Synthesis of desfluorinated nebivolol isomers

Article abstract of DOI:10.1021/acs.joc.5b00263

The syntheses of all possible stereoisomers of desfluorinated side products of the potent antihypertensive β-blocker nebivolol are reported. A straightforward approach using a common racemic precursor was employed to obtain the desired optically active building blocks. For one series of compounds, a Sharpless asymmetric epoxidation (SAE) route yielded in a direct fashion the required compounds whereas a Mitsunobu reaction was selected to obtain the other series of compounds. This offers a flexible approach to all desfluoronebivolol side-products in order to fully characterize them.

Full text of DOI:10.1021/acs.joc.5b00263

Article
pubs.acs.org/joc
Synthesis of Desfluorinated Nebivolol Isomers
Purushothama Chary Khandavalli,§,∥ Oliver Spiess,†,§ Oliver M. Bohm,§ Ilia Freifeld,‡ Kurt Kesseler,‡
̈
Gerhard Jas,*,‡ and Dieter Schinzer*,†,§
†Chemisches Institut, Otto-von-Guericke-Universitat, Universitatsplatz 2, 39106 Magdeburg, Germany
̈
̈
‡Corden Pharma International GmbH, Otto-Hahn-Strasse, 68723 Plankstadt, Germany
§MOLISA GmbH, Universitatsplatz 2, 39106 Magdeburg, Germany
̈
∥Salutas Pharma GmbH, Otto-von-Guericke Allee 1, 39179 Barleben, Germany
S
* Supporting Information
ABSTRACT: The syntheses of all possible stereoisomers of desfluorinated side
products of the potent antihypertensive β-blocker nebivolol are reported. A
straightforward approach using a common racemic precursor was employed to
obtain the desired optically active building blocks. For one series of compounds, a
Sharpless asymmetric epoxidation (SAE) route yielded in a direct fashion the
required compounds whereas a Mitsunobu reaction was selected to obtain the
other series of compounds. This offers a flexible approach to all desfluoronebivolol
side-products in order to fully characterize them.
standard hydrogenation conditions, which is unacceptable from a
INTRODUCTION
■
pharmaceutical point of view. Principally, this side reaction can
be significantly suppressed using chemical transfer hydro-
genation. Unfortunately, the general structure of monodesfluor-
onebivolol has been deducted only from MS investigations, and
the various potential isomers have not been separated.8 From an
analytical point of view, it would be advantageous to have the
various desfluoro compounds available for reaction optimization,
quality control, and final batch release. Since in the manufacture
of nebivolol the isomers NBV 3−10 can be suppressed to less
than 0.1%, we decided to synthesize all potential desfluoro
compounds that can be generated from compounds 1a,b.
Totally, two pairs of enantiomeric monofluoro compounds can
be obtained because of the dissymmetry of nebivolol and two
bisdesfluoro compounds as illustrated in Scheme 1 (generally,
desfluorinated nebivolol compounds can also result from chiral
3,4-dihydro-1H-1-benzopyran-2-carboxylic acid, the desfluoro
starting material of our synthesis, which is carried over during the
synthesis, but as this desfluoro starting material is present at less
than 0.1% in the starting material, with all likelihood the
desfluoro derivatives are obtained only at the hydrogenation
step).9
Strategy. Basically, the simplest way to access the
desfluorinated nebivolol compounds is to perform the hydro-
genation step under forced conditions, but we were not able to
separate the desfluoro compounds from the product by
chromatography. Recently, we have shown a highly economical
entry to nebivolol by enzymatic reduction as the key step,10
which avoids unnecessary chromatographic purification steps
and allows for full control of all stereogenic centers. Although this
route could be used for an effective synthesis of all nebivolol
α,α′-[Iminobismethylene]bis[6-fluoro-3,4-dihydro-2H-1-benzo-
pyran-2-methanol] (1), known as nebivolol, is a potent and
selective β1-adrenergic blocker with potent antihypertensive
activity (Figure 1).1 A general nonstereoselective access to this
Figure 1. Nebivolol (NBV).
pharmacologically active molecule has been disclosed for the first
time by scientists at Janssen1a,2 who also published the first
scalable and stereoselective synthesis.3 Nebivolol is marketed as
hydrochloride salt and is manufactured as a racemate which
consists of the enantiomers (+)- and (−)-nebivolol 1a and 1b
(Figure 2).4
The compound has four chiral centers and can therefore exist
in a theoretical number of 16 stereoisomers. As there is a
symmetry plane through the nitrogen atom, the number of
possible stereoisomers is actually reduced to 105 as illustrated in
Table 1. NBV 1/2, NBV 3/4, NBV 5/6, and NBV 7/8 generate
enantiomeric pairs whereas NBV 9 and NBV 10 are meso
compounds.
A huge number of syntheses of nebivolol have been described
in the patent2,3,6 and scientific7 literature. Usually, the last step in
the manufacturing sequence is the catalytic hydrogenation of N-
Bn-nebivolol 2. A potential side reaction in this step is
desfluorination, leading to various desfluorinated NBV isomers
as depicted in Scheme 1.
Desfluorination has been mentioned for the first time by the
Received: February 9, 2015
Published: March 31, 2015
Zach group6i and was observed at greater than 2% level under
© 2015 American Chemical Society
3965
DOI: 10.1021/acs.joc.5b00263
J. Org. Chem. 2015, 80, 3965−3973

The Journal of Organic Chemistry
Article
Figure 2. Manufactured racemate of nebivolol.
Table 1. Possible Stereoisomers of Nebivolol (NBV)
stereoisomers, we failed to synthesize the desfluoro compounds
by this strategy (formation of chloroaryl derivatives in the
preparation of desfluorochloroketone). Therefore, we planned to
apply an independent route to all desfluorinated nebivolol
building blocks using a common racemic precursor. We selected
a Sharpless asymmetric epoxidation (SAE) route7a,11 for this
purpose. Scheme 2 describes our overall strategy. 1,2-
Dihydrobenzopyranone A is a suitable starting material which
can be easily reduced to the lactol derivative B using DIBAL-H.
Wittig-type chemistry or alternative reduction methodology of
propargylic alcohols should give a stereoselective access to the
allylic alcohols C and D which then can undergo enantioselective
epoxidation to give the chiral epoxides E, F, G, and H,
respectively.
selectivity will be obtained.13 We therefore decided to change our
strategy and switched to a Corey−Fuchs14 protocol, generating
the propargyl alcohol 9, which was readily reduced in the
presence of Red-Al with high stereoselectivity.15 Compound 9
was easily available in an one-pot reaction of n-BuLi and
paraformaldehyde on the geminal dibromide 8. Furthermore,
then we only used the E-series 10 for the SAE protocol and
inverted the absolute configuration of the secondary alcohol in
compounds 11 and 14 by a Mitsunobu10,16 reaction to obtain the
desired opposite configurations (compounds 18 and 22). By this
strategy we could overcome the low selectivity in the SAE route
using the Z-series (D). Altogether, compound 10 offered a
simple and robust manifold to approach all stereoisomers
required for our study.
During the course of experiments, we figured out that in the Z-
series (D) only moderate enantioselectivity could be obtained in
the SAE route furnishing G and H. This is consistent with earlier
findings by K. Barry Sharpless et al., who could demonstrate that
Z-disubstituted allylic alcohols require longer reaction times.12
The authors also found that such slowly reacting substances
require more catalyst and slightly higher reaction temperatures
than in the comparable E-series. All together, Z-disubstituted
allylic alcohols are least reactive and in general lower stereo-
RESULTS AND DISCUSSION
■
2-Chromanone 6 is reduced in the presence of DIBAL-H to
obtain the desired lactol 7 in high chemical yield (Scheme 3).17
Reaction of 7 with carbon tetrabromide and triphenylphosphine
provides geminal dibromide 8, and subsequent addition of n-
butyllithium in the presence of paraformaldehyde affords
propargyl alcohol 9 in high chemical yield. Efficient reduction
of 9 with Red-Al resulted in the formation of the required E-
3966
DOI: 10.1021/acs.joc.5b00263
J. Org. Chem. 2015, 80, 3965−3973

The Journal of Organic Chemistry
Article
Scheme 1. Products and Impurities from the Debenzylation Reaction of N-Bn-Nebivolol
Scheme 2. General Strategy
allylic alcohol 10 in 83% yield. Compound 10 can be directly
transformed into the desired diols 11 and 14 via SAE and in situ
epoxide opening in the presence of sodium hydroxide. Both
enantiomeric series are available based on the absolute
configuration of tartaric acid used in the SAE protocol.
Compound 11 [SAE with (−)-DET)] can be chemoselectively
3967
DOI: 10.1021/acs.joc.5b00263
J. Org. Chem. 2015, 80, 3965−3973

The Journal of Organic Chemistry
Article
Scheme 3. SAE Route to Chiral Epoxides
Scheme 4. Mitsunobu Route to Chiral Epoxides
transformed into tosylate 12 followed by base-induced epoxide
formation in the presence of sodium methoxide to give 13. The
same protocol yields epoxide 16 using (+)-DET as the chiral
auxiliary for SAE.
The reverse absolute configuration concerning the secondary
alcohol group can be achieved by a Mitsunobu reaction of
compounds 11 and 14 with diisopropyl azodicarboxylate
(DIAD), triphenylphosphine (TPP), and p-nitrobenzoic acid
(PNBA). The desired inverted secondary alcohols 18 and 22 are
then generated by saponification of the obtained PNBA esters 17
and 21 without loss of enantiomeric purity. Compounds 18 and
22 can be converted into the required epoxides 20 and 24 using
the same protocol as described before (Scheme 4).
With all epoxide compounds in hand, the coupling with
benzylamine could be envisioned. As shown in Scheme 5, a
smooth transformation took place for each of the intended
compounds. Finally, a transfer hydrogenation provided all vitally
needed desfluoro nebivolol isomers in very high stereochemical
purity and high chemical yield (Figure 3).
CONCLUSION
■
For the first time, a general strategy to obtain all possible
desfluoronebivolol isomers has been described and offers the
3968
DOI: 10.1021/acs.joc.5b00263
J. Org. Chem. 2015, 80, 3965−3973

The Journal of Organic Chemistry
Article
equiv) was added dropwise over 20 min, and stirring of the reaction was
continued at −78 °C. After 4 h, the reaction was complete (TLC
monitoring in pentane/EtOAc 4:1). The reaction was quenched by the
addition of H2O (20 mL) and then warmed to room temperature (2 h).
Anhydrous MgSO4(s) (50 g) was added, and the reaction was stirred
vigorously and then filtered through a sintered funnel. The solids were
thoroughly washed with pentane (100 mL). Combined organic fractions
were concentrated under vacuum and purified by flash chromatography
on silica gel using pentane/EtOAc (9:1 to 4:1) to provide the product 7
(7.89 g, 52.54 mmol) with an isolated yield of 79% as a colorless oil. Rf =
0.39 in 4:1 pentane/EtOAc (vanillin stain); 1H NMR (CDCl3): δ 7.14−
7.15 (m, 2H); 6.90−6.81 (m, 2H); 5.61(dd, 1H, J = 2.71 Hz, 1,05 Hz);
3.32−3.05 (br, OH); 3.07 (ddd, 1H, J = 5.33 Hz, 10.45 Hz, 16.43 Hz),
2.08−1.98 (m, 2H).17
Scheme 5. Coupling with Chromane Epoxides and
Debenzylation
2-(4,4-Dibromo-but-3-enyl)phenol (8). A CH2Cl2 solution (750
mL, 3.2 mL/mmol) of CBr4 (169 g, 468.15 mmol, 2 equiv) in a 2 L
three-necked RB flask equipped with a double-surface water condenser,
N2 inlet, 250 mL pressure equalizing dropping funnel, and a magnetic
bead was cooled to 0 °C under a N2 atmosphere. A CH2Cl2 solution
(500 mL) of PPh3 (245.58 g, 936.30 mmol, 4 equiv) was added dropwise
to the reaction over a period of 90 min and stirred for further 30 min at 0
°C. Subsequently a CH2Cl2 solution (175 mL) of chromanol 2 (35.19 g,
234.07 mmol, 1.00 equiv) was added through a 500 mL pressure
equalizing dropping funnel over a period of 20 min. The reaction slowly
turned from wine-red to a pale brown and was continued for a further 1 h
period at 0 °C. Progress of the reaction was monitored by TLC (Et2O).
The reaction was quenched by the addition of water (400 mL) and then
warmed to room temperature. The layers were separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 150 mL). Combined
organic portions were washed with brine solution (600 mL), dried over
Na2SO4, filtered, and concentrated. To the resulting brown syrupy liquid
was added Et2O (1 L) to precipitate PPh3O. This was removed via
filtration through a sintered funnel, and the solid residue was rinsed with
Et2O (1 L). The combined Et2O fractions were concentrated, and the
resulting suspension was purified by flash chromatography on silica gel
using 7:1 pentane/Et2O as the eluent system to furnish 2-(4,4-
dibromobut-3-enyl)phenol 8 (52.01 g, 169.57 mmol) in 72% isolated
yield. Rf = 0.8 in Et2O (vanillin stain); 1H NMR (400 MHz, CDCl3): δ
7.14−7.14 (m, 2H); 6.89 (t, J = 7.45 Hz, 1H); 6.74 (d, J = 8.49 Hz); 6.45
(t, J = 7.10 Hz, 1H); 4.81 (s, 1H); 2.74 (t, J = 7.41 Hz, 2H); 2.43 (q, J =
7.84 Hz, 2H); HRMS (EI) (m/z) [C10H10OBr2]+: Calcd 303.9093,
Found 303.9090.15
possibility to fully analyze and characterize the side-products in a
very important pharmaceutical manufacturing process. In
addition, the chemistry presented provides useful insights for a
variety of fundamental reactions leading to quite complex
intermediates that could be coupled in a straightforward way to
obtain large quantities of pure isomers that have been observed
only by mass spectroscopy in the past. Altogether, this sheds
some light on the scale-up synthesis of a potent and selective β-
blocker with high antihypertensive activity.
EXPERIMENTAL SECTION
■
General. Solvents were dried by standard procedures and redistilled
under N2 atmosphere prior to use. All organometallic reactions were run
under nitrogen. The products were purified by flash chromatography on
Merck silica gel 60 (40−63 mm). High-resolution mass spectra (EI 70
eV, double focusing sector mass spectrometer) were obtained by the
peak matching method (reference PFK, accuracy 2 ppm). NMR
spectra were recorded at 400 MHz (1H) and 100 MHz (13C).
2-(5-Hydroxypent-3-yn-1-yl)phenol (9). A THF (424 mL) (3.4 mL/
mmol) solution of the dibromide 3 (38.31 g, 124.91 mmol, 1.00 equiv)
was taken into a 2 L three-necked RB flask equipped with a magnetic
bead, low temperature thermometer, 250 mL pressure equalizing
dropping funnel, and water condenser equipped with a nitrogen inlet.
The reaction was cooled to −78 °C under a stream of N2. n-Buli (2.5 M
Chroman-2-ol (7). In a 1 L two-necked round-bottom flask equipped
with magnetic bead and a water condenser connected to a nitrogen inlet,
dihydrocoumarin (10 g, 67.49 mmol, 1.00 equiv) 6 was dissolved in
THF (472 mL, 7 mL/mmol). The mixture was cooled to −78 °C under
a N2 atmosphere. DIBAl-H (1 M in hexane, 81 mL; 81 mmol, 1.20
Figure 3. Synthesized desfluoronebivolol isomers.
3969
DOI: 10.1021/acs.joc.5b00263
J. Org. Chem. 2015, 80, 3965−3973

The Journal of Organic Chemistry
Article
in hexane, 180.89 mL, 452.19 mmol, 3.62 equiv) was dropwise added
over a period of 1 h while maintaining the internal temperature around
−72 to −75 °C. The reaction was continued at −78 °C for 1 h.
Paraformaldehyde (11.20 g, 374.74 mmol, 3 equiv) was added in one
portion at −78 °C to the reaction. After this, the dry ice bath was
removed and the reaction was allowed to warm to room temperature
and continued for an additional 1 h. After the reaction was completed
(TLC monitoring in Et2O), it was quenched at room temperature by the
addition of saturated aqueous NH4Cl solution (600 mL) to the
vigorously stirred reaction. After dilution with EtOAc (150 mL), the
layers were separated and the aqueous portion was extracted with EtOAc
(3 × 150 mL). Combined organic portions were dried over anhydrous
Na2SO4, filtered, and concentrated. Flash chromatography on silica gel
was performed using pentane/EtOAc (7:3 to 1:1) furnishing 2-(5-
hydroxypent-3-ynyl)phenol 9 (19.81 g, 112, 56 mmol) in 90% isolated
yield as a colorless syrupy liquid. Rf = 0.38 in Et2O (KMnO4 stain); 1H
NMR (400 MHz, CDCl3): δ 7.16−7.06 (m, 2H); 6.87 (t, J = 7.44 Hz,
1H); 6.77 (d, J = 7.87 Hz, 1H); 5.89−5.55 (br, 1H, OH); 4.23 (t, J = 2.13
Hz, 2H); 2.84 (2.84, J = 7.45, 2H); 2.53 (m, 2H); 2.35−1.86 (br, 1H,
OH); HRMS (EI) (m/z) [C11H12O2]+: Calcd 176.0832, Found
176.0832.15
(E)-2-(5-Hydroxypent-3-en-1-yl)phenol (10). A solution of Red-Al
(65% in toluene, 47.71 mL, 153.39 mmol, 2.47 equiv) in Et2O (64 mL)
was cooled under a N2 atmosphere to 0 °C. A solution of the alkyne 9
(10.93 g, 62.10 mmol, 1.00 equiv) in Et2O (44 mL) was dropwise added
over 10 min, and then the reaction was warmed to room temperature
and stirred overnight. After 18 h, the reaction mixture was cooled to 0 °C
and a saturated aqueous Rochelle’s salt (366 mL) solution was very
carefully added dropwise. The reaction was stirred vigorously at 0 °C for
a period of 1 h and then warmed to room temperature. The mixture was
extracted with EtOAc (3 × 100 mL), dried over Na2SO4, filtered, and
concentrated. Flash chromatography on silica gel using pentane/Et2O
(1:1 to 3:7) furnished (E)-2-(5-hydroxypent-3-enyl)phenol 10 (9.21 g,
51.74 mmol) in 83% isolated yield. Rf = 0.36 in 100% Et2O (KMnO4
stain); 1H NMR (400 MHz, CDCl3): δ 7.12−7.03 (m, 2H); 6.85 (t, J =
7.58 Hz, 1H); 6.74 (d, J = 7.86 Hz, 1H); 5.81−5.61 (m, 2H); 4.08 (d, J =
5.61 Hz, 2H); 2.70 (t, J = 7.30 Hz); 2.37 (q, J = 7.30 and 14.60 Hz, 2H);
HRMS (EI) (m/z) [C11H14O2]+: Calcd 178.0988, Found 178.0987.15
General Experimental Procedure for the Synthesis of the
Chromane Diols 11 and 14 via One-Pot Sharpless Asymmetric
Epoxidation. Step 1. Sharpless Asymmetric Epoxidation (SAE).
Under a N2 atmosphere, a suspension of the activated 4 Å molecular
sieves (0.5 g/mmol) in CH2Cl2 (5 mL/mmol) was cooled to −20 °C
(ethylene glycol/H2O (1:1) with dry ice). A solution of the appropriate
optically pure diethyl tartrate (1.09 equiv) in CH2Cl2 (2.5 mL/mmol)
was added. Then Ti(OiPr)4 (1.20 equiv) followed by TBHP (5.5 M in
nonane) (3.92 equiv) were successively introduced into the reaction.
The mixture was stirred at −20 °C for 20 min, and then a solution of the
E-allyl alcohol (1.00 equiv) 10 in CH2Cl2 (2 mL/mmol) was dropwise
added in over a period of 30 min. The reaction was continued for further
4 h at −20 °C. After completion of the reaction (TLC monitoring in
Et2O), it was warmed to 0 °C and then poured into a freshly prepared
solution of FeSO4·7H2O (0.330 g/mmol) and tartaric acid (0.100 g/
mmol) in water (1 mL/mmol) which was cooled to 0 °C. The two-phase
mixture was stirred for 45 min, the layers were separated, and the
aqueous phase was extracted with CH2Cl2. Combined organic portions
were concentrated to 1/3 volume and used directly in the next step of
the sequence leading to the chromane diol.
was performed using Et2O/MeOH (96:4 to 92:8) to furnish the
chromane diol as a white crystalline solid product.
(R)-1-((S)-Chroman-2yl-ethane-1,2-diol (11). Yield: 3.29 g (66%) as
colorless solid (mp 78 °C); [α]D20 = +86.7 (c = 0.475 in MeOH); 1H
NMR (400 MHz, CDCl3): δ 7.10−7.01 (m, 2H); 6.90−6.81 (t, J = 8.33
Hz, 1H); 6.81−6.74 (d, J = 8.33 Hz, 1H); 4.07−3.95 (m, 1H); 3.92−
3.76 (m, 3H); 3.36−3.08 (br, OH); 2.88−2.72 (m, 2H); 2.16−2.08 (m,
1H); 1.91−1.77 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 154.3, 129.7,
127.4, 122.2, 120.6, 116.7, 76.4, 73.4, 63.5, 24.4, 23.3; HRMS (EI) (m/z)
[C11H14O3]+: Calcd 194.0937, Found 194.0938.
(S)-1-((R)-Chroman-2-yl)ethane-1,2-diol (14). Yield: 3.30 g (66%)
as colorless solid (mp 76 °C); [α]D20 = −74.9 (c = 0.865 in MeOH); 1H
NMR (400 MHz, CDCl3): δ 7.12−7.01 (m, 2H); 6.89−6.81 (t, J = 7.46
Hz, 1H); 6.81−6.73 (d, J = 8.46 Hz, 1H); 4.10−3.96 (m, 1H); 3.92−
3.77 (m, 3H); 3.04−2.64 (br, 4H); 2.17−2.07 (m, 1H); 2.16−2.08 (m,
1H); 1.92−1.78 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 154.3, 129.7,
127.4, 122.2, 120.7, 116.8, 76.6, 73.4, 63.5, 24.4, 23.4; HRMS (EI) (m/z)
[C11H14O3]+: Calcd 194.0937, Found 194.0939.
General Experimental Procedure for the Two-Step Mitsuno-
bu Inversion of the Chromane Diols 11 and 14 to the Chromane
Diols 18 and 22. Step 1: Chromane Diol to Bis(4-nitrobenzoate)
Esters. Diisopropyl azodicarboxylate (DIAD) (6.00 equiv) was
dissolved in THF (7.14 mL/mmol) and cooled to −20 °C under N2
atmosphere. To this was dropwise added a THF solution (7.14 mL/
mmol) of PPh3 (6.00 equiv) while maintaining the internal temperature
at −20 °C. A solution of chromane diol (1.00 equiv) in THF (2.9 mL/
mmol) was dropwise added. Finally a p-nitrobenzoic acid (6.00 equiv)
solution in THF (6 mL/mmol) was dropwise added. The reaction
mixture was stirred at −20 °C for 5 h. The progress of the reaction was
monitored by TLC (100% Et2O, KMnO4 stain). The cooling bath was
removed, and the reaction was warmed to room temperature. The
solvent was evaporated under vacuum. To the resulting pale yellow
syrup was added Et2O to precipitate PPh3O. The combined organic
portions were concentrated and then purified by flash chromatography
on silica gel using Et2O/MeOH (20:1 to 9:1). Although, the obtained
material still contained PPh3O and diisopropylurea, it was used for the
next step.
Step 2: Saponification of the Bis(4-nitrobenzoate) Ester. The
diester (1.00 equiv) from step 1 was dissolved in MeOH, and NaOMe
(95% pure, 3.00 equiv) was added at room temperature. Slowly the
reaction turned into a homogeneous pale yellow solution. The reaction
was continued at room temperature overnight under nitrogen
atmosphere. After 16 h, the solvent was removed under vacuum.
CH2Cl2 was added to the resulting pale pink solid product to provide a
clear pale yellow solution. After addition of saturated aqueous NH4Cl,
the layers were separated and the aqueous phase was extracted three
times with CH2Cl2. The combined organic portions were successively
washed with H2O and brine solution, dried over Na2SO4, filtered, and
concentrated. Flash chromatography on silica gel was performed using
100% Et2O to Et2O/MeOH (9:1), furnishing the chromane diol.
(S)-1-((S)-Chroman-2-yl)ethane-1,2-diyl Bis(4-nitrobenzoate)
(17). Light yellow solid; mp 119 °C; 1H NMR (400 MHz, CDCl3): δ
8.37−8.30 (m, 4H); 7.92−7.80 (m, 4H); 7.13 (dd, J = 9.28 Hz, 1.94 Hz,
1 H); 7.06 (d, J = 7.34 Hz, 1H); 6.93−6.83 (m, 2H); 5.80 (ddd, J = 8.63
Hz, 5.61 Hz, 3.45 Hz, 1H); 4.91−4.84 (d, J = 5.72 Hz, 2H); 4.46−4.39
(m, 1H); 3.02−2.77 (m, 2H); 2.16−1.90 (m, 2H); HRMS (EI) (m/z)
[C25H20O9N2]+: Calcd 492.1169, Found 492.1163.
(R)-1-((R)-Chroman-2-yl)ethane-1,2-diyl Bis(4-nitrobenzoate)
(21). Light yellow solid; mp 115 °C; 1H NMR (400 MHz, CDCl3): δ
8.36−8.31 (m, 4H); 7.90−7.88 (m, 4H); 7.13 (ddd, J = 8.34 Hz, 7.56
Hz, 1.46 Hz, 1 H); 7.06 (d, J = 7.44 Hz, 1H); 6.92−6.85 (m, 2H); 5.81
(ddd, J = 8.84 Hz, 5.61 Hz, 3.38 Hz, 1H); 5.02−4.92 (m, 2H); 4.89 (d, J
= 5.68 Hz, 2H); 4.44 (ddd, J = 10.87 Hz, 3.28 Hz, 2.37 Hz, 1H); 2.96
(ddd, J = 17.02 Hz, 12.09 Hz, 6.11 Hz, 1H); 2.82 (ddd, J = 16.49 Hz, 5.32
Hz, 2.30 Hz, 1H); 2.16−2.07 (m, 1H); 2.04−1.91 (m, 1H); HRMS (EI)
(m/z) [C25H20O9N2]+: Calcd 492.1169, Found 492.1163.
(S)-1-((S)-Chroman-2-yl)ethane-1,2-diol (18). Yield: 1.27 g (42%
over two steps starting from 11) as a colorless solid (mp 116 °C); 1H
NMR (400 MHz, CDCl3): δ 7.18−7.00 (m, 2H); 6.92−6.75 (m, 2H);
4.13−4.03 (m, 1H); 3.85−3.67 (m, 3H); 2.95−2.82 (m, 2H); 2.82−2.73
Step 2. Base-Catalyzed Intramolecular Cyclization. The pale yellow
viscous epoxide solution obtained from step 1 was cooled to 0 °C under
N2 atmosphere. A 30% aqueous NaOH solution in brine (2.9 mL/
mmol) was added [Note 1: 100 mL of a 30% NaOH in brine solution is
prepared by the addition of NaCl (5 g) to a solution of NaOH (30 g) in
water (90 mL)]. The reaction mixture turned from pale yellow to pale
violet and after about 10 min it turned colorless. The reaction was stirred
at 0 °C for 1 h and subsequently warmed to room temperature. The
layers were separated, and the aqueous phase was extracted thrice with
CH2Cl2. The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated. Flash chromatography on silica gel
3970
DOI: 10.1021/acs.joc.5b00263
J. Org. Chem. 2015, 80, 3965−3973

The Journal of Organic Chemistry
Article
(m, 1H); 2.56−2.39 (br, OH); 2.05−1.86 (m, 2H); 13C NMR (100
MHz, CDCl3): δ 154.2, 129.7, 127.4, 121.8, 120.0, 116.8, 76.8, 73.9,
63.8, 24.6, 23.9; HRMS (EI) (m/z) [C11H14O3]+: Calcd 194.0937,
Found 194.0938.
propanol (0.2 mL/mmol). The crude mixture was filtered through a
short pad of Dicalite over sand and thoroughly washed with 2-propanol
(three times). The combined organic portions were concentrated to
furnish the corresponding chromane epoxide, which were immediately
used for further transformations.
General Experimental Method for the Preparation of N-
Benzylamino Chromanes Alcohol from from Chromane
Epoxides. Benzylamine (5 equiv) was dissolved in 2-propanol (0.6
mL/mmol) and heated to 80 °C under N2 atmosphere. A solution of the
chromane epoxide (1.00 equiv) in 2-propanol (2 mL/mmol) was added
dropwise over a period of 2 h, and the mixture was further heated to 80
°C for an additional 2 h. After completion of the reaction (TLC
monitoring in CH2Cl2/MeOH (5:1) solvent system), the reaction
mixture was cooled to 0 °C (1 h) and additional 2-propanol was added
to facilitate the crystallization. The solid material was isolated by
filtration and dried under high vacuum.
General Experimental Method for the Preparation of the N-
Benzyldesfluoronebivolol Framework. The chromane epoxide
(1.10 equiv) and N-benzylamino alcohol (1.00 equiv) were dissolved in
2-propanol (3.6 mL/mmol) and were heated to reflux under a dry
nitrogen atmosphere. After completion of the reaction (4 to 6 h and
TLC monitoring in CH2Cl2/MeOH (9:1)), the solvent was removed
under vacuum. Flash chromatography on silica gel using a CH2Cl2/
MeOH (15:1) eluent system furnished the product as a white solid in
89% to quantitative yield.
General Experimental Method for the N-Debenzylation via
Transfer Hydrogenation Using Pd/C and Cyclohexene. To a
THF/H2O (6:1) (5.6 mL/mmol) solution of the N-benzyldesfluor-
onebivolol compound (1.00 equiv) were added concentrated aqueous
HCl (1.12 equiv), Pd/C (dry, 10%), and finally cyclohexene (10 equiv),
and the reaction was heated to reflux. After completion of the reaction (2
to 6 h, TLC monitoring in CH2Cl2/MeOH (9:1)), it was brought to
room temperature and filtered through a short pad of Dicalite over sand.
The solids were thoroughly washed with THF (three times). The
combined organic portions were concentrated under vacuum to a small
volume, resulting in a solid−liquid suspension. Isopropyl acetate or
EtOAc (2 mL/mmol) was added to facilitate the crystallization of the
desfluoronebivolol hydrochloride salt, which were obtained in 72% to
95% isolated yields as white solid products.
(R)-1-((R)-Chroman-2-yl)ethane-1,2-diol (22). Yield: 0.94 g (28%
1
over two steps starting from 14) as colorless solid (mp 116 °C); H
NMR (400 MHz, CDCl3): δ 7.12−7.02 (m, 2H); 6.89−6.79 (m, 2H);
4.12−4.06 (m, 1H); 3.89−3.75 (m, 3H); 2.95−2.83 (m, 2H); 2.78 (ddd,
J = 16.33 Hz, 5.49 Hz, 2.69 Hz, 1H); 2.52−2.45 (br, OH); 2.06−1.87
(m, 2H); 13C NMR (100 MHz, CDCl3): δ 154.1, 129.6, 127.3, 121.9,
120.7, 116.7, 76.7, 73.8, 63.6, 24.5, 23.8. HRMS (EI) (m/z)
[C11H14O3]+: Calcd 194.0937, Found 194.0938.
General Experimental Procedure for the Primary Tosylation
of the Chromane Diols. Pyridine (2.42 equiv) was added to a CH2Cl2
(3 mL/mmol) solution of the corresponding chromane diol (1.00
equiv) at room temperature under a nitrogen atmosphere. The mixture
was cooled to 0 °C, and a solution of the tosyl chloride (1.11 equiv) in
CH2Cl2 (1 mL/mmol) was added dropwise. After being stirred at the
same temperature for a further 30 min, the reaction was warmed to room
temperature and stirred overnight. After completion of the reaction (19
to 24 h, TLC monitoring in Et2O), the reaction was quenched by the
addition of saturated aqueous CuSO4 solution (3.7 mL/mmol) and
stirred vigorously at room temperature. The layers were separated, and
the aqueous phase was extracted with CH2Cl2 (three times). The
combined organic portions were dried over anhydrous Na2SO4, filtered,
and concentrated in vacuum. Flash chromatography of the crude
product on silica gel was performed using pentane/Et2O (6:1 to 4:1),
furnishing the corresponding primary tosylate in 56% to 93% isolated
yield. Only one of the four compounds (19) was characterizable by 13C
NMR. We could not obtain 13C NMR spectra of compounds 12, 15, and
23 because of instability.
(R)-2-((S)-Chroman-2-yl)-2-hydroxyethyl 4-methylbenzenesulfo-
nate (12). Yield: 0.70 g (93%) as off-white wax; 1H NMR (400 MHz,
CDCl3): δ 7.81 (d, J = 7.99 Hz, 2H); 7.34 (d, J = 7.99 Hz, 2H); 7.08−
6.86 (m, 2H); 6.87−6.75 (m, 1H); 6.83 (dt, J = 7.73 Hz, 1.26 Hz, 1H);
6.66 (d, J = 8.15 Hz, 1H); 4.38 (dd, J = 10.54 Hz, 2.95 Hz, 1H); 4.25−
4.18 (dd, J = 10.74 Hz, 5.62 Hz, 1H); 3.98−3.89 (m, 2H); 2.84−2.70
(m, 2H); 2.44 (s, 3H); 2.21−2.14 (m, 1H); 1.84−1.72 (m, 1H); HRMS
(EI) (m/z) [C18H20O5S]+: Calcd 348.1026, Found 348.1030.
(S)-2-((R)-Chroman-2-yl)-2-hydroxyethyl 4-methylbenzenesulfo-
nate (15). Yield: 1.56 g (68%) as off-white wax; 1H NMR (400 MHz,
CDCl3): δ 7.81 (d, J = 7.71 Hz, 2H); 7.34 (d, J = 8.48 Hz, 2H); 7.15−
6.97 (m, 2H); 7.15−6.97 (m, 2H); 6.89−6.79 (m, 1H); 6.72−6.61 (d, J
= 7.71 Hz, 1H); 4.42−4.36 (dd, 4.38 (dd, J = 10.79 Hz, 3.08 Hz, 1H);
4.25−4.19 (dd, J = 10.02 Hz, 6.16 Hz, 1H); 3.97−3.87 (m, 2H); 2.85−
2.70 (m, 2H); 2.44 (s, 3H); 2.22−2.14 (m, 1H); 1.84−1.72 (m, 1H);
HRMS (EI) (m/z) [C18H20O5S]+: Calcd 348.1026, Found 348.1030.
(S)-2-((S)-Chroman-2-yl)-2-hydroxyethyl 4-methylbenzenesulfo-
nate (19). Yield: 1.22 g (58%) as off-white wax; 1H NMR (400 MHz,
CDCl3): δ 7.81 (d, J = 8.69 Hz, 2H); 7.33 (d, J = 8.07 Hz, 2H); 7.10−
7.01 (m, 2H); 6.90−6.81 (m, 1H), 6.71 (d, J = 8.69 Hz, 1H); 4.25−4.20
(dd, J = 5.89 Hz, 1.57 Hz, 1H); 4.06−3.99 (m, 1H); 3.98−3.89 (m, 1H);
2.43 (s, 3H): 2.92−2.71 (m, 2H); 2.00−1.99 (m, 2H); 13C NMR (100
MHz, CDCl3): δ 154.1, 145.2, 12.7, 130.1, 129.8, 128.1, 127.4, 121.9,
121.0, 116.8, 76.8, 74.9, 71.3, 70.1, 24.7, 23.6, 21.8); HRMS (EI) (m/z)
[C18H20O5S]+: Calcd 348.1026, Found 348.1027.
(R)-2-((R)-Chroman-2-yl)-2-hydroxyethyl 4-methylbenzenesulfo-
nate (23). Yield: 1.48 g (68%) as off-white wax; 1H NMR (400 MHz,
CDCl3): δ 7.82 (d, J = 8.23 Hz, 2H); 7.34 (dd, J = 8.62 Hz, 0.57 Hz, 2H);
7.10−7.02 (m, 2H); 6.86 (J = ddd, 8.60 Hz, 7.28 Hz, 1.34 Hz, 1H), 6.72
(dd, J = 8.09 Hz, 1.00 Hz, 1H); 4.23 (dd, J = 5.75 Hz, 1.39 Hz, 1H);
4.06−4.01 (m, 1H); 3.98−3.91 (m, 1H); 2.44 (s, 3H): 2.92−2.73 (m,
2H); 1.99−1.92 (m, 2H); HRMS (EI) (m/z) [C18H20O5S]+: Calcd
348.1026, Found 348.1024.
(R)-1-((S)-Chroman-2-yl)-2-(((R)-2-((R)-6-fluorochroman-2-yl)-2-
hydroxyethyl)amino)ethan-1-ol Hydrochloride (3a). Yield: 412 mg
(82%) as white crystals; mp 185 °C; [α]D20 = +16.5 (c = 0.34 in MeOH);
1H NMR (400 MHz, DMSO-d6): δ = 8.99−8.59 (br, NH2); 7.11−7.03
(m, 2H); 6.98−6.87 (m, 2H); 6.82 (t, J = 7.72 Hz, 1.29 Hz, 1H); 6.79−
6.71 (m, 2H); 5.97 (d, J = 5.57 Hz, OH); 5.78 (d, J = 5.57 Hz, OH);
4.15−4.06 (m, 1H); 4.06−3.95 (m, 2H); 3.94−3.85 (m, 1H); 3.43−3.34
(br, 1H masked with water signal); 3.28−3.13 (m, 2H); 3.12−2.99 (m,
1H); 2.89−2.63 (m, 4H); 2.19−2.06 (m, 1H); 1.99−1.86 (m, 1H);
1.84−1.62 (m, 2H); 13C NMR (100 MHz, DMSO-d6): δ = 155.9 (d, J =
235.78 Hz, C−F), 153.9, 150.5, 129.6, 127.1, 123.7 (d, J = 8.49 Hz),
122.2, 120.3, 117.4 (d, J = 8.49 Hz), 116.3, 115.3 (d, J = 22.44 Hz), 113.7
(d, J = 23.04 Hz), 76.0, 76.8, 67.6, 67.3, 50.0, 49.5, 24.2, 23.4, 22.8, 22.2;
IR ν = 3057, 2858, 1491, 1233, 1217, 1080, 749 cm−1; HRMS (EI) (m/
z) [C22H26O4NF]+: Calcd 387.1840, Found 387.1841.
(S)-1-((R)-Chroman-2-yl)-2-(((S)-2-((S)-6-fluorochroman-2-yl)-2-
hydroxyethyl)amino)ethan-1-ol Hydrochloride (3b). Yield: 393 mg
20
(81%) as white crystals; mp 182 °C; [α]D = −28.9 (c = 0.65 in
MeOH); 1H NMR (400 MHz, DMSO-d6): δ = 8.84 (br s, NH2); 7.09−
7.03 (m, 2H); 6.95−6.87 (m, 2H); 6.85−6.79 (m, 1H); 6.78−6.73 (m,
2H); 5.99 (d, J = 5.6 Hz, OH); 5.81 (d, J = 5.6 Hz, OH); 4.16−4.08 (m,
1H); 4.07−3.96 (m, 2H); 3.95−3.88 (m, 1H); 3.42−3.34 (br, 1H partly
overlapped by water signal); 3.28−3.13 (m, 2H); 3.12−3.02 (m, 1H);
2.88−2.65 (m, 4H); 2.18−2.09 (m, 1H); 1.98−1.89 (m, 1H); 1.84−1.64
(m, 2H); 13C NMR (100 MHz, DMSO-d6): δ = 155.9 (d, 1JC−F = 236
Hz), 153.8, 150.5 (d, J = 1.2 Hz), 129.6, 127.0, 123.7 (d, J = 7.5 Hz),
122.2, 120.2, 117.4 (d, J = 8.2 Hz), 116.3, 115.3 (d, J = 22.5 Hz), 113.6
(d, J = 23.0 Hz), 77.0, 76.8, 67.6, 67.3, 50.0, 49.5, 24.1, 23.4, 22.8, 22.2
ppm; IR ν = 3056, 2858, 1491, 1232, 1216, 1080, 749 cm−1; HRMS (EI)
(m/z) [C22H26O4NF]+: Calcd 387.1840, Found 387.1841.
General Experimental Method for the Peparation of
Chromane Epoxides from Tosylates. NaOMe (95% pure, 1.10
equiv) was added in small portions to a solution of the primary tosylate
(1.00 equiv) in 2-propanol (1.15 mL/mmol) at room temperature
under dry nitrogen atmosphere. The mixture was stirred for 1 h. The
reaction was quenched by the addition of AcOH (0.13 equiv) in 2-
3971
DOI: 10.1021/acs.joc.5b00263
J. Org. Chem. 2015, 80, 3965−3973

The Journal of Organic Chemistry
Article
(R)-1-((R)-Chroman-2-yl)-2-(((R)-2-((S)-6-fluorochroman-2-yl)-2-
hydroxyethyl)amino)ethan-1-ol Hydrochloride (4a). Yield: 406 mg
(88%) as white crystals; mp 203 °C; [α]D20 = +21.4 (c = 1 in MeOH);
1H NMR (400 MHz, DMSO-d6): δ = 8.84 (br s, NH2); 7.09−7.03 (m,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
2H); 6.96−6.87 (m, 2H); 6.81 (dt, J = 7.4 Hz; 1.1 Hz, 1H); 6.79−6.73
(m, 2H); 6.00 (d, J = 5.6 Hz, OH); 5.97 (d, J = 5.6 Hz, OH); 4.16−4.09
(m, 1H); 4.07−3.98 (m, 2H); 3.93−3.86 (m, 1H); 3.38 (br s, 1H partly
overlapped by water signal); 3.29−3.13 (m, 2H); 3.12−3.00 (m, 1H);
2.89−2.65 (m, 4H); 2.16−2.07 (m, 1H); 1.99−1.90 (m, 1H); 1.85−1.63
(m, 2H); 13C NMR (100 MHz, DMSO-d6): δ = 156.0 (d, J = 236 Hz,
C−F), 154.2, 150.1 (d, J = 1.6 Hz), 129.5, 127.0, 123.8 (d, J = 7.5 Hz),
122.1, 120.0, 117.4 (d, J = 8.2 Hz), 116.3, 115.3 (d, J = 22.6 Hz), 113.7
(d, J = 23.2 Hz), 77.1, 76.7, 67.5, 67.3, 49.9, 49.5, 24.1, 23.6, 22.5, 22.4;
IR ν = 3374, 3072, 2859, 1488, 1236, 1216, 1075, 745 cm−1; HRMS (EI)
(m/z) [C22H26O4NF]+: Calcd 387.1840, Found 387.1841.
We thank Corden Pharma International GmbH for providing the
fluorinated chromane epoxides.
REFERENCES
■
(1) (a) Van Lommen, G. R. E.; De Bruyn, M. F. L.; Schroven, M. F. J.
Derivatives of 2,2′-iminobisethanol. European Patent 0145067, Jan 25,
1989. (b) Pauwels, P. J.; Gommeren, W.; van Lommen, G.; Janssen, P. A.
J.; Leysen, J. E. Mol. Pharmacol. 1988, 34, 843. (c) van de Water, A.;
Jansssens, W.; van Neuten, J.; Xhonneux, R.; DeCree, J. J. Cardiovasc.
Pharmacol. 1988, 11, 552.
(S)-1-((S)-Chroman-2-yl)-2-(((S)-2-((R)-6-fluorochroman-2-yl)-2-
hydroxyethyl)amino)ethan-1-ol Hydrochloride (4b). Yield: 321 mg
(89%) as white crystals; mp 195 °C; [α]D20 = −24.4 (c = 1 in MeOH);
1H NMR (400 MHz, DMSO-d6): δ = 8.98−8.44 (br, NH.HCl); 7.12−
(2) Van Lommen, G. R. E.; De Bruyn, M. F. L.; Schroven, M. F. J.
Derivatives of 2,2′-iminobisethanol. U.S. Patent 4,654,362, Mar 31,
1987.
(3) Xhonneux, R. M.; Van Lommen, G. R. E. Agents for lowering the
blood pressure. European Patent 0334429, Nov 19, 1992.
7.02 (m, 2H); 7.00−6.86 (m, 2H); 6.86−6.66 (m, 3H); 6.08−5.88 (br,
OH); 5.86−5.84 (br, OH); 4.17−4.06 (m, 1H); 4.06−3.95 (m, 2H);
3.94−3.84 (m, 1H); 3.34 (br, 1H masked with water signal); 3.28−3.12
(m, 3H); 3.05 (dd, J = 12.32 Hz, 9.93 Hz, 1H); 2.90−2.62 (m, 4H);
2.18−2.05 (m, 1H); 2.00−1.88 (m, 1H); 1.86−1.59 (m, 2H); 13C NMR
(400 MHz, DMSO-d6): δ = 155.6 (d, J = 234.67 Hz, C−F), 154.9, 154.3,
150.1 (d, J = 1.69 Hz), 129.5, 127.1, 123.8 (d, J = 6.94 Hz), 122.2, 120.2,
117.4 (d, J = 8.44 Hz), 117.4, 116.3, 115.4 (d, J = 22.34 Hz), 113.8 (d, J =
22.84 Hz), 77.1, 76.7, 67.6, 67.5, 49.9, 49.5, 24.1, 23.6, 22.6, 22.4; IR ν =
3372, 3072, 2858, 1488, 1236, 1216, 1075, 745 cm−1; HRMS (EI) (m/z)
[C22H26O4NF]+: Calcd 387.1840, Found 387.1842.
(R)-1-((R)-Chroman-2-yl)-2-(((R)-2-((S)-chroman-2-yl)-2-
hydroxyethyl)amino)ethan-1-ol Hydrochloride (5a). Yield: 553 mg
(86%) as white crystals; mp 194 °C; [α]D20 = +15.7 (c = 1 in MeOH);
1H NMR (400 MHz, DMSO-d6): δ = 8.81 (br s, NH2); 7.09−7.04 (m,
4H); 6.85−6.79 (m, 2H); 6.78−6.74 (m, 2H); 5.99 (d, J = 5.6 Hz, OH);
5.79 (d, J = 5.6 Hz, OH); 4.16−4.08 (m, 1H); 4.07−3.97 (m, 2H);
3.95−3.88 (m, 1H); 3.43−3.35 (m, 1H partly overlapped by water
signal); 3.29−3.14 (m, 2H); 3.12−3.02 (m, 1H); 2.88−2.65 (m, 4H);
2.18−2.09 (m, 1H); 1.98−1.90 (m, 1H); 1.85−1.65 (m, 2H); 13C NMR
(100 MHz, DMSO-d6): δ = 154.3, 153.9, 129.6, 129.5, 127.1, 127.0,
122.2, 122.1, 120.2, 120.1, 116.3 ( × 2), 77.0, 76.7, 67.6, 67.4, 50.0, 49.5,
24.1, 23.5, 22.8, 22.6; IR ν = 3057, 2861, 1585, 1489, 1232, 1080, 747
cm−1; HRMS (EI) (m/z) [C22H27O4N]+: Calcd 369.1935, Found
369.1934.
(4) Nebivolol is marketed as racemate although both enantiomers are
reported to have slightly different pharmacological properties (see ref 3).
(5) Janssen, P. A. J. Clin. Drug Invest. 1991, 3 (Supplement), 1−2.
(6) (a) Bader, T.; Stutz, A.; Hofmeier, H.; Bichsel, H.-U. A process for
preparation of racemic Nebivolol. European Patent Application
1803715, Jul 24, 2007. (b) Stutz, A. A process for preparation of
racemic Nebivolol. European Patent 1803716, Jul 25, 2012. (c) Noe, C.
R.; Jasic, M.; Kollmann, H.; Lachmann, B. Method for producing
nebivolol. PCT Patent Application WO2007/009143, Jan 25, 2007.
(d) Volpicelli, R.; Maragni, P., Cotarca, L.; Foletto, J. Process for
preparing nebivolol. PCT Patent Application WO2008/040528, Apr 10,
2008. (e) Ullucci, E.; Maragni, P.; Cotarca, L.; Foletto, J. Process for
preparing nebivolol. PCT Patent Application WO2008/064826, Jun 5,
2008. (f) Volpicelli, R.; Maragni, P.; Cotarca, L.; Foletto, J.; Massacesi, F.
Process for preparing nebivolol. PCT application WO2008/064827, Jun
5, 2008. (g) Volpicelli, R.; Maragni, P.; Massaccesi, F.; Munari, D.;
Cotarca, L.; Foletto, J. Process for preparing nebivolol. PCT Patent
Application WO2009/121710, Oct 8, 2009. (h) Derrien, Y.; Chenard,
E.; Burgos, A. Method for preparing nebivolol. PCT Patent Application
WO2010/034927, Apr 1, 2010. (i) Maragni, P.; Michieletto, I.;
Volpicelli, R.; Soriato, G.; Foletto, J.; Cotarca, L.; Verzini, M. Process
for preparing nebivolol. WO2010/049455, May 6, 2010. (j) Cotarca, L.;
Foletto, J.; Maragni, P.; Soriato, G.; Urbani, D.; Verzini, M. Process for
preparing nebivolol. PCT Patent Application WO2011/009628, Jan 27,
2011. (k) Volpicelli, R.; Maragni, P.; Cotarca, L.; Foletto, J.; Massaccesi,
F. Nebivolol formate. European patent 2228374, Jun 5, 2013. (l) Bartoli,
S.; Cipollone, A.; Fattori, D. Process for the preparation of nebivolol.
PCT Patent Application WO2011/098474, Aug 18, 2011. (m) Mauro,
S.; Fattori, D.; D’Andrea, P.; Cipollone, A. Process for the preparation of
nebivolol. PCT Patent Application WO2012/095707, Jul 19, 2012.
(n) Satyanarayana Reddy, M.; Eswaraiah, S.; Sahadeva Reddy, M.
Improved process for the preparation of nebivolol hydrochloride. PCT
Patent Application WO2010/089764, Aug 12, 2010. (o) Sheth, R.;
Attanti, S. V.; Patel, H. M.; Gupta, V.; Nadkarni, S. S. Nebivolol and its
pharmaceutically acceptable salts, process for preparation and
pharmaceutical composition of nebivolol. PCT Patent Application
WO2006/025070, Mar 9, 2006. (p) Parthasaradhi Reddy, B.; Rathnakar
Reddy, K.; Raji Reddy, R.; Muralidhara Reddy, D.; Srinivas Reddy, I. A
novel process for preparation of nebivolol intermediates. PCT Patent
Application WO2006/016376, Feb 16, 2006. (q) Parthasaradhi Reddy,
B.; Rathnakar Reddy, K.; Raji Reddy, R.; Muralidhara Reddy, D.;
Srinivas Reddy, I. Process for isolation of desired isomers of nebivolol
intermediates. PCT Patent Application WO2007/083318, Jul 26, 2007.
(r) Trinka, P.; Reiter, J.; Berecz, G.; Simig, G. New process for the
preparation of racemic ([2S[2R*[R[R*]]]] and ([2R[2S*[S[S*]]]]-
( )-α,α′-[imino-bis[methylene)]-bis[6-fluoro-chroman-2-methanol]
and its pure ([2S[2R*[R[R*]]]] and ([2R[2S*[S[S*]]]] enantiomers.
PCT Patent Application WO2004/041805, May 21, 2004. (s) Khamar,
Thakor, I.; Patel, M.; Jadav, K.; Parikh, A.; Joshi, A. C. An improved
(S)-1-((R)-Chroman-2-yl)-2-(((S)-2-((S)-chroman-2-yl)-2-
hydroxyethyl)amino)ethan-1-ol Hydrochloride (5b). Yield: 154 mg
20
(51%) as white crystals; mp 184 °C; [α]D = −27.3 (c = 0.355 in
MeOH); 1H NMR (400 MHz, DMSO-d6): δ = 9.01−8.52 (br, NH2);
7.18−7.01 (m, 4H); 6.94−6.67 (m, 4H); 5.97 (d, J = 5.62 Hz, OH); 5.78
(d, J = 5.87 Hz, OH); 4.20−4.07 (m, 1H); 4.07−3.96 (m, 2H); 3.96−
3.82 (m, 1H); 3.29−3.14 (m, 2H); 3.34 (br, 1H masked with water
signal at 3.34); 3.14−2.94 (m, 1H); 2.89−2.65 (m, 4H); 2.20−2.04 (m,
1H); 1.99−1.89 (m, 1H); 1.86−1.64 (m, 2H); 13C NMR (100 MHz,
DMSO-d6): δ = 154.3, 153.9, 129.6, 129.5, 127.1, 127.9, 122.2, 122.2,
120.3, 120.1, 116.3, 116.3, 77.0, 76.7, 67.6, 67.4, 50.0, 49.5, 24.1, 23.4,
22.8, 22.6; ; IR ν = 3067, 2858, 1584, 1489, 1232, 1080, 748 cm−1;
HRMS (EI) (m/z) [C22H27O4N]+: Calcd 369.1935, Found 369.1936.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*Fax: (+49) 06202-99-77-3250. E-mail: gerhard.jas@
cordenpharma.com.
*Fax: (+49) 0391-67-12223. E-mail: dieter.schinzer@ovgu.de.
3972
DOI: 10.1021/acs.joc.5b00263
J. Org. Chem. 2015, 80, 3965−3973

The Journal of Organic Chemistry
Article
process for the preparation of nebivolol hydrochloride. European Patent
2163551, Nov 16, 2011. (t) Wang, G.; Chen, X.; Hou, J. Process for
isolation of a mixture of RRRS and SSSR configurations of nebivolol
intermediates. European Patent 2236510, Apr 30, 2014. (u) Cipollone,
A.; D’Andrea, P.; Fattori, D. Process for the preparation of epoxides as
intermediates for the synthesis of nebivolol. PCT Patent Application
WO2013/018053, Feb 7, 2013. (v) Chen, P.; Lv, C. A method for the
preparation of D,L-nebivolol and its hydrochloride salt. PCT Patent
Application WO2006/092086, Sep 08, 2006.
(7) (a) Chandrasekhar, S.; Reddy, M. V. Tetrahedron 2000, 56, 6339−
6344. (b) Johannes, C. W.; Visser, M. S.; Weatherhead, G. S.; Hoveyda,
A. H. J. Am. Chem. Soc. 1998, 120, 8340−8347. (c) Carreno, M. C.;
Hernadez-Torres, G.; Urbano, A.; Colobert, F. Eur. J. Org. Chem. 2008,
2035−2038. (d) Wang, N.-X.; Yu, A.-G.; Wang, G.-X.; Zhang, X.-H.; Li,
Q.-S.; Li, Z. Synthesis 2007, 1154−1158. (e) Yihui, B.; Xinzhi, C. J. Chem.
Res. 2006, 807−808. (f) Yang, Y. X.; Wang, N. X.; Xing, Y. L.; Wang, W.
W.; Zhao, J.; Wang, G. X.; Tang, S. Chin. Chem. Lett. 2005, 16, 1577−
1580.
(8) Formally, all desfluorinated NBV compounds are part of the claims
in refs 2 and 3, and at least one monodesfluoro isomer has been
described in the experimental part of ref 3, but no analytical details are
given.
(9) Jas, G.; Freifeld, I.; Kesseler, K. Verfahren zur Herstellung von
Epoxiden die in der Herstellung von Nebivolol und dessen Derivaten
einsetzbar sind. German Patent Application DE 10 2014 107 132,
submitted May 5, 2014.
(10) (a) Jas, G.; Freifeld, I.; Kesseler, K. Method for producing
nebivolol. PCT Patent Application WO2011/091968, Aug 4, 2011.
(b) Jas, G.; Freifeld, I.; Kesseler, K. A new method for producing
nebivolol hydrochloride of high purity. European Patent Application
14155300, unpublished.
(11) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974−
5976.
(12) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765−5780.
(13) Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH: New York, 1993; pp 103−158.
(14) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769−3772.
(15) Cannon, J.; Olson, A.; Overman, L.; Solomon, N. J. Org. Chem.
2012, 77, 1961−1973.
(16) Mitsunobu, O. Synthesis 1981, 1−28.
(17) Peters, M.; Trobe, M.; Tan, H.; Kleineschwede, R.; Breinbauer, R.
Chem.Eur. J. 2013, 19, 2442−2449.
3973
DOI: 10.1021/acs.joc.5b00263
J. Org. Chem. 2015, 80, 3965−3973