Scalable process for 4-(2-hydroxy-2-methyl)-ethyl-benzylamine

Article abstract of DOI:10.1080/00397910600636733

The preparation of the title compound has been revisited and improved. Starting from inexpensive cuminonitrile, 4-(2-hydroxy-2-methyl)-ethyl- benzylamine is obtained in a scalable two-step process with an overall yield of 55%. Copyright Taylor & Francis G

Full text of DOI:10.1080/00397910600636733

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Scalable Process for
4‐(2‐Hydroxy‐2‐methyl)‐ethyl‐benzylamine
John L. Tucker a , Michel Couturier b , Michael J. Castaldi b , Charles K. F.
Chiu b & Detlef Gestmann c
a Chemical Research and Development, Pfizer Inc., La Jolla Labs, San Diego,
California, USA
b Chemical Research and Development, Pfizer Inc., Groton, Connecticut,
USA
c CarboGen Laboratories, AGSchachenallee, Switzerland
Version of record first published: 16 Feb 2007.
To cite this article: John L. Tucker , Michel Couturier , Michael J. Castaldi , Charles K. F. Chiu & Detlef
Gestmann (2006): Scalable Process for 4‐(2‐Hydroxy‐2‐methyl)‐ethyl‐benzylamine, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:15, 2145-2150
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Synthetic Communicationsw, 36: 2145–2150, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600636733
Scalable Process for 4-(2-Hydroxy-2-
methyl)-ethyl-benzylamine
John L. Tucker
Chemical Research and Development, Pfizer Inc., La Jolla Labs,
San Diego, California, USA
Michel Couturier, Michael J. Castaldi, and Charles K. F. Chiu
Chemical Research and Development, Pfizer Inc., Groton,
Connecticut, USA
Detlef Gestmann
CarboGen Laboratories, AGSchachenallee, Switzerland
Abstract: The preparation of the title compound has been revisited and improved.
Starting from inexpensive cuminonitrile, 4-(2-hydroxy-2-methyl)-ethyl-benzylamine
is obtained in a scalable two-step process with an overall yield of 55%.
Keywords: Catalysis, oxidation, phase transfer
In the course of developing a drug candidate, we required an efficient, large-
scale synthesis of 4-(2-hydroxy-2-methyl)-ethyl-benzylamine (1, Scheme 1).
The sole reported synthesis[1] of this compound, entailing a methyl
Grignard addition to the corresponding ethyl ester, was impractical in our
hands because of voluminous precipation of magnesium salts.
Alternatively, the known methyl Grignard additions to either methyl
4-cyanobenzoate (2) or 4-acetylbenzonitrile (3), followed by nitrile
reduction, could provide an entry to the desired benzylamine.[2,3] These
approaches encounter significant problems due to overaddition of methyl
Received in the USA January 27, 2006
Address correspondence to John L. Tucker, Senior Scientist, Chemical Research
and Development, Pfizer Inc., La Jolla Labs, San Diego, CA 92128, USA. Tel.: 858-
638-6317; Fax: 858-678-8199; E-mail: john.tucker@pfizer.com
2145

2146
J. L. Tucker et al.
Scheme 1.
Grignard to the cyano group and enolization/self-condensation of the acetyl
group, leading to the formation of the acetophenone 5 and 1,3-diol
by-products[4] 6, respectively (Scheme 2).
A new approach is based on the known benzylic oxidation[5] of
inexpensive cuminonitrile (7). The original literature procedures utilize
basic potassium permanganate in water to accomplish oxidation. Unfortu-
nately, the sparse solubility of cuminonitrile in water leads to an extremely
long reaction time. This issue can be addressed by use of t-butanol as a
cosolvent, which improved the solubility of the substrate and shortened the
reaction time from days to hours (Scheme 3).
However, the need for a basic medium in the oxidation causes a separate
issue because the cyano group of 8 is hydrolyzed under the reaction conditions,
first to the corresponding benzamide and then to the benzoic acid. This issue is
easily addressed by switching from potassium hydroxide to sodium carbonate.
Under these favorable conditions, the reaction proceeds smoothly at 408C in
18 h with no observed hydrolysis of the cyano group. The simple workup
entails extraction of the product into ethyl acetate. Upon displacement of
ethyl acetate with heptanes, the carbinol 8 precipitates out as a crystalline
solid in 67–83% yield.
Although this procedure can deliver the desired material in good yield, the
reaction conditions are rather dilute with 65 L of solvent per Kg of cuminoni-
trile. This dilution translates into a low throughput process. In principle,
Scheme 2.

Process for 4-(2-Hydroxy-2-methyl)-ethyl-benzylamine
2147
Scheme 3.
oxidation could be accomplished via a known benzylic oxidation procedure
using tetrabutylammonium permanganate.[6] However, this phase-transfer
process makes use of strongly basic reaction conditions, water, and organic
solvent and is extremely dilute. It is noteworthy that tetrabutylammonium
permanganate itself has been shown to be pyrophoric when isolated as a
solid.[7] Therefore, a soluble permanganate salt formed in a water-exclusive
phase-transfer process and utilized in situ without isolation offers a safer
and potentially higher throughput alternative. A process[8] has recently been
safely applied to oxidize an alcohol to the corresponding acid on production
scale but with higher than desired dilution and use of expensive tetraethylam-
monium hydrogen sulfate as catalyst. In the present case, use of a catalytic
amount of tetrabutylammonium bromide enables the desired benzylic
oxidation of cuminonitrile to be performed exclusively in water, in the
absence of both base and organic solvent, with high throughput. Any
residual oxidant is quenched with sodium thiosulfate, and the isolation is
essentially performed as described previously. Hence, application of this
procedure has enabled significant reaction volume reduction from 65.0 L/
Kg to 12.5 L/Kg of water (Scheme 4).
The cyano-reduction of benzonitrile 8 was fairly straightforward and was
affected by lithium aluminum hydride in THF (Scheme 5). However, the
resulting amine was found to be highly water soluble, and multiple extractions
were required. This issue was easily resolved by applying the Fieser
protocol.[9] Hence, upon quenching of the reaction with caustic, free-
flowing inorganic salts were obtained, allowing for easy filtration. The
tetrahydrofuran was then displaced by heptanes, and the benzylamine (1)
precipitated out as a crystalline white solid in 82% yield.
This two-step process is extremely efficient and eliminates all the problems
associated with the previously described Grignard approach. It is noteworthy
that this chemistry was reproducibly scaled to multikilogram quantities.
Scheme 4.

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J. L. Tucker et al.
Scheme 5.
EXPERIMENTAL
Melting points are uncorrected and were determined with a Thomas-Hoover
1
unimelt apparatus. H and 13C NMR spectra were recorded on a Varian
Inova spectrometer operating at 400 MHz and 50 MHz respectively. The
high-resolution mass spectra were recorded on a M-Scan VG analytical
ZAB2SE high field mass spectrometer.
4-(2-Hydroxy-2-methyl)-ethyl-benzonitrile (8): Method A
p-Cuminonitrile (150 g, 1.03 mol) was added to a slurry of potassium per-
manganate (240 g, 1.52 mol) and sodium carbonate (142 g, 1.34 mol) in
water (7.50 L) and t-butanol (2.25 L) The mixture was heated overnight at
an internal temperature of 408C. The reaction mixture was then cooled and
diluted with ethyl acetate (4.50 L). The mixture was filtered to remove
solids, and the filtrate was allowed to settle. The water layer was removed,
and the product-rich ethyl acetate layer was washed twice with water
(1.5 L) followed by saturated brine (1.5 L). The ethyl acetate layer was con-
centrated, and the residual ethyl acetate was displaced with heptane (4.0 L)
to a final volume of 600 mL. The title compound 8 was isolated as a white
crystalline solid via filtration (112.2 g, 67% yield); mp 48–518C.
1H NMR (400 MHz, DMSO-d6), d, ppm: 7.75 (dd, J ¼ 9, 4 Hz, 2H), 7.68
(dd, J ¼ 9, 4 Hz, 2H), 5.26 (s, 1H), 1.39 (s, 6H). 13C NMR (50 MHz, DMSO-
d6), d, ppm: 156.9, 132.5, 126.3, 119.7, 109.5, 71.4, 32.1 HRMS (M þ 1):
calculated: 162.0919, found: 162.0908.
4-(2-Hydroxy-2-methyl)-ethyl-benzonitrile (8): Method B
p-Cuminonitrile (195 g, 1.34mol) was added to a slurry of 2.5 L of water, tetra-
n-butylammonium bromide (8.66 g, 26.7mmol), and potassium permanganate
(318g, 2.00mol) in water (2.5L) and the resulting mixture was heated
overnight at 45–508C. The reaction mixture was cooled, sodium sulfite (10 g)
was added, and it was stirred for 1 h. The reaction mixture was diluted with
2.5 L of ethyl acetate and filtered to remove solids. The water layer was
removed, and the product-rich ethyl acetate layer was successively washed
with of 2% aqueous sodium bisulfite (1.0L), water (1.0L), and saturated

Process for 4-(2-Hydroxy-2-methyl)-ethyl-benzylamine
2149
brine (1.5L). The ethyl acetate layer was concentrated, and the residual ethyl
acetate was displaced with heptane (4.0 L) to a final volume of 600 mL. The
title compound 8 was isolated as a white solid via filtration (139g, 64%
yield). The quality of the material is consistent with those prepared in method A.
4-(2-Hydroxy-2-methyl)-ethyl-benzylamine (1)
A solution of 4-(2-hydroxy-2-methyl)-ethyl-benzonitrile (320 g, 1.99 mol) in
tetrahydrofuran (900 mL) was added dropwise to a solution of lithium
aluminum hydride (4.0 L, 4.0 mol, 1.0 M in tetrahydrofuran) in tetrahydro-
furan (8.0 L), keeping the temperature less than 358C. When the addition
was complete, the resulting slurry was heated for 2 h at reflux. The reaction
mixture was then cooled to room temperature and carefully quenched with
179 mL of water (179 mL), followed by the addition of aqueous sodium
hydroxide (179 mL, 15%) and water (179 mL). The inorganic salt was
removed via filtration, the product-rich THF filtrate was concentrated, and
the THF was displaced with heptane (4.0 L) to a final volume of 600 mL.
The title compound 1 was isolated via filtration as a white crystalline solid
(270 g, 82% yield); mp 74–768C.
1H NMR (400 MHz, DMSO-d6), d, ppm: 7.30 (d, J ¼ 8 Hz, 2H), 7.27
(d, J ¼ 8 Hz, 2H), 3.69 (s, 3H), 1.44 (s, 6H). 13C NMR (50 MHz, DMSO-
d6), d, ppm: 149.0, 141.7, 127.2, 124.9, 71.3, 32.4. HRMS (M þ 1):
calculated: 166.1232, found: 166.1235.
ACKNOWLEDGMENTS
The authors thank R. Chambers for helpful discussions and D. Mendenhall and
R. S. Ware for their analytical support.
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