Scalable and green process for the synthesis of anticancer drug lenalidomide

Article abstract of DOI:10.1007/s10593-015-1670-0

A new process for the synthesis of anticancer drug lenalidomide was developed, using platinum group metal-free and efficient reduction of nitro group with the iron powder and ammonium chloride. It was found that the bromination of the key raw material, methyl 2-methyl-3-nitrobenzoate, could be carried out in chlorine-free solvent methyl acetate without forming significant amounts of hazardous by-products. We also have compared the known synthetic methods for cyclization of methyl 2-(bromomethyl)-3-nitrobenzoate and 3-aminopiperidinedione to form lenalidomide nitro precursor.

Full text of DOI:10.1007/s10593-015-1670-0

DOI 10.1007/s10593-015-1670-0
Chemistry of Heterocyclic Compounds 2015, 51(2), 133–138
Scalable and green process for the synthesis
of anticancer drug lenalidomide
Yuri Ponomaryov1*, Valeria Krasikova1, Anton Lebedev, Dmitri Chernyak,
Larisa Varacheva, Alexandr Chernobroviy
1 Latvian Institute of Organic Synthesis,
21 Aizkraukles St., Riga LV-1006, Latvia
e-mail: jurijs@osi.lv
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2015, 51(2), 133–138
Submitted September 5, 2014
Accepted February 5, 2015
H2N
O
O
O
O
O
N
NBS
AIBN
·HCl
H
Fe, NH4Cl
O
OMe
Me
OMe
Br
N
O
N
O
MeOAc
, 18 h
H2O, EtOH
80°C, 4 h
K2CO3, NMP
rt to 35°C, 1 h
55°C, 18 h
N
N
H
H
O
O
NO2
NO2
NH2
NO2
Lenalidomide
A new process for the synthesis of anticancer drug lenalidomide was developed, using platinum group metal-free and efficient reduction
of nitro group with the iron powder and ammonium chloride. It was found that the bromination of the key raw material, methyl 2-methyl-
3-nitrobenzoate, could be carried out in chlorine-free solvent methyl acetate without forming significant amounts of hazardous
by-products. We also have compared the known synthetic methods for cyclization of methyl 2-(bromomethyl)-3-nitrobenzoate and
3-aminopiperidinedione to form lenalidomide nitro precursor.
Keywords: lenalidomide, thalidomide, multiple myeloma, bromination, reduction.
An antiemetic and sedative drug thalidomide (1) was
withdrawn from the market after its teratogenic properties
were discovered, but later it was reapproved for treatment
of multiple myeloma, otherwise considered incurable.1,2 It
was also discovered that thalidomide has anti-inflammatory
and anti-angiogenic effects and is suitable for treatment of
cancer, as well as some inflammatory diseases.3–5 This
discovery instigated a new research wave in this field
targeting development of immunomodulatory thalidomide
analogs with reduced toxicity and teratogenicity and
increased anticancer potency. One of the best thalidomide
analogs with direct antitumor effect, ability to inhibit angio-
genesis, and immunomodulatory role is lenalidomide (2).
Lenalidomide have been also successfully used to treat
multiple myeloma.6
concern are the reduction of the manufacturing costs and
the adaptation of the manufacturing process to more
environmentally benign standards. There are several
synthetic schemes for lenalidomide production established
(Scheme 1), employing key intermediate 4, which can be
obtained from ortho-toluic ester 3 via radical bromination
in halogenated solvents.8–10
The longest lenalidomide synthesis was reported by Yan
et al.,11 according to which methylbenzoate derivative 4 is
first treated with ammonia to produce annelated derivative 5,
followed by alkylation with 2-halopentanedioic acid
derivative to provide series of compounds 7. Subsequently,
isoindolinone derivative 8 would undergo internal conden-
sation followed by reduction (R = NO2), or deprotection
(R = NHPG), or amination step (R = Hal) to afford
lenalidomide. Siegel and Weber described12 a less labo-
rious route, featuring direct cyclocondensation of com-
pound 4 with glutamic acid derivatives to provide lactam 7.
In the shortest synthesis of lenalidomide reported by
Muller et al.,13 compound 4 was directly condensed with
3-aminopiperidinone 6 to provide derivative 8, subse-
quently converted to lenalidomide. Another synthetic
scheme is also reported, involving bromination of
glutarimide (9), coupling of the obtained bromo derivative
10 with nitrolactam 5, providing nitro precursor 8, which
O
O
N
O
N
O
N
N
H
H
O
O
O
NH2
Thalidomide (1)
Lenalidomide (2)
The growing demand and rapid increase of lenalidomide
use has created the need to find scalable and safe method
for its preparation on industrial scale.7 Also, of great
0009-3122/15/5102-0133©2015 Springer Science+Business Media New York
133

Chemistry of Heterocyclic Compounds 2015, 51(2), 133–138
Scheme 1
H2N
O
O
O
O
O
N
H
O
6
OMe
Br
OMe
N
O
N
O
N
H
N
Me
H
O
O
R
R
R
NH2
4
3
8
NH2
Lenalidomide (2)
R1
R2
5
NH3
R1
(R = NO2)
K2CO3
DMF
O
O
Hal
O
R2
Br
Br2
AcOH
R2
O
O
O
O
O
N
H
9
O
O
N
O
NH
N
H
R1
R1 = OH, R2 = NH2;
R1 = OAlk, R2 = NH2;
R1 = NH2, R2 = NH2
10
O
R = NO2, NHPG, Hal
(PG = protecting group)
R
R
5
7
then reduced by Fe–HCl system.14 The greatest challenges
in designing the new synthetic approaches to lenalidomide
would pose (1) an improvement of the bromination step,
(2) exclusion the use of halogenated solvents, (3) lowering
the reaction temperatures, and (4) finding new more
efficient methods for reduction of 3-(4-nitro-1-oxoiso-
indolin-2-yl)piperidine-2,6-dione (8).
The reduction of the nitro group of compound 8 utilizing
transition metals, such as iron, was previously reported.14,15
It provided the desired product in moderate to good yields
and requires employing diluted hydrochloric acid as a
solvent and reagent for hydrogen generation in situ. Most
methods utilize platinum group metal-catalyzed hydro-
genation technologies. Some of the most popular hydro-
genation methods employ palladium on carbon16 or palla-
dium hydroxide17 as a catalyst or use transfer hydro-
genation.18 We sought to improve the current synthetic
methods and exclude the use of halogenated solvents,
platinum or palladium metals as catalysts, and acids.
Herein, we describe a new green approach for the
synthesis of lenalidomide amenable for scaling up to
industrial scale (Scheme 2). We have found that bromina-
tion of nitro ester 3a can be carried out in a non-
halogenated solvent, methyl acetate, providing the desired
product at decreased temperatures with high efficiency.
The minor drawback of this process is the formation of the
small amount of impurity resulting from bromination of the
solvent, which can be easily removed by crystallization.
The raw material can be also used directly for the next step
without crystallization.
We began optimization of bromination conditions
employing traditional settings, e.g., using light irradiation
and common radical initiators, such as benzoyl peroxide
and AIBN, in halogenated solvents. That did provide the
product albeit with efficiency lower than expected. Among
the chlorinated solvents used, the best was chlorobenzene.
It was found, however, that methyl acetate was far more
superior solvent for carrying out this transformation,
because it provides full conversion of starting ester 3a and
excellent yield of the brominated product 4a at lower
temperature (Table 1). Also, methyl acetate has significant
advantage, as it is an eco-friendly non-halogenated solvent.
In search for optimal conditions of the cyclization of
bromomethyl derivative 4a with 3-aminopiperidinone 6 to
the nitro precursor 8a we tried different solvents and bases
that are commonly used in such reactions, as well as
K2CO3–dimethylacetamide (DMA) system, reported
exactly for the synthesis of the studied reaction.19 Most of
the bases and solvents gave quite good results (Table 2).
Only using pyridine as base or as solvent did not lead to the
desired product, probably due to the alkylation of pyridine
by bromomethyl derivative 4a. We turned our attention to
the employment of N-methyl-2-pyrrolidone (NMP) as a
solvent. Its use provided a good yield, as well as high
Scheme 2
H2N
·HCl
O
O
N
O
O
H
O
Fe, NH4Cl
6
NBS, AIBN
OMe
OMe
Br
N
O
H2O, EtOH
80°C, 4 h
MeOAc, , 18 h
K2CO3, NMP
rt to 35°C, 1 h
55°C, 18 h
N
Me
H
O
NO2
NO2
NO2
3a
4a
8a
O
N
O
N
H
O
NH2
Lenalidomide (2)
134

Chemistry of Heterocyclic Compounds 2015, 51(2), 133–138
Table 1. Optimization of reaction conditions for bromination of methyl 2-methyl-3-nitrobenzoate (3a)
Radical initiator (equiv)
Solvent
Temperature, °C
Time, h
Conversion*,%
Yield*, %
Radiation by 300 W light bulb
Benzoylperoxide (0.01)
AIBN (0.10)
CHCl3
CHCl3
CHCl3
MeCN
MeCN
PhCl
30
61
17
17
17
17
17
17
17
17
17
24
24
69
73
32
66
49
31
25
60
54
92
89
98
95
61
80
Benzoylperoxide (0.01)
AIBN (0.10)
82
35
82
32
Benzoylperoxide (0.01)
AIBN (0.10)
131
131
90
68
PhCl
67
AIBN (0.10)
PhCl
94
AIBN (0.10)
MeOAc
PhCl
57
92
AIBN (0.10)
90
100
100
AIBN (0.10)
MeOAc
57
* Conversion and yield detected by LC/MS; for two last experiments (marked with bold), isolated yields are given.
purity of the desired product 8a. Potassium carbonate was
used as inorganic base since the product obtained under
these conditions was easily isolable from the reaction
mixture.
magnesium powder was inefficient, while the less active
zinc powder in the presence of ammonium chloride gave
satisfying lenalidomide content in the reaction mixture.
Fast and very pure reduction was observed upon reaction
of nitro compound with the iron powder and ammonium
chloride under practically neutral conditions. Furthermore,
it was found that high dilutions could be avoided when
ethanol–water mixture was employed as a solvent system.
One of the key requirements to a process at scaling-up
step is the reproducibility of the implemented procedures.
We have performed 10 independent experiments with the
loading of the 65 g of nitro derivative 8a (Table 4). The
yields for all the runs reproduced well in the range of 65–
83%, the purity of the obtained product after single
recrystallization was higher than 99.4%.
The main objective of this report, however, was to
develop a new green approach for reduction of nitro
intermediate 8a to lenalidomide (2). As mentioned earlier
we wanted to minimize the by-product content at the final
stage of the synthesis and tried to avoid the use of platinum
group metals and acids. The limiting factor appeared to be
the solubility of the cyclocondensation product 8a, which
was very poor in most of the solvents, particularly in
methanol. Among the tested conditions for the nitro group
reduction not employing platinum group metals, CuSO4–
NaBH4 system afforded quite promissing conversion,
although purity of the product was very low (Table 3). The
same problem persisted when we used Na2S2O4 as a
reductant. Although this reduction was very facile, it was
accompanied with formation of large quantities of
impurities. Furthermore, such mild reducing system as
Finally, we have implemented
a recrystallization
protocol of the technical products obtained as described
above in order to obtain pharmaceutical grade material. To
this end the entire crop of synthesized technical
lenalidomide (2) was divided in three equal portions and
Table 2. Optimization of reaction conditions for synthesis of 3-(4-nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione (8a)
HPLC yield, %
Base (equiv)
Solvent
Temperature, °C
Time, h
Yield, %
210 nm
92.7
88.0
91.2
91.5
97.7
99.5
97.7
99.3
96.7
–
254 nm
96.2
94.3
96.1
96.1
99.8
99.9
98.7
99.7
98.7
–
K2CO3
Butan-2-one
50
50
50
50
50
50
50
50
50
50
50
50
67
28
67
28
28
28
24
45
28
28
28
28
77
95
83
37
89
93
71
65
75
–
Et3N
Butan-2-one
Et2CO3
Et2CO3
NMP
K2CO3
Et3N
K2CO3
Et3N
NMP
Morpholine
K2CO3
Et3N
NMP
DMA
DMA
Pyridine
Pyridine
Pyridine
Et2CO3
NMP
–
–
–
Pyridine
–
–
–
135

Chemistry of Heterocyclic Compounds 2015, 51(2), 133–138
Table 3. Optimization of reaction conditions for conversion of nitro compound 8a to lenalidomide (2)
HPLC yield, %
Reducing system (equiv)
CuSO4, NaBH4
Solvent
MeOH
Temperature,°C
Time, h
Conversion, %
210 nm
254 nm
20.7
65
20
79
79
79
79
79
79
79
79
79
79
79
79
16
2
81
100
100
–
19.9
17.3
–
Na2S2O4
H2O, EtOH
H2O, EtOH
H2O, EtOH
H2O, EtOH
H2O, EtOH
H2O, EtOH
H2O, EtOH
H2O, EtOH
H2O, EtOH
H2O, EtOH
H2O, EtOH
H2O, EtOH
H2O, EtOH
22.0
–
Mg (6), NH4Cl (6)
Mg (6), NH4COOH (6)
Mg (6), NH2NH2 (6), (COOH)2 (6)
Zn (6), NH4Cl (6)
Fe (6), NH4Cl (6)
Fe (4), NH4Cl (6)
Fe (2), NH4Cl (6)
Fe (6), NH4Cl (4)
Fe (6), NH4Cl (2)
Fe (2), NH4Cl (4)
Fe (2), NH4Cl (2)
Fe (2+2), NH4Cl (6)
3
28
1
–
–
100
100
100
100
100
100
100
97
–
–
1
68.7
92.3
93.7
98.4
91.3
93.5
85.0
82.9
99.8
76.5
93.7
96.2
98.6
94.8
94.5
86.0
83.3
99.7
1
1
1
1
1
1
1
93
1
100
Table 4. Reproducibility of lenalidomide (2) synthesis method
by reduction of nitro derivative 8a*
each one was individually recrystallized from ethanol–
water mixture, 3:2 (Table 5). Based on HPLC detectable
impurity profile, all three portions of lenalidomide
perfectly met general quality standards of the European
Pharmacopoeia which allow the content of any undefined
impurity to be not higher than 0.1%.
In conclusion, we have developed a scalable and green
process for the synthesis of lenalidomide. The demon-
strated approach utilizes modified reaction conditions at the
bromination and cyclization steps and does not employ any
halogenated solvents. Also, we have developed modified
approach for the reduction of nitro group without use of
platinum group metal catalysis and obtained the product
that met pharmacopoeia requirements.
HPLC purity***, %
Entry
Yield**, %
210 nm
99.4
99.6
99.7
99.6
99.9
99.7
99.9
99.9
99.9
99.8
254 nm
99.6
99.6
99.6
99.9
100.0
99.6
99.8
99.8
99.8
99.7
1
2
66
65
68
77
83
79
77
83
81
74
3
4
5
6
7
8
9
Experimental
10
1H and 13C NMR spectra were recorded on a Bruker
Fourier 400 spectrometer (400 and 100 MHz, respectively)
in CDCl3 (compound 4a) and in DMSO-d6 (remaining
compounds), internal standard TMS. LC/MS were
performed on a Waters 2695 Alliance instrument, column:
Phenomenex, Gemini 5u C18 11OA, 50 × 2 mm, 5 µm;
mobile phase: MeCN 0.1% aq. HCOOH; ionization method
* Reaction conditions: nitro derivative 8a (65 g, 0.22 mol), Fe powder
(4.0 equiv), NH4Cl (8 equiv), EtOH–H2O (5:1, 3.48 l), reflux for 4 h.
** The yield after single recrystallization of the raw product is given.
Recrystallization solvent: EtOH–H2O mixture (3:2, 0.94 l), with addition
of activated charcoal (6 g).
*** In all experiments, except entry 5, content of one or more impurities
was higher than 0.1%.
Table 5. Recrystallization results of lenalidomide to obtain pharmaceutical grade product*
HPLC purity of raw material, %
HPLC purity of product, %
Raw material mass, g
Product mass, g Yield, %
210 nm
Content of main impurity**, %
210 nm
Content of main impurity**, %
138.0
138.0
138.0
99.63
99.58
99.54
0.14
0.15
0.16
126.8
125.4
127.3
92
91
92
99.83
99.86
99.84
0.03
0.03
0.03
* Recrystallization solvent: EtOH–H2O mixture (3:2, 3.25 l).
** Any undefined impurity with the highest content.
136

Chemistry of Heterocyclic Compounds 2015, 51(2), 133–138
ESI. Melting points were measured by an OptiMelt
for another 30 min. During this period more intensive
stirring (350 rpm) was applied, because the reaction
mixture became thick. The color of the mixture turned to
blue-gray. Then the reaction mixture was heated to 55°C
and stirred at this temperature at 350 rpm for another 18 h.
The resulted yellowish-beige mixture was cooled to 5°C,
methyl tert-butyl ether (300 ml) and H2O (1.5 l) were
added, and stirring was continued at 400 rpm for 30 min.
The precipitate was filtered off, washed with H2O (4×250 ml),
MeOH (2×150 ml), and dried in vacuo (15–20 mbar) at 60°C
for 6 h. Yield 211 g (89%), off-white solid, mp 273–275°C
(mp 274–276°C)19. HPLC purity 99.8%. 1H NMR spectrum,
δ, ppm (J, Hz): 1.97–2.07 (1H, m), 2.51–2.65 (2H, m) and
2.84–2.98 (1H, m, 4,5-CH2); 4.80 (1H, d,
J = 19.3) and 4.91 (1H, d, J = 19.3, 3-CH2 isoindole); 5.18
(1H, dd, J = 13.1, J = 5.2, 3-CH); 7.84 (1H t, J = 7.8, H-6
isoindole); 8.19 (1H, d, J = 7.5, H-7 isoindole); 8.47 (2H,
dd, J = 8.2, J = 0.8, H-5 isoindole); 11.03 (1H, s, NH).
13C NMR spectrum, δ, ppm: 22.2 (C-4); 31.2 (C-5); 48.5
(C-3 isoindole); 51.8 (C-3); 127.1, 129.6, 130.1, 134.7,
137.4 (C isoindole); 143.4 (C-4 isoindole); 165.9 (C=O);
170.7 (C=O); 172.8 (C=O). Mass-spectrum, m/z (Irel, %):
291 (16), 290 [M+H]+ (100).
automated melting point system in open capillaries and
were uncorrected. HPLC analysis was performed on a
Waters Alliance LC system on Apollo C18 column, UV
detection at 210 and 254 nm. Water content determined by
Karl Fischer titration by a Metrohm 701 KF Titrino with
Titrant 5 (5 mg/ml) Hydranal (Fluka), mass determined by
an analytical balance Sartorius CPA225D-0CE and a
precision balance Radwag PS 4500/C2. The progress of the
reactions and purity of the obtained products were
monitored by TLC using Merck TLC Silica gel 60 F254
plates, eluent hexane–EtOAc, 5:1 (compound 4a) or
CH2Cl2–MeOH, 10:1 (compounds 2, 8a), visualization by
UV light (300 W high-pressure mercury lamp with
maximal intensity at 365 nm). Polymorph form was
determined by a Riganu Ultima IV powder X-ray
diffractometer. The starting materials were purchased from
TCI, Acros, Alfa-Aesar, Aldrich, Apollo Scientific, and
Molecula. 3-Aminopiperidine-1,6-dione hydrochloride (6)
was obtained by a known method.16
Methyl 2-(bromomethyl)-3-nitrobenzoate (4a). In a 4 l
reactor, equipped with a reflux condenser and a mechanical
stirrer, methyl 2-methyl-3-nitrobenzoate (3a) (100.0 g,
0.51 mol, 1.0 equiv), NBS (134.0 g, 0.75 mol, 1.5 equiv),
and MeOAc (1.0 l) were placed. AIBN (8.4 g, 0.05 mol,
0.1 equiv) was added and the resulted suspension was
refluxed with stirring at 250 rpm for 18 h. Then the
reaction mixture was cooled to room temperature, 10%
aqueous solution of Na2SO3 (500 ml) was added, and
stirring was continued at 400 rpm for 30 min. The lower
(aqueous) layer was removed from the reactor, 10%
aqueous solution of NaCl (500 ml) was added to the upper
(organic) layer, and stirring at 400 rpm was continued for
10 min. Organic layer was separated, filtered through glass
filter, and evaporated. Immediately after evaporation, the
orange-yellow oil was diluted with 2-PrOH–H2O mixture
(2:1, 90 ml), and intensively stirred at room temperature for
30 min. The precipitated product was filtered, dried in
vacuum (10–20 mbar) at 50–55°C for 6 h. Yield 138.0 g
(98%), pale-yellow crystals, mp 67–69°C (mp 69–70°C)17.
(R,S)-3-(4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-
piperidine-2,6-dione (2). In a 4 l reactor, equipped with a
reflux condenser and a mechanical stirrer, a solution of
NH4Cl (95.6 g, 1.76 mol, 8 equiv) in H2O (580 ml) was
placed, then nitro derivative 8a (65.0 g, 0.22 mol, 1 equiv)
and EtOH (2.9 l) were added. The reaction mixture was
stirred at 350 rpm and heated up to 60°C, after that iron
powder (24.5 g, 0.44 mol, 2 equiv) was added. The
suspension was heated to 80°C and stirred at this
temperature for 1 h, then another portion of iron powder
(24.5 g, 0.44 mol, 2 equiv) was added and stirring was
continued at 80°C for 3 h. When the conversion was
complete, the reaction mixture was filtered hot, the filter
cake washed with hot EtOH–H2O mixture (3:1, 2×200 ml).
The filtrate was evaporated to dryness, suspended in H2O
(200 ml), and stirred for 30 min at room temperature. The
precipitate was filtered off and washed with H2O (2×50 ml).
The raw product was placed in a 2 l round-bottomed flask,
EtOH–H2O mixture (3:2, 940 ml) was added, and the
suspension was refluxed with stirring for 1.5 h. Then
activated charcoal (6 g) was added, the mixture refluxed
with stirring for another 1 h, filtered hot, the filtrate was
slowly cooled with stirring to 0–5°C and stirred at this
temperature for 1 h. The precipitate was filtered off,
washed with EtOH–H2O mixture (3:2, 100 ml), then with
EtOH (100 ml), and dried in vacuum (15–20 mbar) at 60°C
for 6 h. Yield 36.8 g (82%), pale-yellow solid. The product
was recrystalized from EtOH–H2O mixture (3:2, 870 ml),
thus obtaining pure lenalidomide (2) of pharmaceutical
grade. Yield of pure product 33.9 g (75%; recrystallization
yield 92%), slightly yellow crystals, mp 265–267°C (mp
268–269°C)20. HPLC purity 99.8%, content of each
individual impurity is not higher than 0.03%. The product
1
HPLC purity 98.5%. H NMR spectrum, δ, ppm (J, Hz):
3.98 (3H, s, COOCH3); 5.14 (2H, s, CH2Br); 7.53 (1H, t,
J = 8.0, H-5); 7.94 (1H, dd, J = 8.1, J = 1.2, H-6); 8.09
(1H, dd, J = 7.9, J = 1.3, H-4). 13C NMR spectrum, δ, ppm:
22.9 (CH2Br); 53.2 (COOCH3); 128.0, 129.3, 132.5, 132.8,
134.8, 150.7 (C Ar); 166.0 (C=O). Mass-spectrum, m/z (Irel,
%): 276 [M(81Br)+H]+ (24), 274 [M(79Br)+H]+ (22), 194
(100), 165 (37), 152 (56).
(R,S)-3-(4-Nitro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-
piperidine-2,6-dione (8a). In a 4 l reactor, equipped with a
reflux condenser and a mechanical stirrer, 3-amino-
piperidine-1,6-dione hydrochloride (6) (150 g, 0.91 mol,
1.0 equiv), methyl 2-(bromomethyl)-3-nitrobenzoate (4a)
(300 g, 1.09 mol, 1.2 equiv), and K2CO3 (315 g, 2.28 mol,
2.5 equiv) were placed. Then N-methylpyrrolidone (1.50 l)
was added and the resulted suspension was stirred at
250 rpm without heating for 30 min, while the reaction
temperature rose to 30–33°C. Then the external heating
was turned on and the reaction mixture was stirred at 35°C
1
is semihydrate (polymorph form A)21. H NMR spectrum,
δ, ppm (J, Hz): 1.19 (1H, dtd, J = 12.7, J = 5.3, J = 2.3) and
1.46 (1H, qd, J = 13.3, J = 4.4, 4-CH2); 1.77 (1H, ddd,
137

Chemistry of Heterocyclic Compounds 2015, 51(2), 133–138
5. Chen, M.; Doherty, S.; Hsu, D. S. Dermatol. Clin. 2010, 3,
J = 17.2, J = 4.2, J = 2.2) and 2.08 (1H, ddd, J = 17.5,
577.
J = 13.6, J = 5.4, 5-CH2); 3.26 (1H, d, J = 17.0) and 3.36
(1H, d, J = 17.0, 3-CH2 isoindole); 4.27 (1H, dd, J = 13.3,
J = 5.1, 3-CH); 4.57 (2H, s, NH2); 5.96 (1H, d, J = 7.9, H-5
isoindole); 6.08 (1H, d, J = 7.4, H-7 isoindole); 6.35 (1H, t,
J = 7.6, H-6 isoindole); 10.16 (1H, s, NH). 13C NMR
spectrum, δ, ppm: 22.8 (C-4); 31.2 (C-5); 45.5 (C-3
isoindole); 51.5 (C-3); 110.4, 116.4, 125.6, 128.8, 132.3
(C isoindole); 143.6 (C-4 isoindole); 168.9 (C=O); 171.2
(C=O); 172.9 (C=O). Mass-spectrum, m/z (Irel, %): 261 (8),
260 [M+H]+ (100).
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Iosava, G.; Cavo, M.; Kloczko, J.; Bladé, J.; Beksac, M.;
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This work was performed in accordance with market-
oriented study ''Development of technology for cytostatic
and immunomodulating drugs preparation'' with financial
support from Ministry of Education and Science of the
Republic of Latvia, JSC ''Grindex'', and Latvian Institute of
Organic Synthesis. The authors also wish to acknowledge
the financial support of the InnovaBalt (Latvian Institute of
Organic Synthesis) project.
11. Yan, R.; Yang, H.; Xu, Y. WO Patent 2010139266.
12. Siegel, J. S.; Weber, B. WO Patent 2005005409.
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The authors are grateful to Anatoly Mishnev (Latvian
Institute of Organic Synthesis) for determination of
polymorphic forms.
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