz, 1 H), 4.00 (t, J ) 7 Hz, 2
H), 1.77 (m, 2 H), 0.99 (t, J ) 7 Hz, 3 H); 13C NMR (DMSO-
d6) δ 156.97, 132.90, 129.55, 129.29, 129.10, 128.80, 128.48,
119.86, 116.12, 106.55, 69.02, 21.97, 10.38.
6-Propoxy-2-naphthalene Acetic Acid Ethyl Ester (12).
A stirred suspension of 2-bromo-6-propoxynaphthalene 3 (12.8
kg, 48.2 mol), potassium phosphate monohydrate (36.1 kg,
170.0 mol), 2-(di-tert-butylphosphino)-2′-methylbiphenyl (0.30
kg, 0.96 mol), and palladium(II) acetate (0.11 kg, 0.48 mol) in
toluene (92 L) was treated at room temperature with ethyl
acetoacetate (8.2 kg, 63.1 mol). The reaction mixture was heated
to 90 °C over 30 min and held for 2 h. The reaction mixture
was further heated to 100 °C, held for 5 h, and finally cooled
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2-(2-Iodoethyl)-6-propoxynaphthalene (5). A stirred so-
lution of 6-propoxy-2-naphthalene ethanol 4 (8.6 kg, 37.3
mol), triphenylphosphine (12.7 kg, 48.5 mol) and imida-
zole (3.81 kg, 56 mol) in tetrahydrofuran (43 L) was
treated at -20 °C with a solution of iodine (14.1 kg, 56
mol) in tetrahydrofuran (13 L). The iodine solution was
added at such a rate as to maintain an internal temperature
e10 °C. The reaction mixture was warmed to room
temperature, held 15 min, and cooled to 0 °C. The reaction
mixture was quenched with 1.8 M aqueous sodium
thiosulfate solution (10.3 kg) at such a rate as to maintain
an internal temperature 10 °C. The resulting solution was
concentrated under reduced pressure (maximum jacket
temperature ) 25 °C) with water (21 kg) being added
approximately halfway through the concentration. The
concentrate was diluted with ethyl acetate (68 L) and
stirred, and the aqueous layer was separated. The organic
layer was washed twice with 5% aqueous sodium chloride
solution (25 kg per wash) and once with saturated aqueous
sodium chloride solution (25 kg). The organic layer was
concentrated under reduced pressure (maximum jacket
temperature ) 25 °C) to an oil. The concentrate was
diluted with tert-butyl methyl ether (17 L), warmed to 60
°C, and held for 15 min. The resulting solution was diluted
with n-heptane (treated with antistatic agent, 17 L), cooled
to 20 °C, and held for 16 h. The solids (triphenylphosphine
residue was dissolved in tert-butyl methyl ether (70 L)
washed successively with 5% NaHCO3 solution (6 L),
water (10 L), and brine solution (10 L). The organic phase
was dried with MgSO4, filtered, and concentrated to
dryness under vacuum at <50 °C to give 8.3 kg of 10 in
93.8% yield as a liquid. It became a solid after being stored
1
in a refrigerator. H NMR (CDCl3) δ 1.47 (s, 9 H), 1.48
(d, J ) 5.0 Hz, 3 H), 4.04 (q, J ) 5.0 Hz, 1 H), 7.38 (d,
J ) 10 Hz, 2 H), 7.72 (d, J ) 10 Hz, 2 H), 8.25 (s, 1 H);
13C NMR (CDCl3) δ 19.38, 28.02, 68.38, 81.18, 128.81,
129.61, 134.42, 136.87, 161.09, 171.61; mp 25-27 °C.
(R)-2-Amino-2-methyl-4-(6-propoxynaphthalen-2-yl)bu-
tyric Acid ·HCL Salt (9). To a 5-L round-bottomed flask
were charged 10 (267.8 g, 1.0 mol), 5 (452 g, 1.33 mol),
toluene 2.35 L), tert-butyl methyl ether (140 mL), and
phase transfer catalyst 11 (10 g), and the mixture was
stirred until the dissolution of solids. The reaction mixture
was cooled to -3 to -6 °C followed by the addition of
cesium hydroxide monohydrate (840 g, 5.60 mol) in one
portion. The reaction mixture was warmed to -1 to 1 °C,
and stirred vigorously for 7 h. The reaction was monitored
by HPLC and quenched with water (1.0 L). The separated
organic phase was washed successively with water (1 L)
and brine (1 L) and was concentrated to a 500-mL volume
followed by the addition of 6 N HCl in isopropyl alcohol
(670 mL) and water (21 mL). The mixture was heated to
56 °C for 3-4 h. The reaction was monitored by HPLC
followed by the addition of toluene (1.5 L). The resulting
solids were filtered and washed with toluene (500 mL),
until the disappearance of brown color, and dried at 25
°C for 16 h to give 230 g of crude 9 in 68% yield.
Recrystallization of 9. To a 120 L flask were charged
crude 9 (2337 g) and ethanol (9 L, 200 proof), and the
suspension was heated at 56 °C for 45 min followed by
the slow addition of toluene (106 L) while maintaining
the temperature at 50-56 °C. The suspension was stirred
for another 40 min. The reaction mixture was cooled to
16 °C and maintained at this temperature for 1 h. The
solids were filtered, washed with 4 L of toluene, and dried
at 20 °C for 16 h to give 1920 g of pure 9; mp > 200 °C,
oxide) were filtered and washed with
a
1:1
(v/v) tert-butyl methyl ether and n-heptane solution (17
L), and the wash was combined with the filtrate. The
filtrate was passed through silica gel (230-400 mesh, 36
kg). The silica gel pad was washed with a 1:1 (v/v) tert-
butyl methyl ether and n-heptane solution (72 L) and the
wash combined with the eluant. The eluant/wash was
concentrated to a thick slurry and held at 20 °C for 16 h.
The solids were filtered, washed with cold (0 °C)
n-heptane (10 kg), and dried in vacuo at 50 °C for 16 h
to afford 5 (9.6 kg) as a tan, crystalline solid, 99% pure
by HPLC; mp 56-57 °C. The mother liquors were
concentrated, and the resulting solids were filtered to
obtain a second crop of 5 (1.65 kg) as a low-melting solid,
93.3% pure by HPLC. Overall, 11.25 kg (90.6%, cor-
1
dec; H NMR (DMSO-d6) δ 1.02 (t, J ) 5 Hz, 3 H), 1.55
1
rected) of 5 was produced. H NMR (DMSO-d6) δ 7.74
(s, 3 H), 1.79 (m, 2 H), 2.18 (m, 2 H), 2.63 (m, 1 H),
2.92 (m, 1 H), 4.03 (t, J ) 5 Hz, 2 H), 7.13 (m, 1 H),
7.27 (m, 1 H), 7.33 (m, 1 H), 7.61 (s, 1 H), 7.75 (m, 2
H), 8.96 (br s, 3 H), 13.96 (br s, 1 H); 13C NMR (DMSO-
d6) δ 10.42, 22.02, 22.06, 29.22, 38.62, 58.84, 68.96,
106.52, 118.81, 125.82, 126.90, 127.33, 128.48, 128.76,
132.88, 135.46, 156.25, 172.59.
(R)-2-Amino-2-methyl-4-(6-propoxynaphthalen-2-yl)bu-
tan-1-ol (1). To a 5-L flask were charged 9 (90 g, 0.266
mol) and tetrahydrofuran (1.8 L, anhydrous), and the
mixture was cooled to 5 ( 5 °C followed by the slow
addition of lithium aluminum hydride (1 M in THF, 1.07
L, 1.07 mol). The mixture was heated to 56 °C and held
at this temperature for 4-5 h. After the completion of
the reaction, the suspension was cooled to -3 ( 3 °C
followed by the slow addition of water (41 g), NaOH (41
g of 15% solution), and water (123 g). The mixture was
(dd, J ) 9 Hz, 4 Hz, 2H), 7.66, (s, 1 H), 7.36 (d, J ) 9
Hz, 1 H), 7.27 (d, J ) 2 Hz, 1 H), 7.13 (dd, J ) 9, Hz,
3 Hz, 1 H), 4.02 (t, J ) 6 Hz, 2 H), 3.54 (t, J ) 7 Hz, 2
H), 3.23 (t, J ) 7 Hz, 2 H), 1.79 (m, 2 H), 1.01 (t, J )
7 Hz, 3 H); 13C NMR (DMSO-d6) δ 156.36, 135.61,
133.15, 128.90, 128.35, 127.22, 126.78, 126.55, 118.86,
106.44, 68.94, 39.19, 22.05, 10.47, 8.28.
2-{[1-(4-Chlorophenyl)methylidene]amino}propionic Acid
tert-Butyl Ester (10). To a stirred solution of 13 (6 kg, 33
mol) in 48 L of methanol was added triethylamine (5.05
L, 46 mol), and the mixture was stirred for 30 min
followed by the addition of 4.64 kg (33 mol) of 14. To
this solution anhydrous magnesium sulfate (6.1 kg) was
added, and the mixture was stirred for 16 h at rt, filtered,
and the residue was washed with 6 L of methanol. The
combined filtrates were evaporated to dryness, and the
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stirred at this temperature for 2 h, filtered, and the residue
was washed with tetrahydrofuran (200 mL). The combined
filtrates were concentrated to a 200 mL volume under
vacuum at 40 °C followed by the addition of ethyl acetate
(800 mL). The resulting solution was concentrated to a
200 mL volume under vacuum at 40 °C. The mixture was
diluted with heptane (2.4 L). The resulting solids were
filtered and washed with heptane (200 mL) followed by
3% EtOH in heptanes (100 mL, v/v), dried under vacuum
at 45 °C for 16 h to give 61 g of 1 in 79% yield; mp 101
(br s, 1 H), 7.11 (m, 1 H), 7.25 (s, 1 H), 7.31 (m, 1 H),
7.59 (s, 1 H), 7.74 (m, 2 H); 13C NMR (DMSO-d6) δ
10.44, 22.03, 24.59, 29.63, 41.36, 52.47, 68.92, 70.29,
106.49, 118.55, 125.55, 126.52, 127.81, 128.60, 128.63,
132.55, 138.29, 155.97.
Acknowledgment
We thank Prof. Keiji Maruoka for helpful discussions and
for facilitating the supply of the chiral phase transfer catalyst.
1
°C; H NMR (DMSO-d6) δ 1.00 (s, 3 H), 1.03 (t, J ) 5
Hz, 3 H), 1.39 (br s, 2 H), 1.61 (m, 2 H), 1.80 (m, 2 H),
2.73 (m, 2 H), 3.20 (s, 2 H), 4.03 (t, J ) 5 Hz, 2 H), 4.59
Received for review June 19, 2008.
OP800144H
Vol. 12, No. 6, 2008 / Organic Process Research & Development
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