Improved process for pilot-scale synthesis of danshensu ((±)-DSS) and its enantiomer derivatives

Article abstract of DOI:10.1021/op4002593

A pilot-scale process has been developed for green and scalable synthesis of (±)-β-(3,4-dihydroxyphenyl) lactic acid ((±)-DSS) and their two important derivatives, namely, (±)-IDHP [(±)-isopropyl 2-hydroxy-3-(3,4-dihydroxyphenyl)propanoate] and (±)-DBZ [(±)-bornyl 2-hydroxy-3-(3,4-dihydroxyphenyl)propanoate]. Subsequent hydrogenation has been carried out by employing Raney Ni as catalyst. The improved process results in higher yields of 47.5% for (±)-DBZ and 49.2% for (±)-IDHP compared to the initial process with a yield of 12% for (±)-DBZ and 18% for (±)-IDHP in our original medicinal chemistry route. Furthermore, kilograms of optical DBZ [(-)-S-DBZ and (+)-R-DBZ, >99% ee] and IDHP [(-)-S-IDHP and (+)-R-IDHP, >99% ee] have been produced by chiral high-performance liquid chromatography in good yield (>84%).

Full text of DOI:10.1021/op4002593

Article
pubs.acs.org/OPRD
Improved Process for Pilot-Scale Synthesis of Danshensu (( )-DSS)
and Its Enantiomer Derivatives
Yajun Bai,† Qunzheng Zhang,‡ Pu Jia,† Lingjian Yang,† Yuhong Sun,† Yefei Nan,‡ Shixiang Wang,†
Xue Meng,† Yizhen Wu,† Fanggang Qin,† Zhe Sun,† Xiaokang Gao,† Pei Liu,† Kai Luo,⊥ Yajun Zhang,†
Xinfeng Zhao,† Chaoni Xiao,† Sha Liao,† Jianli Liu,† Cuiling Wang,† Jiacheng Fang,† Xiaoxiao Wang,†
Jing Wang,∥ Rong Gao,† Xuexia An,† Xunli Zhang,*,§ and Xiaohui Zheng*,†
†Key Laboratory of Resource Biology and Biotechnology in Western China, College of Life Sciences, Northwest University, Xi’an
710069, China
‡College of Chemistry and Chemical Engineering, Xi’an Shiyou University, Xi’an 710065, China
§Faculty of Engineering and the Environment, University of Southampton, Southampton SO17 1BJ, U.K.
⊥Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry & Material
Science, Northwest University, Xi’an, 710069, China
∥Shaanxi Institute of Zoology, Xi’an, 710032, China
S
* Supporting Information
ABSTRACT: A pilot-scale process has been developed for green and scalable synthesis of ( )-β-(3,4-dihydroxyphenyl) lactic
acid (( )-DSS) and their two important derivatives, namely, ( )-IDHP [( )-isopropyl 2-hydroxy-3-(3,4-dihydroxyphenyl)-
propanoate] and ( )-DBZ [( )-bornyl 2-hydroxy-3-(3,4-dihydroxyphenyl)propanoate]. Subsequent hydrogenation has been
carried out by employing Raney Ni as catalyst. The improved process results in higher yields of 47.5% for ( )-DBZ and 49.2%
for ( )-IDHP compared to the initial process with a yield of 12% for ( )-DBZ and 18% for ( )-IDHP in our original medicinal
chemistry route. Furthermore, kilograms of optical DBZ [(−)-S-DBZ and (+)-R-DBZ, >99% ee] and IDHP [(−)-S-IDHP and
(+)-R-IDHP, >99% ee] have been produced by chiral high-performance liquid chromatography in good yield (>84%).
published strategy;9,12 the process involved five steps resulting
INTRODUCTION
■
in an overall yield of only 12%. To improve its yield and avoid
( )-β-(3,4-Dihydroxyphenyl) lactic acid (( )-DSS) and its
using toxic mercury catalysts, an alternative route10 was utilized.
derivatives have recently attracted considerable interest due to
However, its overall yield of 18% was also not satisfied for
their potential pharmaceutical activities for anti-oxidation,1 anti-
large-scale production. In addition, asymmetric synthesis of
coagulance,2 anti-myocardial ischemia,3 anti-inflammation,4 and
IDHP and DBZ was developed by our group,11 but its high cost
anti-neoplasticism.5 Our previous studies6 on distribution and
made it economically not viable for large-scale production.
metabolites of Danshen (Salvia miltiorrhiza bunge) and
Therefore, there still remain challenges for the production of
Danshen dripping pills (a patented traditional Chinese
these derivatives in quality and quantity sufficient for
medicine consisting of radix salvia miltiorrhizae, radix
pharmaceutical applications.
notoginseng, and borneolum syntheticum) with rabbits
The aim of the present studies was to develop a pilot-scale
suggested that compounds 2 and 3 (Figure 1) might play a
synthetic method which can deliver higher yields for the
key role in the patent medicine of Danshen.
( )-DSS, ( )-IDHP, and ( )-DBZ production. The use of less
Along with studies on the correlation of ( )-DSS,
toxic catalysts was also investigated for a greener process.
( )-IDHP, and ( )-DBZ in vivo and their pharmacokinetics
Furthermore, we developed a method for chiral separation of
and pharmacodynamics, a considerable number of methods to
( )-IDHP and ( )-DBZ to give an optical purity (>99% ee)
synthesize substituted ( )-DSS and their key intermediates7
isomer of R-IDHP, S-IDHP, R-DBZ, and S-DBZ.
have been investigated. For example, we developed a synthesis
process (Scheme 1),8 which was based on a previously
RESULTS AND DISCUSSION
■
Preparation of ( )-DSS 8 (Scheme 2). ( )-DSS was
obtained using literature method12 by treating 3,4-dihydroxyl-
benzaldehyde 4 with N-acetylglycine 5 and anhydrous sodium
Special Issue: Engineering Contributions to Chemical Process
Development
Figure 1. Structures of ( )-DSS, (−)-S-IDHP, (+)-R-IDHP, (−)-S-
Received: September 21, 2013
DBZ, and (+)-R-DBZ.
© XXXX American Chemical Society
A
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Scheme 1. Initial Route for the Preparation of ( )-DSS, ( )-DBZ, and ( )-IDHP
Scheme 2. Improved Process for the Preparation of ( )-DBZ and ( )-IDHP
a
Table 1. Effect of Catalysts, Solvent, and Reaction Time on the Esterification
d
entry
catalyst
solvents
toluene
temperature (°C)
time (h)
yield (%)
1
2
H2SO4
H2SO4
H2SO4
zeolite
zeolite
110
110
68
12
72
12
12
12
12
12
12
12
12
12
12
20
12
12
35
68
53
32
44
47
56
79
84
76
80
75
95
47
63
toluene
b
b
b
b
3
THF/hexane
toluene
4
110
68
5
THF/hexane
toluene
6
acidic cation exchange resin
acidic cation exchange resin
SO42−−Zr(OH)4
SO42−−Zr(OH)4
TsOH
110
68
7
THF/hexane
toluene
8
110
68
9
THF/hexane
toluene
10
11
12
13
14
15
110
68
b
c
TsOH
THF/hexane
THF/hexane
THF/hexane
toluene
TsOH
66
b
TsOH
68
sulfamic acid
sulfamic acid
110
68
b
THF/hexane
a
Reactions were carried out with 10 mmol of α-enol acid 8, 10 mmol D-borneol, and catalyst (10% mmol, according to α-enol acid 8) in 25 mL of
b
c
d
solvent, and then the mixture was heated to reflux. THF/hexane = 5/1 (v/v). THF/hexane = 9/1 (v/v). Determined by HPLC method B after
12−72 h.
acetate in refluxing acetic anhydride to give oxazolone 6,12
which was then converted to 7 (yield 84%) by adding cold
water without separation and purification. Compound 7 was
hydrolyzed by refluxing in 3 M aqueous hydrochloric acid with
addition of acetone to give the α-enol acid 8 (yield 69%), which
must be washed with a considerable amount of water (a total of
20 L/kg of α-enol acid 8) to remove the residual HCl. Low pH
of the filtrate (pH = 4−5) increased the risk of decomposition
of the α-enol acid (8). Clemmensen reduction of 8 with zinc
amalgam in boiling 3 M hydrochloric acid gave the racemic
DSS in fair yield in the small-scale trial.12 Upon performing this
procedure on a large scale (100 kg), we found that the yield was
not reproducible, with only 30−38% yield. Further inves-
tigation13 and evaluation of the reaction revealed that the use of
B
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Table 2. Impact of Reduction Sources on Hydrogenation of Compound 10
HPLC area (%)
entry
reduction source
compound 10
unknown
( )-IDHP
time (h)
yield (%)
a
1
2
3
4
5
6
7
NaBH4
Zn(Hg)/HCl
83−25
13
6−5
11−70
81
5−24
8
20−78
52
b
6
5
1
c
aluminium isopropoxide
0
95
14
89
d
Pd/C, 5%
0
99
2−6
16
36−98
e
Pd/C, 5%
98
0
1.5
99
f
Raney Ni
1
1
2−7
7
30−97
97
e
Raney Ni
0
99
a
b
NaBH4: 1.2 equiv, MeOH/H2O as solvent. Reactions were carried out with 10 mmol of compound 10, 2 g of Zn(Hg)/HCl in 15 mL of solvent.
c
d
e
Aluminium isopropoxide: 1.5 equiv, THF as solvent. Pd/C (5%, wet): carried out at 55 °C, 0.8−1.0 MPa, MeOH as solvent. Run hydrogenation
f
g
for three times. Raney Ni: carried out at 55 °C, 0.8−1.0 MPa, EtOH as solvent. Isolated yield.
Table 3. Chiral Separation Conditions and Results of Optical DBZ [(−)-S-DBZ and (+)-R-DBZ] and IDHP [(−)-S-IDHP and
(+)-R-IDHP]
a
b
b
retention time (min)
yield (%)
(−)-S
ee (%)
a
a
racemate
chemical purity for racemate (%)
ratio, R/S (%)
(−)-S
(+)-R
(+)-R
(−)-S
(+)-R
IDHP
DBZ
95.4
93.5
61/39
58/42
27.0
33.1
31.0
36.3
87
89
92
84
99.3
99.5
99.2
99.2
a
b
For analysis. For preparation.
Pd/C (5%) or Raney Ni with hydrogen was beneficial for
achieving higher yields (>95%). In addition, using Raney Ni as
catalyst in the hydrogenation reaction (yield >93%) was more
advantageous due to its low cost and high reusability.
with TsOH enhanced yield significantly (entries 11 and 13).
Considering the cost factor, TsOH was selected as catalyst in
the large-scale production, although SO42−−Zr(OH)4 gave a
slightly higher yield.
Optimization of 3,4-Dihydroxy Phenylpyruvic Acid
Ester Synthesis. IDHP and DBZ were initially synthesized
following the method of Scheme 1. However, it was difficult to
obtain target compounds with high purity by directly reacting
DSS with corresponding alcohols using acid catalysts, such as
H2SO4.14 During that process, byproduct biDSS (through self-
esterification of DSS) was formed (∼18%, detected by HPLC
and HPLC-MS) which was difficult to remove by crystallization
or column chromatography. In an attempt to avoid producing
this self-coupling byproduct and to obtain a more consistent
yield, D-borneol was selected to react directly with α-enol acid 8
to find optimal conditions for this reaction.15 The results are
summarized in Table 1.
From Table 1, it can be seen that the change of catalysts,
solvent, and ratio of solvent all affected the reaction efficiency
critically. The desired ( )-DBZ 3 was obtained with a yield of
35% using 10 mol % of H2SO4 catalyst and toluene as solvent at
110 °C for 12 h (entry 1). An increase in reaction time gave a
significantly higher yield of 68% (entry 2). The investigation
into solvent effect showed that THF/hexane mixture (5/1, v/v)
was a more effective solvent as it removed the water from the
It should be noted that esters 9 and 10 are unstable in
various solvents at room temperature or lower. As a result, the
hydrogenation reaction had to be carried out as soon as
possible to give corresponding racemic IDHP and DBZ, which
were stable enough under normal conditions.
Optimization of the Reduction of 3,4-Dihydroxy
Phenylpyruvic Acid Esters. It was noticed that Pd/C catalyst
performed well at the beginning of reaction for this
transformation under hydrogen atmosphere, but its catalytic
activity reduced sharply after two runs (Table 2, entry 5).
Attempts to increase conversion by increasing reaction time,
reaction temperature, and hydrogen pressure showed little
success, which made it unsuitable for pilot-scale production.
Other conditions for an effective reduction of the enol
compound 10 to give ( )-IDHP 3 were also evaluated
(Table 2). It showed that the use of aluminium isopropoxide20
in THF provided high conversion (Table 2, entry 3) to the
desired products at room temperature. However, the target
product was difficult to separate from the slurry reaction
mixture, partly attributed to forming aluminium colloidal
solution. In addition, NaBH421 gave just a moderate conversion
and yield (Table 2, entry 1), which was also unsuitable for
scale-up. Raney Ni (W-6)22 was identified as the most reliable
catalyst to give a complete conversion and high yield (Table 2,
entry 6). Moreover, the product can be separated from the
catalyst in a simple way by suction, and the residue catalyst
activity can be renewed just by reloading 10% of Raney Ni
(Table 2, entry 7).
reaction system fast (entries 3 and13). Other acid catalysts,
including zeolite,16 acidic cation exchange resin,17 SO4
−
2−
Zr(OH)4,18 and 4-methylbenzenesulfonic acid (TsOH),19 were
also screened. It was found that the addition of 10 mol % of
acidic cation exchange resin and sulfamic acid gave slightly
higher yields (entries 7 and 15), whereas zeolite gave a
relatively lower yield (entry 5). Both SO42−−Zr(OH)4 and
TsOH gave a good yield of the product (entries 9 and 12,
respectively). Interestingly, a simple increase in reaction time
Chiral Separation of Racemic IDHP and DBZ. Although
asymmetric catalytic hydrogenation is generally regarded as the
C
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most effective method for prochiral ketone hydrogenations,
particularly α-keto (or α-enol) esters,23 it failed, however, to
work in the scale-up of chiral IDHP and DBZ synthesis.
Alternatively, chiral separation by high-performance liquid
chromatography (chiral HPLC) can be a powerful method.24
Table 3 shows the chiral analysis results of the simple and rapid
method we used in this study for successfully obtaining (−)-S-
IDHP, (+)-R-IDHP, (−)-S-DBZ, and (+)-R-DBZ in kilograms
with high optical purity (>99% ee). Their optimization
procedures, for both analysis and preparation, are described
in more detail in Experimental Section (HPLC methods C, D,
E, and F).
elution with hexane/iPrOH (90/10), over 40 min, 1.0 mL/min,
at 25 °C, with UV detection at 237 nm.
HPLC Method D. (For analysis of 3a and 3b) Agilent 1100,
Daicel Chiralcel OJ-H, 5 μm, 4.6 mm × 250 mm column,
elution with hexane/iPrOH (93/7), over 40 min, 1.0 mL/min,
at 25 °C, with UV detection at 237 nm.
HPLC Method E. (For preparation of 2a and 2b)
NOVASEP-SFC 3050, CHIRALPAK AD-H, 5 cm × 25 cm,
elution with aqueous MeOH/H2O (30/70), over 8 min, 120
mL/min, at 35 °C, with UV detection at 260 nm.
HPLC Method F. (For preparation of 3a and 3b)
NOVASEP-SFC 3050, CHIRALPAK AD-H, 5 cm × 25 cm,
elution with aqueous MeOH/H2O (25/75), over 12 min, 150
mL/min, at 35 °C, with UV detection at 254 nm.
CONCLUSIONS
■
Preparation of 2-(Acetylamino)-3-[3,4-bis(acetyloxy)-
phenyl]-(2Z)-2-propenoic acid (7). In a 500 L reactor, a
mixture of sodium acetate (44.0 kg, 536.6 mol), N-acetylglycine
(50.0 kg, 427.4 mol), and 3,4-dihydroxybenzaldehyde (50.0 kg,
362.3 mol) in acetic anhydride (200.0 kg, 1960.8 mol) was
heated to 90−100 °C and stirred for 2 h; then HPLC analysis
indicated that <1% 3,4-dihydroxybenzaldehyde remained
(HPLC method A). The reaction mixture was cooled and
placed in a refrigerator overnight to give a crude brown-yellow
compound 6, which did not need to be purified and was
washed directly with cold water (reaction mixture/cold water =
1:3, w/w) two times and broken up with a stirring rod (for
about 1 h). The mixture were then transferred to a centrifuge
and washed thoroughly with cold water (50 L) to afford 98 kg
wet yellow solid which was dried at 50 °C for about 14 h to give
a dry product (compound 7) at 95.5% purity via HPLC method
A (93 kg, yield 84.5%). The crude product was used in the next
step without further purification. Mp: 186−188 °C (from
A new and efficient process for the synthesis of DSS, IDHP,
and DBZ has been developed on large scale, producing over 20
kg of the target compound. Production and optimization of the
synthesis of intermediates 9 and 10, followed by hydrogenation
with Raney Ni, significantly improved the overall yield of the
process (from 12−18% to 47−49%) and reduced cost and
production time. Furthermore, kilograms of optical DBZ
[(−)-S-DBZ and (+)-R-DBZ, >99% ee] and IDHP [(−)-S-
IDHP and (+)-R-IDHP, >99% ee] were obtained by chiral
HPLC in good yield (total yield >90%). With two pilot-plant
campaigns, clinical trial quality and quantity of DBZ and IDHP
were obtained, which laid the foundation for further
investigation into its pharmacokinetics, pharmacodynamics,
and pharmacological characterization.
EXPERIMENTAL SECTION
■
General. Starting materials, reagents, and solvents were
obtained from commercial suppliers and used without further
purification. Melting points were determined using an XRC-1
1
ethanol). MS (−ESI, negative mode) m/z: 320.1 [M − 1]. H
NMR (CDCl3, 600 MHz): δ 8.06 (s, 1H), 7.88 (d, J = 12 Hz,
1H), 7.27 (d, J = 12 Hz, 1H), 7.06 (s, 1H), 2.40 (s, 1H), 2.33
(s, 1H), 2.31 (s, 1H). 13C NMR (CDCl3, 600 MHz): δ 168.1,
167.8, 167.4, 166.7, 144.1, 142.3, 133.2, 131.8, 130.7, 129.1,
126.7, 123.8, 20.7, 20.6, 15.7. IR (KBr, cm−1): 3423, 3265,
1771, 1692, 1660, 1634, 1535, 1503, 1426, 1372, 1301, 1261,
1208, 1112, 1014, 896, 861, 837, 648, 629, 590.
1
apparatus and are uncorrected. H NMR and 13C NMR were
recorded on a Varian Gemini 2000 (VnmrS 600 MHz, 600/54/
ASP) and were determined in CDCl3 or DMSO-d6. Chemical
shifts were reported in parts per million relative to tetra-
methylsilane (TMS) (0.00 ppm) or solvent peaks as the
internal reference, and coupling constant (J) values were
reported in hertz (Hz). Splitting patterns were indicated as
follows: s, singlet; d, doublet; t, triplet; m, multiplet. Mass
spectra were obtained with Agilent 1200 series HPLC-6520Q-
TOF. Evaporation was performed in vacuo (rotary evaporator).
Analytical TLC was conducted on Merck 0.2 mm precoated
silica gel aluminum sheets (60 F-254). The purity of the target
compounds was determined by HPLC analysis, using an
Agilent 1100 liquid chromatograph (UV detection at 280, 254,
or 237 nm) and a Discovery C18 column (250 mm × 4.6 mm, 5
μm, Zobax). Optical rotations were obtained with a Perkin-
Elmer 343 polarimeter. Infrared spectra were recorded with a
Thermo infrared spectrometer.
HPLC Method A. (For analysis of 6) Agilent 1100, Zobax
C18, 5 μm, 4.6 mm × 250 mm column, elution with MeOH/
H2O (80/20), over 25 min, 0.6 mL/min, at 25 °C, with UV
detection at 254 nm.
HPLC Method B. (For analysis of 8, 9, and 10) Agilent
1100, Zobax C18, 5 μm, 4.6 mm × 250 mm column, elution
with 0.2% aqueous MeOH/H2O (70/30), over 30 min, 0.6
mL/min, at 25 °C, with UV detection at 280 nm.
Preparation of 2-Hydroxy-3-(3,4-dihydroxyphenyl)-
acrylic acid (8). In a 1000 L reactor, a mixture of concd
HCl (36%, w/w) (100 kg) and compound 7 (92.0 kg, 303.6
mol) in water (720.0 kg) was heated to 100 °C and stirred for 6
h, then the mixture was cooled to 40 °C, and acetone (60.0 kg,
882.3 mol) was added into the reactor. The reaction mixture
was heated to reflux for another 3 h. HPLC analysis indicated
<2% of compound 7 (HPLC method B). After that, the
resulting mixture was concentrated in vacuo for about 10 h to
remove water (580 L). The residue was transferred to the barrel
while it was still hot and allowed to cool to room temperature.
The resulting precipitate was filtered in vacuo, washed
consecutively with water, and dried at 50 °C for 16 h to give
a dry yellow-brown solid (41 kg, yield 68.8%) at 92.3% purity
via HPLC method B. The crude product was used in the next
step without further purification. Mp: 192−196 °C (from
methanol).25 MS (−ESI, negative mode) m/z: 195.0 [M − 1].
1H NMR (DMSO-d6, 600 MHz): δ 12.91 (s, 1H), 9.07 (s, 1H),
8.96 (s, 1H), 8.77 (s, 1H),7.37 (s, 1H), 6.96 (dd, J = 6.0 Hz,
1H), 6.71 (d, J = 6.0 Hz, 1H), 6.27 (s, 1H). 13C NMR (DMSO-
d6, 600 MHz): δ 166.3, 145.2, 144.8, 139.1, 126.4, 121.7, 116.5,
115.4, 110.8. IR (KBr, cm−1): 3383, 3239, 2852, 1692, 1658,
HPLC Method C. (For analysis of 2a and 2b) Agilent 1100,
Daicel Chiralcel AD-H, 5 μm, 4.6 mm × 250 mm column,
D
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1596, 1523, 1447, 1384, 1333, 1272, 1245, 1161, 1121, 922,
Preparation of 2-Hydroxy-3-(3,4-dihydroxyphenyl)-
propanoic acid (1). A mixture of compound 8 (6.5 kg, 33.2
mol) and Raney Ni (1.2 kg, W-6) in ethanol (36.0 L) was
placed under 1.0 MPa of hydrogen and heated at 60 °C. The
reaction was monitored by HPLC method B until consumption
of compound 8 (≤0.3%). After 13 h, the hydrogen uptake
ceased. The mixture was cooled and filtered through a bed of
Celite, which was washed with ethanol (5.0 L). The filtrate was
concentrated in vacuo at 55 °C to give a viscous deep brown oil
(7.0 kg, yield >100%) at 96.0% purity via HPLC method B. MS
(−ESI, negative mode) m/z: 197.0 [M − 1]. 1H NMR
(DMSO-d6, 600 MHz): δ 8.76 (s, 1H), 6.63 (dd, J = 24 Hz,
1H), 6.64 (dd, J = 12 Hz, 1H), 6.46 (dd, J = 24 Hz, 1H), 5.47
(s, 1H), 4.06−4.17 (m, 1H), 2.61−2.81 (m, 1H). 13C NMR
(DMSO-d6, 600 MHz): δ 175.4, 174.2, 144.9, 144.8, 143.8,
143.7, 128.9, 128.4, 120.3, 120.2, 117.0, 116.9, 115.4, 115.3,
71.8, 71.6, 51.4. IR (KBr, cm−1): 1725, 1603, 1525, 1443, 1354,
1095, 1020, 860, 805.
886, 864, 810, 771, 717.
Preparation of Nanometer Solid Superacid S2O8
2−
/
ZrO2. The title catalyst was obtained following the procedures
in the literature.26
Preparation of Bornyl 2-Hydroxy-3-(3,4-dihydroxy-
phenyl)acrylate (9). To a slurry of compound 8 (15.4 kg,
78.5 mol) in THF (30.0 L) was added p-toluenesulfonic acid
(1.35 kg, 7.85 mol) in one portion at room temperature. After
completion of the addition, hexane (6.0 L) was charged as an
assistant solvent. Then the resulting mixture was stirred and
heated to 80 °C, while the water was removed from the
reaction system with Dean−Stark equipment. After 27 h, the
reaction progress was monitored by HPLC until consumption
of 8 (≤3%). The slurry was then cooled to 50 °C and
concentrated in vacuo in two parts. Then the viscous slurry was
transferred to a barrel (100 L), and saturated aqueous NaHCO3
(∼3.5 kg) was charged in several portions to adjust the pH to 3.
After agitation for 30 min, the precipitate was collected in vacuo
to obtain a light yellow-brown solid (24.2 kg, yield 93%) at
95.4% purity via HPLC method B and was used in the next
transformation without further purification. Mp: 184−190 °C
(from methanol). MS (+ESI, positive mode) m/z: 333.2 [M +
1], 355.2 [M + 23]. 1H NMR (DMSO-d6, 600 MHz): δ 9.12 (s,
1H), 8.96 (s, 2H), 7.38 (s, 1H), 6.97(d, J = 6.0 Hz, 1H), 6.71
(d, J = 6.0 Hz, 1H), 6.30 (s, 1H), 4.92−4.93 (m, 1H), 2.31−
2.36 (m, 1H), 1.98−2.02 (m, 1H), 1.73−1.77 (m, 1H), 1.71 (t,
J = 6 Hz, 1H), 1.05 (dd, J = 12 Hz, 1H), 0.91 (s, 3H), 0.88 (s,
3H), 0.85 (s, 3H). 13C NMR (DMSO-d6, 600 MHz): δ 165.7,
145.9, 145.3, 139.3, 126.5, 122.4, 117.1, 115.9, 112.1, 80.7, 49.1,
48.0, 44.7, 36.6, 28.0, 27.3, 20.0, 19.1, 14.0. IR (KBr, cm−1):
3472, 3335, 3080, 2953, 2883, 1677, 1616, 1600, 1512, 1452,
1398, 1338, 1284, 1250, 1188, 1161, 1114, 1014, 972, 891, 854,
802, 771, 636.
Preparation of Isopropyl 2-Hydroxy-3-(3,4-dihydroxy-
phenyl)acrylate (10). To a slurry of compound 8 (17.6 kg,
89.8 mol) in isopropyl alcohol (47.0 L) was added p-
toluenesulfonic acid (1.76 kg, 10.2 mol) in one portion at
room temperature. After completion of the addition, hexane
(10.0 L) was charged as an assistant solvent. Then the resulting
mixture was stirred and heated to 70 °C, while the water was
removed from the reaction system with Dean−Stark equip-
ment. After 25 h, the reaction progress was monitored by
HPLC until consumption of compound 8 (≤5%). The slurry
was then cooled to 50 °C and concentrated in vacuo in three
parts. Then the viscous slurry was transferred to a barrel (100
L), and saturated aqueous NaHCO3 (∼4 kg) was charged in
several portions to adjust the pH to 3. After agitation for 30
min, the precipitate was concentrated in vacuo to obtain a light
yellow solid (19.6 kg, yield 92%) at 96.2% purity via HPLC
method B and was used in the next transformation without
further purification. Mp: 159−165 °C (from methanol). MS
(−ESI, negative mode) m/z: 237.1 [M − 1]. 1H NMR
(DMSO-d6, 600 MHz): δ 9.10 (s, 1H), 8.95 (d, J = 12.0 Hz,
2H), 7.37 (s, 1H), 6.95 (d, J = 6.0 Hz, 1H), 6.70 (d, J = 6.0 Hz,
1H), 6.25 (s, 1H), 4.99−5.05 (m, 1H), 1.29 (s, 3H), 1.28 (s,
3H). 13C NMR (DMSO-d6, 600 MHz): δ 164.3, 144.6, 138.7,
125.9, 121.7, 116.4, 116.3, 115.2, 115.1, 111.2, 68.4, 21.4. IR
(KBr, cm−1): 3475, 3357, 2980, 1674, 1616, 1597, 1512, 1469,
1394, 1372, 1334, 1284, 1255, 1187, 1160, 1102, 975, 924, 902,
860, 829, 801, 767, 643.
Preparation of Isopropyl 2-Hydroxy-3-(3,4-dihydroxy-
phenyl)propanoate (2). A mixture of compound 10 (15.0 kg,
63.0 mol) and Raney Ni (1.2 kg, W-6) in ethanol (50.0 L) was
placed under 1.0 MPa of hydrogen and heated at 60 °C. The
reaction was monitored by HPLC method B until consumption
of compound 10 (≤0.5%). After 8 h, the hydrogen uptake
ceased. The mixture was cooled and filtered through a bed of
Celite, which was washed with ethanol (6.6 L). The filtrate was
concentrated in vacuo at 55 °C to give a light brown oil (15.5
kg, yield >100%, chemical purity 95.4% via HPLC method B,
ratio of R/S isomer = 56/44 (%)) which can be solidified after
several hours at room temperature. MS (−ESI, negative mode)
1
m/z: 239.1 [M − 1]. H NMR (DMSO-d6, 600 MHz): δ 8.71
(s, 1H), 8.63 (s, 1H), 6.60 (d, J = 6.0 Hz, 2H), 6.43 (dd, J = 6.0
Hz, 1H), 5.39 (d, J = 6.0 Hz, 1H), 4.81−4.88 (m, 1H), 4.05−
4.08 (m, 1H), 2.70−2.73 (m, 1H), 2.63−2.66 (m, 1H), 1.17 (d,
J = 6.0 Hz, 3H), 1.10 (d, J = 6.0 Hz, 3H). 13C NMR (DMSO-
d6, 600 MHz): δ 173.5, 145.2, 144.1, 128.6, 120.5, 117.3, 115.6,
72.2, 67.7, 22.0. IR (KBr, cm−1): 2979, 2930, 1693, 1604, 1531,
1458, 1360, 1296, 1238, 1205, 1179, 1146, 1107, 1014, 976,
953, 933, 894, 953, 867, 837, 818, 806, 775, 687, 601, 551, 525.
Preparation of Bornyl 2-Hydroxy-3-(3,4-dihydroxy-
phenyl)propanoate (3). A mixture of compound 9 (23.0
kg, 69.3 mol) and Raney Ni (1.6 kg, W-6) in ethanol (90.0 L)
was placed under 1.0 MPa of hydrogen and heated at 60 °C.
The reaction was monitored by HPLC method B until
consumption of compound 9 (≤0.5%). After 10 h, the
hydrogen uptake ceased. The mixture was cooled and filtered
through a bed of Celite, which was washed with ethanol (12 L).
The filtrate was concentrated in vacuo at 55 °C to give brown
oil (24.1 kg, yield >100%, chemical purity 93.5% via HPLC
method B, ratio of R/S isomer = 57/43 (%)). MS (−ESI,
negative mode) m/z: 333.2 [M − 1]. 1H NMR (DMSO-d6, 600
MHz): δ 8.70 (s, 1H), 8.62 (s, 1H), 6.60 (d, J = 12 Hz, 2H),
6.44 (d, J = 12 Hz, 1H), 5.43 (t, J = 6 Hz, 1H), 4.72 (dd, J = 24
Hz, 1H), 4.11−4.19 (m, 1H), 2.66−2.77 (m, 1H), 2.14−2.27
(m, 1H), 1.76−1.84 (m, 1H), 1.59−1.71 (m, 2H), 1.05−1.24
(m, 3H), 0.69−0.91 (m, 13H). 13C NMR (DMSO-d6, 600
MHz): δ 173.8, 173.7, 144.8, 144.7, 143.6, 128.0, 127.9, 119.9,
119.9, 116.7, 115.1, 79.0, 78.9, 74.8, 71.8, 71.5, 48.3, 48.2, 47.3,
47.3, 44.5, 44.2, 44.1, 38.4, 36.1, 35.8, 27.9, 27.5, 27.3, 26.6,
26.5, 25.7, 20.1, 19.4, 18.5, 13.4, 13.3, 13.1. IR (KBr, cm−1):
3401, 2953, 1708, 1616, 1520, 1454, 1388, 1360, 1280, 1114,
1080, 995, 978, 897, 852, 809, 761, 704.
Preparation of Raney Ni. This catalyst was obtained
following the procedures in the literature.27
E
dx.doi.org/10.1021/op4002593 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Preparation of (S)-Isopropyl 2-Hydroxy-3-(3,4-di-
hydroxyphenyl)propanoate (2a). The title product (1.6
kg) was separated from crude enantiomers of compound 2 (3
kg, chemical purity: 95.4%) by the HPLC method E with high
optical purity (99.3% ee). [α]D25 = −7.5 (MeOH).11a 1H NMR
(DMSO-d6, 600 MHz): δ 8.71 (s, 1H), 8.63 (s, 1H), 6.62 (d, J
= 6 Hz, 2H), 6.60 (s, 1H), 6.44 (dd, J = 6 Hz, 1H), 5.39 (d, J =
6 Hz, 1H), 4.82−4.88 (m, 1H), 4.06−4.09 (m, 1H), 2.74 (dd, J
= 12 Hz, 1H), 2.66 (dd, J = 12 Hz, 1H), 1.17 (d, J = 6 Hz, 3H),
1.10 (d, J = 6 Hz, 3H). 13C NMR (DMSO-d6, 600 MHz): δ
173.1, 144.7, 143.7, 128.1, 120.1, 116.9, 115.2, 71.7, 67.3, 21.6,
21.5.
Preparation of (R)-Isopropyl 2-Hydroxy-3-(3,4-di-
hydroxyphenyl)propanoate (2b). The title product (1.1
kg) was separated from crude enantiomers of compound 2 (3
kg, chemical purity: 95.4%) by the HPLC method E with high
optical purity (99.2% ee). [α]D25 = +6.4 (MeOH).11a 1H NMR
(DMSO-d6, 600 MHz): δ 8.72 (s, 1H), 8.63 (s, 1H), 6.62 (d, J
= 6 Hz, 2H), 6.61 (s, 1H), 6.45 (dd, J = 6 Hz, 1H), 5.39 (d, J =
6 Hz, 1H), 4.83−4.89 (m, 1H), 4.07−4.10 (m, 1H), 2.74 (dd, J
= 12 Hz, 1H), 2.67 (dd, J = 12 Hz, 1H), 1.17 (d, J = 6 Hz, 3H),
1.11 (d, J = 6 Hz, 3H). 13C NMR (DMSO-d6, 600 MHz): δ
173.0, 144.6, 143.5, 128.0, 120.0, 116.7, 115.1, 71.6, 67.2, 48.5,
21.5, 21.4.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: xl.zhang@soton.ac.uk.
*E-mail: zhengxh@nwu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work was financially supported by National Key
Technology R&D Program: Research on Identification
Technique of Effective Components of Chinese Herb Medicine
(2008BAI51B01), Important Science & Technology Specific
Projects of Innovative Program of Shaanxi Province
(2010ZDKG-46), the National Natural Science Foundation of
China: Specialized Research Fund for the Doctoral Program of
Higher Education in 2011 (20106101110001), Program for
Changjiang Scholars and Innovative Research Team in
University on 2011: Research on drug development and
innovation based on biological resources in Qin-Ba mountains
(IRT1174), Key Scientific and Technological Innovation Team
Plans of Shaanxi Province: The team for drug development and
innovation based on Chinese herb medicine resources in Qin-
Ba mountains (2013KCT-24), Scientific Research Plan Projects
of Shaanxi Education Department (12JK0582), and The
Development and Application of Supercritical Fluid Chromato-
graph (2013YQ170525; subproject: Application Research of
Supercritical Fluid Chromatography in Chinese Traditional
Medicine and Its Metabolites, 2013YQ17052509).
Preparation of (2S)-1,7,7-Trimethylbicyclo[2.2.1]-
heptan-2-yl 2-Hydroxy-3-(3,4-dihydroxyphenyl)-
propanoate (3a). The title product (1.9 kg) was separated
from crude enantiomers of compound 3 (3.7 kg, chemical
purity: 93.5%) by the HPLC method F with high optical purity
11b
1
(99.5% ee). H NMR
(DMSO-d6, 600 MHz): δ 8.69 (s,
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(dd, J = 6 Hz, 1H), 2.14−2.19 (m, 1H), 1.76−1.81 (m, 1H),
1.61−1.66 (m, 1H), 1.58−1.60 (m, 1H), 1.19−1.23 (m, 1H),
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S
* Supporting Information
1H NMR, 13C NMR, and MS spectra of all compounds are
provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
F
dx.doi.org/10.1021/op4002593 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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