Facial synthesis of key intermediate of obeticholic acid via Pd-catalyzed Kumada-Tamao-Corriu cross-coupling reaction

Article abstract of DOI:10.1016/j.steroids.2020.108657

Obeticholic acid (OCA) is used to treatment for Primary Biliary Cholangitis and other Famesoid X Receptor related diseases. Through the palladium catalyzed Kumada-Tamao-Corriu cross-coupling reaction, a novel and efficient method for synthesis of OCA with satisfied yield was successfully developed. The absolute configuration of the key intermediate was confirmed by Single-crystal X-ray Diffraction. It affords good strategy for large-scale synthesis of OCA.

Full text of DOI:10.1016/j.steroids.2020.108657

Steroids160(2020)108657
Contents lists available at ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
Facial synthesis of key intermediate of obeticholic acid via Pd-catalyzed
Kumada-Tamao-Corriu cross-coupling reaction
Xiangjie Dia,b,c, Jie Hanb,c, Sheng Zoub, Xia Weib,c, Qingfei Huangb, Jin Zhub, Yuanhua Wangd,
Liu Zhonga, Qiwei Wanga,b
a Department of Chemistry, Xihua University, Chengdu 610039, China
b Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
c University of Chinese Academy of Sciences, Beijing 100049, China
d College of Chemistry, Sichuan University, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Obeticholic acid (OCA) is used to treatment for Primary Biliary Cholangitis and other Famesoid X Receptor
related diseases. Through the palladium catalyzed Kumada-Tamao-Corriu cross-coupling reaction, a novel and
efficient method for synthesis of OCA with satisfied yield was successfully developed. The absolute configuration
of the key intermediate was confirmed by Single-crystal X-ray Diffraction. It affords good strategy for large-scale
synthesis of OCA.
Obeticholic acid
Key intermediate
Catalyzed
Cross-coupling reaction
1. Introduction
Herein, we designed and accomplished a novel and economical
synthetic method of intermediate 6-alpha vinyl-7-KLCA (4) under mild
Obeticholic acid (OCA) is a semi-synthetic bile acid analogue stu-
died and patented by Pellicciari et al which was reported to treat
Primary biliary cholangitis (PBC) and Nonalcoholic steatohepatitis
(NASH) [1–3]. As a 6-ethyl derivative of the natural human Bile Acid,
the OCA is a first-in-class selective FXR (Farnesoid X Receptor) agonist
which is ∼100-fold more potent than the chenodeoxycholic [4]. Except
the PBC and NASH, the OCA is taken as the candidate drug for other
liver diseases and other FXR related disorders, such as alcoholic hepa-
titis, obesity patients with gallstone disease, portal hypertension and
bile acid diarrhea [5,6].
Although the OCA is an ideal chemical tool to study the function of
FXR, the present synthesis methods suffered from harsh conditions or
low yields to obtain the key intermediate 6-alpha-ethyl-7-KLCA (6-
alpha-ethyl-7-keto-lithocholic acid), which limited the large-scale pre-
paration of OCA. As described in Scheme 1 route a, air sensitive strong
base such as t-BuLi was needed to generate carbanion at position 6 from
7-KLCA, which in situ reacted with ethyl bromide to provide the 6-
alpha-ethyl-7-KLCA (II) in 12% yield [7]. As shown in Scheme 1 route
b, an alternative method using Mukaiyama-aldol reaction was devel-
oped to synthesize the key intermediate with the yield of 50% [8]. The
key intermediate (IV) of this route was constructed through reaction of
water sensitive silyl enol ether (III) with acetaldehyde at −68 ℃. It is
urgent to develop an easily operated synthetic route of OCA under mild
reaction conditions.
condition using Kumada cross-coupling from commercially available
cholic acid. It could be reduced by hydrogenation, then deprotected and
transposed to OCA under alkaline conditions as reported method in the
previous literature (Scheme 2) [9]. To our knowledge, this is the first
report about synthesizing OCA by using catalyzed cross-coupling re-
action in a facial condition.
First, the carboxyl group of 7-KLCA is transformed to methyl ester
(compound 1). Subsequently, the hydroxyl group is protected by acetyl
group to obtain compound 2. Then, the compound 2 is treated with
hydrobromic acid and bromine to give the alpha-carbonyl brominated
compound 3, which then coupled with vinyl magnesium bromide to
obtain compound 4 under palladium catalyst system. It’s noted that
inversion of configuration of 6-carbon was observed. The beta config-
uration of compound 4 was confirmed by X-ray analysis. Compound 5
was obtained from compound 4 by hydrogenation. Under alkaline
conditions, acetyl and methyl ester group were removed to obtain
compound 6. At last, the compound 6 was reduced by sodium bor-
ohydride to provide desired obeticholic acid.
2. Experimental
2.1. General procedures
All reagents and chemicals were purchased from commercial
E-mail addresses: qfhuang@cioc.ac.cn (Q. Huang), yhwang@scu.edu.cn (Y. Wang), wqw@cioc.ac.cn (Q. Wang).
https://doi.org/10.1016/j.steroids.2020.108657
Received 5 February 2020; Received in revised form 29 April 2020; Accepted 14 May 2020
Availableonline18May2020
0039-128X/©2020ElsevierInc.Allrightsreserved.

X. Di, et al.
Steroids160(2020)108657
O
O
20
O
O
22
21
17
18
R2
12
OH
O
R2
O
24
a
route
23
X
11
9
OH
13
19
5
C
D
16
1
2
key step
strong base
low temperature
14
O
15
R1
10
8
A
B
6
R1
3
HO
O
O
O
HO
O
O
7
4
7-KLCA
I
II
OCA
key step
strong base
low temperature
b
route
O
O
O
O
O
R4
R4
O
O
OH
R4
O
low temperature
R3
O
R3
R3
O
R3
O
O
O
O
HO
O
III
X=Br or I
IV
V
OCA
R1=Bn, THP, MOM
R2=Me, Bn
R3=TMS, TBDMS
R4=Me,Et
Scheme 1. Previously reported synthesis routes.
O
O
O
OH
O
O
a
b
c
O
HO
O
HO
O
O
O
2
1
7-KLCA
by-product
O
O
O
O
O
O
f
d
e
O
O
O
O
O
O
O
O
O
Br
3
5
4
O
O
OH
OH
g
HO
O
HO
OH
6
OCA
Scheme 2. Synthesis of obeticholic acid from 7-KLCA. Reagents and conditions: (a) H2SO4, MeOH, rt, 99%; (b) Ac2O, Pyridine, DMAP, 93%; (c) 48% HBr, Br2, rt,
76%; (d) Pd(PPh3)4, (S,S)-Ph-BOX, CH2 = CHMgBr, THF, rt, 31%; (e) Pd/C, H2, MeOH, 55 °C, 99%; (f) NaOH, H2O, 95 °C, 2 h, 95%; (g) NaOH, H2O, NaBH4, 75 °C,
5 h, 72%.
suppliers and used without further purification unless otherwise stated.
When needed, the reactions were carried out in oven-dried glassware
under a positive pressure of dry N2 or Ar. Column chromatography was
performed on silica gel (QingDao Huanghai, 100–200 mesh) using the
indicated eluents. Thin-layer chromatography was carried out on silica
gel plates (QingDao Huanghai) with a layer thickness of 0.25 mm. 1H
(300 MHz) and 13C (75 MHz) NMR spectra were recorded on Bruker
300 MHz spectrometer with CDCl3 or CD3OD as solvent and tetra-
methylsilane (TMS) as the internal standard. All chemical shift values
were reported in units of δ (ppm). The following abbreviations were
used to indicate the peak multiplicity: s = singlet; d = doublet;
t = triplet; m = multiplet; br = broad. High-resolution mass data were
obtained on a Bruker micro TOF-Q II spectrometer.
2.2. Chemical synthesis
2.2.1. Methyl 3α-dihydroxy-7-keto-5β-cholan-24-UDCA (1)
To a solution of 7-KLCA (10.01 g, 21 mmol) in MeOH (280 mL) was
2

X. Di, et al.
Steroids160(2020)108657
added H2SO4 (6 mL) at room temperature. The reaction mixture was
refluxed for 1 h, and then concentrated. The residue was dissolved in
CH2Cl2 (200 mL). Organic layer was washed with H2O and brine, dried
over anhydrous Na2SO4 and concentrated to give compound 1 (10.29 g,
99%) as a white solid. IR (ATR) cm−1: 3526, 3447, 2937, 2870, 1739,
1718, 1688, 1637. 1H NMR (300 MHz, CDCl3): 3.60 (1H, s, 24-OAc),
3.53 (1H, tt, 3-H), 2.80(1H, dd, 8-H), 2.37 (1H, s, 3-OH), 1.14(3H, s,
18-H), 0.87 (3H, d, 20-H), 0.59 (3H, s, 19-H); 13C NMR (75 MHz,
CDCl3) δ = 212.18, 174.45, 77.42, 77.00, 76.58, 70.41, 54.58, 51.28,
49.27, 48.75, 45.93, 45.19, 42.55, 42.43, 38.77, 37.11, 35.01, 34.93,
33.99, 30.83, 30.77, 29.59, 28.07, 24.59, 22.85, 21.47, 18.15, 11.83.
HRMS (ESI): calcd for C25H40O4 [M+Na]+, 427.2824, found 427.2824.
72.58, 61.80, 54.72, 51.38, 50.55, 48.61, 46.01, 42.68, 42.43, 38.68,
35.89, 35.14, 34.42, 30.94, 30.90, 28.11, 25.58, 25.05, 24.71, 21.38,
21.20, 18.27, 11.96. HRMS (ESI): calcd for C29H44O5 [M + Na]+
495.3086, found 495.3184.
,
2.2.5. Methyl 3α-acetoxy-6β-ethyl-7-keto-5β-cholan-24-UDCA (5)
To a solution of 4 (2.63 g, 5.6 mmol) in MeOH (26 mL), Pd/C
(0.26 g, 10% w/w) was added at room temperature. The reaction
mixture was heated to reflux and stirred for 4 h. The mixture was fil-
tered with diatomite and the filtrate was evaporated to dryness to get
compound 5 (2.64 g, 99%) as a colorless oil. IR (ATR) cm−1: 3448,
2950, 2868, 1742, 1703. 1H NMR (300 MHz, CDCl3) δ 4.63 (s, 1H), 3.64
(s, 3H), 2.54 (t, J = 11.3 Hz, 1H), 2.33 (dd, J = 12.8, 7.6 Hz, 1H), 2.20
(dd, J = 19.0, 12.5 Hz, 2H), 1.97 (s, 4H), 1.90 (t, J = 11.2 Hz, 3H),
1.86–1.58 (m, 8H), 1.56–1.03 (m, 17H), 0.90 (d, J = 6.1 Hz, 4H),
0.86–0.75 (m, 4H), 0.65 (s, 3H). 13C NMR (75 MHz, CDCl3) δ = 215.21,
215.10, 174.60, 170.55, 72.73, 61.83, 54.77, 51.43, 49.19, 48.62,
45.49, 42.90, 42.45, 38.73, 35.56, 35.23, 35.18, 34.91, 30.98, 30.94,
29.64, 28.13, 26.46, 25.87, 25.69, 24.84, 21.43, 21.27, 18.30, 13.01,
12.05. HRMS (ESI): calcd for C26H44O4 [M + Na]+, 443.3135, found
443.3137.
2.2.2. Methyl 3α-acetoxy-7-keto-5β-cholan-24-UDCA (2)
To a solution of 1 (10.29 g, 25 mmol) in CH2Cl2 (90 mL) stirred at
0 °C, Ac2O (6 mL, 63.4 mmol), TEA (10.5 mL, 75.3 mmol) and DMAP
(0.16 g, 1.27 mmol) were added at 0 °C, then return to room tempera-
ture. The reaction mixture was stirred overnight. The reaction mixture
was washed with H2O and brine, dried with anhydrous Na2SO4 and
concentrated to give 2 (10.57 g, 93%) as a yellow solid. IR (ATR) cm−1
:
3441, 3389, 3018, 2978, 2952, 2898, 2868, 2852, 1735, 1705. 1H NMR
(300 MHz, CDCl3): 4.65 (1H, tt, 3-H), 3.62 (1H, s, 24-OCH3), 2.83 (1H,
dd, 8-H), 1.96 (3H, s, 3-Ac), 1.17 (3H, s, 18-H), 0.87 (3H, d, 20-H), 0.62
(3H, s, 19-H) 13C NMR (75 MHz, CDCl3) δ 211.63, 211.49, 174.47,
170.36, 77.42, 77.00, 76.58, 72.83, 54.74, 51.34, 49.39, 48.83, 45.76,
45.15, 42.67, 42.55, 38.86, 35.11, 35.08, 33.75, 33.04, 30.95, 30.91,
29.58, 28.16, 25.97, 24.69, 22.92, 21.64, 21.16, 18.28, 11.96. HRMS
(ESI): calcd for C27H42O5 [M+Na]+, 469.2930, found 469.2932.
2.2.6. 3α-dihydroxy-6α-ethyl-7-keto-5β-cholan-24-UDCA (6)
A 30% aqueous sodium hydroxide (10 mL) was added into a round
bottom flask containing compound 6 (1.00 g, 2.11 mmol, 1equiv). The
mixture was stirred at 70 °C for 24 h and then return to room tem-
perature. The mixture was neutralized to pH = 4 by 1 M/L HCl. The
organic phase was separated, dried with anhydrous Na2SO4 and con-
centrated to provide compound 8 as colorless oil (0.84 g, 95%). This
compound can be crystalized by EtOH to provide get off-white solid. IR
(ATR) cm−1: 3395, 2968, 2940, 2871, 2624, 1708. 1H NMR (300 MHz,
CDCl3): δ 5.66 (s, 2H), 3.52 (s, 1H), 2.76–2.61 (m, 1H), 2.46–2.08 (m,
4H), 1.96 (d, J = 12.9 Hz, 2H), 1.86–1.74 (m, 4H), 1.69 (dd, J = 14.0,
6.9 Hz, 3H), 1.55–1.35 (m, 4H), 1.34–1.01 (m, 11H), 1.00–0.85 (m,
5H), 0.79 (dd, J = 14.3, 7.0 Hz, 3H), 0.63 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ 213.05, 179.54, 77.42, 77.00, 76.58, 71.15, 54.75, 51.97,
50.68, 49.89, 48.93, 43.68, 42.62, 38.94, 35.63, 35.16, 34.20, 31.56,
31.02, 30.73, 29.67, 28.23, 24.55, 23.47, 21.82, 18.77, 18.29, 12.02,
11.93. HRMS (ESI): calcd for C26H44O4 [M + Na]+, 443.3135, found
443.3137.
2.2.3. Methyl 3α-acetoxy-6α-bromo-7-keto-5β-cholan-24-UDCA (3)
Bromine (1.5 mL, 0.5 mmol) was dissolved in acetic acid (21 mL) at
0 °C and added dropwise to compound 2 (10.57 g, 23.7 mmol) at 0 °C.
After finished, the solution of 48% HBr in water 1.1 mL was added into
mixture. The reaction mixture was stirred at room temperature with
TLC monitoring. After the reaction had finished, the mixture was
poured into NaHCO3 (aq), extracted with ethyl acetate 20 mL, then
washed with Na2S2O3(aq), water and brine, dried with anhydrous
Na2SO4 and concentrated. The residence was recrystallized by 10 mL
MeOH at −20 °C, then filtered to give compound 3(9.433 g, 76%) as a
light yellow solid. IR (ATR) cm−1: 3439, 2951, 2875, 2836, 1728. 1H
NMR (300 MHz, CDCl3): 5.17 (1H, d, 6-H), 4.66 (1H, tt, 3-H), 3.62 (1H,
s, 24-OCH3), 2.44 (1H, t, 8-H), 1.99 (3H, s, 3-Ac), 1.26 (3H, s, 18-H),
0.88 (3H, d, 20-H), 0.64 (3H, s, 19-H); 13C NMR (75 MHz, CDCl3) δ
201.28, 174.53, 170.30, 77.42, 77.00, 76.58, 72.37, 59.02, 54.68,
53.89, 51.45, 49.46, 49.25, 42.96, 42.76, 38.60, 38.05, 35.07, 33.90,
30.93, 30.85, 28.46, 28.09, 25.98, 24.40, 23.18, 21.68, 21.18, 18.28,
11.98. HRMS (ESI): calcd for C27H41BrO5 [M+Na]+, 547.2035, found
547.2034.
2.2.7. Obeticholic acid
Compound 8 (1.03 g,2.3 mmol, 1 equiv), NaOH (0.19 g, 4.7 mmol, 2
equiv), and H2O (7 mL) was added to the reaction flask. The mixture of
NaBH4 (0.10 g, 2.80 mmol, 1.2 equiv), NaOH (1.2 mg), and H2O (1 mL)
was added to the stirring mixture at room temperature, and then, the
mixture was stirred at 75 °C for 6 h. Then reaction mixture was cooled
to room temperature. Citric Acid aqueous solution was added slowly to
the reaction mixture until pH = 6 and then the reaction mixture was
extracted with CH2Cl2 (10 mL) three times. The organic phase was dried
by anhydride Na2SO4 and evaporated to dryness to get OCA 0.81 g as a
white solid, yield: 86%. M.p.104.5–106.5 °C. [α]D25 + 5.1 (c 1 g/
100 mL MeOH). IR (ATR) cm−1: 3449, 2964, 2935, 2870, 2611, 1734,
1712. 1H NMR (300 MHz, CDCl3) δ 4.19 (s, 3H), 3.70 (s, 1H), 3.41 (s,
1H), 2.46–2.31 (m, 1H), 2.30–2.14 (m, 1H), 2.02–1.72 (m, 6H),
1.71–1.54 (m, 3H), 1.53–1.06 (m, 15H), 1.01 (d, J = 11.3 Hz, 1H), 0.90
(dd, J = 16.0, 6.0 Hz, 9H), 0.65 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
179.13, 77.42, 77.00, 76.58, 72.34, 70.98, 55.78, 50.41, 45.14, 42.72,
41.16, 40.00, 39.57, 35.47, 35.40, 33.76, 33.15, 31.04, 30.81, 30.39,
28.16, 23.64, 23.12, 22.22, 20.72, 18.24, 11.76, 11.64. HRMS (ESI):
calcd for C26H44O4 [M+Na]+, 443.3135, found 443.3137.
2.2.4. Methyl 3α-acetoxy-6β-vinyl-7-keto-5β-cholan-24-UDCA (4)
To a solution of 3 (9.43 g, 17.9 mmol) in anhydride THF (94 mL), Pd
[P(Ph)3]4 (0.16 g, 0.9 mmol) and (S,S)-Ph-BOX (0.30 g, 0.9 mmol) was
added into a Schlenk flask under nitrogen atmosphere at 0 °C. Then
vinylmagnesium bromide (1 M/L in THF, 59 mL) was added dropwise
into the mixture and stirred overnight. The reaction was quenched with
water (1 mL) then filtered with diatomite. The filtrate was concentrated
and extracted with 100 mL ethyl acetate, then evaporated to oil and
then purified with silica gel (petroleum ether: ethyl acetate = 20:1) to
get compound 4 as a white solid (2.63 g, 31%) and compound 2 (4.82 g,
60%). M.p. 146.2–146.8 °C. [α]D25 + 63.3 (c 1 g/100 mL MeOH). IR
(ATR) cm−1: 3449, 3389, 2946, 2874, 1739, 1703, 1653, 1626. 1H
NMR (300 MHz, CDCl3): 6.02 (1H, ddd, 6-vinyl-CH), 5.00 (1H, dd, 6-
vinyl-AH) 4.78 (1H, dd, 6-vinyl-BH), 4.64 (1H, tt, 3-H), 3.63 (1H, s, 24-
OCH3), 2.79 (1H, d, 6-H), 2.69 (1H, t, 8-H), 1.99 (3H, s, 3-Ac), 1.26
(3H, s, 18-H), 0.88 (3H, d, 20-H), 0.64 (3H, s, 19-H) 13C NMR (75 MHz,
CDCl3) δ 212.29, 174.50, 170.42, 138.37, 115.41, 77.42, 77.00, 76.58,
3. Results and discussion
The synthetic route of OCA is shown in Scheme 2. Compound 1 was
obtained by methylation with MeOH and H2SO4 in 90% yield, then
3

X. Di, et al.
Steroids160(2020)108657
Fig. 1. The single-crystal x-ray diffraction of compound 3(a) and compound 4(b).
esterification of 3α-OH with Ac2O in the presence of pyridine and
DMAP provided ester 2 in 90% yield. Compound 3 was prepared by Br2
with HBr in 94% yield. The key intermediate 4 was obtained by reac-
tion of compound 3 with vinylmagnesium bromide solution in anhy-
dride THF catalyzed by Pd(PPh3)4 and (S,S)-Ph-BOX at room tem-
perature with 31% yield. In addition, compound 2 was recovered as the
byproduct in 60% yield, which could be reutilized to prepare com-
pound 3. Compound 4, the key intermediate, was successfully synthe-
sized for the first time. To confirm the absolute configuration of com-
pound 3 and 4, we successfully obtained their single crystal and
characterized the absolute configuration by single-crystal x-ray dif-
fraction. As shown in Fig. 1, configuration inversion of 6-carbon from
alpha (compound 3) to beta (compound 4) was detected after cross-
coupling reaction. Configuration at 6-carbon of compound 5 was re-
tained after reduction of compound 4 under H2 and Pd/C in MeOH at
75 °C. Demethylation and deacetylation were performed with NaOH in
H2O with configuration conversion to obtained compound 6 in the yield
of 95%. In this step, compound 5 was converted into enol formula
through keto-enol tautomerism under base catalyzed condition and
then transferred into 6-alpha-ethyl ketone. As show in Fig. 1(b), ring A
is twist-boat form and 6-ethyl is in axial bond, so compound 4 is a
thermodynamically unstable species. Like compound 4, compound 5 is
also a thermodynamically unstable species, so after forming an enol
structure, it will release energy and convert into thermodynamically 6-
alpha ethyl ketone. Finally, OCA was afforded by stereoselective re-
duction of 7-ketone group to 7β-OH of compound 6 in 93% yield. The
total yield of this route was up to 15%. The higher yield would be
obtained when the byproduct of compound 2 generated in the coupling
reaction was reutilized.
and IR. The absolute configuration of the key intermediates (com-
pounds 3 and 4) was confirmed by single crystal X-ray diffraction. We
hope that this work can provide a new strategy for the synthesis of bile
acids and promote the development of new synthetic methods of bile
acids analogs. The application of this method to other bile acid analogs
is under study.
Acknowledgement
We are gratefully acknowledged, the Science
Department of Sichuan Province (2019JDJQ0010).
& Technology
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.steroids.2020.108657.
References
[1] S. Fiorucci, S. Cipriani, A. Mencarelli, F. Baldelli, G. Bifulco, A. Zampella, Farnesoid
X receptor agonist for the treatment of liver and metabolic disorders: focus on 6-
ethyl-CDCA, Mini Rev. Med. Chem. 11 (9) (2011) 753–762.
[2] L. Adorini, M. Pruzanski, D. Shapiro, Farnesoid X receptor targeting to treat non-
alcoholic steatohepatitis, Drug Disc. Today 17 (17–18) (2012) 988–997.
[3] B.A. Neuschwander-Tetri, R. Loomba, A.J. Sanyal, J.E. Lavine, M.L. Van Natta,
M.F. Abdelmalek, N. Chalasani, S. Dasarathy, A.M. Diehl, B. Hameed, Farnesoid X
nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohe-
patitis (FLINT): a multicentre, randomised, placebo-controlled trial, Lancet 385
(9972) (2015) 956–965.
[4] R. Pellicciari, G. Costantino, E. Camaioni, B.M. Sadeghpour, A. Entrena,
T.M. Willson, S. Fiorucci, C. Clerici, A. Gioiello, Bile acid derivatives as ligands of the
farnesoid X receptor. Synthesis, evaluation, and structure− activity relationship of a
series of body and side chain modified analogues of chenodeoxycholic acid, J. Med.
Chem. 47 (18) (2004) 4559–4569.
[5] L. Verbeke, R. Farre, J. Trebicka, M. Komuta, T. Roskams, S. Klein, I.V. Elst,
P. Windmolders, T. Vanuytsel, F. Nevens, Obeticholic acid, a farnesoid X receptor
agonist, improves portal hypertension by two distinct pathways in cirrhotic rats,
Hepatology 59 (6) (2014) 2286–2298.
[6] Justine H. Zhang, Jonathan D. Nolan, Sarah L. Kennie, Ian M. Johnston, Tracy Dew,
Peter H. Dixon, Catherine Williamson, Julian R.F. Walters, Potent stimulation of fi-
broblast growth factor 19 expression in the human ileum by bile acids, Am. J.
Physiol. Gastrointestinal Liver Physiol. 304 (10) (2013) G940–G948, https://doi.org/
10.1152/ajpgi.00398.2012.
[7] R. Pellicciari, Steroids as agonists for FXR, Google Patents, 2006.
[8] A. Steiner H. Waenerlund Poulsen E. Jolibois Preparation, Uses and Solid Forms of
Obeticholic Acid PCT Int. Appl. WO2013/192097, 2013.
[9] D. Yu, D.L. Mattern, B.M. Forman, An improved synthesis of 6α-ethylchenodeoxy-
cholic acid (6ECDCA), a potent and selective agonist for the Farnesoid X Receptor
(FXR), Steroids 77 (13) (2012) 1335–1338.
4. Conclusion
In summary, we have successfully developed a novel efficient syn-
thetic route of Obeticholic acid. Through Kumada-Tamao-Corriu cou-
pling reaction, 6-bromo KLCA (compound 3) could couple with vinyl
magnesium bromide to construct 6-vinyl intermediate (compound 4),
then converted to the target compound acid. The by-product of the
cross-coupling reaction is the 6-carbon dehalogenated intermediate
(compound 2), which can be reutilized. This method shows good yield
and avoids the use of low temperature and strong alkali conditions. All
the compounds have been well verified by HRMS, 1H NMR, 13C NMR
4