An efficient synthesis of an NMDA receptor antagonist via stereoselective fluorination

Article abstract of DOI:10.1055/s-2008-1032181

Herein is described the development and use of a novel bis(dialkylamino) sulfur difluoride reagent to effect the stereoselective conversion of a benzylic alcohol into a benzylic fluoride. A new method for the synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-ami

Full text of DOI:10.1055/s-2008-1032181

PAPER
891
An Efficient Synthesis of an NMDA Receptor Antagonist via Stereoselective
Fluorination
N
MD
A
Receptor
Antaa
gonist tthew M. Bio,*a Marjorie Waters,*b Gary Javadi,b Zhiguo Jake Song,b Fei Zhang,b Dave Thomasb
a
Amgen, Inc., One Kendall Square, Bldg 1000, Cambridge, MA 02139, USA
Fax +1(617)6213916; E-mail: mbio@amgen.com
b
Merck Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
Received 9 November 2007; revised 29 November 2007
including the rational design and use of a deoxygenative
fluorination reagent to install the key stereogenic benzylic
fluoride. In addition, we have developed a novel and prac-
tical route to 4-substituted 1H-pyrazolo[3,4-d]pyrim-
Abstract: Herein is described the development and use of a novel
bis(dialkylamino)sulfur difluoride reagent to effect the stereoselec-
tive conversion of a benzylic alcohol into a benzylic fluoride. A new
method for the synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-amines
is reported. Additionally, a practical method for the addition of a idines.
hindered alkoxide to an epoxide is demonstrated.
The construction of 1 can be logically separated into the
Key words: fluorine, stereoselective synthesis, heterocycles, de-
synthesis of two fragments; the ether fragment 2 and
the known 4-chloro-1H-pyrrazolo[3,4-d]pyrimidine 3
(Scheme 1).4 The assembly of 2 requires formation of the
ether bond and the stereoselective introduction of fluorine
at the benzylic position. We envisioned introduction of
the fluorine through a fluoride displacement of an activat-
ed alkoxide. This immediately simplified the problem of
asymmetric fluorination to an asymmetric synthesis of the
benzylic alcohol 4. Furthermore, we hoped to make the re-
quired ether bond and introduce the non-racemic benzylic
alcohol in a single step by opening epoxide 5 with the cy-
clohexanolamine 6. Successful execution of this synthetic
plan would result in an atom-efficient and practical asym-
metric synthesis of the target molecule 1.
oxygenation, ethers
The unique physical and pharmacodynamic properties of
fluorinated hydrocarbons have led to their wide-spread
use in the pharmaceutical industry.1 The use of fluorinated
molecules, in combination with the trend toward single
enantiomer active pharmaceutical ingredients, presents a
significant challenge to the process chemist; to design ef-
ficient routes to enantiopure compounds with stereogenic
C–F bonds.2 The recent discovery of compound 1, bearing
a stereogenic C–F moiety, as a NR2B selective N-methyl-
D-aspartate (NMDA) receptor antagonist, required us to
undertake the design of an efficient and practical synthesis
of 1 in order to enable biological studies.3 Herein we re-
port a practical solution to the asymmetric synthesis of 1,
The addition of hindered alkoxides to epoxides is a noto-
riously poor reaction5 given that the product itself is a re-
Cl
N
N
N
F
F
NH
N
F
F
N
N
H
O
3
O
N
N
NH2
H
2
1
F
OH
F
O
HO
O
+
NH2
NH2
5
6
4
Scheme 1
SYNTHESIS 2008, No. 6, pp 0891–0896
x
x
.
x
x
.2
0
0
8
Advanced online publication: 18.02.2008
DOI: 10.1055/s-2008-1032181; Art ID: M08507SS
© Georg Thieme Verlag Stuttgart · New York

892
M. M. Bio et al.
PAPER
F
F
F
OH
crystallization from toluene and heptane. The process is
rendered efficient by the fact that the excess 4-aminocy-
clohexanol can be recycled following recovery from the
aqueous phase as a crystalline solid. Conversion of (S)-4
into the crystalline Boc-amide (S)-11 under typical condi-
tions set the stage for the introduction of fluorine.
O
Br
O
OH
NHR
9
10
R = H, (S)-4
R = Boc, (S)-11
Scheme 2
Several activated derivatives of alcohol 11 were prepared,
including the mesylate, triflate, phosphate and acetate,
however, reaction of these with a range of fluoride sources
(TBAF, tetrabutylammonium triphenyldifluorosilicate,
CsF, KF or HF) gave either no or poor conversion into the
desired fluoride.9,10 An alternative to the step-wise con-
version of the alcohol group into fluorine is the direct
deoxygenative fluorination of alcohols using dialkylami-
nosulfur trifluorides such as the commercially available
bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-
fluor®)11 or diethylaminosulfur trifluoride (DAST).12 Fol-
lowing a typical literature procedure, alcohol (S)-1213 was
added to a solution of Deoxofluor® in dichloromethane at
–70 °C. Under these conditions, the fluoride (R)-15 was
obtained in 50% ee with the stereocenter inverted as ex-
pected (entry 1).14 The higher stereoselectivity observed
in non-polar solvents suggests that racemization occurs
through a competing SN1 pathway rather than participa-
tion by the a-ether oxygen (see Table 1, entries 1–4).
active alkoxide.6 Indeed, treatment of 6 with potassium
tert-butoxide in dimethylsulfoxide (DMSO), followed by
slow addition of the epoxide did give the desired product
4, albeit in only 28% yield. Oligomeric products resulting
from the coupling of product alkoxide 4 with epoxide 5
accounted for the majority of the mass balance.7 As ex-
pected, the use of excess alkoxide was found to be benefi-
cial, using five equivalents of 6 increased the assay yield
to 62%, and ten equivalents gave 73% yield.
A variety of methods are available for the preparation of
enantiomerically enriched epoxides. We initially focused
on 2-fluoroacetophenone as a starting material due to its
availability and cost. Bromination with bromine gave the
a-bromoketone, which was asymmetrically reduced with
borane-N,N-diethylaniline complex in the presence of 4
mol% (S)-5,5-diphenyl-2-methyloxazaborolidine to give
10 in 97% ee (Scheme 2).8 Crystallization from n-heptane
upgraded the enantiopurity to 99.2% ee with an overall
yield of 76% from 9. The a-bromohydrin 10 could be used
directly in the etherification reaction, with in situ forma-
tion of the epoxide under the strongly basic conditions.
Slow addition of 10 to five equivalents of the commercial-
ly available, inexpensive 6 and excess potassium tert-
butoxide in DMSO gave (S)-4 in 62% assay yield. (S)-4
was isolated in 55% yield following aqueous workup and
Having exploited the effect of solvent to little advantage,
basic additives were investigated with the expectation that
added base should reduce the reaction acidity and mini-
mize ionization of postulated intermediate 13 and enhance
the fluoride nucleophilicity (Scheme 3). As evident from
Table 1 (entries 6–8, 9, 10 and 12), added base had mini-
mal effect on selectivity. In order to further suppress the
Table 1 Deoxygenative Fluorination
Entry
1
Solvent
Temperature (°C)
Fluorinating agent
Deoxofluor®
Deoxofluor®
Deoxofluor®
Deoxofluor®
Deoxofluor®
Deoxofluor®
Deoxofluor®
Deoxofluor®
Deoxofluor®
Deoxofluor®
DAST
Additive
ee of (R)-15 (%)
CH2Cl2
–70
–70
–70
–70
–70
–70
–70
–70
–70
–70
–70
–70
–70
0
none
50
2
toluene
none
40
3
1,2-dimethoxyethane
MTBE
none
0
4
none
69
5
CH2Cl2
HF·pyridine
pyridine
33
6
CH2Cl2
58
7
CH2Cl2
aniline
74
8
CH2Cl2
2,6-lutidine
2-chloropyridine
N,N-diethylaniline
none
48
9
CH2Cl2
53
10
11
12
13
14
CH2Cl2
65
CH2Cl2
38
CH2Cl2
DAST
2,6-lutidine
Et2N–SiMe3
SiMe3–morpholine
72
CH2Cl2
toluene
DAST
99
Deoxofluor®
96 [(R)-14]
Synthesis 2008, No. 6, 891–896 © Thieme Stuttgart · New York

PAPER
NMDA Receptor Antagonist
893
R
O
R
N
S
F
F
OH
F
F
FH
F
O
O
OR'
NHR
NHR
F
R = Boc, (S)-11
R = Cbz, (S)-12
13
R = Boc, (R)-14
R = Cbz, (R)-15
Scheme 3
SN1 pathway a more fundamental change would be re- however, difficulties in both the protection and chlorina-
quired. tion steps led us to seek an alternate solution.
If two amines were pendant on the sulfur we would expect Under standard conditions, 2,6-dihydroxypyrimidine can
to attenuate the propensity for the activated alcohol to ion- be formylated and chlorinated in one pot (Scheme 5).
ize. Indeed, addition of Et2N–SiMe3 to DAST to generate Treatment of 19 with fluoroether salt 21 followed by con-
the bis(diethylamino)sulfur difluoride in situ followed by densation with hydrazine did provide the desired product
addition of the alcohol (S)-12 gave the desired (R)-15 with 1, albeit in modest yield. Condensation of the aldehyde
nearly perfect stereoselectivity (entry 13).15 Although the with a protected hydrazine equivalent gave the stable,
stereoselectivity in this reaction was excellent, the yield crystalline intermediate 20 in 55% overall yield. Although
was modest due to competing elimination of the activated 20 readily reacts with fluoroether 21, all attempts to cy-
alcohol. In addition, DAST has poor thermal stability, clize to 1 via deprotection of the Boc group failed. How-
presenting a hazard on large scale. Substituting DAST ever, we did find that in the presence of excess hydrazine,
with the more stable Deoxofluor®16 in this reaction gave the intermediate 22 cleanly converted into the desired pyr-
similar stereoselectivity but still resulted in elimination. razolo[3,4-d]pyrimidine in high yield. Thus, reaction of
The elimination reaction is probably favored as a result of 21 with 20 in the presence of diisopropylethylamine fol-
increased steric bulk of the bis(dialkylamino) sulfur sub- lowed by addition of hydrazine, gave (R)-1 in 90% overall
stituent. Replacing Et2N–SiMe3 with N-(trimethyl- yield and 98.6% ee (Scheme 6).
silyl)morpholine (see Scheme 4) gave minimal
elimination product and retained excellent stereoselectiv-
ity in the product. Significantly, the increased stability of
the reactive intermediate allowed the fluorination reaction
to be performed at 0 °C instead of –70 °C with minimal
loss of selectivity (Table 1, entry 14).
Cl
N
N
N
N
N
N
a
b
Cl
Cl
N
NHBoc
HO
OH
CHO
Cl
18
20
19
Scheme 5 Reagents and conditions: a) POCl3, DMF, 90 °C, then
H2O; b) H2NNHBoc, H3PO4, EtOAc, 55% over 2 steps.
O
O
(MeOH2CH2C)2N SF3
+
N
F
N(CH2CH2OMe)2
F
N
S
SiMe3
A practical and efficient enantioselective synthesis of the
NR2B subtype NMDA receptor antagonist 1 has been ac-
complished in six linear steps with an overall yield of 23%
from commercially available 2-fluoroacetophenone. The
route features the asymmetric introduction of a benzylic
fluoride using a novel deoxygenative fluorination proto-
col to convert a benzylic alcohol into the required fluorine
with nearly complete stereochemical fidelity. Additional-
ly, a practical etherification of a secondary alcohol is re-
ported and a new route to 4-amino-1H-pyrrazolo[3,4-
d]pyrimidines was developed.
Deoxofluor®
A
Scheme 4
In practice, a solution of Deoxofluor® in toluene at 0 °C
was first treated with 1-(trimethylsilyl)morpholine and
then the alcohol (S)-11, as a solution in toluene, was added
dropwise. The resulting fluoride (R)-14 assayed at 96.4%
ee. After Boc cleavage with toluenesulfonic acid, the
crude amine (R)-2 was isolated as its (R)-mandelic acid
salt in 65% overall yield from 11.17
With an asymmetric route of our key fluoroether (R)-2 de-
fined, we next turned our attention to the synthesis of the
pyrrazolo[3,4-d]pyrimidine and the coupling of the two
fragments. The synthesis of 3 from allopurinol was evalu-
ated and determined to be unsuitable for large scale prep-
aration due to poor stability of the product with respect to
polymerization.18 Protection of the pyrrazole nitrogen as
its tetrahydropyran aminal did give stable intermediates,
All reactions were conducted under N2 atmosphere using standard
air-free manipulation techniques. Solvents and common reagents
were purchased from commercial source and used without further
purification. Concentration in vacuo refers to removal of the solvent
at reduced pressure. NMR spectra were recorded on a Bruker
Ultrashield 400 MHz spectrometer. Chemical shifts are reported in
ppm downfield from tetramethylsilane (TMS). Elemental analyses
were carried out by QTI, Whitehouse, NJ. All new compounds are
fully characterized below.
Synthesis 2008, No. 6, 891–896 © Thieme Stuttgart · New York

894
M. M. Bio et al.
PAPER
NHBoc
F
O
F
OH
F
a, b
c, d
Br
OH
O
99.2% ee (S)-10
(S)-11
e–g
H
N
NH2
Ph
F
F
Boc
N
Cl
F
O
h
N
F
OH
CO2H
N
H
N
O
(R)-22
98.4% ee (R)-21
i
N
F
F
NH
O
N
N
N
H
(R)-1
Scheme 6 Reagents and conditions: (a) Br2, MtBE, 35 °C; (b) BH3·DEA, 4 mol% (S)-OAB; 76% yield over two steps; (c) 6 (5 equiv), t-BuOK
(6.5 equiv), DMSO, 50 °C; (d) Boc2O, Et3N (5 mol%), MeOH; 51% yield from 10; (e) Deoxofluor®, 4-(trimethylsilyl)morpholine, toluene,
0 °C→r.t.; (f) TsOH·H2O, toluene, 70 °C; (g) (R)-mandelic acid, MeOH, THF; 65% yield from 11; (h) (R)-21, aq NaOH, isopropyl acetate then
20, i-Pr2NEt, NMP, 30 °C; (i) H2NNH2, 60 °C; 90% yield from (R)-21.
(S)-2¢-Bromo-1-(2-fluorophenyl)ethanol (10)
1 H). 1 H), 7.18–7.23 (m, 1 H), 7.04–7.08 (m, 1 H), 5.25 (dt,
J = 8.50, 3.68 Hz, 1 H), 3.75 (dd, J = 10.44, 3.20
13C NMR (100 MHz, CDCl3): d = 160.98, 158.53, 129.95, 129.87,
127.53, 127.49, 127.40, 124.54, 124.50, 115.60, 115.38, 68.02,
68.00, 38.93.
To a solution of 2-fluoroacetophenone (0.997 kg, 7 mol) in MTBE
(8 L) was added Br2 (1.23 kg, 7.7 mol) over 1.5 h, whilst maintain-
ing the temperature at <35 °C. The reaction solution was concen-
trated in vacuo to 3 L, MTBE (10 L) was added and the reaction was
again concentrated to 5 L. The solution of 10 was used crude in the
next step.
Anal. Calcd for C8H8BrFO: C, 43.86; H, 3.68. Found: C, 43.66; H,
3.58.
1H NMR (400 MHz, CDCl3): d = 7.87–7.89 (m, 1 H), 7.65–7.67 (m,
1 H), 7.24–7.35 (m, 2 H), 4.63–4.64 (m, 2 H).
(S)-2-(trans-4-Aminocyclohexyloxy)-1-(2-fluorophenyl)ethanol
(4)
To a solution of borane-N,N-diethylaniline complex (1.26 kg, 7.7
mol) in MTBE (6 L) was added (S)-5,5-diphenyl-2-methyl-3,4-pro-
pano-1,3,2-oxazaborolidine (1 M solution in toluene, 280 mL, 4
mol%). The crude solution of bromo-1-(2-fluorophenyl)ethanone
was added to the borane solution over 10 h. The reaction was
quenched by slow addition of HCl (1 N, 20 L) (Caution! Gas evo-
lution!). The layers were separated and the aqueous layer was ex-
tracted with MTBE (3 × 2 L). The combined organic layers were
washed with HCl (1 N, 10 L), dried over MgSO4 (1 kg) and filtered.
The solvent was removed and heptane (6 L) was added. The result-
ing slurry was heated to 30 °C and then cooled to –13 °C, resulting
in crystallization. The solid was isolated by filtration, washed with
–20 °C heptane (4 L) and dried under a stream of nitrogen to give
10.
To a solution of trans-4-aminocyclohexanol (2.93 kg, 25.4 mol) in
DMSO (5.5 L) was added t-BuOK (3.71 kg, 33.1 mol). After 30
min, 10 (1.1 kg, 5.0 mol) was added with an exotherm to 52 °C. Af-
ter cooling to ambient temperature, the reaction was transferred into
a mixture of NaCl (4.8%, 5 L) and toluene (16.5 L). The phases
were separated and the aqueous layer was extracted with toluene
(11 L then 3 × 5.5 L). The combined organic phases were washed
with NaCl (4.8%, 11 L) and then concentrated in vacuo to 10 L. Tol-
uene (10 L) was added and the distillation was continued until a fi-
nal volume of 4.6 L was reached. The solution was seeded and
cooled to 16 °C giving precipitation. Heptane (3.8 L) was added and
the solid was isolated by filtration, washed with toluene–heptane
(1:1, 3 L) and dried under a nitrogen stream to give 4.
Yield: 1.16 kg (76% from 2-fluoroacetophenone); crystalline color-
less solid; 99.2% ee (chiral HPLC assay); mp 33.0–34.0 °C.
Yield: 722 g (55%; 2.76 mol, corrected for 97 wt% purity); mp 96–
97 °C.
1H NMR (400 MHz, CDCl3): d = 7.54–7.55 (m, 1 H), 7.27–7.33 (m,
Hz, 1 H), 3.56 (dd, J = 10.32, 8.50 Hz, 1 H), 2.67 (d, J = 4.18 Hz,
1H NMR (400 MHz, CDCl3): d = 7.57–7.53 (m, 1 H), 7.26–7.21 (m,
1 H), 7.17–7.13 (m, 1 H), 7.03–6.98 (m, 1 H), 5.15 (dd, J = 8.7, 3.1
Hz, 1 H), 3.71–3.68 (m, 1 H), 3.42 (t, J = 9.1 Hz, 1 H), 3.32–3.25
Synthesis 2008, No. 6, 891–896 © Thieme Stuttgart · New York

PAPER
NMDA Receptor Antagonist
895
(m, 1 H), 2.71–2.64 (m, 1 H), 2.04–1.99 (m, 2 H), 1.87–1.83 (m,
2 H), 1.36–1.25 (m, 2 H), 1.15–1.05 (m, 2 H).
(m, 2 H), 3.35–3.29 (m, 1 H), 3.00–2.94 (m, 1 H), 2.08–1.95 (m,
4 H), 1.41–1.23 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 160.0 (d, JC–F = 244.9 Hz), 129.2
(d, JC–F = 8.0 Hz), 128.0 (d, JC–F = 4.0 Hz), 127.9 (d, JC–F = 12.8
Hz), 124.4 (d, JC–F = 3.2 Hz), 115.2 (d, JC–F = 21.7 Hz), 78.3, 72.7,
67.1 (d, JC–F = 2.4 Hz), 50.0, 34.5, 31.9 (d, JC–F = 14.0 Hz).
13C NMR (100 MHz, DMSO-d6): d = 175.7, 159.9 (dd, JC–F = 245.9,
5.6 Hz), 143.6, 131.9 (d, JC–F = 8.0 Hz), 128.2 (dd, JC–F = 7.2, 4.0
Hz), 127.5, 126.4, 126.3, 124.7 (d, J = 4.0 Hz), 124.0 (dd, JC–F
=
20.8, 13.6 Hz), 115.6 (d, JC–F = 21.6 Hz), 88.2, (dd, JC–F = 173, 1.6
Hz), 76.7, 73.8, 69.6 (d, J = 23.2), 48.4, 29.4 (d, JC–F = 8.8 Hz),
28.1.
19F NMR (376 MHz, CD3OD): d = –121.4, –190.3.
19F NMR (376 MHz, CDCl3): d = –119.9.
Anal. Calcd for C14H20FNO2: C, 66.38; H, 7.96; N, 5.53. Found: C,
66.01; H, 8.05; N, 5.45.
Anal. Calcd for C22H27F2NO4: C, 64.85; H, 6.68; N, 3.44. Found: C,
64.89; H, 6.54; N, 3.52.
tert-Butyl trans-4-[(S)-2-(2-Fluorophenyl)-2-hydroxyethoxy]cy-
clohexylcarbamate (11)
To a solution of 4 (662 g, 2.61 mol) and Et3N (18 mL, 0.13 mol) in
MeOH (2.6 L) was added Boc2O (723 g, 3.31 mol), maintaining the
reaction temperature below 35 °C (Caution! gas evolution!). After
30 min, H2O (3.8 L) was added slowly to crystallize the product.
The solid was isolated by filtration, washed with H2O–MeOH
(60:40; 2 × 1 L) and dried in vacuo to give 11.
4,6-Dichloropyrimidine-5-carbaldehyde tert-Butylcarbazate
Hydrazone (20)
4,6-Dihydroxypyrimidine (700 g, 6.25 mol) was slurried in POCl3
(3.5 L) and the reaction placed under N2. The slurry was warmed to
40 °C and DMF (1.26 L, 2.60 equiv) was added dropwise over 30
min, maintaining the temperature at 35–45 °C using an ice-water
bath. The slurry was stirred for 2 h and then heated to 90–95 °C and
stirred until all the solids dissolved. The reaction was cooled to
15 °C and transferred over 3 h into a mixture of H2O (21 L), finely
crushed sodium phosphate dibasic heptahydrate (15.7 kg, 9.4 equiv)
and EtOAc (14 L), maintaining the temperature below 0 °C. The re-
sulting aqueous phase was removed and the organic phase washed
with H2O (7 L) then brine (1 L). The organic layer was shown by
GC assay to contain 4,6-dichloropyrimidine-5-carbaldehyde 19
(676 g, 61% assay yield). H3PO4 (0.36 L, 1.00 equiv) was added to
the solution of 19, followed by tert-butyl carbazate (536 g, 0.65
equiv), maintaining the temperature below 25 °C. The resulting
slurry was stirred overnight then the product was isolated by filtra-
tion, washed with EtOAc (2.1 L) then H2O (2 × 3.5 L) and dried un-
der a nitrogen stream to give 20.
Yield: 886 g (92%; 2.41 mol, corrected for 96 wt% purity); mp 109–
110 °C.
1H NMR (400 MHz, CDCl3): d = 7.57–7.53 (m, 1 H), 7.26–7.22 (m,
1 H), 7.17–7.13 (m, 1 H), 7.03–6.98 (m, 1 H), 5.18–5.14 (m, 1 H),
4.4 (br s, 1 H), 3.73–3.69 (m, 1 H), 3.43–3.38 (m, 2 H), 3.33–3.26
(m, 1 H), 2.93 (d, J = 2.7 Hz, 1 H), 2.05–1.97 (m, 4 H), 1.44 (s,
9 H), 1.43–1.33 (m, 2 H), 1.17–1.08 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 159.7 (d, JC–F = 245.7 Hz), 155.2,
129.1 (d, JC–F = 8.0 Hz), 127.7 (d, JC–F = 4.8 Hz), 127.5 (d, JC–F
=
13.7 Hz), 124.2 (d, JC–F = 3.2 Hz), 115.0 (d, JC–F = 21.7 Hz), 79.2,
77.6, 72.4, 67.0 (d, JC–F = 2.4 Hz), 48.8, 30.9, 30.5 (d, JC–F = 15.3
Hz), 28.4.
19F NMR (376 MHz, CDCl3): d = –119.7.
Yield: 1002 g (55%); orange solid; mp 230 °C (dec.).
1H NMR (400 MHz, DMSO-d6): d = 11.36 (br s, 1 H), 8.85 (s, 1 H),
8.14 (s, 1 H), 1.46 (s, 9 H).
Anal. Calcd for C19H28FNO4: C, 64.57; H, 7.99; N, 3.96. Found: C,
64.65; H, 8.11; N, 3.82.
13C NMR (100 MHz, DMSO-d6): d = 159.9, 157.0, 152.3, 135.4,
126.6, 80.5, 28.3.
trans-4-[(R)-2-Fluoro-2-(2-fluorophenyl)ethoxy]cyclohexan-
amine (R)-Mandelate Salt (21)
To a solution of Deoxofluor® (50 wt% solution in toluene, 2 L, 4.5
mol) in toluene (1.6 L) at –10 °C was added 4-(trimethylsilyl)mor-
pholine (739 g, 4.6 mol) slowly to maintain the reaction temperature
below 0 °C. The resulting slurry was warmed to ambient tempera-
ture and stirred for 2.5 h. The reaction was again cooled to –10 °C
and 11 (774 g, 2.2 mol) in toluene (10.4 L) was added dropwise,
maintaining the internal temperature below 5 °C. The reaction was
warmed to ambient temperature and stirred overnight. The complet-
ed reaction was cooled to <0 °C and quenched by addition of aq
K2CO3 (10%, 2.4 L). The quenched reaction was allowed to warm
to r.t. and stirred for 1 h. The aqueous phase was removed and the
organic phase was washed with NaHSO4 (10%, 2.4 L) and then H2O
(2 × 2.4 L). TsOH·H2O (646 g, 3.4 mol, 1.55 equiv) was added and
the reaction was heated to 70 °C to affect complete Boc-deprotec-
tion. The resulting solution was washed with NaOH (1N, 2.2 L)
then H2O (4 × 2 L) and the organic phase was concentrated to an oil.
THF (10 L) was added, the solution was heated to 40 °C then (R)-
mandelic acid (297 g, 2.0 mol) in MeOH (500 mL) was added. The
resulting slurry was heated to 60 °C for 3 h, then cooled to ambient
temperature. The solid was isolated by filtration, washed with THF
(2 × 1.5 L) and dried under a nitrogen stream to give 21 as the (R)-
mandelate salt.
Anal. Calcd for C10H12Cl2N4O2: C, 41.25; H, 4.15; N, 19.24. Found:
C, 41.19; H, 4.10; N, 19.20.
N-{trans-4-[(R)-2-Fluoro-2-(2-fluorophenyl)ethoxy]cyclohex-
yl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1)
The mandelate salt 21 (541 g, 1.33 mol) was dissolved and parti-
tioned with isopropyl acetate (2.5 L) and NaOH (1 N, 2.7 L). The
aqueous phase was removed and the organic layer was washed with
H2O (2 × 1.6 L). The organic layer was concentrated in vacuo to a
thick oil. 1-Methyl-2-pyrrolidinone (NMP; 1 L) was added and the
mixture was concentrated until no further distillate was obtained.
To the NMP solution of 2, DIPEA (460mL, 2.63 mol) was added,
followed by hydrazone 20 (398 g, 1.37 mol). The resulting red so-
lution was heated to 70 °C for 1 h then hydrazine (35 wt% in H2O,
300 mL, 3.28 mol) was added and the solution was stirred at 70 °C
overnight. The reaction was cooled and transferred into a mixture of
EtOAc (8 L) and aq NaCl (10 wt%, 4 L). The aqueous phase was
removed and the organic phase was washed with aq NaCl (10 wt%,
4 L), aq NaHSO4 (10 wt% , 3 × 4 L) then aq NaCl (10 wt%, 4 L).
The organic phase was concentrated in vacuo and the solvent was
exchanged to toluene (4 L) resulting in crystallization of the prod-
uct. The solid was isolated by filtration, washed with toluene (2 L)
and dried under a nitrogen stream to give 1. The product could be
further purified to give pharmaceutical quality material by two re-
crystallizations from MeOH–H2O (1:1) in 92% recovery.
Yield: 594 g (66% overall yield from 11); mp 166–167 °C.
1H NMR (400 MHz, CD3OD): d = 7.49–7.44 (m, 3 H), 7.41–7.35
(m, 1 H), 7.30–7.26 (m, 2 H), 7.23–7.20 (m, 2 H), 7.14–7.09 (m,
1 H), 5.79 (ddd, J = 47.8, 7.2, 3.2 Hz, 1 H), 4.85 (s, 1 H), 3.90–3.71
Yield: 448 g (90%); colorless solid; 98.6% ee; mp 193–194.
Synthesis 2008, No. 6, 891–896 © Thieme Stuttgart · New York

896
M. M. Bio et al.
PAPER
ion, resulted in epoxide opening by the amine, not the
1H NMR (400 MHz, DMSO-d6): d = 13.30 (br s, 1 H), 8.17 (s, 1 H),
8.07 (s, 1 H), 7.88 (d, J = 7.6 Hz, 1 H), 7.50–7.39 (m, 2 H), 7.25–
7.19 (m, 2 H), 5.82 (ddd, J = 47.7, 7.3, 2.9 Hz, 1 H, CHF), 4.03 (br
m, 1 H), 3.90–3.67 (m, 2 H), 3.35 (br m, 1 H), 1.98 (m, 4 H), 1.29
(m, 4 H).
13C NMR (100 MHz, DMSO-d6): d = 159.6 (dd, JC–F = 245.7, 5.6
Hz), 156.13 (two overlapping), 155.0, 132.8, 131.3 (d, JC–F = 8.0
Hz), 128.6 (dd, JC–F = 7.2, 4.0 Hz), 125.1 (d, JC–F = 3.2 Hz), 124.5
(dd, JC–F = 20.9, 12.8 Hz), 116.0 (d, JC–F = 21.7 Hz), 100.4, 88.6
(dd, JC–F = 172.7, 2.4 Hz), 77.8, 70.0 (d, JC–F = 24.1 Hz), 48.6, 31.0
(d, JC–F = 5.6 Hz), 30.4.
alkoxide.
(8) Chung, J. Y. L.; Cvetovich, R.; Amato, J.; McWilliams, J.
C.; Reamer, R.; DiMichele, L. J. Org. Chem. 2005, 70, 3592.
(9) While fluoride displacement reactions have a long history,
they have a rather mixed record of success. Recent reports
suggest that ionic liquids suppress competing reactions and
favor fluoride displacement, see: Kim, D. W.; Song, C. E.;
Chi, D. Y. J. Am. Chem. Soc. 2002, 124, 10278.
(10) For benzylic sulfonates specifically, the stereoselectivity is
rather substrate dependent. See for instance: (a) Fritz-
Langhals, E. Tetrahedron Lett. 1994, 35, 1851. (b) Fritz-
Langhals, E. Tetrahedron: Asymmetry 1994, 5, 981.
(11) Singh, R. P.; Shreeve, J. M. Synthesis 2002, 2561.
(12) Hudlicky, M. Fluorinations with Diethylaminosulfur
Trifluoride and Related Aminosulfurans, In Organic
Reactions, Vol. 35; John Wiley & Sons, Inc.: New York,
1988, 513–637.
19F NMR (376 MHz, DMSO-d6): d = –118.8, –185.1.
HRMS: m/z calcd for C19H21F2N5O: 374.1787; found: 374.1798.
Anal. Calcd for C19H21F2N5O: C, 61.12; H, 5.67; N, 18.76. Found:
C, 61.19; H, 5.54; N, 18.72.
(13) In our early studies toward the synthesis of 1, the Cbz-
protected amine (S)-12 was used in the fluorination studies.
We have established that the nature of the amide or
carbamate present at the nitrogen has no effect on the
stereoselectivity of the fluorination reaction.
References
(1) For an excellent recent review of fluorine in
pharmaceuticals, see: Müller, K.; Faeh, C.; Diederich, F.
Science 2007, 317, 1881.
(2) Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.;
Müller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004,
5, 637.
(14) (a) Paulsen, H.; Antons, S.; Brandes, A.; Lögers, M.; Müller,
S. N.; Naab, P.; Schmeck, C.; Schneider, S.; Stoltefuß, J.
Angew. Chem. Int. Ed. 1999, 38, 3373. (b) Walba, D. M.;
Razavi, H. A.; Clark, N. A.; Parmar, D. S. J. Am. Chem. Soc.
1988, 110, 8686.
(15) The synthesis of bis(dialkylamino)sulfur difluorides has
been reported, although the use of these compounds as
fluorination reagents for organic synthesis is unknown to the
best of our knowledge. See: Messina, P. A.; Mange, K. C.;
Middleton, W. J. J. Fluorine Chem. 1989, 42, 137.
(16) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M. Chem.
Commun. 1999, 215.
(17) This salt formation improved the enantiomeric purity of (R)-
2 to 98.4% ee, which was critical for preparing the final
product with the required high optical purity.
(18) The polymerization resulting from reaction of 3 with itself
via displacement of the chloride by the pyrrazole ring
nitrogen of another molecule of 3 (Scheme 7).
(3) (a) Thompson, W.; Young, S. D.; Phillips, B. T.; Munson,
P.; Whitter, W.; Liverton, N.; Dieckhaus, C.; Butcher, J. WO
Patent 2005019222 A1, 2005. (b) Thompson, W.; Young, S.
D.; Phillips, B. T.; Munson, P.; Whitter, W.; Liverton, N.;
Dieckhaus, C.; Butcher, J.; McCauley, J. A.; McIntyre, M.
E.; Layton, M. E.; Sanderson, P. E. US Patent 2007/0037829
A1, 2007. (c) NR2B selective NMDA (N-methyl-D-
aspartate) receptor antagonists have shown promise as non-
dopaminergenic drugs for the treatment of Parkinson’s, see:
Nash, J. E.; Hill, M. P.; Brotchie, J. M. Exp. Neurol. 1999,
155, 42. (d) For a discussion of the molecular and functional
distinctions of the NMDA subtypes, see: Monyer, H.;
Sprengel, R.; Schoepfer, R.; Herb, A.; Miyoko, H.; Lomeli,
H.; Burnashev, N.; Sakmann, B.; Seeburg, P. H. Science
1992, 256, 1217.
(4) Robbins, R. K. J. Am. Chem. Soc. 1956, 78, 784.
(5) Posner, G. H.; Rogers, D. Z. J. Am. Chem. Soc. 1977, 99,
8280.
(6) (a) Campbell, J. C.; Greengrass, C. W.; Plews, R. M. J. Med.
Chem. 1988, 31, 516. (b) Kachinsky, J. L. C.; Salomon, R.
G. J. Org. Chem. 1986, 51, 1393. (c) Tanaka, Y.;
Nishimura, K.; Tomioka, K. Tetrahedron 2003, 59, 4549.
(7) Note that there was no need to protect the primary amine.
Under these conditions, N-alkylation was not observed. In
contrast, the use of bases generating a Mg, Li or Na counter-
Cl
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
H
N
3
Scheme 7
Synthesis 2008, No. 6, 891–896 © Thieme Stuttgart · New York