Note: Descriptions are shown in the official language in which they were submitted.
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PROCESSES OF PREPARING 3-FLUOR0-5-(01S,2AR)-1,3,3,4,4-PENTAFLUOR0-2A-
HYDROXY-2,2A,3,4-TE TRAHYDRO-1H-CYCLOPENTAICDJINDEN-7-YL)OXY)-
BENZONITRILE
Cross-Reference to Related Applications
This application is a PCT International Application claiming the benefit of
PCT
International Application No. PCT/CN2020/121745, filed on October 19, 2021,
which is
incorporated by reference herein in its entirety,
Field of the disclosure
Disclosed herein are processes for preparing 3-fluoro-5-(41S,2aR)-1,3,3,4,4-
pentafluoro-
2a-hydroxy-2,2a,3,4-tetrahydro-1H-cyclopenta[cdlinden-7-yl)oxy)benzonitrile
(hereinafter
Compound (I)) having the structure:
NC F F
# 0 H
(I)
or a pharmaceutically acceptable salt thereof
Background
Compound (I) is a hypoxia inducible factor -2a (HIF-2a) inhibitor and is being
developed
for treating diseases mediated by aberrant activity of HIF-2a including
cancer, such as renal
cancer, glioblastoma, neuroblastoma, pheochromocytomas and paragangliomas,
somatostatinomas, hemangioblastomas, gastrointestinal stromal tumors (GIST),
pituitary tumors,
leiomyomas, leiomyosarcomas, polycythaemia, and retinal tumors and non-cancer
diseases such
as pulmonary artery hypertension (PAH), reflux esophagitis, hepatic steatosis,
NASH,
inflammatory disease such as inflammatory bowel disease, autoimmune disease
such as Graft-
versus-Host-Disease, and iron overload.
Synthesis of Compound (I) is disclosed in Example 5 of PCT Application
Publication No.
WO 2020/214853, filed on April 16, 2020. There is a need for alternative
processes that allow for
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large scale synthesis of Compound (I) in a cost-effective manner. The
processes disclosed herein
fullfill this and related needs.
Summary
Provided herein is a process that make it feasible to produce Compound (I) in
high purity,
including enantiomeric purity, and yield in a cost-effective manner and that
is suitable for use on a
commercial scale. Also, provided are processes for preparing certain
intermediates used in such
process.
In one aspect, provided is a process of preparing compound (11)
NC F F
F ''''OH
HO
(11)
comprising reducing the keto moiety of compound (10):
NC F F
# O'''OH
0
(10)
with:
(a) sodium borohydride in an organic solvent selected from a group
consisting of (i)
an alcohol containing acetic acid or trifluoroacetic acid, (ii) a cyclic
ether, and (iii) a mixture of a
cyclic ether and an alcohol wherein the cyclic ether of (ii) and the mixture
of a cyclic ether and an
alcohol of (iii) optionally contain acetic acid or trifluoroacetic acid; or
(b) lithium borohydride in a suitable organic solvent optionally
containing acetic acid
or trifluoroacetic acid.
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In a first embodiment of a second aspect, provided is a process of preparing
Compound (I):
NC F
110 0 OH
(I)
comprising:
(i) preparing compound (11):
NC F
F = 'OH
HO
(11)
comprising reducing the keto moiety of compound (10):
NC F
F .'"OH
0
(10)
with:
(a) sodium borohydride in an organic solvent selected from a group
consisting of (i)
an alcohol containing acetic acid or trifluoroacetic acid, (ii) a cyclic
ether, and (iii) a mixture of a
cyclic ether and an alcohol wherein the cyclic ether of (ii) and the mixture
of a cyclic ether and an
alcohol of (iii) optionally contain acetic acid or trifluoroacetic acid; or
(b) lithium borohydride in a suitable organic solvent optionally containing
acetic acid
or trifluoroacetic acid; and
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(ii) converting compound (11):
NC F F
110 0
HO
(11)
to Compound (I):
NC FE
0 OH
5
(I)
by reacting compound (11) with a deoxyfluorinating agent in the presence of an
organic
base in a suitable organic solvent.
In a second embodiment of a second aspect, the process of the first aspect,
further
10 comprises converting compound (11):
NC F F
10 0
OH
HO
(11)
to Compound (I):
NC FE
F OH
(I)
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by reacting compound (11) with a deoxyfluorinating agent in the presence of an
organic
base in a suitable organic solvent.
In a third aspect, provided is a process of preparing compound (10):
NC F F
F0OH
0
(10)
comprising reacting compound (9):
F F
OH
0
(9)
with 3-fluoro-5-hydroxybenzonitrile in the presence of a base in a suitable
organic solvent other
than dimethylformamide.
In a fourth aspect, the processes of the first aspect and each embodiment of
the second
aspect, further comprise preparing compound (10):
NC F F
F*OOH
0
(10)
by reacting compound (9):
F F
F
OH
0
(9)
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with 3-fluoro-5-hydroxybenzonitrile in the presence of a base in a suitable
organic solvent.
In a fifth aspect, provided is a process for preparing compound (9):
F F
, F
/OH
0
(9)
comprising carrying out oxidative cleavage of the vinylidene moiety of
compound (8):
F F
'OFH
(8)
with (i) sodium periodate in the presence of ruthenium chloride in aqueous
acetonitrile, (ii)
Oxone in the presence of ruthenium chloride in a suitable organic solvent, or
(iii) Ozone in a
suitable organic solvent.
In a sixth aspect, the processes of the third and fourth aspects, further
comprise preparing
compound (9):
F F
F
/OH
0
(9)
by carrying out oxidative cleavage of the vinylidene moiety of compound (8):
F F
, F
/OH
(8)
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with a suitable oxidizing agent in a suitable organic or aqueous organic
solvent.
In a seventh aspect, provided is a process for preparing compound (8):
F F
F
'OH
(8)
.. comprising performing intramolecular cyclization between the alkene and
bromo groups in
compound (7):
F F
''OH
Br
(7)
by treating compound (7) with a palladium catalyst in the presence of a base
in a suitable organic
solvent other than dimethylformamide.
In an eighth aspect, the processes of the fifth and sixth aspects, further
comprise preparing
compound (8):
F F
, F
(8)
by performing intramolecular cyclization between the alkene and bromo groups
in compound (7):
F F
./OH
Br
(7)
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with a palladium catalyst in the presence of a base in a suitable organic
solvent.
In a ninth aspect, provided is a process for preparing compound (7):
F F
, F
'OH
Br
(7)
comprising brominating compound (6):
F F
'OH
(6)
with 1,2-dibromo-1,1,2,2-tetrafluoroethane in the presence of a deprotonating
agent in a suitable
organic solvent.
In a tenth aspect, the processes of the seventh and eighth aspects, further
comprise
preparing compound (7):
F F
, F
'OH
Br
(7)
by treating compound (6):
F F
'OH
ii
(6)
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with a brominating agent in the presence of a deprotonating agent in a
suitable organic
solvent.
In an eleventh aspect, the processes of the ninth and tenth aspects, further
comprise
preparing compound (6):
F F
bH
(6)
by treating compound (5):
F
FF
F
0
(5)
with 4,4,5,5-tetramethy1-2-(prop-2-en-1-y1)-1,3,2-dioxaborolane in the
presence of (S)-2-43-(tert-
buty1)-2-hydroxybenzypamino)-N,N,3-trimethylbutanamide and a base in a
suitable organic
solvent.
In a twelfth aspect, the process of eleventh aspect, further comprises
preparing compound
(5):
F
110 FF
F
0
(5)
by treating compound (4):
F F F
0 op Br
(4)
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with an organolithium reagent in a suitable organic solvent.
In a thirteenth aspect, the process of twelfth aspect, further comprises
preparing compound
(4):
F F F
O Br
(4)
by treating compound (3):
F F
0
=0 Br
(3)
with a fluorinating agent in a suitable organic solvent.
In a fourteenth aspect, the process of thirteenth aspect, further comprises
preparing
compound (3):
F F
0
O Br
(3)
by treating compound (2):
F F
OH
O Br
(2)
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with an oxidizing agent in a suitable organic solvent.
In a fifteenth aspect, the process of fourteenth aspect, further comprises
preparing
compound (2):
F F
OH
0 Br
(2)
by treating compound (1):
,0
=Br
(1)
with ethyl 2-bromo-2,2-difluoroacetate in the presence of zinc metal,
trimethylsilyl chloride, and
1,2-dibromoethane in a suitable organic solvent.
Detailed Description
Definitions:
Unless otherwise stated, the following terms used in the specification and
claims are
defined for the purposes of this Application and have the following meaning:
As used herein, the term "reacting" or "treating" when describing a certain
process is used
as known in the art and generally refers to the bringing together of chemical
reagents in such a
manner so as to allow their interaction at the molecular level to achieve a
chemical or physical
transformation. The reacting steps of the processes described herein can be
conducted for a time
and under conditions suitable for preparing the identified product.
"Suitable organic solvent" refers to an organic solvent which, under the
reaction conditions
of the processes disclosed herein, does not enter into any appreciable
reaction with either the
reactants, intermediates an/or the products at the temperatures at which the
reactions are carried
out. A given reaction disclosed herein can be carried out in one organic
solvent or a mixture of
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two or more organic solvents. Examples of suitable organic solvents that can
be used in the
reactions described herein include: halogenated solvents such as carbon
tetrachloride, chloroform,
dichloromethane, and the like; ethers such as tetrahydrofuran, 2-
methyltetrahydrofuran,
1,3-dioxane,1,4-dioxane, diethyl ether, methyl t-butyl ether, and the like;
alcohols such as
methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, n-butyl
alcohol, tert-butyl
alcohol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, and the like; hydrocarbons
(including, for
example, alkane solvent) such as benzene, toluene, xylene, cyclohexane,
pentane, hexane,
heptane, and the like. Additional organic solvents that can be used in the
reactions described
herein include polar organic solvents including, but not limited to,
acetonitrile,
dimethylformamide, ethyl acetate, alcohols, and the like. When polar organic
solvents (e.g.,
alcohols, acetonitrile, DMF) contain water they are referred to herein as
aqueous organic solvent.
Depending on the reaction step, solvents that are suitable for the particular
reaction step can be
readily selected by a person skilled in the art.
For example, in the preparation of compound (2), besides, THF, the reaction
was also
.. carried out in MTBE, 2-methylTHF, or toluene solvent. In the preparation of
compound (3), the
reaction was also carried out in THFsolvent. In the preparation of compound
(4), the reaction was
also carried out in CHC13solvent. In the preparation of compound (5), the
reaction was also
carried out in 2-methyl THF, n-heptane, or MTBE solvent. In the preparation of
compound (8),
the reaction was also carried out in DMF, 1,4-dioxane, THF, 2-methyl THF,
toluene, oracetonitrile
.. solvent. In the preparation of compound (9), the reaction was also carried
out in a mixture of
DCM/ACN/water. In the preparation of compound (10), the reaction was also
carried out in DMF,
ACN, 2-methyl THF, or toluene solvent. In the preparation of compound (11),
the reaction was
also carried out in THF, CH3OH, TFA/THF, or HOAc/THF solvent. In the
preparation of
compound (I), the reaction was also carried out in DCM, CH3CN, 2-methyl THF,
ethyl acetate,
DMF, MTBE or toluene solvent.
In addition, the reactions were carried out at various temperatures. Reaction
temperatures
that were used in the preparation of compound (2) included 20 C, 40 C, 60
C, and refluxing.
Reaction temperatures that were used in the preparation of compound (3)
included 0 ¨ 15 C and
15 ¨ 25 C. Reaction temperatures that were used in the preparation of
compound (4) included
0 ¨ 10 C, 10 ¨ 20 C, 20 ¨ 30 C, and 30 ¨ 40 C. Reaction temperatures that
were used in the
preparation of compound (5) included -30 to -40 C, -40 to -50 C, -50 to -60
C, and -60 to -70
C. Reaction temperatures that were used in the preparation of compound (6)
included 35 C, 45
C, and 60 C. Reaction temperatures that were used in the preparation of
compound (7)
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included -100 to -80 C, -80 to -60 C, and -60 to -40 C. Reaction
temperatures that were used in
the preparation of compound (8) included 60 C, 70 C and refluxing. Reaction
temperatures that
were used in the preparation of compound (10) included 20 to 30 C, and 40 C.
Reaction
temperatures that were used in the preparation of compound (11) included 10 to
20 C and -5 to 5
C. And Reaction temperatures that were used in the preparation of compound (I)
included 20 to
30 C and -5 to 5 C.
Additionally, bases that were used in the preparation of compound (8) included
Na0Ac,
KOAc, and K2CO3;
brominating reagents that were used in the preparation of compound (7)
included CBr4 and
CF2BrCF2Br;
catalysts that were used in the preparation of compound (8) included
Pd(dppf)C12,
Pd2(dba)3/XPhos, Pd(0Ac)2/PPh3, and Pd(PPh3)C12;
fluorinating reagents that were used in the preparation of compound (4)
included DAST,
4-tert-buty1-2,6-dimethylphenylsulfur trifluoride, and HF/SF 4;
fluorinating reagents that were used in the preparation of compound (I)
included DAST,
PyFluor, AlkylFluor and SulfoxFluor;
oxidizing agents that were used in the oxidation of compound (2) to (3)
included
2-iodoxybenzoic acid (IBX), RuC13/NaBr03; TEMPO/NaC10, Mn02, and TPAP/NMO.
oxidizing agents that were used in the oxidation of compound (8) to (9)
included
.. RuC13/NaI04, RuCl3/0xone and 03; and
reducing agents that were used in the reduction of compound (10) to (11)
included LiBH4
and NaBH4.
The reactions of the processes described herein can be carried out in air or
under an inert
atmosphere. Typically, reactions containing reagents or products that are
substantially reactive
with air can be carried out using air-sensitive synthetic techniques that are
well known to the
skilled artisan.
The processes described herein can be monitored according to any suitable
method known
in the art. For example, product formation can be monitored by spectroscopic
means, such as
nuclear magnetic resonance spectroscopy (e.g., 1I-1 or 13C), infrared
spectroscopy,
spectrophotometry, or mass spectrometry; or by chromatography such as high
performance liquid
chromatography (HPLC) or thin layer chromatography. The compounds obtained by
the reactions
can be purified by any suitable method known in the art. For example,
chromatography (medium
pressure) on a suitable adsorbent (e.g., silica gel, alumina and the like),
HPLC, or preparative thin
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layer chromatography; distillation; sublimation, trituration, or
recrystallization. The purity of the
compounds, in general, are determined by physical methods such as measuring
the melting point
(in case of a solid), obtaining an NMR spectrum, or performing a HPLC
separation.
"Cyclic ether" refers to tetrahydrofuran, 2-methyltetrahydrofuran, or 1,4-
dioxane.
"Alcohol" refers to an aliphatic hydrocarbon compound that carries a hydroxy
group.
Representative examples include, but are not limited to, methanol, ethanol,
propanol, butanol, and
the like.
"About" as used herein means + 10%, preferably + 5% of listed value. For
example, a
reaction carried out at about 10 C includes 9 C, 11 C, and all temperatures
contained in
between 9 C and 11 C.
Embodiments:
1. In embodiment 1, provided is a process of preparing compound
(11)
NC F F
10 0
HO
(11)
comprising reducing the keto moiety of compound (10):
NC F F
1110 0
0
(10)
with:
(a) sodium borohydride in an organic solvent selected from a group
consisting of (i)
an alcohol containing acetic acid or trifluoroacetic acid, (ii) a cyclic
ether, and (iii) a mixture of a
cyclic ether and an alcohol; wherein the cyclic ether of (ii) and the mixture
of a cyclic ether and an
alcohol of (iii) optionally contain acetic acid or trifluoroacetic acid; or
(b) lithium borohydride in a suitable organic solvent optionally containing
acetic acid
or trifluoroacetic acid.
2. In embodiment 2, provided is a process of preparing Compound (I) as
described in
the first and second embodiments of the second aspect of the Summary.
2a. In embodiment 2a, provided is a process of preparing Compound
(I) as described in
the first embodiment of the second aspect of the Summary.
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2b. In embodiment 2b, provided is a process of preparing Compound
(I) as described
in the second embodiment of the second aspect of the Summary.
3. In embodiment 3, the process of embodiment 2, 2a or 2b is wherein the
deoxyfluorinating agent is diethylaminosulfur trifluoride, PhenofluorTm, N-
tosy1-4-chlorobenzene-
.. sulfonimidoyl fluoride, pyridine-2-sulfonyl fluoride, or AlkylFluor.
4. In embodiment 4, the process of embodiment 2, 2a (in step (ii)), 2b, or
3 is wherein
the organic solvent is halogenated hydrocarbon, cyclic ethers, ethers,
aromatic hydrocarbon, or a
polar solvent. Preferably, the organic solvent is dichloromethane,
acetonitrile, tetrahydrofuran,
2-methyltetrahydrofuran, ethylacetate, dimethylformamide, methyl tert-
butylether, or toluene.
5. In embodiment 5, the process of embodiment 2, 2a, or 2b is wherein the
deoxyfluorinating agent is pyridine-2-sulfonyl fluoride and the base is 1,8-
diazabicyclo-
[5.4.0]undec-7-ene or 7-methyl-1,5,7-triaza-bicyclo[4.4.0]dec-1-ene.
6. In embodiment 6, the process of embodiment 1, 2a, 2b or 2b is wherein
the
reduction of the keto group of compound (10) is carried out with sodium
borohydride in
.. tetrahydrofuran, 2-methyltetrahydrofuran, a mixture of tetrahydrofuran or 2-
methyltetrahydrofuran and methanol, tetrahydrofuran containing acetic acid or
trifluoroacetic acid,
2-methyltetrahydrofuran containing acetic acid or trifluoroacetic acid, or
methanol containing
acetic acid or trifluoroacetic acid.
7. In embodiment 7, the process of embodiment 6 is wherein the organic
solvent is a
mixture of tetrahydrofuran and methanol and the reaction is carried out at
about -5 C to about
C.
8. In embodiment 8, the process of embodiment 6 is wherein the organic
solvent is a
mixture of tetrahydrofuran and methanol and the reaction is carried out at
about -5 C to about 5
C.
25 9. In embodiment 9, the process of embodiment 5 is wherein the molar
ratio of 1,8-
diazabicyclo[5.4.0]-undec-7-ene to compound (11) is at least about 2 to about
1 and the organic
solvent is tetrahydrofuran.
10. In embodiment 10, the process of embodiment 5 or 9 is wherein
the reaction is
carried out at 20 C to about 30 C.
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11. In embodiment 11, provided is process of preparing compound (10):
NC F F
F OH
0
(10)
comprising reacting compound (9):
F F
F
/OH
0
(9)
with 3-fluoro-5-hydroxybenzonitrile in the presence of a base in a suitable
organic solvent other
than dimethylformamide.
12. In embodiment 12, the process of any one of embodiments 1 to 10 further
comprises preparing compound (10):
NC F F
FP OOH
OH
0
(10)
by reacting compound (9):
FF
OH
0
(9)
with 3-fluoro-5-hydroxybenzonitrile in the presence of a base in a suitable
organic solvent.
13. In embodiment 13, the process of embodiment 11 or 12 is wherein the
base is an
inorganic base.
14. In embodiment 14, the process of embodiment 13 is wherein the inorganic
base is
cesium carbonate or potassium carbonate.
15. In embodiment 15, the process of any one of embodiments 11 to 14 is
wherein the
organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran,
dimethylformamide, acetonitrile, or
toluene.
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16. In embodiment 16, the process of embodiment 15 is wherein the organic
solvent is
tetrahydrofuran.
17. In embodiment 17, the process of any one of embodiments 11 to 16 is
wherein the
reaction is carried out at about 20 C to about 40 C.
18. In embodiment 17, the process of any one of embodiments 11 to 17
further
comprises crystallizing compound (10) from a mixture of an ether and an alkane
solvent.
19. In embodiment 19, the process of embodiment 18 is wherein
compound (10) is
crystallized from a mixture of methyl tert-butyl ether and n-heptane.
20. In embodiment 20, provided is a process for preparing compound
(9):
FF
F)5<
'F
F
OH
0
(9)
comprising carrying out oxidative cleavage of the vinylidene moiety of
compound (8):
FF
/
, F
OH
(8)
with (i) sodium periodate in the presence of ruthenium chloride in aqueous
acetonitrile, (ii)
Oxone in the presence of ruthenium chloride in a suitable organic or aqueous
organic solvent, or
(iii) Ozone in a suitable organic or aqueous organic solvent.
21. In embodiment 21, the process of any one of embodiments 11 to
19 further
comprises preparing compound (9):
FF
, F
'OH
0
(9)
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by carrying out oxidative cleavage of the vinylidene moiety of compound (8):
F F
F
'OH
(8)
with a suitable oxidizing agent agent in a suitable organic or aqueous organic
solvent.
22. In embodiment 22, the process of embodiment 21 is wherein the oxidative
cleavage
of the vinylidene is carried out with (i) sodium periodate or Oxone in the
presence of ruthenium
chloride or (ii) Ozone.
23. In embodiment 23, the process of embodiment 21, is wherein the
solvent is a
mixture of dichloromethane, acetonitrile and water or the solvent is aqueous
acetonitrile.
24. In embodiment 24, the process of any one of embodiments 20 to 23 is
wherein the
oxidative cleavage of the vinylidene is carried out with sodium periodate in
the presence of
catalytic amount of ruthenium chloride in aqueous acetonitrile.
24a. In embodiment 24a, the process of any one of embodiments 20 to 24 further
comprises purification of compound (9) from a mixture of an ether and an
alkane solvent.
24b. In embodiment 24b, the process of embodiment 24a is wherein purification
of
compound (9) is from a mixture of methyl tert-butyl ether and n-heptane.
25. In embodiment 25, provided is a process for preparing compound
(8):
F F
OH
(8)
comprising performing intramolecular cyclization between the alkene and bromo
groups in
compound (7):
F F
, F
'OH
Br
(7)
by treating compound (7) with a palladium catalyst in the presence of a base
in a suitable organic
solvent other than dimethylformamide.
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26. In embodiment 26, the process of any one of embodiments 20 to 24
further
comprises preparing compound (8):
FF
, F
'OH
(8)
by performing intramolecular cyclization between the alkene and bromo groups
in compound (7):
F F
ADH
Br
(7)
with a palladium catalyst in the presence of a base in a suitable organic
solvent.
27. In embodiment 27, the process of embodiment 25 or 26 is wherein the
palladium
catalyst is Pd(PPh3)4, Pd(dppf)C12, Pd(PPh3)2C12, Pd(PPh3)2(0Ac)2,
Pd2(dba)3/XPhos, or Pd(1,2-
bis(diphenylphosphino)ethane)(0Ac)2, and the organic solvent is acetonitrile,
tetrahydrofuran,
2-methyltetrahydrofuran, toluene, 1,4-dioxane, or dimethylformamide.
28. In embodiment 28, the process of embodiment 27 is wherein the base is
sodium
acetate, potassium acetate, sodium carbonate, potassium carbonate or cesium
carbonate.
29. In embodiment 29, the process of any one of embodiments 25, 26, or 28
is wherein
the palladium catalyst is Pd(PPh3)2C12, the base is potassium acetate, and the
solvent is
acetonitrile.
30. In embodiment 30, the process of embodimen 29 is wherein the reaction
is carried
out between about 60 C to about 80 C.
31. In embodiment 31, provided is a process for preparing compound (7):
F F
ADH
Br
(7)
comprising brominating compound (6):
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F F
"OH
(6)
with 1,2-dibromo-1,1,2,2-tetrafluoroethane in the presence of a deprotonating
agent in a suitable
organic solvent.
32. In embodiment 32, the process of any one of embodiments 25 to 30
further
comprises preparing compound (7):
F F
"oH
Br
(7)
by treating compound (6):
F F
"OH
(6)
with a brominating agent in the presence of a deprotonating agent in a
suitable organic
solvent.
33. In embodiment 33, the process of embodiment 32 is wherein the
brominating agent
is carbon tetrabromide or 1,2-dibromo-1,1,2,2-tetrafluoroethane.
33a. In embodiment 33a, the process of embodiment 32 is wherein the
brominating
agent is bromotrichloromethane, 1,2-dibrorno-I,1,2,2-tetrachloroethane, 1,2-
dibrorno-I,1,2,2-
tetrafluoroetbane, carbon tetrabromide, N-bromosuccinimide, N-
bromophtbalimide,
/V-bromosaccharin, _AT-bromoacetamide, 1,3-di bromo-5,5-dirnethylhyda.ntoin,
dibromoisocyanuric
acid, monosodium brornoisocyanurate, brornodimethylsulfonium bromide, 5,5-
dibromomeldrum's
acid, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, bis(2,4,6-trimethylpyridine)-
bromonium
hexafluoropitosphate; and bromine and its equivalents, such as bromine - 1,4-
dioxane complex,
tetra butylammonium tribroinide, trimethylphenylammonium tribromide,
benzyltritnethylammonium tribromide, and I -butyl-3-methylimidazolium
tribromide.
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34. In embodiment 34, the process of embodiment 31 or 32 is wherein the
brominating
agent is 1,2-dibromo-1,1,2,2-tetrafluoroethane, the deprotonating agent is
lithium
diisopropylamide and the solvent is tetrahydrofuran.
35. In embodiment 35, the process of embodiment 34 is wherein the reaction
is carried
at out at about -100 C to about -20 C.
36. In embodiment 36, the process of any one of embodiments 31 to 35
further
comprises preparing compound (6):
F F
'OH
(6)
by treating compound (5):
F F
FF
F
0
(5)
with 4,4,5,5-tetramethy1-2-(prop-2-en-1-y1)-1,3,2-dioxaborolane in the
presence of (S)-2-43-(tert-
buty1)-2-hydroxybenzypamino)-N,N,3-trimethylbutanamide and a base in a
suitable organic
solvent.
37. In embodiment 37, the process of embodiment 36 is wherein the base is
sodium
tert-butoxide and the organic solvent is a mixture of methanol and toluene.
38. In embodiment 38, the process of claim 36 or 37 further comprises
preparing
compound (5):
FE
F Ole
0
(5)
by treating compound (4):
F F F
0 Br
(4)
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with an organolithium reagent in a suitable organic solvent.
39. In embodiment 39, the process of claim 38 is wherein the organolithium
reagent is
n-butyllithium and the organic solvent is tetrahydrofuran, 2-
methyltetrahydrofuran, n-heptane and
methyl tert-butylether.
40. In embodiment 40, the process of embodiment 38 or 39 is wherein the
solvent is
tetrahydrofuran.
41. In embodiment 41, the process of any one of embodiments 38 to 40
further
comprises preparing compound (4):
F F
FF
O Br
(4)
by treating compound (3):
F F
0
O Br
(3)
with a fluorinating agent in a suitable organic solvent.
42. In embodiment 42, the process of claim 41 is wherein the fluorinating
agent is
diethylaminosulfur trifluoride, 4-tert-buty1-2,6-dimethylphenylsulfur
trifluoride, or sulfur
tetrafluoride and hydrofluoric acid.
43. In embodiment 43, the process of embodiment 42 is wherein the
fluorinating agent
is sulfur tetrafluoride and hydrofluoric acid and the solvent is
dichloromethane.
44. In embodiment 44, the process of any one of embodiments 41 to 43
further
comprises preparing compound (3):
F F
0
O Br
(3)
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by treating compound (2):
F F
OH
0 Br
(2)
with an oxidizing agent in a suitable organic solvent.
45. In embodiment 45, the process of embodiment 44 is wherein the oxidizing
agent is
dimethyl sulfoxide/oxalyl chloride, 2-iodoxybenzoic acid, RuC13/NaBr03, Mn02,
NaBr03/NaHS03, or TPAP/NMO.
46. In embodiment 46, the process of embodiment 45 is wherein the oxidizing
agent is
is TPAP/NMO and reaction is carried in dichloromethane, acetonitrile or
tetrahydrofuran,
preferably dichloromethane.
47. In embodiment 47, the process of any one of embodiments 44 to 46
further
comprises preparing compound (2):
F F
OH
=0 Br
(2)
by treating compound (1):
,0
40 Br
(1)
with ethyl 2-bromo-2,2-difluoroacetate in the presence of zinc metal,
trimethylsilyl chloride, and
1,2-dibromoethane in a suitable organic solvent.
48. In embodiment 48, the process of embodiment 47 is wherein the organic
solvent is
tetrahydrofuran or 2-methyl tetrahydrofuran.
EXAMPLES
Abbreviations:
ACN: acetonitrile
AcOH or HOAc: acetic acid
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AlkylFluor: CAS Registry No. 2043361-32-4
Cs2CO3 cesium carbonate
DAST: diethylaminosulfur trifluoride
DCM: dichloromethane
.. HF: hydrofluoric acid
HC1: hydrochloric acid
KOAc: potassium acetate
LDA: Lithium diisopropylamide
MTBE: methyl tert-butyl ether
NMO: N-Methylmorpholine N-oxide
MeOH: methanol
NaBH4. sodium borohydride
NaI04: sodium perodiate
n-BuLi: n-butyllithium
Pd(PPh3)2(0Ac)2: bis(acetato)bis(triphenylphosphine)palladium(II)
Pd(PPh3)2C12: bis(triphenylphosphine)palladium(II) dichloride
Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0)
PyFluor: 2-pyridinesulfonyl Fluoride
RuC13=3H20: ruthenium (III) chloride hydrate
SF4: sulfur tetrafluoride
SulfoxFluor: [methyl (ox o)11- [6-(trifluoromethyl)-3 -py ri dyl] ethyl} 2P-
sulfanylidene] cyanamide
TEMPO: (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl or (2,2,6,6-
tetramethylpiperidin-1-yl)oxidanyl
TFA: trifluoroacetic acid
THF: tetrahydronfuran
TPAP: tetrapropylammonium perruthenate
t-BuONa: sodium tert-butoxide
XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
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Example 1
Synthesis of 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one
0
Step 1: ethyl 3-(2-bromo-4-fluorophenyl) -2,2-difluoro-3-hydroxypropanoate
0 FE
Et OH
Br
0 Br
To a mixture of zinc (211.36 g, 3.23 mol, 1.31 eq.) in THF (1.50 L) was
added 1,2-dibromoethane (13.88 g, 73.89 mmol, 0.030 eq.) and TMSC1 (53.52 g,
492.59 mmol,
0.20 eq.) in one portion. The mixture was stirred at 25 C for 0.5 h, then a
solution of 2-bromo-4-
fluoro-benzaldehyde (500 g, 2.46 mol, 1.00 eq.) and ethyl 2-bromo-2,2-difluoro-
acetate (549.93 g,
2.71 mol, 1.10 eq.) in THF (1.50 L) was added to the mixture dropwise over 1 h
under refluxing,
and the reaction mixture was stirred continually under refluxing for 1 h. The
reaction mixture was
cooled, then filtered, and the cake was washed with ethyl acetate. The
filtrate was quenched with
1.0 M aqueous HC1 (800 mL), then adjusted to pH = 5 - 6 and the mixture was
extracted with
ethyl acetate. The combined organic phase was washed with 10% brine, dried
with Na2SO4,
concentrated in vacuum to give the title compound (857.0 gõ 88.8% assay
purity, 94.5% assay
yield) as a yellow oil, which was used for next step without further
purification.
Step 2: ethyl 3-(2-bromo-4-fluoropheny1)-2,2-difluoro-3-oxopropanoate
F F F F
Et0 OH Et0 0
0 Br _____________ 0 Br
A mixture of NMO (297.86 g, 2.54 mol, 1.40 eq.), TPAP (15.96 g, 45.41 mmol,
0.025 eq.)
and 4A MS (94.0 g) in DCM (1000 mL) was degassed and purged with N2 and a
solution of ethyl
3-(2-bromo-4-fluoropheny1)- 2,2-difluoro-3-hydroxypropanoate (669.00 g, 1.82
mol, 88.8% assay,
1.00 eq.) in DCM (1000 mL) was added dropwise at 0-5 C over 1.5 h. The
resulting mixture was
further stirred at 25 C for 2 h under N2 atmosphere, then was filtered
through silica gel pad and
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the pad cake was washed with MTBE. The combined filtrate was washed with 1.0 M
aqueous
HC1. The combined aqueous phase was extracted with MTBE. The combined MTBE
organic
phase was washed with H20, filtered through a silica gel pad and the pad cake
was washed with
MTBE. The combined filtrate was concentrated to give the title compound (561.0
g, 95.1% yield)
as a yellow oil, which was used for next step without further purification.
Alternative Method:
To a stirred mixture of ethyl 3-(2-bromo-4-fluoropheny1)- 2,2-difluoro-3-
hydroxy-
propanoate (285.9 g, after assay adjustment, 0.874 mol, 1.00 eq.) in
acetonitrile (900 mL) and
water (900 mL) were added NaH2PO4 (63.0 g, 0.525 mol, 0.60 eq.) and RuC13
(1.81 g, 8.726
mmol, 0.010 eq.) sequentially at 20-30 C. NaBrO3 (158.27 g, 1.049 mol, 1.20
eq.) was then
added in portions at 20-30 C. After further stirring at 20-30 C for 2 h, the
reaction mixture was
diluted with Et0Ac, followed by washing with water, aqueous Na2S03, water and
then brine. The
organic layer was concentrated to obtain the title compound (272.8 g, 95.2%
purity, 91.4% yield)
as a yellow oil, which was used for next step without further purification.
Step 3: ethyl 3-(2-bromo-4-fluoropheny1)-2,2,3,3-tetrafluoropropanoate
F F F F
Et 0 Et0
0 Br 0 Br
To an autoclave was charged ethyl 3-(2-bromo-4-fluoropheny1)-2,2-difluoro-3-
oxopropanoate (550.00 g, 1.69 mol, 1.00 eq.) and DCM (55.5 mL). The mixture
was cooled to -78
C and HF (33.85 g, 1.69 mol, 1.00 eq.) was charged, followed by SF4 (202.00 g,
1.87 mol, 1.11
eq.). The reaction mixture was warmed to room temperature and stirred at this
temperature for 16
h. The reaction mixture was quenched by added slowly into saturated aqueous
Na2CO3 (2.5 L) and
then extracted with petroleum ether. The combined organic layer was washed
with 10% brine,
dried over Na2SO4, filtered and concentrated. The residue was further purified
by vacuum
distillation to afford the title compound (474.0 g, 81.1% yield) as yellow
oil.
Step 4: 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one
F F
Et0
0 Br
0
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A stirred solution of ethyl 3-(2-bromo-4-fluoropheny1)-2,2,3,3-
tetrafluoropropanoate
(100Ø g, 288.11 mol, 1.00 eq.) in THF (1.0 L) was cooled to -65 C, and n-
BuLi (2.5 M, 138.0
mL, 345.0 mol, 1.20 eq.) was added dropwise at -60 to -70 C over 1 h under
nitrogen
atmosphere. The resulting mixture was stirred further at -65 C for 1 h, then
was quenched with
saturated aqueous NH4C1 at -30 to -40 C, followed by dilution with ethyl
acetate and H20. After
phase separation, the aqueous phase was extracted with ethyl acetate and the
combined organic
layer was washed with 10% brine, dried over Na2SO4, filtered and concentrated
to give a residue.
The residue was purified by vacuum distillation, and the distillate was
triturated with petroleum
ether at low temperature to give the title compound (41.0 g, 64.1% yield) as a
white solid.
Example 2
Synthesis of (R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-
cyclopenta[cdlinden-1-
one
F F F F
OH FOH
0
Step 1: (R)-1-ally1-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol
F F
F F
F
0
To a dry 3-neck flask were added 2-ally1-4,4,5,5-tetramethy1-1,3,2-
dioxaborolane (94.57 g,
562.78 mmol, 1.21 eq.), (S)-2-43-(tert-buty1)-2-hydroxybenzypamino)-N,N,3-
trimethyl-
butanamide (36.51 g, 119.14 mmol, 0.26 eq.), t-BuONa (4.33 g, 45.06 mmol,
0.097 eq.), toluene
(900 mL) and Me0H (28.8 g, 898.88 mmol, 1.94 eq.). The mixture was stirred at
20 C under
nitrogen atmosphere until a clear solution formed. The reaction mixture was
heated to 60 C, and a
solution of 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one (103.09 g, 464.14
mmol, 1.00 eq.)
in toluene (100 mL) was added slowly over 2 h at 60 C. The resulting mixture
was stirred
continually for 16 h at 60 C, then cooled to room temperature, quenched with
water, and
extracted with MTBE. The organic layer was cooled to 0 C andwashed with 1.0 M
aqueous HC1,
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0.5 M aqueous NaOH, water and 10% brine. The organic layer was concentrated to
give the title
compound (146.71g, 73.5% assay purity, 87.9% assay yield, 90.7% e.e.).
Step 2: (R)-1-ally1-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-l-ol
F F
F _______________________________________________________ F
F
Br
To a dry 3-neck flask were added THF (500 mL) and LDA (356.82g, 25%, 832.76
mmol,
2.21 eq.) and then the solution was cooled to -50 C under nitrogen
atmosphere. A solution of
(R)-1-ally1-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-ol (100.00 g, 378.50
mmol, 1.00 eq.) in
THF (200 mL) was added slowly at -50 C. The resulting mixture was stirred at -
50 C for lh,
then cooled to -80 C to form solution A.
To another dry 3-neck flask were added dibromotetrafluoroethane (196.66 g,
756.91
mmol, 2.00 eq.) and THF (100 mL), and the solution was cooled to -80 C.
Solution A was slowly
added with stirring and while maintaining the reaction temperature at about -
80 C. The mixture
was stirred at -80 C for additional 30 min and then slowly quenched by slowly
adding a solution
of AcOH (75.00 g, 1248.96 mmol, 3.30 eq.) in THF (75 mL) at temperature below -
60 C. The
mixture was warmed slowly to room temperature anddiluted with water. The
mixture was
extracted with MTBE, and the combined organic layer was washed with water and
10% brine. The
organic layer was concentrated to give the title compound as a solution in THF
(204.40g, 50.4%
assay purity, 79.3% assay yield).
Step 3: (R)-3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-tetrahydro-2aH-
cyclopenta[cdlinden-2a-ol
F F
F
'"OH
Br
Into a solution of (R)-1-ally1-7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-
inden-l-ol
(100.00 g, 291.47 mmol, 1.00 eq.) in acetonitrile (1.50 L) were added KOAc
(86.50g, 881.39
mmol, 3.03 eq.) and Pd(PPh3)2C12 (10.30 g, 14.67 mmol, 0.050 eq.) under N2
atmosphere. The
mixture was stirred for 4 h at 80 C and then concentrated under vacuum to
about 1/3 volume. The
residue was diluted with MTBE and washed with water. The organic layer was
diluted with
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n-heptane and passed through a silica gel pad (200 g). The pad was rinsed with
MTBE/n-heptane=1/3 to wash out the product. The eluent was concentrated and
exchange the
solvent into acetonitrile to give the title compound as a solution in
acetonitrile (120.15g, 51.7%
assay purity, 81.3% assay yield, 90.6% e.e.).
Step 4: (R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-tetrahydro-1H-
cyclopenta[cdlinden-1-one
F F F F
OH FOH
0
To a stirred mixture of (R)-3,3,4,4,7-pentafluoro-1-methylene-1,2,3,4-
tetrahydro-2aH-
cyclopenta[cdlinden-2a-ol (80.00 g, 305.13 mmol, 1.00 eq.) in ACN (1200 mL)
and H20 (3200
mL) was added RuC13=3H20 (4.00 g, 15.30 mmol, 0.050 eq.), followed by NaI04
(456.87 g, 2.14
mol, 7.01 eq.) in portions while maintaining the reaction temperature at 10
to20 C. After stirring
further at 10 to 20 C for 1 h, MTBE (800 mL) was added to the mixture and the
mixture was
filtered through a Celite layer. The Celite solid cake was washed with MTBE.
The organic layer
was separated from the combined filtrate, and the aqueous layer was extracted
with MTBE. The
combined organic layer was washed with 5% aqueous Na2S03 and 10% aqueous
Na2SO4. The
organic layer was concentrated, and the residue was dissolved in MTBE and n-
heptane. The
solution was filtered through a silica gel pad (200 g) and the pad solid cake
was rinsed with
MTBE/n-heptane=1/3. The combined eluent was concentrated to about 3V to
precipitate out the
product which was filtered and dried to give the title compound as a white
solid (70.62 g, 88.4%
assay purity, 77.5% assay yield, ¨ 91.7% e.e.).
Example 3
Synthesis of 3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy-
2,2a,3,4-tetrahydro-1H-
cyclopenta[cdlinden-7-yl)oxy)benzonitrile
\ F
110 0
HO
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Step 1: (R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-2,2a,3,4-
tetrahydro-1H-
cyclopenta[cdlinden-7-yl)oxy)benzonitrile
F F F F
"'OH
0 0
To a stirred mixture of (R)-3,3,4,4,7-pentafluoro-2a-hydroxy-2,2a,3,4-
tetrahydro-1H-
.. cyclopenta[cdlinden -1-one (100.00 g, after assay adjustment, 378.57 mmol,
1.00 eq.) in THF
(500 mL) were added 3-fluoro-5-hydroxybenzonitrile (57.10 g, 416.45 mmol, 1.10
eq.) and
Cs2CO3 (74.01 g, 227.15 mmol, 0.60 eq.) at room temperature. The resulting
mixture was stirred
at 40 C for 20 h. The mixture was cooled to room temperature and MTBE was
added, followed
by water. After layer separation, the aqueous layer was extracted with MTBE
and the combined
.. organic layer was washed with 5% aqueous Na2CO3 and then 10% brine. The
organic layer was
concentrated and the residue was recrystallized from MTBE/n-heptane = 3/20 to
give the title
compound as a yellow solid (145.78 g, 84.4% assay purity, 85.2% assay yield,
98.4% e.e.).
Step 2: 3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-dihydroxy- 2,2a,3,4-
tetrahydro-1H-
.. cyclopenta[cdlinden-7-yl)oxy)benzonitrile
11 F F 11 F F
FS OH H
0
H
0 HO
To a stirred solution of (R)-3-fluoro-5-((3,3,4,4-tetrafluoro-2a-hydroxy-1-oxo-
2,2a,3,4-
tetrahydro-1H- cyclopenta[cdlinden-7-yl)oxy)benzonitrile (50.00 g, after assay
adjustment, 131.14
.. mmol, 1.00 eq.) in Me0H (53.0 mL, 1.31 mol, 10.00 eq.) and THF (500 mL) was
added NaBH4
(1.84 g, 48.64 mmol, 0.37 eq.) in portions at -5 to 0 C. The reaction mixture
was stirred at -5 to 0
C for an additional hour, then quenched with 2.0 M aqueous HC1 (about 30.0 g)
below 5 C to
pH = 5 ¨ 7 and diluted with water. The mixture was extracted with MTBE, and
the combined
organic layer was washed with water and 10% brine. The organic layer is
concentrated and the
.. solvent was exchanged to THF to obtain a THF solution of the title compound
(286.66 g, 16.6%
assay purity, 94.7% assay yield, 97.7% e.e.). 1H NMR (400MHz, CDC13) 6 = 7.55
(d, 1H), 7.18 -
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7.16 (m, 2H), 7.13 (d, 1H), 7.08 (d, 1H), 5.89- 5.84 (m, 1H), 3.06 (s, 1H),
2.83 -2.78 (m, 1H),
2.47 - 2.42 (m, 1H), 2.35 (d, 1H).
Example 4
Synthesis of 3-fluoro-5-(((1S,2aR)-1,3,3,4,4-pentafluoro-2a-hydroxy-2,2a,3,4-
tetrahydro-1H-
cyclopenta[cdlinden-7-yl)oxy)benzonitrile
NC F F
F* 0'0H
OH
To a stirred solution of 3-fluoro-5-(((1R,2aR)-3,3,4,4-tetrafluoro-1,2a-
dihydroxy-2,2a,3,4-
tetrahydro-1H-cyclopenta[cdlinden-7-y0oxy)benzonitrile (54.30 g, 141.68 mmol,
1.00 eq.) and
DBU (43.14 g, 283.37 mmol, 2.00 eq.) in THF (1200 mL) was added a solution of
pyridine-2-
sulfonyl fluoride (32.00 g, 198.57 mmol, 1.40 eq.) in THF (200 mL) dropwise at
20-30 C over 2
h under nitrogen atmosphere. The resulting mixture was stirred further for 20
h at 20-30 C,
quenched with 0.5N aqueous NaOH (600 mL). After stirring at 20-30 C for 30
min, the layers
were separated. The aqueous layer was extracted with MTBE. The combined
organic layers were
concentrated, and the residue was dissolved in MTBE. The organic layer was
washed with water,
0.5 N aqueous HC1, water and 10% brine. The organic layer was concentrated and
the residue was
purified with a silica gel column, eluted with n-heptane/ethyl acetate=4/1, to
obtain crude product
(49.0g), which was further recrystallized from MTBE/n-heptane=1/9 to give the
title product
(42.0g, 76.9% yield). The HPLC purity of the title compound was 95.4%. 11-1NMR
(400MHz,
CDC13) 6 = 7.71 - 7.67 (m, 1H), 7.29 - 7.26 (m, 2H), 7.25 - 7.09 (m, 2H), 6.60
- 5.80 (ddd, 1H),
2.87 (s, 1H), 2.91 - 2.57 (m, 2H).
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