Novel methods for the synthesis of 2-[(4R)-2-oxo-4-phenylpyrrolidin-1-yl]- acetamide ((R)-phenotropil)

Article abstract of DOI:10.1007/s10593-012-1050-y

Two novel methods have been developed for the preparation of 2-[(4R)-2-oxo-4-phenylpyrrolidin-1-yl]acetamide ((R)-Phenotropil). In the first, n-butyl (3R)-4-amino-3-phenylbutyrate is alkylated with haloacetamide in DMF in the presence of potassium phospha

Full text of DOI:10.1007/s10593-012-1050-y

Chemistry of Heterocyclic Compounds, Vol. 48, No. 5, August, 2012 (Russian Original Vol. 48, No. 5, May, 2012)
NOVEL METHODS FOR THE SYNTHESIS OF
2-[(4R)-2-OXO-4-PHENYLPYRROLIDIN-1-YL]-
ACETAMIDE ((R)-PHENOTROPIL)
M. Vorona1, G. Veinberg1*, S. Vikainis1, E. Kuznetsov1, A. Lebedev1,
Yu. Ponomarev, A. Chernobrovijs1, L. Zvejniece1 and M. Dambrova1
Two novel methods have been developed for the preparation of 2-[(4R)-2-oxo-4-phenylpyrrolidin-
1-yl]acetamide ((R)-Phenotropil). In the first, n-butyl (3R)-4-amino-3-phenylbutyrate is alkylated with
haloacetamide in DMF in the presence of potassium phosphate monohydrate, and the intermediate
4-carbamoylmethylamino-3-phenylbutyrate is subsequently cyclized by refluxing in toluene in the
presence of potassium phosphate monohydrate and tetrabutylammonium bromide. In the second,
chloroacetonitrile is used under similar conditions in place of the haloacetamide. Both methods lead to
(R)-Phenotropil in 40-60% yields calculated on the starting n-butyl (3R)-4-amino-3-phenylbutyrate .
Keywords: n-butyl (3R)-4-carbamoylmethylamino-3-phenylbutyrate, n-butyl (3R)-4-cyanomethyl-
amino-3-phenylbutyrate, 2-[(4R)-2-oxo-4-phenylpyrrolidin-1-yl]acetamide, alkylation, cyclization.
Phenotropil (2-[(4R)-2-oxo-4-phenylpyrrolidin-1-yl]acetamide) is a member of the racetam group of
nootropic drugs, which contain a 2-pyrrolidone ring [1]. The presence of a chiral center at the position 4 of the
Phenotropil molecule leads to its possible medicinal use both as a racemic mixture and also in an enantiomeric
form. Until 2006, there were no data in the literature on methods of synthesis and the activity of the (R)- and
(S)-enantiomers of Phenotropil. Our method for the preparation of the stereoisomers and a comparative study of
their pharmacological properties revealed the marked predominance of antidepressant activity in the (R)-
Phenotropil, when compared to its (S)-antipode. It was also shown that an identical effect on muscle tone and
movement coordination in mice is achieved with a lower dose of the (R)-Phenotropil, compared to its (S)-isomer
[2].
Ph
Ph
Ph
Ph
BrCH2COOEt
NaH
O
NH4OH
O
N
N
O
–
N
O
Na+
N
H
OEt
NH2
1
2
O
O
3
4
_______
*To whom correspondence should be addressed, e-mail: veinberg@osi.lv.
1Latvian Institute of Organic Chemistry, 21 Aizkraukles St., Riga LV-1006, Latvia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 775-778, May, 2012. Original
article submitted May 10, 2011.
720
0009-3122/12/4805-0720©2012 Springer Science+Business Media, Inc.

Our previously reported route of the (R)-Phenotropil 4 synthesis [2] was based on known methods [3,
4]. The action of sodium hydride on (4R)-4-phenyl-2-pyrrolidone (1) gave the sodium derivative 2, which could
then, without isolation, be alkylated by ethyl bromoacetate. The obtained ester 3 was subjected to ammonolysis
with aqueous ammonia, to yield the target product 4.
With the ability of N-alkylated 4-aminobutyrates to cyclize to N-alkylpyrrolidin-2-ones [5] we
considered the possible synthesis of n-butyl (3R)-4-carbamoylmethylamino-3-phenylbutyrate (7) and its
cyclization to the target product 4 (method A).
O
O
Ph
O
Hal
H
H2N
N
H2N
O
Ph
O
6a–c
3
OBu
-n
+
4
2
K3PO4·H2O
KI, DMF
20–60°C
N
Method A
-n
OBu
O
NH2
7

NH2
K3PO4·H2O
Bu4NBr, PhMe
8
Ph
O
H2N
OBu
-n
4
5
NC
Cl
H2O
9
Method B
K3PO4·H2O, Bu4NBr
Ph
KI, DMF, 40°C
K3PO4·H2O
Bu4NBr
Ph
O
H
O
N
N
OBu-n
95% EtOH
CN
CN

10
11
6 a Hal = Cl, b Hal = Br, c Hal = I
The (R)-enantiomer of the n-butyl 4-amino-3-phenylbutyrate (5) can be prepared by our previously
reported biocatalytic method for separating the racemic ester 5 using -chymotrypsin [6]. The starting material
for the synthesis of ester 5 is 4-amino-3-phenylbutyric acid, also known as the tranquilizing agent Phenibut.
Investigation of the proposed method has shown that the base plays a decisive role in the process of
N-alkylation of ester 5. With the use of sodium hydroxide, potassium hydroxide, triethylamine, morpholine, or
N-methylmorpholine, compound 5 predominantly cyclizes to (4R)-4-phenyl-2-pyrrolidone (1), and this is
accompanied by cleavage of n-butanol. However, the use of potassium phosphate monohydrate in a polar
solvent (DMF) at room temperature or heating at 60ºC gave principally the N-alkylated product 7. The yield
was increased with the use of chloroacetamide (6a) and a catalytic amount of potassium iodide. Excess bromo-
(6b) or iodoacetamide (6c) promoted formation of the N,N-bisalkylated product 8. Cyclization of the n-butyl
(3R)-4-carbamoylmethylamino-3-phenylbutyrate (7) to the target 2-[(4R)-2-oxo-4-phenylpyrrolidin-1-yl]-
acetamide (4) took place virtually quantitatively in toluene, when refluxed in the presence of a mixture of
potassium phosphate monohydrate and tetrabutylammonium bromide (TLC data).
The optimization of method A included the removal of inorganic salts from the reaction mixture by
filtration, substitution of DMF for toluene, addition of potassium phosphate monohydrate and
tetrabutylammonium bromide to the obtained solution, and refluxing the mixture for 2 h. This excluded the
stage of separation and purification of the monoalkylated intermediate product 7. Purification of the obtained
(R)-Phenotropil from pyrrolidone 1, the N,N-bis-alkylation product 8 and other impurities was carried out by
column chromatography or by recrystallization from water, and the final product was obtained in 63% and 48%
yields, respectively (calculated on the starting ester 5).
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The method B is based on a reaction of n-butyl 4-amino-3-phenylbutyrate (5) and chloroacetonitrile (9).
The reaction conditions were the same as those mentioned above for the reaction with the acetamides 6a-c.
Short heating of the n-butyl (3R)-4-cyanomethylamino-3-phenylbutyrate (10) in 95% ethanol in the presence of
a base led to cyclization and hydrolysis of the cyano group to give the (R)-Phenotropil 4 in a 44% yield, based
on the starting ester 5.
The methods developed for the preparation of (R)-Phenotropil are not inferior in efficiency to those
reported in the literature [2, 3]. Based on the use of n-butyl (3R)-4-amino-3-phenylbutyrate hydrochloride they
extend the material and methodological basis for the preparation of not just this product, but also similarly
structured racetams.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian Mercury-400 (400 MHz) instrument using CDCl3 with
HMDS ( 0.05 ppm) as internal standard. Elemental analysis was carried out on a Carlo Erba 1108 analyzer.
Monitoring of the reaction course was carried out by TLC on Merck Kieselgel plates and visualized with UV
light. Chiral HPLC was performed on a Waters Alliance instrument on a Chiralpac IC column (4.6250 mm)
from Daicel, filled with tris-(3,5-dichlorophenylcarbamoyl)cellulose immobilized on silica gel (5 microns). The
eluent was ethanol–hexane–ethanolamine (35:65:0.1%), the flow rate was 1 ml/min, and the spectrophotometric
detection was done at =210 nm. Preparative column chromatography was performed on Merck Kieselgel
(0.06-0.20 mm) grade silica gel with CH2Cl2–MeOH eluent (10:1, for compound 4) or CH2Cl2–ethanol (15:1,
for the remaining compounds). The reagents and materials used in the experiments were from Acros.
n-Butyl (3R)-4-Carbamoylmethylamino-3-phenylbutyrate (7). K3PO4·H2O (0.691 g, 3 mmol) and
4 Å molecular sieves (2 g) were added to a solution of the n-butyl (3R)-4-amino-3-phenylbutyrate hydrochloride
(5) (0.272 g, 1 mmol) and bromoacetamide (6b) (0.137 g, 1 mmol) in DMF (20 ml). The suspension was stirred
at room temperature for 48 h, filtered, and the filtrate was evaporated in vacuo. Compound 7 was isolated by
column chromatography. Yield 0.155 g (53%). Oily product, Rf 0.52. The use of a mixture of chloroacetamide
(6a) (0.094 g, 1 mmol) and KI (0.008 g, 0.05 mmol) in place of bromoacetamide (6b) gave a 0.193 g (66%)
yield of the ester 7. With the use of the iodoacetamide (6c) (0.185 g, 1 mmol) in place of bromoacetamide (6b)
1
the yield of ester 7 was 0.181 g (62%). H NMR spectrum, , ppm (J, Hz): 0.88 (3H, t, J = 7.5,
CH2CH2CH2CH3); 1.17-1.39 (2H, m, CH2CH2CH2CH3); 1.43-1.63 (2H, m, CH2CH2CH2CH3); 2.63 (1H, d,
J = 3.8) and 2.67 (1H, d, J = 3.8, 2-CH2); 2.84 (2H, d, J = 7.5, 4-CH2); 3.20 (2H, d, J = 4.2, COCH2NH);
3.22-3.37 (1H, m, 3-CH); 4.01 (2H, t, J = 7.5, CH2CH2CH2CH3); 5.54 (1H, br. s) and 6.23 (1H, br. s, CONH2);
6.89 (1H, br. s, NH); 7.13-7.41 (5H, m, H Ph). Found, %: C 65.86; H 8.37; N 9.67. C16H24N2O3. Calculated, %:
C 65.73; H 8.27; N 9.58.
n-Butyl (3R)-4,4-Bis(carbamoylmethyl)amino-3-phenylbutyrate (8). K3PO4·H2O (2.36 g,
10.26 mmol), 4Å molecular sieves (3 g), and Bu4NBr (0.011 g, 0.036 mmol) were added to a solution of n-butyl
(3R)-4-amino-3-phenylbutyrate hydrochloride (5) (1.00 g, 3.42 mmol) and iodoacetamide (6c) (2.04 g, 11.00
mmol) in DMF (50 ml). The suspension was stirred at 40ºC for 48 h, filtered, and the filtrate was evaporated in
vacuo. Compound 8 was isolated by column chromatography. Yield 0.55 g (46%). Using bromoacetamide (6b)
(1.52 g, 11 mmol) in place of iodoacetamide (6c) gave 0.51 g (43%) compound 8. Amorphous substance,
1
Rf 0.20. H NMR spectrum, , ppm (J, Hz): 0.87 (3H, t, J = 7.2, CH2CH2CH2CH3); 1.16-1.37 (2H, m,
CH2CH2CH2CH3); 1.42-1.59 (2H, m, CH2CH2CH2CH3); 2.61-2.92 (4H, m, 2,4-CH2); 3.19 (4H, s, N(CH2)2);
3.24-3.42 (1H, m, 3-CH); 4.01 (2H, t, J = 6.5, CH2CH2CH2CH3); 5.77 (2H, br. s, CONH2); 6.24 (1H, br. s) and
6.89 (1H, br. s, CONH2); 7.16-7.39 (5H, m, H Ph). Found, %: C 61.98; H 7.84; N 12.13. C18H27N3O4.
Calculated, %: C 61.87; H 7.79; N 12.03.
n-Butyl (3R)-4-Cyanomethylamino-3-phenylbutyrate (10). K3PO4·H2O (3.4 g, 14.72 mmol), KI
(0.123 g, 0.74 mmol), 4Å molecular sieves (3 g), and Bu4NBr (0.024 g, 0.074 mmol) were added to a solution
722

of the n-butyl (3R)-4-amino-3-phenylbutyrate hydrochloride (5) (2.0 g, 7.36 mmol) and chloroacetonitrile
(0.7 ml, 11.04 mmol) in DMF (60 ml). The suspension was stirred at 40ºC for 48 h, filtered, and the filtrate was
evaporated in vacuo. Compound 10 was isolated by column chromatography. Yield 0.95 g (47%). Oily product,
1
Rf 0.64. H NMR spectrum, , ppm (J, Hz): 0.87 (3H, t, J = 7.5, CH2CH2CH2CH3); 1.38-1.66 (2H, m,
CH2CH2CH2CH3); 1.42-1.60 (2H, m, CH2CH2CH2CH3); 1.99 (1H, br. s, NH); 2.53-3.11 (4H, m, 2,4-CH2); 3.26-
3.43 (1H, m, 3-CH); 3.55 (2H, d, J = 1.4, CH2NH); 4.00 (2H, t, J = 7.5, CH2CH2CH2CH3); 7.15-7.46 (5H, m,
H Ph). Found, %: C 70.16; H 8.21; N 10.33. C16H22N2O2. Calculated , %: C 70.04; H 8.08; N 10.21.
2-[(4R)-2-Oxo-4-phenylpyrrolidin-1-yl]acetamide (4). A. K3PO4·H2O (19.07 g, 82.8 mmol) and 4Å
molecular sieves (10 g) were added to a solution of the n-butyl (3R)-4-amino-3-phenylbutyrate hydrochloride
(5) (7.50 g, 27.6 mmol) and iodoacetamide (6c) (5.61 g, 30.3 mmol) in DMF (150 ml). The suspension was
stirred at 60ºC for 14 h, filtered, and the filtrate was evaporated in vacuo. The residue was dissolved in toluene
(150 ml) and K3PO4·H2O (2 g, 8.68 mmol) and Bu4NBr (0.05 g, 0.15 mmol) were added to the solution. The
suspension was refluxed for 2 h, cooled, filtered, and the filtrate was evaporated to dryness. The final product 4
was purified from impurities by column chromatography. Yield 3.55 g (63%). In a variant of the synthesis using
the same amounts of starting materials, the final product was purified by recrystallization from water (35 ml).
Yield 2.70 g (48%).
B. K3PO4·H2O (0.550 g, 2.40 mmol) and Bu4NBr (0.050 g, 0.15 mmol) were added to a solution of the
ester 10 (0.549 g, 2.00 mmol) in 95% ethanol (40 ml). The suspension was refluxed for 2 h, cooled, filtered, and
the filtrate was evaporated to dryness. The target product 4 was isolated by column chromatography. Yield
0.192 g (44%); mp 110-112ºC (mp 110ºC [2]; for the racemic product mp 129-130ºC [3]). Rf 0.40. []D20 +8.5º
(c 3.0, MeOH), optical purity 97%. The 1H NMR spectrum of the obtained compound 4 agreed with that given
in the literature [2].
This work was carried out within the scope of the European Regional Development Fund (ERDF)
(project 2DP/2.1.1.1.0/10/APIA/VIAA/059).
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