Practical large-scale preparation of (r)-rolipram using chiral nickel catalyst

Article abstract of DOI:10.1080/00397911.2011.580880

Antidepressant drug (R)-rolipram was readily prepared on a large scale from isovanilline via a succinct route. The key reaction was carried out using a 1 mol% loading of nickel(II)-bis[(S,S)-N,N-dibenzylcyclohexane-1,2-diamine]Br2 complex as the catalyst.

Full text of DOI:10.1080/00397911.2011.580880

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Practical Large-Scale Preparation of (R)-
Rolipram Using Chiral Nickel Catalyst
Lixin Wen a b , Feiyu Tang a c , Chengsheng Ge a c , Xiaodong Wang c ,
Zhi Han c & Jianyi Wu a b d
a College of Biology and Chemical Engineering, Jiaxing University,
Jiaxing, China
b School of Petrochemical Engineering, Changzhou University,
Changzhou, China
c Jiaxing Epochem Pharmtech Co. Ltd., Jiaxing, China
d Key Laboratory of Clean Chemical Process of Jiaxing, Zhejiang,
China
Accepted author version posted online: 12 Jan 2012.Version of
record first published: 18 Jul 2012.
To cite this article: Lixin Wen, Feiyu Tang, Chengsheng Ge, Xiaodong Wang, Zhi Han & Jianyi Wu
(2012): Practical Large-Scale Preparation of (R)-Rolipram Using Chiral Nickel Catalyst, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
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Synthetic Communications1, 42: 3288–3295, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.580880
PRACTICAL LARGE-SCALE PREPARATION OF
(R)-ROLIPRAM USING CHIRAL NICKEL CATALYST
Lixin Wen,1,2 Feiyu Tang,1,3 Chengsheng Ge,1,3
Xiaodong Wang,3 Zhi Han,3 and Jianyi Wu1,2,4
1College of Biology and Chemical Engineering, Jiaxing University,
Jiaxing, China
2School of Petrochemical Engineering, Changzhou University,
Changzhou, China
3Jiaxing Epochem Pharmtech Co. Ltd., Jiaxing, China
4Key Laboratory of Clean Chemical Process of Jiaxing, Zhejiang, China
GRAPHICAL ABSTRACT
Abstract Antidepressant drug (R)-rolipram was readily prepared on a large scale from iso-
vanilline via a succinct route. The key reaction was carried out using a 1 mol% loading of
nickel(II)-bis[(S,S)-N,N0-dibenzylcyclohexane-1,2-diamine]Br2 complex as the catalyst.
The ee% could reach to 99%, and the catalyst could be recovered and used in the next reac-
tion cycle with high ee%.
Keywords Asymmetric synthesis; Michael addition; (R)-rolipram
INTRODUCTION
(R)-Rolipram (Fig. 1), an antidepressant drug known to be a selective phos-
phodiesterase type IV inhibitor,[1] is of great interest as a therapeutic agent for the
treatment of central nervous system disorders, such as depression and mental disor-
ders.[2–4] Among the various reported synthetic strategies, the key step introducing
the chiral center is still problematic, which increases the cost of this drug. Numerous
Received December 9, 2010.
Address correspondence to Jianyi Wu, College of Biology and Chemical Engineering, Jiaxing
University, Jiaxing 314001, China. E-mail: jianyi_wu@163.com
3288

PREPARATION OF (R)-ROLIPRAM
3289
Figure 1. (R)-Rolipram.
Figure 2. Nickel complex 1.
approaches have been developed to introduce the chiral center, which include (a)
conjugate addition of the chiral enolate to b-nitrostyrene,[5] (b) the conjugate
addition of nucleophilic substrate to chiral a,b-unsaturated bicyclic lactam or oxazo-
line,[6] and (c) a Claisen rearrangment process with the transfer of chiral site.[7]
Recently, the application of chiral metal catalyst and organocatalyst has created a
new process for (R)-rolipram,[8] but loaded catalysts are expensive and difficult to
recover in the following cycles. Therefore, developing a new practical symmetric
synthesis of (R)-rolipram has become increasingly urgent.
Evans et al.[9] invented
a
readily prepared nickel(II)–bis[(S,S)-N,N0-
dibenzylcyclohexane-1,2-diamine]Br2 complex that could catalyze the Michael
addition of 1,3-dicarbonyl compounds to nitroalkenes to achieve high enantioselec-
tive transformation. In this article, we first applied this air- and moisture-stable
nickel complex 1 (Fig. 2) to the preparation of (R)-rolipram. In addition, the catalyst
could be recovered in 90% yield and was used in the next batch of the reaction,
affording high ee% and yield.
RESULTS AND DISCUSSION
O-Alkylation of isovanillin (2) with cyclopentyl bromide, followed by standard
Henry condensation of 3-(cyclopentyloxy)-4-methoxybenzaldehyde (3) with nitro-
methane, provided (E)-2-(cyclopentyloxy)-1-methoxy-4-(2-nitrovinyl) benzene(4)
with a yield of 92%. The key Michael addition of diethyl malonate to compound
4 catalyzed by the chiral nickel catalyst was described as follows. The mixture of
compound 4 (10.5 g, 40 mmol), diethyl malonate (8.3 g, 52 mmol), and nickel
complex 1 (0.36 mg, 0.4 mmol) was stirred under nitrogen at 0 ꢀC. The reaction
was monitored by high-perfomance liquid chromatography (HPLC). The effect of

3290
L. WEN ET AL.
solvent for Michael addition of diethyl malonate to compound 4 catalyzed by nickel
complex 1 is illustrated in Table 1. Generally, nickel compelx 1 could be dissolved in
a range of solvents and provided perfect reactivity and enantioselectivity. In the
polar solvent ethanol, the enantiomeric excess was 80%. The enantioselectivity in
neat reaction was normal. Excellent reactivity and enantioselectivity could be
obtained in toluene, dichloromethane, and dichloroethane. Decreasing temperature
could improve the enantioselectivity slightly, but longer reaction time was required.
Interestingly, the use of dichlormethane gave the best results. It might be explained
by the best solubility of nickel complex 1 and compound 3 in dichloromethane. In
addition, the enantioselectivity could not be improved in tetrahydrofuran (THF)
or ethyl acetate.
With the extended reaction time, good yield, and ee% were achieved by using
less loaded catalyst (0.1 mol%). We turned our attention to the recovery of catalyst.
The catalyst was the complex of (1R,2R)-N1,N2-dibenzylcyclohexane-1,2-diamine
with Ni(II). Hydrochloride could decompose the complex, and the chiral ligand
could be dissolved in water as hydrochloride salt, which could be extracted with
organic solvent after neutralized with a base. In our experiments, we washed the mix-
ture with 2 N hydrochloride twice, and the combined water phases were neutralized
with 2 N NaOH to pH 8. The resulting water phase was extracted with dichloro-
methane, which resulted in the recovering the chiral ligand in 90% yield. Complex
1 could be synthesized from the recovered chiral ligand and reused. The synthesis
route of compound 5 from compound 4 is shown in Scheme 1, and the catalytic
asymmetric Michael reaction with catalyst recycling is presented in Table 2. The
recovered complex 1 was reused several times. Although slight loss of activity was
observed, the recovered complex 1 promoted the Michael reaction to obtain the
desired product 5 in very high ee even after five runs.
The application of the Michael addition was further evaluated by performing a
large-scale experiment. The Michael addition of ethyl malonate with compound 4
catalyzed by 1 mol% catalyst in dichlormethane at room temperature obtained
Table 1. Effect of solvent on enantioselective Michael addition of 4 with diethyl malonate
Reaction
temperature (ꢀC)
Reaction
timea (h)
Entry
Solvent
THF
EtOAc
Yieldb (%)
Eec (%)
1
2
20
20
20
0
9
12
9
92
96
98
98
93
98
95
98
98
95
92
90
97
98
97
91
80
93
95
88
3
CH2Cl2
CH2Cl2
4
20
9
5
ClCH2CH2Cl
ClCH2CH2Cl
EtOH
20
0
6
21
24
10
20
100
7
20
20
0
8
Toluene
Toluene
Neat
9
10d
20
aAll the reactions stopped with conversion of more than 99%.
bIsolated yield.
cEnantiomeric excess was determined by HPLC with chiracel AD column.
dNeat reaction with 1.5 equivalent of diethyl malonate.

PREPARATION OF (R)-ROLIPRAM
3291
Scheme 1. Catalytic asymmetric Michael reaction with catalyst.
Table 2. Catalytic asymmetric Michael reaction with catalyst recycling
Cycle
Parameter
1
2
3
4
5
Yield (%)a
Ee (%)b
98
98
95
98
94
97
92
97
89
97
aIsolated yield.
bEnantiomeric excess was determined by HPLC with chiracel AD column.
1 kg of compound 5 in 98% yield with 97% ee. Optically pure compound 6 (950 g)
was obtained after recrystallization in petroleum ether=methyl-tert-butyl ether
(4:1) with a yield of 95%.
Eventually, hydrogenlysis of the compound 5 by Raney Ni catalyst gave the
lactam 6, which was further decarboxylated to give compound 7. One-pot, ring-
closure reaction gave (R)-rolipram as a single enantiomer in 72.5% overall yield over
six steps.
In conclusion, for the first time, nickel(II)–bis[(S,S)-N,N0-dibenzylcyclohexane-
1,2-diamine]Br2 complex was used as the catalyst to make the key intermediate of
(R)-rolipram. On a large scale, (R)-rolipram was prepared in a succinct route with
good yield, and the ee% reached to 99%. This method provided an efficient, low-cost
protocol to make the antidepressant drug (R)-rolipram (Scheme 2).
Scheme 2. General strategy for synthesis of (R)-rolipram.

3292
L. WEN ET AL.
EXPERIMENTAL
The melting point was determined on WRS-2 melting-point apparatus
(Shanghai, China) and uncorrected. The NMR spectra were recorded on a Varian
400-MHz spectrometer using CDCl3 as solvent and tetramethylsilane (TMS) as
internal standard. Mass spectra were recorded on Jeol AX-505 or SX-102 spectro-
meters. Optical rotations were measured on a Jasco DIP-0181 digital polarimeter
with a sodium lamp.
Synthesis of 3-(Cyclopentyloxy)-4-methoxybenzaldehyde, 3
To a solution of 3-hydroxy-4-methoxybenzaldehyde (50 g, 0.33 mol) and bro-
mocyclopentane in DMF (400 mL), K2CO3 (68.3 g, 0.5 mol) was added and refluxed
for 12 h. After completion of the reaction, the mixture was cooled to room tempera-
ture. The mixture was taken into water (200 mL), extracted with ethyl acetate
(3 ꢁ 200 mL), dried over anhydrous Na2SO4, and evaporated to give the brown oily
compound 3 (68.0 g); 94% yield; 1H NMR (400 MHz, CDCl3): d 9.80 (s, 1 H, CHO),
7.39 (dd, J ¼ 8.1, 1.7, 1 H, Ar-H), 7.33 (d, J ¼ 1.7, 1 H, Ar-H), 6.96 (d, J ¼ 8.1, 1 H,
Ar-H), 4.85–4.74 [m, 1 H,OCH(CH2)4], 3.90 (s, 3 H, Ar-OCH3), 2.14–1.80 (m, 6 H,
cyclopentyl-H), 1.64–1.52 (m, 2 H, cyclopentyl-H); MS: m=z (M þ 1) 221. The data
were consistent with those reported in the literature.[10]
Synthesis of (E)-2-(Cyclopentyloxy)-1-methoxy-
4-(2-nitrovinyl)benzene, 4
A mixture of 3-(Cyclopentyloxy)-4-methoxybenzaldehyde (68 g, 0.31 mol),
ammonium acetate (40.6 g, 0.53 mol), and nitromethane (94.6 g, 1.55 mol) in acetic
acid (400 mL) was refluxed for 12 h. The reaction mixture was cooled to room tem-
perature. Water was added drop by drop. The solid was filtered and dried to give
1
compound 4 (75.1 g); 92% yield; H NMR (400 MHz, CDCl3): d 7.93 (d, J ¼ 13.6,
=
=
1 H, -CH CHNO2), 7.54 (d, J ¼ 13.6, 1 H, -CH CHNO2), 7.24 (dd, J ¼ 8.3, 1.8,
1 H, Ar-H), 7.07 (br d, J ¼ 1.8, 1 H, Ar-H), 6.87 (d, J ¼ 8.3, 1 H, Ar-H), 4.81 [td,
J ¼ 9.0, 3.0, 1 H, -OCH(CH2)4], 3.93 (s, 3 H, Ar-OCH3), 2.01–1.82 (m, 6 H,
cyclopentyl-H), 1.72–1.61 (m, 2 H, cyclopentyl-H); MS: m=z (MNaþ) 286; mp
138.5–139.5 ꢀC. The data were consistent with the literature.[10]
Synthesis of (S)-Diethyl-2-(1-(3-(cyclopentyloxy)-4-
methoxyphenyl)-2-nitroethyl)malonate, 5
Catalyst
1 (357 mg, 0.4 mmol) was added to a solution of (E)-2-
(cyclopentyloxy)-1-methoxy-4-(2-nitrovinyl)benzene (10.5 g, 40 mmol) and diethyl
malonate (8.3 g, 52 mmol) in CH2Cl2(10 mL) under the protection of nitrogen and
stirred for 9 h at 0 ꢀC. CH2Cl2 was removed under vacuum, and then water
(10 mL) was introduced. The solid was filtered and dried to give compound 5, which
was the white solid (17.8 g); 98% yield. Optically pure compound 5 was obtained
after recrystallization by petroleum ether=methyl tert-butyl ether (MTBE) (4:1).
Racemic sample was prepared by racemic catalyst according to the general

PREPARATION OF (R)-ROLIPRAM
3293
procedure. 1H NMR (CDCl3=300 MHz) d 6.81–6.72 (m, 3H), 4.90 (dd, J ¼ 12.9, 1H),
4.82 (dd, J ¼ 12.9, 1H), 4.73–4.69 (m, 1H), 4.29–4.14 (m, 3H), 4.05 (q, 2H), 3.76 (s,
3H), 3.79 (d, 1H), 2.02–1.79 (m, 5H), 1.64–1.59 (m, 3H), 1.29 (t, 3H), 0.91 (t, 3H);
MS: m=z ðMNHþ4 Þ 441; mp 94.5–95.5 ꢀC; [a]D: 30–9.4 (c 1.15 CHCl3), ee > 99%.
Chiral HPLC condition: Agilent 1200 HPLC, Chiracel AD column (250 ꢁ 4.6 mm
i.d.) with a mixture of hexane and 2-propanol (95:5) at a flow rate 1.0 ml=min as
the mobile phase, oven temperature 25 ꢀC, 210 nm, tmajor ¼ 20.22 min, tminor
¼
26.22 min. The data were consistent with literature.[11]
Synthesis of (4R)-Ethyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)-2-
oxopyrrolidine-3-carboxylate, 6
Raney nickel (5 g, washed with 95% MeOH) was placed in a flask equipped with
a magnetic stirrer and charged with a solution of compound 5 (19.9 g, 47 mmol) in
MeOH (500 mL) under a nitrogen atmosphere. The reaction system was then flushed
and filled with H2. After stirring the mixture at room temperature for 12 h, the cata-
lyst was filtered off and the filtrate was condensed to produce a light-grey oily com-
pound. Then, petroleum ether was added to give target product 6 (15.7 g); 96% yield;
1H NMR (400 MHz, CDCl3): 7.74 (br s, 1 H, NH), 6.86–6.68 (m, 3 H, Ar-H),
4.78–4.69 (br m, 1 H, Ar-ꢂCH), 4.23 (q, J ¼ 7.1, 2 H, OCH2CH3), 3.42 (dd,
J ¼ 18.0, 8.6, 1 H, CHAHB-NH), 3.85–3.71 (m, 4 H, Ar-OCH3 and CHAHB-NH),
3.51 (d, J ¼ 9.8, 1 H, CH-ꢂC), 3.39 [t, J ¼ 9.0, 1 H, OCH(CH2)2], 1.96–1.73 (m, 6H,
cyclopentyl-H), 1.62–1.51 (m, 2 H, cyclopentyl-H), 1.26 (t, J ¼ 7.1, 3 H, OCH2CH3);
MS: m=z (MHþ) 348. The data were consistent with the literature.[10]
Synthesis of (R)-Rolipram
The mixture of compound 6 (15.6 g, 45 mmol) in THF (50 mL) and 2 N NaOH
aqueous solution (50 mL, 100 mmol) was refluxed for 2 h. The pH value of the resulting
solution was adjusted to 1 with 1 N HCl and extracted with CH2Cl2(100 mL ꢁ 3). The
combined organic layer was washed with brine, dried over anhydrous Na2SO4, and
evaporated. The residue was dissolved in MeOH (50 mL), and thionly chloride
(10 mL) was added in an ice bath. It was stirred at room temperature for 2 h. The
mixture was evaporated into dryness and diluted with toluene (50 mL). The resulting
solution was neutralized with 2 N NaOH aqueous solution, and the water was dec-
anted. The resulting toluene solution was refluxed for 2 h and evaporated to oil, which
1
was titrated to give yellow solid (R)-Rolipram (11.2 g, 90% overall yield); H NMR
(400 MHz, CDCl3): 7.23 (br s, 1 H, NH), 6.82 (d, J ¼ 8.5, 1H, Ar-H), 6.75–6.71 (m,
2 H, Ar-H), 4.75 [m, 1 H, OCH(CH2)2], 3.82 (s, 3 H, Ar-OCH3), 3.75 (app. t,
J ¼ 8.9, 1 H, CHAHB-NH), 3.64–3.56 (m, 1 H, Ar-ꢂCH), 3.37 (dd, J ¼ 9.4, 7.7, 1 H,
CHAHB-NH), 2.70 (dd, J ¼ 16.9, 8.9, 1 H, CHAHBCO), 2.47 (dd, J ¼ 16.9, 8.9, 1
H, CHAHþBCO), 1.93–1.75 (m, 6 H, cyclopentyl-H), 1.66–1.51 (m, 2 H, cyclopentyl-H);
m=z (MH ) 276; mp 131.5–132.5 ꢀC [a]D: 25–31 (c 1.05, MeOH); ee > 99%. Chiral
HPLC condition: Agilent 1200 HPLC, Chiracel AD-H column (250 ꢁ 4.6 mm i.d.)
with a mixture of hexane and 2-propanol (90:10) at a flow rate of 1.0 ml=min as the
mobile phase, oven temperature was 28 ꢀC, 210 nm, tmajor ¼ 10.22 min, tminor
¼
10.65 min. The data were consistent with those reported in the literature.[10]

3294
L. WEN ET AL.
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