Process development for (S,S)-reboxetine succinate via a sharpless asymmetric epoxidation

Article abstract of DOI:10.1021/op700007g

Reboxetine mesylate is a selective norepinephrine uptake inhibitor (NRI) currently marketed as the racemate. The (S,S)-enantiomer of reboxetine is being evaluated for the treatment of neuropathic pain and a variety of other indications. (S,S)-Reboxetine has usually been prepared by resolution of the racemate as the (-)-mandelate salt, an inherently inefficient process. A chiral synthesis starting with a Sharpless asymmetric epoxidation of cinnamyl alcohol to yield (R,R)-phenylglycidol was developed. (R,R)-Phenylglycidol was reacted without isolation with 2-ethoxyphenol to give 4, which was isolated by direct crystallization. Key process variables for the asymmetric epoxidation were investigated. Conversion of (R,S)-4 to reboxetine parallels the racemic synthesis with streamlined and optimized processing conditions. (S,S)-Reboxetine free base was converted directly to the succinate salt without isolation as the mesylate salt.

Full text of DOI:10.1021/op700007g

Organic Process Research & Development 2007, 11, 354−358
Process Development for (S,S)-Reboxetine Succinate via a Sharpless
Asymmetric Epoxidation
Kevin E. Henegar* and Mateusz Cebula
Pfizer Global Research and DeVelopment, 2800 Plymouth Road, Ann Arbor, Michigan 48105, U.S.A.
Abstract:
was epoxidized to yield (R,R)-phenylglycidol (3) which was
Reboxetine mesylate is a selective norepinephrine uptake
inhibitor (NRI) currently marketed as the racemate. The (S,S)-
enantiomer of reboxetine is being evaluated for the treatment
of neuropathic pain and a variety of other indications. (S,S)-
Reboxetine has usually been prepared by resolution of the
racemate as the (-)-mandelate salt, an inherently inefficient
process. A chiral synthesis starting with a Sharpless asymmetric
epoxidation of cinnamyl alcohol to yield (R,R)-phenylglycidol
was developed. (R,R)-Phenylglycidol was reacted without isola-
tion with 2-ethoxyphenol to give 4, which was isolated by direct
crystallization. Key process variables for the asymmetric
epoxidation were investigated. Conversion of (R,S)-4 to rebox-
etine parallels the racemic synthesis with streamlined and
optimized processing conditions. (S,S)-Reboxetine free base was
converted directly to the succinate salt without isolation as the
mesylate salt.
reacted without isolation with 2-ethoxyphenol to give 3,
which was isolated by direct crystallization. Key process
variables for the asymmetric epoxidation were investigated.
Changes were made to the racemic process to optimize
and simplify the following steps: (1) in step 5, methylene
chloride was substituted for ethyl acetate due to the low
solubility of 4 in ethyl acetate; (2) intermediate 6 was
crystallized as the free base form rather than as the mesylate
salt; (3) a process was developed for the conversion of 6 to
9 using toluene as the single solvent for these three steps,
eliminating dimethyl carbonate and a series of solvent
exchanges; (4) the acylation of 6 was done under Schotten-
Baumann conditions which gives a much cleaner reaction;
(5) S,S-reboxetine succinate was obtained directly via
crystallization of the free base, eliminating the need for the
intermediate formation of its mesylate salt (Scheme 1).
Results and Discussion
The synthesis starts with a Sharpless asymmetric epoxi-
dation of cinnamyl alcohol, establishing the two chiral centers
early in the process. Sharpless asymmetric epoxidation of
cinnamyl alcohol is reported to give 3 with >98% enantio-
meric excess and in 89% yield after product crystallization.4
We found the enantiomeric excess of crude 3 to be about
Introduction
Reboxetine mesylate is a selective norepinephrine uptake
inhibitor (NRI) currently marketed as the racemate. The (S,S)-
enantiomer is significantly more active than the racemate in
a number of assays, and studies are currently underway for
the use of (S,S)-reboxetine succinate 1 for the treatment of
,5
9
2%. Intermediate 4 is upgraded to >98% ee by crystal-
1
neuropathic pain and a variety of other indications. Enan-
tioselective syntheses have also been described, but (S,S)-
lization, eliminating the need to recrystallize the relatively
low-melting (2R,3R)-phenylglycidol. 3 was obtained as a
solution in methylene chloride which was reacted with
2
reboxetine is usually prepared by resolution of the racemate
as the (-)-mandelate salt.3 This process is inherently
inefficient due to the throughput limitations of a classical
resolution.
To sustain a future supply of (S,S)-reboxetine succinate
an enantioselective synthetic route was developed utilizing
2
-ethoxyphenol and sodium hydroxide under phase transfer
conditions. The resulting 4 was extracted into MTBE, washed
with sodium hydroxide solution to remove unreacted 2-ethoxy-
phenol and phenylglycerol, precipitated, and then recrystal-
lized from MTBE/isooctane. Enantiomeric excess at this
point was about 98%. Further enantiomeric upgrading
occurred in the crystallizations of 6 and (S,S)-reboxetine
succinate.
4
a Sharpless asymmetric epoxidation. Cinnamyl alcohol 2
*
Author for correspondence. E-mail: kevin.e.henegar@pfizer.com.
(1) Hughes, B.; McKenzie, I.; Stoker, M. J. WO2006/000903, 5/1/06. Allen,
A. J.; Hemrick-Luecke, S.; Sumner, C. R.; Wallace, O. B. WO2005/060949,
The catalyst load, reaction concentration, and the equiva-
lents of TBHP in asymmetric epoxidation reaction were
varied to find the optimal conditions for performing this
transformation, and most observations were in agreement
7
/7/05. Kelsey, D.K. WO2005/021095, 10/3/05. Allen, A. J.; Kelsey, D.
K. WO 2005/020976, 10/3/05. Sumner, C. R. WO2005/020975, 10/3/05.
Hassan, F. WO2004/016272, 2/26/04. Wong, E. H. F. WO2004/002463,
1
/8/04. Dursun, S. M.; Devarajan, S. WO2002/076461, 10/3/01. Wong, E.
H. F.; Ahmed, S.; Marshall, R. C.; McArthur, R.; Taylor, D. P.; Birgerson,
L.; Cetera, P. WO2001/001973, 1/11/01.
4
with the published data on this reaction. The tolerable limits
(
2) Brenner, E.; Baldwin, R. M.; Tamagnan, G. Org. Lett. 2005, 7, 937-939.
Cebula, M.; Henegar, K. E. U.S. Patent 2005/187388, 8/25/05.
3) Melloni, P.; Della Torre, A.; Lazzari, E.; Mazzini, G.; Meroni, M.
Tetrahedron 1985, 41, 1393-1399. Prabhakaran, J.; Majo, V. J.; Mann, J.
J.; Kumar, J. S. D. Chirality 2004, 16, 168-173.
for water in the TBHP solutions were established by running
reactions with TBHP solutions containing 0.2, 0.3, 0.4, and
(
0.5% of water. The reactions were run in MultiMax experi-
ments, monitoring heat flow; all these reactions performed
(
4) Hanson, R. M.; Sharpless, K.B. J. Org. Chem. 1986, 51, 1922-1925. Gao,
Y.; Hanson R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K.
B. J. Am. Chem. Soc. 1987, 109, 5765-5780. Wang, Z.M.; Zhou, W.S.
Tetrahedron 1987, 43, 13, 2935-2944.
(5) All compounds in this process are single enantiomers and diastereomers as
shown. Commercial cinnamyl alcohol is typically >99.5% trans.
3
54
•
Vol. 11, No. 3, 2007 / Organic Process Research & Development
10.1021/op700007g CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/23/2007

Scheme 1a
a
Reagents and conditions: (a) L-DIPT, Ti(i-PrO)
4 3 3 2
, TBHP, EtOAc. (b) 2-Ethoxyphenol, NaOH. (c) i. TMSCI, Et N; ii. MsCI, Rt N; iii HCI, H O; iiii. NaOH. (d)
CH
3
OH. (e) CICH COCI, Na CO . (f) t-AmONa. (g) i. Vitride; ii. C H O .
2
2
3
4 6 4
about the same as the reference reaction, containing no
additional water in the TBHP.
Aqueous solutions of NaI, NaCl, KBr, and NaBr with sodium
thiosulfate were used, but even in the presence of carbon
dioxide as a weak acid to enhance reduction of TBHP these
condition gave negative results. TBHP was not effectively
reduced by dimethyl sulfide, DMSO, or by diethylphosphite.
In contrast, trimethylphosphite and triethylphosphite were
found to be very effective at reducing TBHP, and both
exothermically reduced TBHP even at -20 °C to the
corresponding phosphates.
These experiments demonstrate the importance of mo-
lecular sieves in the asymmetric epoxidation reaction since
the calculated amount of water in the reaction solutions
exceeds the equivalents of titanium isopropoxide used. For
optimal reaction performance, 10 mol % titanium isopro-
poxide and 15 mol % of DIPT were used. Two equivalents
of TBHP were needed for this reaction to go to 97%
completion in 3 h. An unexpected result from these experi-
ments was the observation of a significant induction period
and exotherm at the outset of the TBHP addition. To maintain
process control, a portion of the TBHP was added initially.
The addition was stopped until the exotherm was observed,
and the TBHP was then added slowly, maintaining the
reaction temperature below -15 °C.
In situ reactions of Sharpless epoxidation products are
6
well-known; however, the procedures invariably involve a
hydrolysis step to destroy the phosphates and phosphites
before product isolation. We found that 4 crystallized from
MTBE-isooctane without hydrolyzing the phosphate. In-
termediate 4 is soluble in both trimethylphosphate and
triethylphosphate. Since triethyl phosphate is miscible with
isooctane while trimethylphosphate is immiscible, trieth-
ylphosphite was chosen as the TBHP quench reagent. Crude
4 was concentrated to oil still containing triethylphosphite,
and isooctane or branched octanes were added to cause
product crystallization. After a short stir period, 4 crystallized
as an easily stirrable slurry. The solids were filtered and
recrystallized from MTBE. This produced small, easily
filtered white crystals of 4 in 48% yield from cinnamyl
alcohol and with 98% ee. 4 could be further upgraded by
recrystallization to >99% ee.
Because the physical properties of the (S,S)-enantiomer
of 4 vary significantly from the racemic diol, modifications
were made to the racemic reboxetine process. In the reaction
leading to the formation of 5, ethyl acetate was replaced with
methylene chloride due to the low solubility of 4 in EtOAc.
In the original process the crude free base of 6 was converted
to its mesylate salt before it was crystallized, but in the (S,S)
process 6 was crystallized from an EtOAc-heptane mixture
as a free base, eliminating two chemical steps.
The quench to destroy the excess TBHP was critical. The
II
standard TBHP quench with Fe sulfate was unsuitable for
this application due to epoxide decomposition. Under these
quench conditions, the mixture became acidic, leading to
decomposition of the very acid-sensitive epoxide; the pH of
II
the Fe sulfate solution by itself was initially about 3.5 and
dropped to 1.5 after the quench.
A search for a new quenching reagent was done. The main
difficulty in evaluating TBHP quenches is the fact that TBHP
is not effectively detected by standard peroxide test strips.
Iodometric titration, although effective at determining TBHP
concentration, lacks adequate sensitivity at <100 ppm level.
We found that 4-aminophenol is a very sensitive TBHP color
indicator at ppm level; after reaction mixtures are resolved
on TLC plates, it stains the TBHP spot pink.
A variety of reducing agents were examined. Aqueous
sodium thiosulfate and sodium sulfite gave only a slight
II
reduction of the TBHP concentration. Fe salts of weak
II
organic acids were also considered: Fe oxalate was tried,
but its poor solubility in water precludes its use. Conditions
resembling the peroxide titration procedure were also tried.
(
6) Ko, S. Y.; Sharpless, K. B. J. Org. Chem. 1986, 51, 5413-5415. Klunder,
J. M.; Ko, S. Y.; Sharpless, K. B. J. Org. Chem. 1986, 51, 3710-3712.
Vol. 11, No. 3, 2007 / Organic Process Research & Development
•
355

Scheme 2a
<10% overall yield via resolution. The asymmetric process
described reduces solvent use and waste generation by
approximately 50% compared to the resolution route to (S,S)-
reboxetine, resulting in a greener process.
Experimental Section
Materials were obtained from commercial suppliers and
used without purification. Melting points were run in open
tube capillaries and are uncorrected. IPA refers to 2-propanol;
MTBE refers to methyl-tert-butyl ether. NMR spectra were
a
Regents and conditions: (a) t-AmONa.
Rationalization of the process for the conversion of 6 to
reboxetine was examined. The process currently used was a
relic of the original racemic process, which was not
substantially changed when the process was redeveloped. It
used two reactive solvents (dimethyl carbonate and IPA),
had multiple solvent exchanges, proceeded in relatively low
overall yield, and gave 7 that was darkly colored, requiring
a carbon treatment for decolorization of the final product.
Changing the solvent for the acylation from dimethyl
carbonate to methylene chloride improved the workability
but still gave 7 that was highly colored with multiple
impurities. The colored impurities presumably arise from the
polymerization of chloroketene formed by reaction of chlo-
roacetyl chloride and triethylamine. Acylation under Schot-
1
run on Varian INOVA operating at 400 MHz for H and
1
3
1
00 MHz for C. Mass spectra were recorded on a
Micromass Platform LC mass spectrometer.
2S,3R)-3-(2-Ethoxyphenoxy)-2-hydroxy-3-phenyl-1-
(
propanol (4). Cinnamyl alcohol (150 g, 1.12 mol), 60 g of
activated 4Å molecular sieves, and methylene chloride (2.25
L) were charged to a 5 L, three-necked, jacketed flask
equipped with a mechanical stirrer and a 500-mL addition
funnel. D-DIPT (39 g, 0.17 mol) was added to the flask via
syringe, and the mixture was cooled to -15 to -20 °C. When
the temperature was below -15 °C, Ti(OiPr)
mol) was added via a syringe. The mixture was stirred for
0 min, maintaining the reaction temp at -20 °C to -25
4
(33.2 mL, 0.11
3
2 3
ten-Baumann conditions (aqueous Na CO -toluene) gave
7
°C. TBHP solution (500 mL, 4.47 M, 2.24 mol) in isooctane
a clean reaction and eliminated the formation of highly
colored byproducts. The reaction started with a slurry of 6
and went to completion in essentially quantitative yield to
give a colorless 7.
was added to the addition funnel. After about 20% of the
TBHP solution had been added, an exothermic reaction was
noted, and the addition was stopped. The solution exothermed
to about -12 °C (from -20 °C), and then the temperature
fell. After the temperature of the reaction mixture was again
Step 7 was run in the racemic process with t-BuOK in
IPA. With purified 7, reactions were done with t-BuOK in
THF, KHMDS in toluene, and sodium tert-amylate in
toluene. All of these reactions performed well. Since the 8
reduction was performed in toluene, sodium tert-amylate in
toluene was selected for a further study. A temperature study
showed that an impurity increases as the reaction temperature
increases. This was isolated and shown to be the tert-amylate
displacement product (Scheme 2). In practice, the 7 solution
was dried by azeotropic distillation and taken directly into
the cyclization step to produce 8. After an aqueous workup,
the toluene solution of 8 was used directly in the Vitride
step.
No changes were made to the Vitride reduction (step 9)
except that the carbon treatment was omitted since the
material was already colorless. Formation of the succinate
salt was done after solvent exchange from toluene to IPA.
Only one crystallization was required to obtain 1 of very
high purity in 55% overall yield from 6, and intermediate
isolation of the methanesulfonate salt was found to be
unnecessary.
-20 °C, addition of the TBHP solution was resumed. Total
time for addition of the TBHP solution was about 90 min.
The reaction mixture was stirred for 3 h at about -20 °C.
When the reaction was complete, P(OEt) (210 mL, 1.23
3
mol) was added slowly, allowing the mixture to exotherm
to +20 °C. The mixture was filtered through a Celite 545
cake. The filtered solution of 3 was used immediately in the
next step.
Sodium hydroxide (49.2 g, 1.23 mol), tetrabutylammo-
nium chloride (15.53 g, 0.056 mol), 2-ethoxyphenol (169.9
g, 1.23 mol), and 1080 mL of water were charged to a 5-L
three-necked round-bottom flask. The solution of 3 from
above was added, and the mixture was gradually heated to
distill the methylene chloride. The distillation was continued
until the internal temperature was 65 °C. Heating was
continued for 3 h after completion of the methylene chloride
removal.
The mixture was cooled to 30 °C, MTBE (1.5 L) was
added, and the mixture was stirred for 30 min. The phases
were separated, and the organic layer was washed with 1 M
NaOH solution (2 × 1 L). The organic layer was washed
with 1 L of water and with 1 L of brine. The solution was
heated to reflux with an attached Dean-Stark trap and
refluxed until the KF was <1%. The solution was distilled
Conclusion
An efficient enantioselective process for the synthesis of
S,S)-reboxetine was developed. The conditions for the key
(
asymmetric epoxidation were optimized and defined. The
processing for the remaining steps was simplified and
streamlined to allow efficient processing. (S,S)-Reboxetine
succinate was produced with high chemical and enantiomeric
purity. The overall yield of (S,S)-reboxetine succinate by this
process is about 19% from cinnamyl alcohol, compared to
(7) Caution: A serious explosion occurred during engineering development of
this process when TBHP was dried by azeotropic distillation using the
4
published procedure. The explosion is believed to have been caused by an
inadvertent heating of a very concentrated TBHP solution. The use of
commercial anhydrous TBHP solutions in hydrocarbons or material dried
over molecular sieves is recommended.
356
•
Vol. 11, No. 3, 2007 / Organic Process Research & Development

until about 950 mL of distillate was collected. Isooctane (200
mL) was added, and the solution was cooled to about 20
was cooled, and 340 mL of methylene chloride was added.
The aqueous phase was extracted with methylene chloride
(2 × 150 mL). The organic phases were combined and
distilled atmospherically to a final volume of 450 mL.
Methylene chloride (250 mL) was added, and the organic
phase was washed with 375 mL of water. HCl (375 mL, 0.5
M) was added. The phases were separated, and the aqueous
phase was washed with 70 mL of methylene chloride. The
pH of the aqueous was adjusted to greater than 12 with 50%
aqueous NaOH. The mixture was extracted with methylene
chloride (2 × 100 mL). The organic solution was distilled
to an oil, and then 116 mL of EtOAc followed by 116 mL
of heptane was added to the flask. The mixture was heated
to dissolve the material and then cooled to rt to crystallize.
Heptane (116 mL) was added and the slurry cooled to -15
°C. The solids were filtered and dried with rt nitrogen to
yield 23.8 g, 60% overall from 4; mp 98.8-100.5 °C (lit.
°
C. Once crystallization had initiated, 700 mL of isooctane
was added in portions. The slurry was cooled to -20 °C.
The solids were filtered and washed with 500 mL of
isooctane. The solids were redissolved in 300 mL of MTBE
with heating. The solution was cooled to rt. Isooctane (400
mL) was added in portions, the slurry was cooled to -15
°
C, and the solids were filtered, washed with 300 mL of
isooctane, and dried with rt nitrogen. Yield of 4: 187.3 g,
(
(
58%) mp 93.5-95.1 °C (lit. mp 87-89 °C).3 H NMR
399.76 MHz, CDCl ) δ 0.09 (s, 9H), 1.48 (t, J ) 7.0 Hz,
H), 3.23-3.26 (m, 1H), 3.63-3.70 (m, 1H), 3.86-3.98 (m,
1
3
3
2
6
7
6
1
H), 4.1 (q, J ) 7.0 Hz, 2H), 5.25 (d, J ) 4.1 Hz, 2H),
.61-6.4 (m, 1H), 6.68-6.74 (m, 1H), 6.86-6.92 (m, 2H),
.27.7.42 (m, 5H). 13C NMR (100.53 MHz, CDCl
) δ 15.0.
3
2.4, 64.4, 74.6, 86.3, 112.8, 116.5, 121.0, 122.59, 126.66,
28.3, 128.9, 138.19, 147.3, 149.3. LRMS-APCI m/z calcd
3
1
mp 97-99 °C). H NMR (400.13 MHz, CDCl ) δ 1.49 (t,
3
+
for C17
1
C, 70.68; H, 7.02. [R]
+
H
21
O
4
(M + H) : 289. Found: m/z ) 289 [M +
J ) 7.0 Hz, 3H), 2.56 (dd, J ) 13.0, 6.4 Hz, 1H), 2.66 (dd,
J ) 13.0, 3.5 Hz, 1H), 3.94 (m, 1H), 4.1 (t, J ) 7.0 Hz,
2H), 4.75 (d, J ) 8 Hz, 1H), 4.58 (d, J ) 8.2 Hz, 1H), 6.60-
+
] . Anal. Calcd for C17
H O
20 4
: C, 70.81; H, 6.99. Found:
32.8
o
20
D
+18.98 (c 0.5, EtOH); (lit [R]
7.8° (c 1, EtOH)). Chiral HPLC: Chiracel OD-H; 90:10
hexanes-IPA; 1 mL/min; 215 nm; 2R,3S 5.9 min; 2S,3R
D
3
13
6.93 (m, 4H), 7.31-7.39 (m, 5H); C NMR (100.53 MHz,
CDCl ) δ 15.07, 43.42, 64.48, 76.92, 87.94, 113.17, 119.82,
3
5
.3 min.
121.07,123.53,127.50,128.55, 128.82, 138.98, 148.34, 150.27.
+
(2S,3S)-3-Amino-1-(2-ethoxy-phenoxy)-1-phenylpropan-
LRMS-APCI m/z calcd for C17
H
21NO
3
(M + H) : 364.
+
2-ol (6). Intermediate 4 (40.0 g, 0.138 mol), triethylamine
Found: m/z ) 364 [M + 1] . Anal. Calcd for C17
H21NO
3
:
(
17.0 g, 0.168 mol, 23.4 mL), and 400 mL of methylene
C, 71.06; H, 7.37; N, 4.87. Found: C, 70.94; H, 7.48; N,
3
2.4
20
chloride were charged to a 1-L, three-necked Morton flask.
The solution was cooled to about -20 °C. Chlorotrimeth-
ylsilane (16.0 g, 0.147 mol) was dissolved in 28 mL of
methylene chloride, and this solution was added to the 4
solution, keeping the internal temperature below -15 °C.
After the addition was complete, the mixture was stirred for
4.80. [R]
EtOH)).
D
+41.0° (c 0.5 EtOH); (lit. [R]
D
+34.4° (c 1,
3
(2S,3S)-Reboxetine Succinate (9). Intermediate 6 (20.0
g, 0.069 mol) was slurried in 200 mL of toluene. A solution
of sodium carbonate (14.7 g, 0.139 mol) in 74 mL of water
was added, and the mixture was cooled to 5 °C. Chloroacetyl
chloride (13.36 g, 0.118 mol, 9.4 mL) was dissolved in 66
mL of toluene, and this solution was added to the slurry over
1 h. The mixture was stirred at about 5 °C. When the reaction
was complete, 200 mL of water was added, and the mixture
1
5 min when the temperature reached less than -15 °C.
Methanesulfonyl chloride (19.5 g, 0.17 mol, 13.2 mL)
was added to the solution, keeping the temperature between
20 and -15 °C. Triethylamine (14.1 g, 0.14 mol, 19.5 mL)
-
o
was, added keeping the temperature below -15 °C. The
mixture was stirred for 15 min after completion of triethyl-
amine addition. HCl (141 mL, 1 M) was added to the
mixture, which was allowed to warm to rt and was stirred
until the hydrolysis was complete (about 3 h). The phases
were separated, and the organic phase was washed with 131
mL of 5% (w/v) solution of sodium bicarbonate.
was heated to 50 C. The phases were separated, and the
organic phase was washed with water (200 mL) and brine
(200 mL). The solution was distilled under vacuum until the
KF was LT 0.20%. The total volume was adjusted to 150
mL with toluene.
Sodium tert-amylate (14.97 g, 0.135 mol) was dissolved
in 247 mL of toluene and the solution cooled to -5 °C. The
toluene solution of 7 was added, maintaining the temperature
of the reaction at NMT -5 °C. When the reaction was
complete, 309 mL of water was added and the mixture stirred
10 min. The phases were separated, and the organic phase
washed with water (2 × 309 mL). The solution was dried
by distillation. Toluene was added back during the distillation
to maintain a volume of about 120 mL.
Sodium hydroxide (25 g, 0.62 mol), 1.92 g of tetrabutyl-
ammonium chloride, and 100 mL of water were charged to
a 1-L, three-necked Morton flask. The methylene chloride
solution was added, and the mixture was stirred at rt. When
reaction was complete, the phases were separated, and the
aqueous phase was extracted with 100 mL of methylene
chloride. The combined organic phases were washed with
7
6 mL of brine. The organic phase was concentrated to an
Vitride (65 wt %, 102 mL, 0.339 mol) was diluted with
100 mL of toluene and the solution cooled to -10 °C. The
solution of 8 was added at a constant rate to the Vitride
solution, keeping the temperature of the reaction mixture
between 0 to +10 °C. When complete, the reaction was
quenched with 22 mL of 50% NaOH in 184 mL of water.
The mixture was allowed to exotherm to 45-55 °C. The
oil. Methanol (300 mL) was added, and the solution was
again concentrated to an oil.
The oil (5), methanol (280 mL), and concd ammonium
hydroxide (450 mL, 6.75 mol) were charged to a 1-L, one-
neck Ace pressure flask equipped with a magnetic stirrer.
The flask was sealed and heated to 40 °C for 3 h. The mixture
Vol. 11, No. 3, 2007 / Organic Process Research & Development
•
357

phases were separated, and the organic phase was washed
with 5% (w/v) Na CO
mL) was added to the toluene solution, and 8% HCl was
added to give a pH of 3. The phases were separated, and the
aqueous phase was adjusted to pH 10-12 with 10% NaOH.
Toluene (408 mL) was added, and the phases were separated.
145.2-147.1 °C (lit. mp 148 °C).8 1H NMR (400.13 MHz,
CDCl ) δ 1.41 (t, J ) 7.0 Hz, 3H), 2.4 (s, 4H), 2.9-3.06
2
3
solution (3 × 274 mL). Water (335
3
(m, 2H), 3.15-3.22 (m, 2H), 3.81-3.86 (m, 1H), 4.02-
4.09 (m, 3H), 4.17-4.24 (m, 1H), 5.13 (d, J ) 4.3 Hz),
1
3
6.66-6.90 (m, 4H), 7.26-7.39 (m, 5H). C NMR (100.62
MHz, CDCl ) δ 15.08, 31.89, 43.24, 44.84, 64.72, 76.91,
3
The organic phase was washed with 5% Na
2
CO
3
solution
82.91, 113.94, 118.27, 121.1, 127.38, 128.66, 136.94, 149.8,
+
(
3 × 100 mL) and then with water (100 mL). The organic
178.73. LRMS-APCI m/z calcd for C19
314. Found: m/z ) 314 [M + 1] . Anal. Calcd for C19
H
23NO
3
(M + H) :
+
phase was concentrated to an oil (9) under vacuum at 65 °C
bath temperature.
H
23
-
NO
3
4 6 4
-C H O : C, 64.02; H, 6.77; N, 3.25. Found: C, 63.99;
3
2.4
Intermediate 9 was dissolved in 474.6 mL of IPA.
Succinic acid (9.9 g, 0.083 mol) was added to the solution,
and the mixture was heated to about 75 °C and stirred until
the solids dissolved. The solution was cooled to rt and stirred
for 2 h. The solids were filtered, washed with 88.3 mL of
IPA, and dried with rt nitrogen. Yield: 16.4g, 54.6%; mp
H, 6.77; N, 3.16. [R]
D
+17.24° (c 0.5, EtOH).
Acknowledgment
We thank William C. Schinzer and Mike Gangwer for
expert analytical support.
Received for review January 8, 2007.
OP700007G
(8) Zampieri, M.; Airoldi, A.; Martini, A. WO2003/106441, 12/24/03.
358
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Vol. 11, No. 3, 2007 / Organic Process Research & Development