Syntheses of a selective peroxisome proliferator activated receptor modulator and practical new preparations of 2-(4-Alkoxyphenyl) ethylamines t

Article abstract of DOI:10.1021/op800215a

This article describes chemistry that was developed to give access to multigram quantities of the selective peroxisome proliferator activated receptor modulator (SPPARM), compound 1.¹ Fischer esteriflcations, phase transfer-catalyzed alkylations, amide couplings, crystallizations, and a new synthesis were developed to accomplish this task. In addition, an efficient method for preparing 2-(4-alkoxyphenyl) ethylamines 7a - d from tyramine 9 was developed that involves O-alkylation of intermediate Schiff base 11 and subsequent acid-catalyzed hydrolysis to afford the target molecules as crystalline hydrochloride salts.

Full text of DOI:10.1021/op800215a

Organic Process Research & Development 2009, 13, 280–284
Syntheses of a Selective Peroxisome Proliferator Activated Receptor Modulator and
Practical New Preparations of 2-(4-Alkoxyphenyl)ethylamines†
Nicholas A. Magnus,* Bret A. Astleford, John Brennan, James R. Stout, and Roger W. Tharp-Taylor
Eli Lilly and Company, Chemical Product Research and DeVelopment DiVision, Indianapolis, Indiana 46285, U.S.A
Abstract:
obviate the need for chromatography, the cesium carbonate was
replaced with potassium carbonate, and a phase transfer catalyst
(TBAI; tetrabutylammonium iodide) was added to greatly
improve the yield of diester 5. (3) To remove the undesirable
chlorinated solvent from the ionization step in the conversion
of tert-butyl ester 5 into carboxylic acid 6, the dichloromethane
was replaced with toluene. (4) To improve the productivity of
the amide coupling of 6 to give 8, remove the chlorinated
solvent, and simplify the coupling agents and resultant byprod-
ucts, the imidazolide of 6 was generated with 1,1′-carbonyldi-
imidazole (CDI) in EtOAc, and 2-(4-ethoxyphenyl)ethylamine
7b3 introduced to the reaction mixture to give high yields of
amide 8 with low levels of byproducts. The LiOH wet THF
reaction conditions for the hydrolysis of ester 8 to give acid 1,
from the Scheme 1 synthesis, gave a high yield and did not
epimerize the stereocenter, so there was no further development
of this reaction for the Scheme 2 preparation. (5) Last,
compound 1 had previously been isolated as an amorphous
solid, so crystallization conditions from IPA were identified and
developed to ensure control of the purity and potency of the
active pharmaceutical ingredient (API). These process improve-
This article describes chemistry that was developed to give access
to multigram quantities of the selective peroxisome proliferator
activated receptor modulator (SPPARM), compound 1.1 Fischer
esterifications, phase transfer-catalyzed alkylations, amide cou-
plings, crystallizations, and a new synthesis were developed to
accomplish this task. In addition, an efficient method for preparing
2-(4-alkoxyphenyl)ethylamines 7a-d from tyramine 9 was devel-
oped that involves O-alkylation of intermediate Schiff base 11 and
subsequent acid-catalyzed hydrolysis to afford the target molecules
as crystalline hydrochloride salts.
Introduction
The selective peroxisome proliferator activated receptor
modulator (SPPARM), compound 1, was being developed at
Lilly as an orally active compound for the treatment of type 2
diabetes with associated cardiovascular disease.1 The goal for
this SPPARM program was to develop a compound with an
improved clinical profile compared to PPAR agonists currently
on the market.
(1) Ferritto-Crespo, R., Martin Ortega, M. D. (Eli Lilly and Co., U.S.A.).
SelectiVe Peroxisome Proliferator ActiVated Receptor ModulatorsPCT
Int. Appl. WO 2005/061441 A1, 2004.
(2) (a) Haigh, D.; Birrell, H. C.; Cantello, B. C. C.; Hindley, R. M.;
Ramaswamy, A.; Rami, H. K.; Stevens, N. C. Tetrahedron: Asymmetry
1999, 10, 1335–1351. (b) Andersson, K.; Lindstedt Alstermark, E. WO
9962870, 1999. (c) Ebdrup, S.; Deussen, H.-J.; Zundel, M. Process for
the preparation of substituted 3-phenyl-propanoic acid esters and
substituted 3-phenyl-propanoic acids. PCT Appl. WO 0111072, 2001.
(d) Sauerberg, P.; Pettersson, I.; Jeppesen, L.; Bury, P. S.; Mogensen,
J. P.; Wasserman, K.; Brand, C. L.; Sturis, J.; Wo¨ ldike, H. F.; Fleckner,
J.; Andersen, A.-S. T.; Mortensen, S. B.; Svensson, L. A.; Rasmussen,
H. B.; Lehman, S. V.; Polivka, Z.; Sindelar, K.; Panajotova, V.; Ynddal,
L.; Wulff, E. M. J. J. Med. Chem. 2002, 45, 789–804. (e) Deussen,
H. J.; Zundel, M.; Valdois, M.; Lehmann, S. V.; Weil, V.; Hjort, C. M.;
Østergaard, P. R.; Marcussen, E.; Ebdrup, S. Process Development on
the Enantioselective Enzymatic Hydrolyses of the (S)-Ethyl 2-Ethoxy-
3-(4-hydroxyphenyl)propanoate. Org. Process Res. DeV. 2003, 7, 82–
88. (f) Ebdrup, S.; Pettersson, I.; Rasmussen, H. B.; Deussen, H.; Jensen,
A. F.; Mortensen, S. B.; Fleckner, J.; Pridal, L.; Nygaard, L.; Sauerberg,
P. J. Med. Chem. 2003, 46, 1306. (g) Martin, J. A.; Brooks, D. A.;
Prieto, L.; Gonzalez, R.; Torrado, A.; Rojo, I.; Lopez de Uralde, B.;
Lamas, C.; Ferritto, R.; Martin-Ortega, M. D.; Agejas, J.; Parra, F.;
Rizzo, J. R.; Rhodes, G. A.; Robey, R. L.; Alt, C. A.; Wendel, S. R.;
Zhang, T. Y.; Reifel-Miller, A.; Montrose-Rafizadeh, C.; Brozinick,
J. T.; Hawkins, E.; Misener, E. A.; Briere, D. A.; Ardecky, R.; Fraser,
J. D.; Warshawsky, A. M. Bioorg. Med. Chem. Let 2005, 15 (1), 51.
(h) Houpis, I. N.; Patterson, L. E.; Alt, C. A.; Rizzo, J. R.; Zhang,
T. Y.; Haurez, M. Org. Lett. 2005, 7 (10), 1947. (i) Aikins, J. A.;
Haurez, M.; Rizzo, J. R.; Van Hoeck, J.-P.; Brione, W.; Kestemont,
J.-P.; Stevens, C.; Lemair, X.; Stephenson, G. A.; Marlot, E.; Forst,
M.; Houpis, I. N. J. Org. Chem. 2005, 70 (12), 4695. (j) Rizzo, J. R.;
Zhang, T. Y. Chimia 2006, 60 (9), 580.
Results and Discussion
The medicinal chemistry group at Lilly employed the
synthesis depicted in Scheme 1 in order to make multigram
quantities of compound 1 for biological evaluation. This
synthesis had undesirable solvents, reagents, and chromato-
graphic purifications, lacked a final crystallization to efficiently
control the purity of compound 1, and gave an overall yield of
about 47% from the available carboxylate 2.1,2
Due to the interesting biological properties of compound 1,
Lilly scientists required 300 g of this material, and the potential
need for kilogram quantities was apparent. To fund a rapid 300 g
delivery of compound 1, modifications to the Scheme 1
chemistry were identified and made (Scheme 2): (1) The highly
toxic MeI alkylation to prepare ester 3 was replaced with an
acid-catalyzed Fischer esterification employing methanesulfonic
acid (MSA) in MeOH. (2) To improve the productivity of the
alkylation of the phenol moiety of 3 with alkyl bromide 4 and
* Author to whom correspondence may be sent. E-mail: magnus_nicholas@
lilly.com.
† This paper is dedicated to the memory of our friend and former colleague
Dr. Christopher R. Schmid.
(3) Buck, J. S. J. Am. Chem. Soc. 1937, 59, 726.
280
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10.1021/op800215a CCC: $40.75
2009 American Chemical Society
Published on Web 11/07/2008

Scheme 1
Scheme 2
Scheme 3
ments gave an overall yield of 72%, removed the need for
chromatography, and gave high-quality crystalline API, com-
pound 1.
In order to develop a process suitable for preparing kilogram
quantities of compound 1 and meet the cost and efficiency
objectives of a potential manufacturing process, the Scheme 3
synthesis was devised. During the course of investigating the
Scheme 3 chemistry, the multigram (>100 g) supply of 2-(4-
ethoxyphenyl)ethylamine 7b ran out. Over the last century, there
have been numerous accounts of a variety of syntheses of 2-(4-
alkoxyphenyl)ethylamines.4 After review and evaluation of the
literature precedents for preparing 2-(4-alkoxyphenyl)ethyl-
Vol. 13, No. 2, 2009 / Organic Process Research & Development
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281

amines, it was found that the new method of preparation
illustrated in Scheme 3 was the most direct and practical. The
synthesis of 7b began by condensing tyramine 95 with p-
tolualdehyde 10 in refluxing toluene while removing water via
distillation. After slowly cooling the reaction mixture, the
resulting Schiff base 11 was isolated as a crystalline solid in
96% yield. The Schiff base 11 was subsequently dissolved in
a 1 to 1 mixture of DMF and tert-butylmethyl ether (TBME)
and reacted with cesium carbonate and ethyl iodide at 50 °C to
form the corresponding Schiff base ethyl ether 12. After an
aqueous workup, 12 was dissolved in a mixture of IPA and
EtOAc and treated with aqueous HCl to precipitate 7b as a
hydrochloride salt in 91% yield. This technique of preparing
tyramine ether 7b was applied to the preparation of methyl ether
7a (85% yield), isopropyl ether 7c (92% yield), and benzyl ether
7d (92% yield) with good to excellent yields (Scheme 3).
The 2-(4-ethoxyphenyl)ethylamine 7b was reacted in a
Schotten-Baumann amide coupling with chloroacetyl chloride
13 in a dichloromethane lower phase and an aqueous K2CO3
upper phase to afford a 99% yield of amide 14 (Dichlo-
romethane solvent was used for the preparation of amide 14 to
avoid uncontrolled precipitation of the product.). In Scheme 3,
the ester 3 was prepared as before via acid catalysis in MeOH
with the switch made from methanesulfonic acid to the less
expensive sulfuric acid. In addition, a crystallization of ester 3
from TBME and methylcyclohexane was utilized to afford a
77% yield. The amide 14 was reacted with ester 3 under phase
transfer conditions in CH3CN in the presence of K2CO3, KI,
and TBAI to give ether adduct 8 in 89% yield after crystal-
lization from IPA/water. The hydrolysis of ester 8 and final
crystallization from IPA to afford 1 were not changed from
the Scheme 2 synthesis. In the Scheme 3 chemistry, the
expensive chiral carboxylate 2 underwent two transformations
instead of the previous four (Schemes 1 and 2) to arrive at the
ester 8, which is an ester hydrolysis removed from the API,
compound 1.
amide couplings, crystallizations, and the design and demonstra-
tion of a new synthesis. In addition, new efficient methods for
preparing 2-(4-alkoxyphenyl)ethylamines were developed in
order to accomplish this task.
Experimental Section
HPLC Methods. Column: Chromolith Performance RP-18
4.6 mm × 100 mm. Flow: 5 mL/min. Wavelength: 230 nm.
Solvent A: 0.05% trifluoroacetic acid in acetonitrile. Solvent
B: 0.1% trifluoroacetic acid in water.
Gradient
time (min)
A%
B%
0
10
10
90
90
10
10
90
90
10
10
90
90
1
7
8
9
10
Retention times
compd
time (min)
1
3.6-3.8
1.0-1.1
2.2-2.3
0.7-0.9
4.2-4.3
3.3-3.5
2
3
7b
8
14
Chiral HPLC method (used for chiral separation of 1).
Column: Chiralpak AD, 0.46 cm × 25 cm. Flow: 1.0 mL/min.
Wavelength: 270 nm. Eluent: heptane/isopropanol/trifluoroacetic
acid, 80/20/0.1
Retention time
cmpd
time (min)
1
9.5-9.7
Experimental Procedures. (S)-Methyl 3-(4-hydroxyphenyl)-
2-methoxypropanoate (3). Fischer esterification was done with
sulfuric acid. Under a nitrogen atmosphere, carboxylate 2 (750.0
g, 3.44 mol, 99.9% ee) and MeOH (4050 mL) were combined
at 23 °C, and sulfuric acid (269.7 g, 2.75 mol) was slowly added
to the resulting mixture (an exotherm from 22 to 36 °C occurred
during this addition). The reaction was heated to 40 °C, and
held for 3 h. Analysis by HPLC indicated that 2.9% of 2
remained. The reaction mixture was cooled to 23 °C and slowly
quenched into saturated sodium bicarbonate solution (4000 mL)
while monitoring the pH to ensure basicity was maintained (the
final pH was 7.8). TBME (4050 mL) and water (4000 mL)
were added to the mixture and the layers separated. The
resulting aqueous layer was extracted again with TBME (4000
mL). The TBME layers were combined and washed with
saturated sodium chloride solution (4000 mL), followed by
water (4000 mL). The organic phase was concentrated under
vacuum at 32 °C to remove ∼2500 mL of distillate. Methyl-
cyclohexane (3.5 L) was then added to the organic mixture at
a rate comparable to the rate of distillate removal. With a final
solvent ratio of methylcyclohexane (3500 mL) to TBME (1950
mL), the product had separated as an oil. Seed crystals were
Conclusion
In short, an efficient and “scalable” synthesis of the SP-
PARM compound 1 was achieved. This involved developing
Fischer esterifications, phase transfer-catalyzed alkylations,
(4) Methods and references for preparing 2-(4-alkoxyphenyl)ethylamines:
(a) Oxime reduction: Rosenmund, K. W. Chem. Ber 1909, 42, 4779.
(b) Cyanohydrin reduction: Kindler, K. Arch. Pharm. 1931, 70, 76. (c)
Azide reduction: Battersby, A. R.; Ewan, J. T.; Staunton, J. J. Chem.
Soc., Perkin Trans. 1 1980, 31. (d) Nitrile reduction: Barton, D. H. R.;
Kirby, G. W.; Taylor, J. B.; Thomas, G. M. J. Chem. Soc. 1963, 4545.
(e) Friedel-Crafts with methoxybenzene and aziridine: Bras, G. I.
Doklady Akad. Nauk SSSR 1952, 87, 589; Chem. Abstr. 1954, 113. (f)
Curtius rearrangement: Oesterlin, M. Angew. Chem. 1932, 45, 536. (g)
1-Alkoxy-4-(2-nitro-vinyl)benzene reduction (hydrogenation): Skita, A.;
Keil, F. Chem. Ber. 1932, 429. Kindler, K.; Brandt, E. Arch. Pharm.
1935, 478, 482. LiAlH4: Klemm, L. H.; Mann, R.; Lind, C. D. J. Org.
Chem. 1958, 23, 349. Bernstein, J.; Yale, H. L.; Losee, K.; Holsing,
M.; Martins, J.; Lott, W. A. J. Am. Chem. Soc. 1951, 73, 906. (h)
Hofman rearrangement: Barger, G.; Walpole, G. S. J. Chem. Soc. 1909,
95, 1722. Callow, R. K.; Gulland, J. M.; Haworth, R. D. J. Chem. Soc
1929, 1448. Kindler, K. Arch. Pharm. 1931, 70, 76. Buck, J. S. J. Am.
Chem. Soc. 1931, 53, 2192.
(5) (a) Tyramine 9 via decarboxylation of tyrosine: Barger, G.; Walpole,
G. S. Chem. Zentralbl. 1909, 80, 1591. (b) Schmitt, R.; Nasse, O. Justus
Liebigs Ann. Chem. 1865, 133, 214. (c) Nakazawa, H.; Sano, K.;
Matsuda, K.; Mitsugi, K. Biosci. Biotechnol. Biochem 1993, 57 (7),
1210.
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added at 43 °C, which caused nucleation to occur, and the
resulting mixture was slowly cooled to 23 °C. The colorless
crystalline product was collected by filtration, washed with
methylcyclohexane (500 mL), and vaccuum-dried at 30 °C over
6 h to a constant weight. The product 3 was afforded in 77.3%
yield (558.6 g). HPLC assay of the product 3 indicated 99.8
500 mL. After cooling the mixture to 25 °C, a thick slurry
formed, and 37% aqueous hydrochloric acid (40.96 g) and
EtOAc (100 mL) were added. After 4 h, the reaction mixture
was cooled to 0-5 °C, stirred at that temperature for 1 h, and
filtered. The isolated solid was washed with cold IPA (500 mL)
and TBME (300 mL) and then vaccuum dried at 40 °C to afford
7b as a white crystalline solid (77.36 g, 91.8% yield). Mp
203.3-204.1 °C; IR (KBr pellet) 3447, 2979, 2937, 2890, 2781,
2723, 2050, 1609, 1581, and 1514 cm-1. 1H NMR (DMSO-d6,
400.0 MHz) δ 1.26 (3H, t, J ) 7.1 Hz), 2.76-2.80 (2H, m),
2.89-2.94 (2H, m), 3.95 (2H, q, J ) 7.1 Hz), 6.82 (2H, d, J )
4.4 Hz), 7.11 (2H, d, J ) 4.4 Hz), 8.10 (3H, bs). 13C NMR
(DMSO-d6, 100 MHz) δ 15.1, 32.5, 63.4, 114.9, 129.6, 130.1,
157.7. HRMS (AP+; accurate mass) calcd for C10H16NO
166.1226, found 166.1226. Anal. Calcd for C10H15NO: C, 59.55;
H, 8.00; N, 6.94. Found: C, 59.52; H, 7.81; N, 7.01.
area %, and 100.0% ee. Mp 85.5-86.1 °C; [R]22.3 -13.6 (c
D
) 5.0 MeOH); IR (KBr pellet) 3329, 3023, 3001, 2955, 2926,
2837, 1740, 1614, 1519, and 1517 cm-1. 1H NMR (DMSO-d6,
400.0 MHz) δ 2.74-2.78 (2H, m) 3.18 (3H, s), 3.57 (3H, s),
3.92 (1H, dd, J ) 5.7, 7.5 Hz), 6.60 (2H, d, J ) 8.4 Hz), 6.92
(2H, d, J ) 8.4 Hz), 9.15 (1H, s). 13C NMR (DMSO-d6, 100
MHz) δ 37.9, 51.9, 57.8, 81.4, 115.4, 127.2, 130.6, 156.4, 172.4.
HRMS (AP+; accurate mass) calcd for C11H15O4 211.0963,
found 211.0965. Anal. Calcd for C11H14O4: C, 62.85; H, 6.71.
Found: C, 63.08; H, 6.75.
4-(2-(4-Methylbenzylideneamino)ethyl)phenol (11). Under a
nitrogen atmosphere, tyramine 9 (470.0 g, 3.426 mol) and
toluene (7.0 L) were combined, and the resulting slurry was
heated to 82 °C. p-Tolualdehyde 10 (444.6 g, 3.700 mol) was
added over 53 min. to the reaction mixture with continued
heating to reflux. Over an additional 40 min., the temperature
of the reaction mixture increased to 111 °C, while toluene and
water were removed by atmospheric distillation. A total of 1570
mL of distillate was collected. The amount of water collected
was 60 mL (Theory ) 61.7 mL). The reaction mixture was
cooled to 33 °C over 4.25 h, and an ice bath was used to further
cool the slurry to 0-5 °C. After stirring at 0-5 °C for 1 h, the
mixture was filtered, a toluene (1.5 L, 5 °C) wash was utilized,
and drying was achieved under vacuum at 50 °C to afford 11
(789.0 g, 96.2% yield, GC assay 99.6 area %) as a white
crystalline solid. Mp 178.4-180.5 °C; IR (KBr pellet) 3436,
2-Chloro-N-(4-ethoxyphenethyl)acetamide (14). Under a
nitrogen atmosphere, 2-(4-ethoxyphenyl)ethanamine hydro-
chloride 7b (275.0 g, 1.36 mol), potassium carbonate (305.3 g,
2.21 mol), DCM (1650 mL), and water (825 mL) were
combined. The resulting mixture was cooled to about 5 °C, and
a solution of choroacetyl chloride 13 (188.6 g, 1.64 mol) in
DCM (290 mL) was slowly added to the reaction. During the
addition, the temperature increased due to the exothermic nature
of the reaction. When the reaction temperature exceeded 10
°C, gas evolution was observed, so that the addition rate was
adjusted to maintain controllable off-gassing, which encom-
passed a total of 71 min. with a peak temperature of 12 °C.
The clear, biphasic mixture was allowed to stir for nearly 2.5 h,
and the temperature increased to 18 °C (HPLC analyses
indicated no starting 7b in the aqueous layer and 99.1 area %
14 in the organic layer). Water (100 mL) and DCM (250 mL)
were used to aid the transfer of the reaction for phase separation.
The organic layer was washed with water (1000 mL) and
concentrated under vacuum at 40 °C. DCM (1000 mL) was
added to the mixture for a subsequent concentration at 40 °C
to azeotropically remove residual water. The amide 14 was
isolated in 99.9% yield (329.1 g) with a purity of 99.1 area %
by HPLC. Mp 97.9-99.0 °C; IR (KBr pellet) 3438, 3258, 3083,
2987, 2976, 2933, 2886, 2859, 1683, 1650, 1564, and 1513
1
2920, 2887, 2853, 1648, 1609, and 1514 cm-1. H NMR
(DMSO-d6, 400.0 MHz) δ 2.29 (3H, s), 2.74 (2H, t, J ) 7.5
Hz), 3.67 (2H, t, J ) 7.5 Hz), 6.61 (2H, d, J ) 4.4 Hz), 6.98
(2H, d, J ) 4.4 Hz), 7.19 (2H, d, J ) 7.4 Hz), 7.55 (2H, d, J
) 7.4 Hz), 8.45 (1H, s), 9.09 (1H, bs). 13C NMR (DMSO-d6,
100 MHz) δ 21.5, 36.6, 63.0, 115.4, 128.2, 129.7, 130.1, 130.4,
134.0, 140.7, 155.9, 161.1. HRMS (AP+; accurate mass) calcd
for C16H18NO 240.1381, found 240.1383. Anal. Calcd for
C16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C, 80.43; H,
7.25; N, 5.98.
1
cm-1. H NMR (DMSO-d6, 400.0 MHz) δ 1.26 (3H, t, J )
7.1 Hz), 2.62 (2H, t, J ) 7.3 Hz), 3.23 (2H, dt, J ) 7.3, 5.7
Hz), 3.93 (2H, q, J ) 7.1 Hz), 3.98 (2H, s), 6.79 (2H, d, J )
4.4 Hz), 7.10 (2H, d, J ) 4.4 Hz), 8.21 (1H, t, J ) 5.7 Hz). 13C
NMR (DMSO-d6, 100 MHz) δ 15.1, 34.4, 41.2, 43.1, 63.3,
114.7, 130.0, 131.3, 157.4, 166.2. HRMS (AP+; accurate mass)
calcd for C12H17NO2 242.0941, found 242.0942. Anal. Calcd
for C12H16ClNO: C, 59.63; H, 6.67; N, 5.79. Found: C, 59.61;
H, 6.68; N, 5.90.
2-(4-Ethoxyphenyl)ethanamine Hydrochloride (7b). Under
a nitrogen atmosphere, 11 (100.0 g, 0.42 mol), cesium carbonate
(204.2 g, 0.63 mol), DMF (350 mL), and TBME (350 mL)
were combined. The resulting mixture was warmed to 40 °C,
and iodoethane (69.8 g, 0.45 mol) was added over 15 min. The
temperature was increased to 50-53 °C, and after 4 h, the
1
reaction was determined to be complete by H NMR. After
cooling the reaction mixture to 20-30 °C, purified water (450
mL) was added slowly, keeping the temperature below 30 °C.
TBME (225 mL) was added to the reaction mixture, and the
layers were separated. The organic layer was washed with
purified water (100 mL) and concentrated in Vacuo to about
one-third of its original volume. IPA (500 mL) was added to
the mixture, followed by concentration in Vacuo until 500 mL
of distillate was collected. IPA (800 mL) was added to the
mixture, followed again by concentration to a final volume of
(S)-Methyl 2-Ethoxy-3-(4-(2-(4-ethoxyphenethylamino)-2-
oxoethoxy)phenyl)propanoate (8). Under a nitrogen atmosphere,
14 (250.0 g, 1.03 mol), 3 (217.0 g, 1.03 mol), potassium
carbonate 325 mesh (290.0 g, 2.10 mol), potassium iodide (86.0
g, 0.52 mol), tetrabutylammonium iodide (58.0 g, 0.16 mol),
and CH3CN (625 mL) were combined. The resulting mixture
was heated to 55-60 °C for 24 h, and allowed to cool to 23
°C (HPLC analysis indicated 95.1 area % 8, 1.6 area % 3, and
1.0 area % 1). The mixture was cooled to 10-15 °C, and 2 N
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HCl (620 mL) added, while maintaining the temperature below
25 °C. EtOAc (1000 mL) was added, and a final pH adjustment
to 7.2 with 2 N HCl (620 mL) was made. The layers were
separated, and the aqueous layer was extracted with EtOAc (250
mL). The organic layers were combined and concentrated under
vacuum at 45-50 °C to a weight of 525.5 g. EtOAc (625 mL)
was added, followed by a second concentration to eliminate
residual CH3CN. The remaining residue was dissolved in EtOAc
(2000 mL) and water (1250 mL) added. The layers were
separated, and the organic layer was washed with water (1250
mL). The resulting organic layer was concentrated under
vacuum at 45-50 °C to 497.8 g, which was then dissolved in
IPA (625 mL) and concentrated again to displace residual
EtOAc. The resulting residue was dissolved in IPA (1250 mL)
and water (500 mL), and the mixture was seeded with 8 at 23
°C. Nucleation occurred, and additional water (750 mL) was
added over 1 h, and the slurry stirred for another 3 h. After
cooling to 0-5 °C and stirring for 2 h, the product 8 was
collected by filtration. Three washes were applied to the filter
cake (2 × 305 mL of 2:1 water/IPA and 1 × 610 mL water;
all precooled to 0-10 °C). Vacuum drying at 45-50 °C to a
constant weight resulted in an isolated yield for 8 of 386.4 g
(89.9% yield) as a white crystalline solid. The HPLC purity of
compound 8 was 99.7 area %. Mp 67.8-68.0 °C; [R]22.3D -7.60
(c ) 5.0 MeOH); IR (KBr pellet) 3424, 3347, 3077, 3038, 2973,
2955, 2918, 2873, 1755, 1656, 1543, and 1513 cm-1. 1H NMR
(DMSO-d6, 400.0 MHz) δ 1.26 (3H, t, J ) 7.1 Hz), 2.63 (2H,
t, J ) 7.3 Hz), 2.77-2.88 (2H, m), 3.18 (3H, s), 3.24-3.29
(2H, m), 3.58 (3H, s), 3.94 (2H, q, J ) 7.1 Hz), 3.95-3.99
(1H, m), 4.36 (2H, s), 6.78 (4H, d, J ) 6.6 Hz), 7.04 (2H, d,
J ) 8.8 Hz), 7.06 (2H, d, J ) 8.8 Hz), 8.02 (1H, t, J ) 5.7
Hz). 13C NMR (DMSO-d6, 100 MHz) δ 15.1, 34.7, 37.8, 51.9,
57.8, 63.3, 67.4, 81.2, 114.7, 114.8, 129.9, 130.0, 130.6, 131.4,
156.8, 157.4, 168.0, 172.3. HRMS (AP+; accurate mass) calcd
for C23H30NO6 416.2071, found 416.2068. Anal. Calcd for
C23H29NO6: C, 66.49; H, 7.03; N, 3.37. Found: C, 66.62; H,
7.03; N, 3.49.
(50 mL), while maintaining the temperature between 15-25
°C. EtOAc (8.0 L) was added to the mixture and the pH reduced
to 2.1 with 5 N HCl (532 mL). The aqueous layer was separated
and extracted with EtOAc (8.0 L). The combined organic layers
were washed with water (2 × 2.0 L) and concentrated under
vacuum at 35-40 °C. IPA (2.0 L) was added to the mixture,
the temperature increased to 45-50 °C, and the reduced
pressure concentration continued to give 1 as a crude solid. The
crude solid 1 was suspended in IPA (3.5 L), and the resulting
slurry heated to give a solution at 69 °C. The resulting mixture
was cooled to 57-58 °C, seeded, and slowly cooled to 0-5
°C. After stirring for 1-2 h at 0-5 °C, the resulting slurry was
filtered and washed with cold IPA (600 mL, 0-5 °C). The acid
1 was produced as a white crystalline solid that was dried under
vacuum at 40-45 °C to a constant weight of 930.6 g (96%
yield). HPLC: 99.8 area %; 99.8 wt %; ee > 99.9%. Mp
126.6-127.2 °C. [R]22.3 -13.21 (c ) 5.0 MeOH); IR (KBr
D
pellet) 3389, 3368, 3065, 3023, 2972, 2929, 2871, 2820, 1733,
1631, 1553, and 1511 cm-1. 1H NMR (DMSO-d6, 400.0 MHz)
δ 1.26 (3H, t, J ) 7.1 Hz), 2.63 (2H, t, J ) 7.5 Hz), 2.77 (1H,
dd, J ) 7.9, 14.1 Hz), 2.87 (1H, dd, J ) 4.9, 14.1 Hz), 3.18
(3H, s), 3.25-3.30 (2H, m), 3.84 (1H, dd, J ) 4.9, 7.9 Hz),
3.94 (2H, q, J ) 7.1 Hz), 4.37 (2H, s), 6.78 (4H, d, J ) 6.2
Hz), 7.04 (2H, d, J ) 8.8 Hz), 7.09 (2H, d, J ) 8.8 Hz), 8.02
(1H, t, J ) 5.7 Hz), 12.66 (1H, s). 13C NMR (DMSO-d6, 100
MHz) δ 15.1, 34.7, 37.8, 57.7, 63.3, 67.4, 81.2, 114.7, 114.8,
130.0, 130.5, 130.6, 131.4, 156.8, 157.4, 168.0, 173.4. HRMS
(AP+; accurate mass) calcd for C22H28NO6 402.1918, found
402.1911. Anal. Calcd for C22H27NO6: C, 65.82; H, 6.76; N,
3.49. Found: C, 65.90; H, 6.76; N, 3.63.
Acknowledgment
We thank Eric P. Seest of the chromatography laboratory
at Eli Lilly for developing chiral assays. We also thank Duane
A. Pierson and David K. Robbins of the API Route Selection
Analytical Laboratory and Richard M. Kattner of the Analytical
Testing Laboratory at Eli Lilly for developing ppm level assays.
(S)-3-(4-(2-(4-ethoxyphenethylamino)-2-oxoethoxy)phenyl)-
2-methoxypropanoic Acid (1). Under a nitrogen atmosphere, 8
(1.0 kg, 2.41 mol), THF (8.0 L), and water (5.0 L) were
combined, and an aqueous solution of lithium hydroxide (63.4
g, 2.65 mol in 3.0 L of water) was charged to the reaction
mixture at 15-25 °C over 19 min. After 1 h, HPLC indicated
0.6% 8. TBME (8.0 L) was added to the reaction mixture and
the organic phase was separated. The resulting aqueous layer
was washed two more times with TBME (2 × 4.0 L). The pH
of the mixture was lowered to 6.4 by the addition of 5 N HCl
Supporting Information Available
Experimental procedures and spectral data for compounds
3 (prepared with methanesulfonic acid in MeOH), 5, 6, 8
(prepared via CDI coupling of 6 and 7b), 7a, 7c, and 7d. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Received for review September 3, 2008.
OP800215A
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Vol. 13, No. 2, 2009 / Organic Process Research & Development