An Efficient Method for Synthesis of Tofacitinib Citrate

Article abstract of DOI:10.1002/jhet.2384

An efficient and mild synthetic method was developed for tofacitinib citrate from 3-amino-4-methylpyridine and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine. The related reactions were systematically optimized. Sodium hydride instead of potassium tert-butoxide employed in the methoxycarbonylation reaction of compound 9 made the reaction proceed effectively to present compound 8 in a better yield. The replacement of benzaldehyde with benzyl bromide simplified the protection process of amino group. Red-Al provided a cost-effective method for the reduction of amides. The introduction of tosyl group into compound 10 enhanced the nucleophilic substitution of 10 with compound 4 dramatically. Thus, under the optimized conditions, tofacitinib citrate was obtained in 13.3% yield (based on compound 9) with a purity of 99.9%, much better than the reported yield 8.6%. This cost-effective and environmental friendly process is more suitable for scale-up production.

Full text of DOI:10.1002/jhet.2384

Month 2015
An Efficient Method for Synthesis of Tofacitinib Citrate
a
b
b
b
a
a
Shuang Zhi, Dengke Liu, Ying Liu, Bingni Liu, Donghua Wang, and Ligong Chen *
a
School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
b
Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin
3
00193, China
*
E-mail: lgchen@tju.edu.cn
Received August 31, 2014
DOI 10.1002/jhet.2384
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
An efficient and mild synthetic method was developed for tofacitinib citrate from 3-amino-4-
methylpyridine and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine. The related reactions were systematically opti-
mized. Sodium hydride instead of potassium tert-butoxide employed in the methoxycarbonylation reaction
of compound 9 made the reaction proceed effectively to present compound 8 in a better yield. The replace-
ment of benzaldehyde with benzyl bromide simplified the protection process of amino group. Red-Al pro-
vided a cost-effective method for the reduction of amides. The introduction of tosyl group into compound
1
0 enhanced the nucleophilic substitution of 10 with compound 4 dramatically. Thus, under the optimized
conditions, tofacitinib citrate was obtained in 13.3% yield (based on compound 9) with a purity of 99.9%,
much better than the reported yield 8.6%. This cost-effective and environmental friendly process is more
suitable for scale-up production.
J. Heterocyclic Chem., 00, 00 (2015).
INTRODUCTION
drawbacks limited their application in scale-up production:
i) an aqueous Diels-Alder reaction required 70h at 35°C
(
Tofacitinib (CP-690,550) citrate, chemically named as
3R,4R)-3-[4-methyl-3-[N-methyl-N-(7H-pyrrolo[2,3-d]
to give compound 18 only in 59% yield [6]. (ii) Boron
fluoride ethyl ether hydrolyzed rapidly in damp air to
release toxic hydrogen fluoride. (iii) The sulfur-based oxi-
dations left the product contaminated with dimethyl sulfide
leading to handling problems.
Ultimately, Pfizer Inc established a new four-step
method for compound 20 from 3-amino-4-methylpyridine,
an appropriately functionalized and commercially avail-
able pyridine. It only requires condensation with dimethyl
carbonate, hydrogenation of pyridine ring, protection of
sec-amino group in piperidine ring, and finally reduction
of the amides to yield the target compound 20 as shown
in Scheme 2 [9]. Although this route looks reasonable, it
still suffers from the following troublesome problems: (i)
the cream solid is easily formed in the condensation step.
(
pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile
citrate (Fig. 1), is a novel JAK3 inhibitor [1] discovered and
developed by Pfizer. It was approved for oral treatment of
rheumatoid arthritis in the US, Japan, and Russia. Today,
this agent is further being evaluated for treatment of
immune-mediated diseases, including psoriasis, Crohn’s
disease, and inflammatory bowel disease, as well as the pre-
vention of organ transplant rejection [2–5].
Based on its pharmaceutical importance, the synthesis of
tofacitinib citrate was extensively studied. As reported, its
key intermediate, (3R,4R)-1-benzyl-N,4-dimethylpiperidin-
-amine 20, was synthesized from isoprene 16 [6] or 4-
methylpyridine 17 [7,8] (Scheme 1). However, some
3
©
2015 HeteroCorporation

S. Zhi, D. Liu, Y. Liu, B. Liu, D. Wang, and L. Cheng
Vol 000
carbonate to carbamate was realized with t-BuOK as a cat-
alyst in 2-methyltetrahydrofuran (2-MeTHF). However,
when we repeated this experiment, the cream solid was
formed when dimethyl carbonate was added to the mixture
of compound 9 and t-BuOK in 2-MeTHF due to poor sol-
ubility of compound 9 in 2-MeTHF, so a great volume of
solvent was required. Thus, methyl chloroformate, instead
of dimethyl carbonate, was used as the carbalkoxylation re-
agent. Unfortunately, its high activity resulted in more im-
purities. Alternatively, several bases were chosen and
examined for this reaction. It was found that sodium hy-
dride (NaH) exhibited excellent catalytic performance in
the condensation reaction and made the reaction proceed
effectively to present better yield of compound 8. Further-
more, the employment of NaH resulted in more convenient
work-up procedure. One interesting phenomenon was that
the addition of NaH to the compound 9 in THF did not
cause the obvious release of hydrogen, even prolonging
the reaction time or increasing the reaction temperature. In-
stead, during the addition of dimethyl carbonate, hydrogen
was released rapidly. It is possibly attributed to the weaker
acid strength of N–H at C3 than that of amino group at C2
and C4 positions (Fig. 2). Hence, without stable resonance
structures, amino anion at C3 failed to form quantitatively,
dimethyl carbonate reacted with the trace amino anion and
promoted the reaction to move forward.
Figure 1. The chemical structure of tofacitinib citrate.
Scheme 1. Two routes to synthesize compound 20 reaction conditions:
(
a) BnNH
NaBH , EtOH, 15°C, 73%; (d) (i) BF
HCl, H ; (iii) TsOH, 88%; (e) SO
MeNH , NaHB(OAc) , toluene, EtOH, THF, HOAc; (g) HCl, EtOH,
EtOAc, 53%, three steps.
2
, HCHO, H
2
O, 59%; (b) BnCl, acetone, 55°C, 73%; (c)
· OEt , BH · THF, THF; (ii)
· pyridine, DMSO, Et N; (f)
4
3
2
3
2
O
2
3
3
2
3
(
ii) the cost of reducing agent and quenching agent in the
protection of amino group. In addition, a thick emulsion
layer was easily formed when the medium pH was con-
trolled improperly during the quenching step. (iii) flamma-
ble and explosive lithium aluminum hydride (LAH) with
poor solubility in aprotic solvents.
Changelian et al. [10] reported that the nucleophilic sub-
stitution of compound 10 with compound 20 is so ineffi-
cient that only poor yield compound 3 was obtained after
In the benzyl protection of sec-amino group in piperidine
ring, benzaldehyde and sodium triacetoborohydride were
utilized by Pfizer. Except for the cost of the agent, a thick
emulsion layer was easily formed during the quenching
process. Here, we chose the cheap and commercially avail-
able benzyl bromide as benzylation reagent and anhydrous
potassium carbonate as catalyst. The reaction parameters,
including molar ratio, reaction temperature and catalyst
amount were optimized to improve the chemoselectivity
of nucleophilic substitution reaction. Thus, under the opti-
mized conditions, the reaction proceeded effectively to af-
ford compound 6 in a satisfied yield.
9
0h reaction. This is possibly attributed to the low reaction
activity of compound 10.
Thus, in order to overcome the aforementioned prob-
lems, we attempted to optimize the synthetic route of
tofacitinib citrate. The obtained results were summarized
and reported here.
RESULTS AND DISCUSSION
First, the condensation reaction of 3-amino-4-
methylpyridine with dimethyl carbonate was examined,
as shown in Scheme 3. The carbalkoxylation of 3-amino
group, not only protected the amino group, but also pro-
vided a convenient way to install methyl group in the final
product by reduction of the obtained amide. In which,
carbomethoxy is the best one in accordance with the “atom
economy” principle. Cai et al. [9] reported that the carbal-
koxylation of 3-amino-4-methylpyridine with dimethyl
The obtained methyl carbamate was reduced to the met-
hylamino compound by LAH. However, LAH was charac-
terized with poor solubility in aprotic solvents and high
activity in atmosphere. Red-Al, as a solution of sodium
dihydro-bis-(2-methoxyethoxy) aluminate in toluene, is
always an ideal alternative for the reduction of amide
[11,12] with advantages of good solubility in aromatic sol-
vents and low cost. Thus, Red-Al was employed in our ex-
periments, as expected, it mildly and effectively promoted
2
Scheme 2. The synthesis of compound 20 from 9 reaction condition: (a) t-BuOK, (MeO) CO, 2-MeTHF; toluene, 87%; (b) 5% Rh/C (JM type C101023-5),
AcOH, H ; (c) PhCHO, NaHB(OAc) , toluene, 73%, 2steps; (d) LiAlH , THF; HCl, IPO, 87%.
2
3
4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
An Efficient Method for Synthesis of Tofacitinib Citrate
Scheme 3. Synthetic route for tofacitinib citrate reaction conditions: (a) p-toluenesulfonyl chloride, H
Rh/C, H , AcOH, 1.5 MPa; (d) PhCH Br, K CO , 2 M HCl/EtOH; (e) Red-Al, toluene, 40°C; (f) L-DTTA, H
reflux; saturated aqueous solution of NaOH; (h) Pd(OH) /C, TFA, MeOH; (i) ethyl 2-cyanoacetate, DBU, n-BuOH; citrate acid, H
2
O, acetone; (b) (MeO)
O, IPA, MeOH; (g) 10a, K
O.
2
CO, NaH, THF, 35°C; (c)
2
2
2
3
2
2
CO , H O,
3
2
2
2
the reduction reaction of compound 6 to compound 5 at
room temperature for only 1 h.
Subsequently, the tosyl group was hydrolyzed in aqueous
solution of sodium hydroxide to afford compound 3 in a
nice yield. Thus, a combination of nucleophilic substitution
and hydrolysis was successfully carried out in one pot un-
der alkaline condition.
After the chiral resolution of compound 5 with di-p-
toluoyltartrate, optical pure compound 4 was successfully
obtained by recrystallization. The nucleophilic substitution
of compound 10 with compound 4 yield compound 3.
However, this reaction always displayed poor yield due to
the low activity of compound 10. Thus, we introduced a
tosyl group [13] into compound 10 to promote its activity
CONCLUSION
To summarize, an environmental friendly, economical
and efficient route was successfully developed for the syn-
thesis of tofacitinib citrate. All the related reactions and
purification processes were systematically optimized, in-
cluding the selections of catalyst, benzyl protection agent,
and reduction agent, these works obviously improved the
yield of tofacitinib citrate. The combination of nucleo-
philic substitution reaction and hydrolyzation reaction in
one pot provided a more acceptable way to compound 3.
The structures of all products and intermediates were con-
firmed by high-resolution mass spectrometry (HRMS) and
(
compound 10a). As a result, shown in Scheme 3, the nu-
cleophilic substitution of compound 10a with compound
underwent smoothly in shorter reaction time and an
4
improved yield. This indicated that tosyl group effectively
reduced the electron density of pyrrolopyrimidine ring by
its strong electron-withdrawing and conjugative effect.
1
H-NMR. Thus, with the improved synthetic route,
tofacitinib citrate was obtained in a total yield of 13.3%
with a purity of 99.9% (based on compound 9) compared
with 8.6% [8,9,14]. This synthetic route is more suitable
for large-scale production.
EXPERIMENTAL
Reagentsandsolventswereobtainedfromcommercialsuppliers.
All reactions were monitored by thin-layer chromatography. Flash
Figure 2. The resonance structures of amino-substituted pyridines.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Zhi, D. Liu, Y. Liu, B. Liu, D. Wang, and L. Cheng
Vol 000
chromatography was conducted by Reveleris® X2 flash chroma-
tography system (petroleum ether and ethyl acetate, or dichloro-
methane and methanol, gradient elution). The purity of synthetic
compounds was determined with an Agilent 1260 equipped with a
Grace C18 column (5 μ, 250 mm × 4.6 mm, Lot No. 55/182). The
optical purity was confirmed using an instrument with a Chiralpak
ID column (5 μ, 250 mm × 4.6 mm, Lot No.ID00CE-PI029) and a
cis-N-Benzyl-3-methoxycarbonylamino-4-methylpiperidine Hy
drochloride (6). To the slurry of 7 (23.2 g, 100 mmol) in
dichloromethane (200mL) was added anhydrous potassium
carbonate (34.5 g, 250mmol) and benzyl bromide (18.8 g,
110 mmol). The reaction mixture was stirred at 40°C for 5 h. The
reaction was monitored by GC (90.5% cis). After quenching with
water (150 mL), the organic phase was separated and the aqueous
phase was extracted by dichloromethane (50 mL× 3). The organic
1
mobile phase of ethanol/hexane or isopropanol/hexane. H-NMR
was recorded on BRUKER AV400 NMR. HRMS was detected on
Bruker microTOF-Q II. Optical rotations were collected at 589 nm
on a WXG-4 Disc Polarimeter.
4
phases were combined, dried over anhydrous MgSO , and
concentrated. The residue was dissolved in the solution of HCl in
ethanol (2M, 60mL). After the resulting mixture was stirred for at
4
-Chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (10a). To a
suspension of 4-chloro-7H-pyrrolo[2,3-d] pyrimidine (15.3 g,
00 mmol), prepared by method of Davoll [15] and Kima [16],
in acetone (70 mL) was added p-toluenesulfonyl chloride
20.9 g, 110 mmol). After the reaction mixture was cooled below
0°C, sodium hydroxide solution (2 M, 60 mL) was added at a
least 1 h, the precipitate was filtered to afford the desired product 6
1
3
(27.9 g, 93.7%), H-NMR (400 MHz, CDCl ) δ: 0.89 (d,
1
J = 6.8 Hz, 3H), 1.29–1.41 (m, 2H), 1.55–1.60 (m, 1H), 1.92 (t,
J = 13.0Hz, 3H), 2.13 (d, J = 11.6Hz, 1H), 2.76 (d, J = 11.2Hz,
2H), 3.425 (s, 2H), 3.67 (s, 3H), 3.64 (s, 3H), 3.77 (d, J = 8.8 Hz,
1H), 5.41 (d, J = 9.2 Hz ,1H), 7.20–7.30 (m, 5H). ESI-HRMS:
(
1
rate to maintain the temperature below 10°C. Then the reaction
mixture was warmed to 35°C and stirred for 5 h. After being
cooled to room temperature, the resulting solid was isolated by
filtration and washed with acetone/water (1:1). After drying under
22 2 2
Calcd for C15H N O (M+ H) 263.1754, found 263.17763.
cis-N-Benzyl-3-methylamino-4-methylpiperidine (5). Compound
6 (3.0 g, 10 mmol) was added to toluene (30 mL), followed by
the addition of sodium bis(2-methoxyethoxy) aluminum
dihydride (Red-Al) in toluene (70% solution in toluene,
8.7 g) at a rate to maintain the temperature below 10°C. The
resulting orange solution was stirred for 1 h at 40°C and
then cooled to 0°C. Aqueous NaOH (1 M, 60 mL) was added
over 30 min. The solid was separated and washed with water
(30 mL × 3). The aqueous phase was extracted with toluene
(30 mL × 3). The organic phases were combined, dried over
anhydrous Mg SO , and concentrated to afford the compound
vacuum, 27.4g (89.4%) of the title compound as white solid was
1
obtained. H-NMR (400 MHz, CDCl
3
) δ: 2.40 (s, 3H), 6.70 (d,
J = 4.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 4.0 Hz, 1H),
.09 (d, J = 8.4 Hz, 2H), 8.77 (s, 1H). ESI-HRMS: Calcd for
8
C H ClN O S (M+ H) 308.0255, found 308.0260.
13
10
3 2
3
-Methoxycarbonylamino-4-methylpyridine (8).
To
a
solution of 3-amino-4-methylpyridine (21.6 g, 200 mmol) in
absolute tetrahydrofuran (THF, 150 mL) was added the
suspension of sodium hydride (5.1 g, 200 mmol) in absolute THF
2
4
5 (2.6 g, 93.2% cis by GC) in 90.1% yield, which was directly
used in chiral resolution without further purification.
(100 mL) in batches at 0°C. The reaction mixture was stirred at room
temperature for 1 h. After being cooled to 0–5°C, dimethyl carbonate
was dropwise added to avoid hydrogen rapid release. The reaction
mixture was stirred at 40°C for 9 h and then was quenched with water
Bis-(3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine
di-p-toluoyl-L-tartrate (4). Compound 5 (2.9 g, 10 mmol) was
added in the mixture of methanol (4 mL) and isopropanol
(16 mL), followed by the addition of water (20 mL) and di-p-
toluoyl-L-tartrate (2.0 g, 5.1 mmol). The reaction mixture was
heated to reflux until homogeneous. After being slowly cooled
to room temperature, the reaction mixture stood still until the
(30 mL). The organic solvent was evaporated to yield a slurry.
Petroleum ether was added to it and stirred for 1 h below 5°C. The
light brown solid was obtained by filtration and dried in vacuum
drying oven at 50°C to afford the crude product 8 (31.0 g, 93.4%),
which was directly used in the next step without further purification.
appearance of compound 4 as white solid, filtered to present
1
1
Purity: 98.7% (HPLC), H-NMR (400 MHz, CDCl ) δ: 2.27 (s, 3H),
target compound (1.7 g, 41.4%). H-NMR (400 MHz, CD OD)
3
3
3
1
1
.8 (s, 3H), 6.39 (s, 1H), 7.10 (d, J= 5.2Hz, 1H), 8.27 (d, J=4.8Hz,
δ: 1.00 (d, J = 7.2 Hz), 1.49–1.62 (m, 4H), 1.88–1.90 (m, 2H),
2.17–2.23 (m, 2H), 2.37 (d, J = 6.8 Hz, 12H), 2.82–2.92 (m,
4H), 3.07 (s, 2H), 3.40 (d, J = 12.8 Hz, 2H), 3.61 (d,
J = 12.8 Hz, 2H), 5.84 (s, 2H), 7.22–7.28 (m, 6H), 7.30–7.34
(m, 8H), 8.03 (d, J = 8.0 Hz, 4H). ESI-HRMS: Calcd for
8 10 2 2
H), 8.86 (s, 1H). ESI-HRMS: Calcd for C H N O (M + H)
67.0815, found 167.0818.
cis-3-Methoxycarbonylamino-4-methylpiperidine acetate salt
A solution of methyl (4-methyl-pyridin-3-yl) carbamate
8, 33.2 g, 200 mmol) in acetic acid (200 mL), 5% Rh/C (4.2 g)
(
(
7).
C
14
H
22
N
2
(M + H) 219.1856, found 219.1862.
and acetic acid (100 mL) were added to a autoclave. The
reaction mixture was stirred for at least 15 min and then purged
sequentially with nitrogen and hydrogen, heated to 55–60°C
and pressurized with hydrogen gas at 1.5 MPa until hydrogen
uptake ceased. After being cooled to room temperature, the
catalyst was filtered through a pad of Celite, and the solvent
was removed by azeotropic distillation with toluene. The
residue was stirred in ethyl ether (50 mL) for at least 30 min
N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7H-pyrrolo
[2,3-d]pyrimidin-4-amine (3). To a three-necked flask were added 4
(8.2 g, 10 mmol), potassium carbonate (4.1 g, 30 mmol), water (50 mL),
and 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine 10a (6.2 g,
20 mmol). The reaction mixture was stirred at reflux for 10 h. At that
time, a sample was taken from the reaction mixture, which was
cooled to room temperature and the resulting solid was filtered to give
N-((3R,4R)-1-benzyl-4-methylpiperidin-3-yl)-N-methyl-7-tosyl-7H-
25
1
(adding several drops of ethanol to improve the dispersion of
pyrrolo[2,3-d]pyrimidin-4-amine. [α]
D 3
= +23.8 (c 0.84, CH Cl), H-
precipitate), and the precipitate was filtered to give the desired
product 7 (16.1 g, 69.3%) as white solid. H-NMR (400 MHz,
NMR (400 MHz, DMSO-d ) δ: 0.82 (d, 3H), 1.52–1.57 (m, 1H),
6
1
1.58–1.65 (m, 1H), 1.97–1.99 (m, 1H), 2.05–2.07 (m, 1H), 2.34 (s,
3H), 2.51(s, 1H), 2.61 (s, 1H), 2.72–2.76 (m, 1H), 3.42–3.46 (m, 5H),
5.04 (brs, 1H), 6.89 (s, 1H), 7.18–7.23 (m, 1H), 7.28–7.31 (m, 4H),
7.41 (d, J= 8.4 Hz, 2H), 7.56 (d, J= 4.0 Hz, 1H), 7.96 (d, J=8.4Hz,
CDCl ) δ: 0.96 (d, J = 6.4 Hz, 3H), 1.52–1.63 (m, 2H), 1.79–
3
1
.80 (m, 1H), 2.04 (s, 3H), 2.72 (t, J = 10.8 Hz, 1H), 2.90 (d,
J = 12.0 Hz, 1H), 3.18 (t, J = 5.4 Hz, 2H), 3.67 (s, 3H), 4.01 (d,
J = 8.4 Hz, 1H), 7.12–7.15 (m, 3H). ESI-HRMS: Calcd for
26 6 3
2H), 8.18 (s, 1H). ESI-HRMS: Calcd for C23H N O S (M+H)
8 16 2 2
C H N O (M + H) 173.1285, found 173.1289.
490.2271, found 490.2274.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
An Efficient Method for Synthesis of Tofacitinib Citrate
J= 5.6 Hz, 1H), 11.63 (s, 1H), 12.24–12.41 (brs, 2H). ESI-HRMS:
Then, the reaction mixture was cooled to room temperature,
saturated NaOH solution (100 mL) was added at a rate of control-
ling the temperature below 30°C. The resulting reaction mixture
was refluxed for 6 h. After being cooled to room temperature,
the reaction mixture was stirred for 2 h at room temperature.
The solid was isolated by filtration to afford off-white solid 3
Calcd for C H N O (M + H) 313.1771, found 313.1777.
16 20
6
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2
5
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(
5.0 g, 75.0%). [α]
D
= +29.4 (c 1.01, MeOH); purity: 99.8%
(
C18 HPLC); 100% ee (chiralpak ID, 95:5 hexane/ isopropanol,
1
retention time of 16.86 min); H-NMR(400 MHz, DMSO-d ) δ:
6
0
.88 (d, J = 6.8 Hz, 3H), 1.59–1.63 (m, 1H), 1.70 (s, 1H), 2.13
(
s, 1H), 2.28 (s, 1H), 2.54 (dd, J
1
2
= 4.0 Hz, J = 11.2 Hz, 1H),
2
.61 (s, 1H), 2.77 (dd, J
1
= 6.0 Hz, J
2
= 11.2 Hz, 1H), 3.44–3.52
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(
m, 5H), 5.09 (s, 1H), 6.53 (s, 1H), 7.08 (t, J = 2.6 Hz, 1H),
7
1
3
.20–7.23 (m, 1H), 7.28–7.31 (m, 4H), 8.05 (s, 1H), 11.55 (s,
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36.2189.
25 5
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4
10% aqueous NaOH, dried over anhydrous MgSO , and
concentrated to afford colorless oil 2, which was directly used in
the next step without further purification.
[
8] Wu, J. J.; Tang, W. J.; Pettman, A.; Xiao, J. L. Advanced Syn-
thesis & Catalysis 2013, 355, 35.
9] Cai, W. L.; Colony, J. L.; Frost H.; Hudspeth, J. P.; Kendall, P. M.;
3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)
[
amino)piperidin-1-yl)-3-oxopropanenitrile citrate (1). To the
mixture of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.5 g,
Krishnan, A. M.; Makowski, T.; Mazur, D. J.; Phillips, J.; Brown Ripin, D. H.;
Ruggeri, S. G.; Stearns, J. F.; White, T. D. Organic Process Research &
Development 2005, 9, 51.
10 mmol) and ethyl cyanacetate (3.4 g, 30 mmol) in n-BuOH
(20 mL) was added the amine 2 (4.9 g, 20 mmol). The reaction
[10] Changelian, P. S.; Zwillch, S. H. International Patent,
2
,008,029,237; Chem Abstr 2008, 148, 347337.
11] Hoffmann-Emery, F.; Hilpert, H.; Scalone, M.; Waldmeier, P.
J Org Chem 2006, 71, 2000.
12] Dix, A. V.; Meseck, C. M.; Lowe, A. J.; Mitchell, M. O.
Bioorg Med Chem Lett 2006, 16, 2522.
13] Ruggeri, S.G.; Hawkins, J. M.; Makowski, T. M.; Rutherford,
mixture was stirred at 40°C for 18 h. Upon reaction completion,
citric acid monohydrate (6.3 g, 30 mmol) was added, followed by
the addition of water (1 mL) and 1-butanol (10 mL). The mixture
was heated to 80°C and held at that temperature for 30 min. After
being cooled slowly to 10–15°C and standing for 12 h, the solid
was filtered, washed with 1-butanol (20 mL), and dried in a vacuum
[
[
[
J. L.; Urban, F. J. International patent, 2,007,012,953; Chem Abstr 2007,
146, 206328.
25
oven to afford 1 (9.1, 87.6%) as an off-white solid. [α]D (free base)
10.1 (c 0.99, MeOH); Purity (free base): 99.9% (C18 HPLC);
00% ee (chiralpak ID, 70:30 hexanes/ethanol, retention time of
[14] Price, K. E.; Larrivée-Aboussafy, C.; Lillie, B. M.;
=
McLaughlin, R. W.; Mustakis, J.; Hettenbach, K. W.; Hawkins, J. M.;
Vaidyanathan, R. Org Lett 2009, 11, 2003.
1
2
1
4
4
1
6
1.16 min). H-NMR (400 MHz, DMSO-d ) δ: 1.00–1.01 (m, 3H),
[15] Davoll, J. J Am Soc 1960, 82, 131.
.54–1.79 (m, 2H), 2.35–2.50 (m, 1H), 2.69 (ABq, J= 15.2 Hz,
H), 3.16–3.17 (m, 3H), 3.36–3.45 (m, 1H), 3.61–4.14 (m, 5H),
.85 (s, 1H), 6.55 (s, 1H), 7.12 (d, J=2.8Hz, 1H), 8.09 (d,
[16] Kima, J; Wang, L. G.; Li, Y. F.; Becnel, K. D.; Frey, K. M.;
Garforth, S. J.; Prasad, V. R.; Schinazi, R. F.; Liotta, D. C.; Anderson,
K. S. Bioorg Med Chem Lett 2012, 22, 4064.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet