Synthesis of hydroxy-γ-sanshool

Article abstract of DOI:10.1007/s00706-021-02762-2

Hydroxy-γ-sanshool was prepared with 19.5% overall yield through eight steps. Wittig reactions of ylides with ethyl 4-oxobut-2-enoate as well as (2E,4E)-hex-2,4-dienal were key steps to construct a carbon skeleton. The 2E,4Z-isomer in ethyl 8-hydroxyocta-

Full text of DOI:10.1007/s00706-021-02762-2

Monatshefte für Chemie - Chemical Monthly (2021) 152:545–549
https://doi.org/10.1007/s00706-021-02762-2
ORIGINAL PAPER
Synthesis of hydroxy‑γ‑sanshool
Jiyu Gao1 · Jianjun Zhou1 · Taiping Chen1 · Yan Xiao1 · Zicheng Li1 · Wencai Huang1
Received: 18 January 2021 / Accepted: 29 March 2021 / Published online: 17 April 2021
© Springer-Verlag GmbH Austria, part of Springer Nature 2021
Abstract
Hydroxy-γ-sanshool was prepared with 19.5% overall yield through eight steps. Wittig reactions of ylides with ethyl 4-oxobut-
2-enoate as well as (2E,4E)-hex-2,4-dienal were key steps to construct a carbon skeleton. The 2E,4Z-isomer in ethyl 8-hydrox-
yocta-2,4-dienoate can be isomerized to the desired 2E,4E-isomer with iodine as a catalyst, and free tetradeca-2,4,8,10,12-
pentaenoic acid can be purifed through crystallization in 1% ethyl acetate in n-hexane. The impurities in other intermediates
can be easily removed, the synthetic process can avoid the synthesis or use of 4-bromobutyraldehyde which comes from the
oxidation of unstable 4-bromobutan-1-ol, and the work-ups were simple.
Graphic abstract
Keywords Pentaenamide · Total synthesis · Wittig reaction · Isomers
Introduction
Aoki et al. synthesized hydroxyl-γ-sanshool using
4Z,6E,8E-deca-4,6,8-trienenitrile-Fe(CO)3 complex as a
key intermediate [6]. Although high yield was achieved, the
process involved highly toxic carbonyl iron, and reaction
conditions were harsh.
Sanshools are isolated from Zanthoxylum bungeanum,
mainly including α-sanshool, β-sanshool, γ-sanshool,
δ-sanshool, and hydroxy-sanshool analogs which contain
hydroxyl on amino part (Fig. 1) [1].
Crombie et al. synthesized hydroxyl-γ-sanshool from
ethyl (2E,4E)-8-hydroxyocta-2,4-dienoate by Horner-Wads-
worth-Emmons (HWE) reaction. The ethyl (2E,4E)-8-chlo-
roocta-2,4-dienoate was prepared from 4-chlorobutan-1-ol
[7, 8]. But the activity of 8-chloroocta-2,4-dienoate is not
satisfactory in the next reaction of forming phosphonium
salt.
Ren et al. found that hydroxy-γ-sanshool could activate
the mammalian target of rapamycin (mTOR) pathway and
improve the metabolism of diabetic rats [2]. Katina et al.
proved that hydroxy-γ-sanshool was a good antagonist of
the cannabinoid 1 (CB1) receptor. Thus, hydroxy-γ-sanshool
may be a potential candidate for the treatment of type-1 dia-
betes [3]. In addition, other pharmacological efects had
been discovered, such as anesthesia [4] and gastrointestinal
regulation [5]. However, the content of hydroxy-γ-sanshool
in Zanthoxylum bungeanum is very low (less than 0.01%)
[1]. Thus, chemical synthesis became only the source of
hydroxyl-γ-sanshool.
Xia et al. synthesized γ-sanshool and hydroxy-γ-sanshool
from sorbaldehyde and (6-ethoxy-6-oxohexyl)triphenylphos-
phonium bromide to construct triene fragment. A three-step
Corey-Fuchs reaction was used to reduce the ester to an alde-
hyde and the aldehyde to the triene [9]. Although a good
yield had been achieved, the substrate was expensive and
harsh conditions were required.
* Zicheng Li
As one of our projects, we have fnished the synthe-
sis of hydroxyl-α-sanshool from ethyl 2-oxoacetate and
4-bromobutyl acetate [10], here we reported the synthesis
sculzc@scu.edu.cn
1
School of Chemical Engineering, Sichuan University,
Chengdu, China
Vol.:(0123456789)
1 3

546
J. Gao et al.
of hydroxy-γ-sanshool from ethyl 4-oxobut-2-enoate and
4-bromobutyl acetate, the synthetic route was depicted in
Scheme 1. The impurities in the process can be separated
by utilizing the insolubility of phophonium salts 1 and 5
in ethyl acetate and ethyl ether, most of the 2E,4Z-isomer
in compound 3 can be isomerized into the desired 2E,4E-
structure with iodine as a catalyst and the desired 8Z-iso-
mer free acid 7 can be crystallized in 1% ethyl acetate in
n-hexane.
Results and discussion
The key steps in the preparation of hydroxyl-γ-sanshool
were the formation of several double bonds of carbon–car-
bon. Hydroxyl-γ-sanshool can be synthesized in two routes,
one is as the procedures of Xia et al., another is the ylide
from ethyl (2E,4E)-8-bromooct-2,4-dienoate reacted with
(2E,4E)-hex-2,4-dienal followed by amidation. Ethyl
(2E,4E)-8-bromooct-2,4-dienoate can be relatively easily
prepared as Fig. 2.
Fig. 1 Chemical structure of
O
O
sanshools
N
H
N
H
R
R
R=H α-sanshool
R=H β-sanshool
R=OH hydroxy-α-sanshool
R=OH hydroxy-β-sanshool
O
H
N
R
N
H
R
O
R=H γ-sanshool
R=OH hydroxy-γ-sanshool
R=H δ-sanshool
R=OH hydroxy-δ-sanshool
Scheme 1
COOEt
Br
+
CHO
R
R
Ph3P
R
COOEt
Br
COOEt
(R=OH, Br, AcO)
COOEt
PPh3
Br
+
OHC
Fig. 2 The synthetic route of ethyl (2E,4E)-8-bromooct-2,4-dienoat
1 3

Synthesis of hydroxy-γ-sanshool
547
Initially, 1,4-butanediol or 4-bromobutan-1-ol was chosen
to prepare 4-bromobutyraldehyde which involved the oxida-
tion reaction with PCC [11–13]. However, 4-bromobutan-
1-ol is unstable during its synthesis, storage, and oxidation.
The yield of aldehyde was low and the purifcation was very
difcult. Relatively, 4-bromobutyl acetate can be easily pre-
pared from tetrahydrofuran reacting with acetyl bromide.
And 4-bromobutyl acetate can be easily transformed into
ylide which was reacted with commercially available ethyl
4-oxobut-2-enoate. Although the 2E,4Z-isomer was main
product, it can be isomerized to its 2E,4E-isomer. This pro-
cess can avoid utilizing oxidation reaction with PCC and
unstable 4-bromobutan-1-ol.
room temperature (20 2 °C). 1H and 13C chemical shifts
are quoted in parts per million downfield from TMS.
High-resolution mass spectra (HRMS) were obtained on
a MicrOTOF-Q II mass spectrometer with an ESI source
(Waters, Manchester). As for known compounds, only 1H
NMR and 13C NMR spectra were confrmed with previ-
ously reported literature and the main intermediates were
1
characterized by H NMR, 13C NMR spectra, and mass
spectra. HPLC was performed on LC-3000 HPLC system
using a Welchrom C18 column (4.6 mm × 250 mm, 5 μm)
or U-3000 HPLC system using a Syncroni C18 column
((4.6 mm × 250 mm, 5 μm).
(4-Acetoxybutyl)triphenylphosphonium bromide (1) [16]
A mixture of 15.66 g of 4-bromobutyl acetate (80 mmol)
(which was prepared according to the reported procedures
[14]) and 21 g of triphenylphosphine (80 mmol) in 100
cm3 of acetonitrile was refuxed for 12 h under nitrogen
[15]. Then it was cooled to room temperature and acetoni-
trile was removed to obtain a colorless oil. 50 cm3 of ether
was added to the oil and frozen in the refrigerator for 2 h.
The mixture was ground to obtain a white granular solid,
which was fltered, washed with ether and ethyl acetate,
respectively, and dried in vacuum to obtain a white pow-
dery solid, 34.3 g with a yield of 93%. The product can be
used directly in the next step without further purifcation.
1H NMR (DMSO-d6): δ=7.85–7.73 (m, 15H, Ar–H), 4.09
(t, J=7.1 Hz, 2H, -CH2O-), 3.64 (t, J=7.2 Hz, 2H, -CH2-),
2.24 (s, 3H, COCH3), 1.69–1.73 (m, 2H, -CH2-), 1.18–1.20
(m, 2H, -CH3) ppm; 13C NMR (DMSO-d6): δ = 165.86,
135.29, 130.65, 122.42, 119.06, 60.14, 32.39, 20.89, 20.27,
14.25 ppm.
4-Bromobutyl acetate was reacted with Ph3P to aford 1,
1 was reacted with ethyl 4-oxobut-2-enoate to give 2, com-
pound 2 was hydrolyzed and 2E,4Z-3 was isomerized to
2E,4E-3, 3 was then transferred into 4 with CBr4 and Ph3P.
All impurities in 4 including those that existed in 4-bro-
mobutyl acetate can be separated during the synthesis of
quaternary phosphonium salt 5, because 5 can’t be dissolved
in ethyl acetate or ether while other compounds can. The
2E,4Z-isomer in compound 3 was converted into the desired
2E,4E-isomer with iodine as a catalyst. The initial ratio of
2E,4Z:2E,4E in compound 3 was 58:42; after the isomeriza-
tion, the ratio of 2E,4Z:2E,4E was 89.6:10.4.
The phosphonium salt 5 was reacted with (2E,4E)-hex-
2,4-dienal in the presence of Cs2CO3 to give 6, the percent-
age of 2E,4E,8Z,10E,12E-isomer in 6 was 62% by relative
peak area in HPLC. Compound 6 was hydrolyzed with
NaOH in a 33% methanol aqueous solution, and pure 7 was
obtained by crystallization in 1% ethyl acetate in n-hexane.
Finally, hydroxy-γ-sanshool was obtained smoothly by the
condensation reaction with 1-amino-2-methylpropan-2-ol
catalyzed by HBTU.
Ethyl (2E,4Z/2E,4E)-8-acetoxyocta-2,4-dienoate (2,
C12H18O4) A mixture of 32 g of compound 1 (70.4 mmol),
9 g of ethyl (E)-4-oxobut-2-enoate (70.4 mmol) and 46.0 g
of Cs2CO3 (141 mmol) in 100 cm3 of CH2Cl2 was refuxed
for 24 h under nitrogen. After cooling to ambient tempera-
ture, the solvent was removed. Then 250 cm3 of n-hexane
was added to the residue and stirred for 30 min. The solid
was fltered, and washed twice with 200 cm3 of n-hexane.
Combined organic layer was evaporated to obtain a yel-
low oil, 12.1 g, with a yield of 76% (2E,4E:2E,4Z=42:58).
The product can be used directly in the next step without
Conclusion
Hydroxy-γ-sanshool was synthesized with an overall yield
of 19.5% including two Wittig reactions to construct carbon
skeleton, the process was easily operation, raw materials
were available, and work-ups were simple. All intermedi-
ates and the target product have been characterized by 1H
NMR, 13C NMR, and HRMS.
1
further purifcation. H NMR (DMSO-d6): δ = 7.50 (dd,
J=15.2, 11.8 Hz, 0.42H,=CH-), 7.21 (dd, J=15.3, 9.5 Hz,
0.58H, = CH-), 6.27 (d, J = 9.1 Hz, 1H, = CH), 6.24–5.93
(m,1H, = CHCO-), 5.87(d, J = 15.3 Hz, 1H, = CH-), 4.12
(q, J = 7.3 Hz, 2H, -OCH2-), 3.99 (q, J = 6.3 Hz, 2H,
-CH2CO-), 2.37–2.16 (m, 2H, = CHCH2-), 1.99 (s, 3H,
-COCH3), 1.66–1.73 (m, 2H, -CH2-), 1.21 (t, J= 7.1, 3H,
-CH2CH3) ppm; 13C NMR (DMSO-d6): δ=170.72, 166.62,
145.14, 139.21, 129.06, 119.78, 63.57, 60.11, 29.23, 27.61,
21.00, 14.51 ppm; HRMS (ESI): m/z calcd. for C12H18O4
([M+Na]+) 249.1103, found 249.1106.
Experimental
All the reagents were purchased from commercial suppli-
ers without further purifcation unless otherwise speci-
1
fed. H NMR and 13C NMR spectra were recorded on
a Bruker Avance 400 MHz spectrometer. NMR spectra
were recorded in DMSO-d6 or chloroform-d solutions at
1 3

548
J. Gao et al.
Ethyl (2E,4E)-8-hydroxyocta-2,4-dienoate (3) [17] A
mixture of 11.5 g of compound 2 (50.7 mmol) and 10 g
of pre-treated strong acidic styrene type cation exchange
resin 732 in 50 cm3 of ethanol was refuxed for 5 h. After
cooling to ambient temperature, the resin was fltered out
and washed with ethanol. To the filtrate was added 10
drops of 0.1 g/cm3 iodine in ethanol solution, the reaction
was then refuxed for 12 h. The solvent was evaporated
to obtain a brown oil, which was dissolved in 50 cm3 of
CH2Cl2, and washed three times with 30 cm3 of water. After
the organic phase was dried over Na2SO4, the solvent was
evaporated to obtain a yellow oil, 8.2 g with a yield of 87%
(2E,4E:2E,4Z=89.6:10.4). The product can be used directly
a white granular solid. The solid was fltered and washed
with 20 cm3 of ether and 20 cm3 of ethyl acetate, respec-
tively. The obtained solid was dried in vacuum, 14.9 g with
a yield of 91%. The product can be used directly in the next
1
step without further purifcation. H NMR (DMSO-d6):
δ=7.94–7.73 (m, 15H, Ar–H), 7.47 (dd, J=15.2, 11.8 Hz,
0.53H,=CHCH2-), 7.18 (dd, J=15.4, 9.8 Hz, 0.47H), 6.28
(d, J = 9.0 Hz, 1H, = CH-), 6.25–5.92 (m, 1H, = CHCO-),
5.96–5.81 (m, 1H, = CH-), 4.12 (dq, J =14.1, 7.1 Hz, 2H,
-CH2CH3), 3.67 (q, J = 6.4 Hz, 2H, = CHCH2-), 1.66 (dt,
J = 8.9, 4.4 Hz, 2H, -CH2-), 1.20 (dt, J = 8.7, 7.1 Hz, 3H,
-CH3), 1.00–1.13 (m, 2H, -CH2-) ppm; 13C NMR (DMSO-
d6): δ = 166.70, 145.116, 143.05, 139.67, 135.44, 135.44,
135.41, 134.13, 134.03, 130.82, 130.69, 129.74, 127.88,
122.42, 120.13, 119.31, 118.46, 60.41, 33.31, 28.59, 20.77,
14.66 ppm; HRMS (ESI): m/z calcd. for C28H30O2P+
429.1983, found 429.2011.
1
in the next step without further purification. H NMR
(DMSO-d6): δ = 7.53 (dd, J = 15.2, 11.7 Hz, 0.9H, = CH),
7.22 (dd, J=15.3, 10.0 Hz, 0.1H,=CH), 6.27 (d, J=5.8 Hz,
1H, = CH-), 5.99–5.85 (m, 2H, = CH), 4.46 (s, 1H, -OH),
4.13 (q, J=7.4 Hz, 2H, -OCH2CH3), 3.43 (t, J=7.8 Hz, 2H,
-CH2OH), 2.36–2.15 (m, 2H, = CHCH2-), 1.52–1.57 (m,
2H, -CH2-), 1.22 (t, J=7.1, 3H, -CH2CH3) ppm; 13C NMR
(DMSO-d6): δ = 166.74, 145.44, 145.26, 128.68, 119.44,
60.54, 60.13, 31.99, 29.49, 14.59 ppm; HRMS (ESI): m/z
calcd. for C10H16O3 ([M+H]+) 185.1178, found 185.1173.
Ethyl (2E,4E)-8-bromoocta-2,4-dienoate (4) [18] CBr4
(7.1 g, 21.3 mmol) was added to a solution of 10.8 g of Ph3P
(41.1 mmol) in 100 cm3 of CH2Cl2 cooled in ice bath, and
the reaction was stirred for 1 h. To the reaction was added
a solution of 7.8 g of compound 3 (42.3 mmol) in 10 cm3
of CH2Cl2, the reaction was stirred for 2 h in ice bath and
another 2 h at ambient temperature. The solvent was evapo-
rated to obtain a viscous yellow solid, 50 cm3 of n-hexane
was added to the viscous solid and stirred vigorously until
the mixture was dispersed into a granular solid, the solid
was fltered and washed with n-hexane (2 × 20 cm3). The
fltrate was evaporated to give 4 as a light-yellow oil, which
was used directly in the next reaction, 8.4 g with a yield of
81%. 1H NMR (DMSO-d6): δ=7.53 (dd, J=15.1, 11.9 Hz,
0.05H,=CH-), 7.21 (dd, J=15.4, 10.0 Hz, 0.95H,=CH-),
6.35–6.21 (m, 2H,=CH-), 5.90 (d, J=15.4 Hz, 1H,=CH-),
4.11 (q, J=7.1 Hz, 2H, -CH2CH3), 3.53 (t, J=6.6 Hz, 2H,
-CH2-), 2.28 (q, J = 7.2 Hz, 2H, = CHCH2-), 1.89–1.96
(m, 2H, -CH2-) ppm; 13C NMR (DMSO-d6): δ = 166.72,
145.21, 143.40, 129.45, 119.94, 60.22, 31.61, 31.22,
31.15, 14.64 ppm; HRMS (ESI): m/z calcd. for C10H15BrO2
([M + H]+) 247.0334 and 249.0313, found 247.0336 and
249.0309.
Ethyl (2E,4E,8Z,10E,12E)-tetradeca-2,4,8,10,12-pentae-
noate (6, C16H22O2) A mixture of 14.2 g of compound 5
(27.9 mmol), 2.67 g of (2E,4E)-2,4-hexadienal (27.8 mol),
and 36.4 g of Cs2CO3 (55.9 mmol) in 100 cm3 of CH2Cl2
was refuxed for 24 h under nitrogen. After cooling to ambi-
ent temperature, 15 g of diatomite was added and stirred for
30 min. The solid was fltered and washed with 20 cm3 of
CH2Cl2, combined organic layer was concentrated to obtain
a yellow viscous oil. Subsequently 50 cm3 of n-hexane was
added to the oil and the mixture was stirred vigorously at
ambient temperature for 30 min. The solid was fltered and
washed with 60 cm3 of n-hexane, combined organic layer
was concentrated to obtain a pale-yellow oil. The crude
oil was purifed by fash silica gel column chromatography
(ethyl acetate-petroleum ether, 1:30) to give a colorless oil,
5.42 g with a yield of 79%. 1H NMR (DMSO-d6): δ=7.49
(dd, J = 15.2, 11.7 Hz, 0.38H, = CH-), 7.20 (dd, J = 15.3,
9.9 Hz, 0.62H,=CH-), 6.74–6.34 (m, 1H,=CH-), 6.35–6.25
(m,1H,=CH-), 6.21 (d, J=11.3, 1H,=CH-), 6.18–6.11 (m,
1H,=CH-), 6.07 (d, J=20.6 Hz, 1H,=CH-), 6.03–5.91 (m,
1H, = CH-), 5.87 (d, J = 15.2 Hz, 1H, = CH-), 5.55–5.32
(m 1H, = CH-), 4.09–4.16 (m, 2H, -CH2CH3) 2.32 (dt,
J=22.7, 7.4 Hz, 2H,=CHCH2-), 2.22 (dt, J=11.3, 5.4 Hz,
2H, = CHCH2-), 1.74 (d, J = 6.9 Hz 3H, = CHCH3), 1.21
(td, J = 6.8 Hz, 2H, -CH2CH3) ppm; 13C NMR (DMSO-
d6): δ = 166.69, 145.28, 139.48, 133.65, 132.36, 130.55,
130.15, 129.79, 129.10, 126.03, 119.74, 60.17, 32.09, 26.92,
18.56, 14.62 ppm; HRMS (ESI): m/z calcd. for C16H22O2
([M+H]+) 247.1698, found 247.1698.
((4E,6E)-8-Ethoxy-8-oxoocta-4,6-dien-1-yl)triphe-
nylphosphonium bromide (5, C28H30BrO2P) A solution
of 8.5 g of Ph3P (32.4 mmol) and 8.0 g of compound 4
(32.4 mmol) in 30 cm3 of acetonitrile was refuxed 24 h
under nitrogen. The solvent was evaporated to obtain a
colorless oil. 20 cm3 of ether was added to the oil, which
was placed in the refrigerator for 2 h, then ground to obtain
(2E,4E,8Z,10E,12E)-Tetradeca-2,4,8,10,12-pentaenoic
acid (7) [9] A mixture of 5.2 g of compound 6 (20.8 mmol)
and 3.2 g of NaOH (80 mmol) in 20 cm3 of methanol and
40 cm3 of water was refuxed for 2 h. The solvent was con-
centrated and 20 cm3 of water was added to the solution.
After washing with ether (3 × 50 cm3), the aqueous phase
was adjust to pH 1 with hydrochloric acid (1 mol/dm3). Then
1 3

Synthesis of hydroxy-γ-sanshool
549
the aqueous phase was extracted with CH2Cl2 (3×50 cm3),
the combined organic layer was washed with brine, dried
over Na2SO4, and evaporated to obtain a yellow sticky solid.
The solid was recrystallized with 1% ethyl acetate in n-hex-
ane solution, 2.4 g with a yield of 52%. 1H NMR (CDCl3):
δ = 7.32 (dd, J = 15.3, 9.9 Hz, 1H, = CH-), 6.53–6.23 (m,
1H,=CH-), 6.24–6.19 (m, 1H,=CH-), 6.17 (s, 1H,=CH-),
6.14 (d, J=4.1 Hz, 1H,=CH-), 6.08 (dq, J=11.6, 2.2 Hz,
1H, = CH-), 6.02 (t, J = 11.0 Hz, 1H, = CH-), 5.78 (dd,
J = 15.3, 2.2 Hz, 1H, = CH-), 5.74–5.56 (m, 1H, = CH-),
5.57–5.28 (m, 1H), 2.29 (tdd, J = 19.8, 10.4, 6.4 Hz,
4H, =CHCH2-), 1.76 (td, J=6.6, 1.4 Hz, 3H, -CH3) ppm;
13C NMR (CDCl3): δ = 172.74, 147.44, 145.11, 133.61,
131.85, 130.37, 129.74, 129.58, 128.81, 125.33, 118.72,
33.15, 26.96, 18.51 ppm; HRMS (ESI): m/z calcd. for
C14H18O2 ([M+Na]+) 241.0728, found 241.0729.
133.65, 132.41, 130.14, 127.66, 126.30, 126.07, 124.13,
69.97, 50.26, 27.71, 20.74, 17.56, 16.99 ppm; HRMS (ESI):
m/z calcd. for C18H27NO2 ([M + Na]+) 312.1940, found
312.1935.
Supplementary Information The online version contains supplemen-
tary material available at https://doi.org/10.1007/s00706-021-02762-2.
Acknowledgements We thank the State Key Laboratory of Bio-
therapy, West China Hospital, Sichuan University for 1H NMR, 13C
NMR, and HRMS determination. This work was fnancially supported
by the Sichuan Provincial Administration of Traditional Chinese
Medicine2018HJZX04.
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mun 52:3532
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as an authentic sample in HPLC. H NMR (DMSO-d6):
δ = 8.03–7.87 (m, 1H, -NH), 7.50–7.14 (m, 1H, = CH-),
7.03 (s, 1H,=CH-), 6.28 (d, J=13.5 Hz, 1H,=CH-), 6.17
(t, J = 5.6, 1H, = CH-), 6.10 (d, J = 15.1 Hz, 1H, = CH-),
6.09–5.82 (m, 1H, = CH-), 5.82–5.76 (m, 1H, = CH-),
5.75 (d, J=6.9 Hz, 1H, =CH-), 5.63–5.39 (m 1H,=CH-),
3.16 (t, J = 5.9 Hz, 3H, -OH, -NHCH2-), 2.43–2.30 (m
2H, =CHCH2-), 1.80 (d, J=7.7 Hz, 2H, =CHCH2-), 1.25
(d, 3H, = CHCH3), 1.09–1.06 (m, 6H, -CH3, -CH3) ppm;
13C NMR (DMSO-d6): δ=166.01, 139.58, 138.02, 134.04,
18. Cooper SP, Booker-Milburn KI (2015) Angew Chem 127:6596
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