Organic Process Research & Development
Article
and did not get extracted into the toluene layer. The crude
propofol thus obtained can then be easily purified by high-
vacuum distillation (0.05 mm) wherein pure propofol distills
out at 80−85 °C with HPLC purity >99.8% (Scheme 1).
Impurity profiling (i.e., identification as well as quantification
of impurities) of an active pharmaceutical ingredient is of
fundamental significance for medical safety reasons and also for
the drug effectiveness and is now receiving vital attention from
regulatory authorities.15 A literature survey on propofol
revealed that a number of process-related and degradation
impurities have been reported in USP9 and EP;10 some of the
critical ones are shown in Figure 4.
tion events involved in an earlier reported process, which
simplified the isolation of intermediate 3 as well as crude
propofol (1). Recently, we completed the validation of this
process on multikilogram scale in our plant. In the coming
months, we are also planning to further scale up the process as
the market requirement of final API is expected to be huge.
EXPERIMENTAL SECTION
■
All materials were purchased from commercial suppliers. Unless
specified otherwise, all reagents and solvents were used as
1
supplied by manufacturers. H NMR spectra and 13C NMR
Impurity standards (4, 5, and 6) are commercially available
from USP/EP albeit in very small packs; thus, a number of
packs are required for completing the analytical method
development/validation and becomes hugely expensive. Alter-
natively, either all these can be isolated by preparative HPLC
from the residue after vacuum distillation or can be easily
prepared from propofol by straightforward transformations. We
could prepare enough quantities of impurities 4, 5, and 6
starting from propofol using transformations depicted in
Scheme 2. Thus, 4 was obtained on treatment of 1 with
iron(III) chloride followed by reduction with sodium
borohydride. Alkylation of phenolic hydroxyl using 2-
bromopropane and NaOH as base afforded compound 5,
whereas treatment of 1 with CAN furnished quinone 6.
Impurities 7 and 8 are part of the EP specification but are not
commercially available, and these two impurities were not at all
observed (by HPLC) either in crude propofol or in the residue
after distillation. Since the availability of these impurities was a
must to complete the analytical method validation, we intended
to synthesize these two impurities in-house. While, several
approaches can be devised for the synthesis of these impurities,
we adopted common strategy which allowed us to get enough
quantities of both of these impurities in quick time. We
envisaged that compound 7 could be synthesized by treatment
of boronate ester (11) with H2O216 (would result in dihydroxy
compound 13) followed by isopropylidene protection, whereas
C−C bond formation between 11 and 1-bromo-1-propene
using Pd(0) (under Suzuki conditions)17 followed by hydro-
genation of the double bond would provide us impurity 8.
Thus, 2-isopropyl phenol (9) became our obvious starting
material which was converted to MOM protected derivative 10.
Treatment of 10 with n-BuLi followed by triethyl borate
afforded the boronate 11. Subsequent in situ oxidative cleavage
of boronate 11 with H2O2 afforded the desired hydroxyl
derivative 12 which was easily manipulated to impurity-7
(MOM deprotection to give 13 followed by isopropylidene
protection).
spectra were recorded on a Varian 400 MR spectrometer in
CDCl3 and DMSO-d6, and mass spectra were determined on an
API-2000LCMS mass spectrometer from Applied Biosystems.
Elemental analysis was done with a VarioEL III instrument. In
1H NMR, the unknown signal in the 1.5−1.6 ppm area is due
the moisture present in CDCl3/sample.
Preparation of 3,5-Diisopropyl-4-hydroxybenzoic
Acid (3). Concentrated sulfuric aid (36 L) was added gradually
to a flask containing water (2.5 L) cooled to 5 °C. 4-
Hydroxybenzoic acid (10 kg, 72.4 mol) was added, followed by
slow addition of isopropyl alcohol (16.6 L, 217.08 mol) at the
same temperature. The reaction mixture was heated to 55−60
°C (preferably 57−58 °C) till completion of reaction as
indicated by HPLC. The reaction mixture was cooled to room
temperature and carefully poured into a precooled (5 °C)
mixture of water (100 L) and toluene (80 L) while maintaining
temperature below 20 °C over a period of 1.5 h. The organic
layer was separated, washed with brine (20%, 30 L), and
concentrated under reduced pressure to provide a residue,
which was dissolved in methanol (30 L) and gradually diluted
with water (90 L) at 20 °C to precipitate the product, which
was then filtered. The wet cake was slurry washed with
cyclohexane (40 L) and dried to give the desired intermediate
3,5-diisopropyl-4-hydroxybenzoic acid (3) as white solid (14
1
kg, 84%). H NMR (DMSO-d6, 400 MHz): δ 12.37 (s, 1H),
8.87 (s, 1H), 7.61 (s, 2H), 3.34−3.27 (m, 2H), 1.16 (d, J = 6.8
Hz, 12H); 13C NMR (DMSO-d6, 100 MHz): δ 167.72, 155.29,
134.77, 124.94, 121.88, 26.12, 22.81. ESI-Mass: For C13H18O3,
(M+)/z: 222.29, Found: (M − H)/z: 220.8, Melting point
143−145 °C. HPLC purity >98%.
Preparation of 2,6-Diisopropylphenol (Propofol, 1).
To a mixture of 3,5-diisopropyl-4-hydroxybenzoic acid (3) (10
kg, 45 mol) in 2-ethoxyethanol (30 L) was added sodium
hydroxide (4.2 kg, 105.0 mol). The reaction mixture was heated
at 125−130 °C until completion of the reaction as monitored
by HPLC. The reaction mixture was cooled to room
temperature and diluted with water (100 L) followed by
toluene (60 L). The organic layer was separated, washed with
brine (20%, 30 L), and concentrated under reduced pressure to
provide an oily residue which was then distilled (0.05 mm, 80−
85 °C) under reduced pressure to provide propofol as a
colorless liquid (6 kg, 74%).
Moreover, coupling of the same in situ boronate 11 with 1-
bromo-1-propene in presence of Pd(0) followed by MOM
deprotection afforded the critical olefin intermediate 14 which
was converted to impurity 8 by hydrogenation of the double
bond as shown in Scheme 3. Thus, we were able to prepare
good quantities of both of these impurities in relatively quick
time which enabled our analytical team to complete all the
activities.
1H NMR (CDCl3, 400 MHz): δ 7.09 (d, J = 7.6 Hz, 2H),
6.93 (t, J = 7.6 Hz, 1H), 4.80 (s, 1H), 3.24−3.14 (m, 2H), 1.30
(d, J = 6.8 Hz, 12 H); 13C NMR (CDCl3, 100 MHz): δ 149.90,
133.64, 123.38, 120.62, 27.09, 22.70. ESI-Mass: For C12H18O,
(M+)/z: 178.28, Found: (M − H)/z: 177.1, Anal. for C12H18O,
calcd: C, 80.85; H, 10.18, Found: C, 80.73; H, 10.23. HPLC
purity >99.8%.
CONCLUSION
■
In conclusion, our efforts resulted in a much more convenient
and user-friendly process for commercial manufacturing of
propofol. During the course of the work we could successfully
eliminate a couple of highly exothermic acid−base neutraliza-
155
dx.doi.org/10.1021/op400300t | Org. Process Res. Dev. 2014, 18, 152−156