3-Aminopyrrolidines from α-aminoacids: Total synthesis of (+)-nemonapride from D-alanine

Article abstract of DOI:10.1021/jo702278k

(Chemical Equation Presented) The antipsychotic compound nemonapride 1 was synthesized in nine steps from D-alanine 2. The key steps for the synthesis of the 3-aminopyrrolidine moiety include a Birch reduction of a cyclic enaminoester and the reduction of a pyrrolidinone to the pyrrolidine 7. Final coupling with the benzoic acid derivative 9 gave 1 as a single enantio- and diastereomer.

Full text of DOI:10.1021/jo702278k

SCHEME 1. Synthesis of 4-Aminopyrrolidinones from
r-Aminoacids
3-Aminopyrrolidines from r-Aminoacids: Total
Synthesis of (+)-Nemonapride from D-Alanine
Cam Thuy Hoang, Viet Hoang Nguyen, Vale´rie Alezra, and
Cyrille Kouklovsky*
Laboratoire de Chimie des Proce´de´s et Substances Naturelles,
Institut de Chimie Mole´culaire et des Mate´riaux d’Orsay (UMR
CNRS No. 8182), UniVersite´ Paris-Sud, F-91405 Orsay, France
cykouklo@icmo.u-psud.fr
ReceiVed October 22, 2007
on the reduction conditions (cyanoborohydride reduction or
Birch reduction), this synthetic sequence led to cis- or trans-
disubstituted cyclic ureas, the hydrolysis of which gives rise to
enantio- and diastereomerically defined 4-amino-5-alkylpyrro-
lidinones (Scheme 1). Since pyrrolidinones are obvious precur-
sors to pyrrolidines, the whole synthetic sequence could provide
a short and efficient access to the enantiomerically pure
pyrrolidine subunit of nemonapride by hydrolysis of a trans-
alanine-derived urea.6
The synthesis started by transformation of D-alanine 2 into
the cyclic enaminoester 3 in five steps without loss of enan-
tiomeric purity (Scheme 2). Reduction under Birch conditions
(sodium, ammonia in anhydrous THF) gave a mixture of reduced
compounds; the crude mixture was immediately treated with
an aqueous sodium hydroxide solution to give a mixture of the
carboxylic acid 4 and the overreduced alcohol 5. Both com-
pounds were obtained as single diastereomers and could be
easily separated by chromatography. The alcohol 5 may be
recycled by oxidation to 4 (PDC, DMF, quantitative yield).
The antipsychotic compound nemonapride 1 was synthesized
in nine steps from D-alanine 2. The key steps for the synthesis
of the 3-aminopyrrolidine moiety include a Birch reduction
of a cyclic enaminoester and the reduction of a pyrrolidinone
to the pyrrolidine 7. Final coupling with the benzoic acid
derivative 9 gave 1 as a single enantio- and diastereomer.
In the search for new benzamide-derived neuroleptic agents,
the Yammanouchi company reported in 1978 the structure of
nemonapride 1, a highly active antipsychotic compound.1
Nemonapride (formerly called emonapride) has been com-
mercialized (under its racemic form) since 1991, and further
studies underlined its activity as a dopamine receptor antagonist.2
The structure of 1 consists of a 3-benzoylated 2,3-cis-3-amino-
1-benzyl-2-methylpyrrolidine. Since the first synthesis of race-
mic nemonapride 1, two enantioselective syntheses of the
pyrrolidine moiety have been disclosed, one from L-malic acid3
and the other one by using a catalytic asymmetric Mannich
reaction.4 In this note, we wish to report a new synthesis of
(+)-nemonapride 1 from D-alanine.
Hydrolysis of the trans-disubstituted cyclic urea 4 proved to
be more difficult than its cis counterpart. Nevertheless, treatment
of 4 with 3 N HCl solution at 140 °C for 5 days gave a
quantitative yield of the aminopyrrolidinone hydrochloride 6.
Standard reduction (LiAlH4, THF, reflux) gave the target
3-aminopyrrolidine 7 in excellent yield. This compound was
identical in all respects to those previously described in the
literature.7
The total synthesis of nemonapride 1 requires the synthesis
of 5-chloro-4-methylamino-2-methoxybenzoic acid 9 and its
coupling with 7. Since compound 8 is commercially available
at a low price, it was selected as the starting material for the
synthesis of 9. Thus, N-methylation of 8 with methyl sulfate in
acetone followed by N-deacetylation and ester hydrolysis by
acidic treatment gave the target benzoic acid derivative 9 (as
its sulfate salt) in good overall yield. Final coupling was
achieved using a slight modification of literature conditions4
(ClCO2Et, Et3N, CH2Cl2, 0 °C) to give nemonapride 1 in 74%
yield.8
We have recently reported a new method for aminoacid
homologation, consisting of the Blaise condensation of R-bro-
moesters onto R-aminoacid-derived aminonitriles, followed by
reduction of the subsequent cyclic enaminoester.5 Depending
(1) (a) Murakami, K.; Takahashi, M.; Hirata, Y.; Takashima, M.;
Iwanami, S.; Hasegawa, O.; Nozaki, Y.; Tashikawa, S.; Takeda, M.; Usuda,
S. U.S. Patent 4097487, 1978. (b) Takashima, M.; Iwanami, S.; Usuda, S.
U.S. Patent 4210660, 1980. (c) Iwanami, S.; Takashima, H.; Hirata, Y.;
Hasagewa, O.; Usuda, S. J. Med. Chem. 1981, 24, 1224.
(2) (a) Furuya, T.; Iwanami, S.; Takenaka, A.; Sasada, Y. Bull. Chem.
Soc. Jpn 1982, 55, 2321. (b) Yamamoto, M.; Usuda, S.; Tachikawa, S.;
Maeno, H. Neurophamacology 1982, 21, 945.
(6) For the synthesis and properties of 3-aminopyrrolidines, see: (a)
Davies, S. G.; Garner, A. C.; Goddard, E. C.; Kruchinin, D.; Roberts, P.
M.; Rodriguez-Solla, H.; Smith, A. D. Chem. Commun. 2006, 2664 and
references cited therein. (b) See also: Vargas-Sanchez, M.; Couty, F.; Evano,
G.; Prim, D.; Marrot, J. Org. Lett. 2005, 7, 5861.
(3) Huang, P. Q.; Wang, S. L.; Zheng, H.; Fei, X. S. Tetrahedron Lett.
1997, 38, 271.
(4) Shibugushi, T.; Mihara, H.; Kuramochi, A.; Ohshima, T.; Shibasaki,
M. Chem. Asian J. 2007, 2, 794.
(5) Hoang, C. T.; Alezra, V.; Guillot, R.; Kouklovsky, C. Org. Lett. 2007,
9, 2521.
(7) The enantiomeric purity of 8 was checked by HPLC analysis on a
chiral column and comparison with a racemic standard (prepared according
to the same synthetic sequence from racemic alanine) and was found to be
>99%.
10.1021/jo702278k CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/05/2008
1162
J. Org. Chem. 2008, 73, 1162-1164

SCHEME 2. Total Synthesis of (+)-Nemonapride 1 from D-alanine
to give a yellow residue which was redissolved in water (10 mL)
and extracted with CH2Cl2 (3 × 10 mL). The combined organic
extracts were dried (MgSO4), filtered, and concentrated in vacuo
to give the pyrrolidine 7 as a white solid, which was sufficiently
Nemonapride 1 was synthesized as a single enantio- and
diastereomer in nine steps from D-alanine 2, with an overall
yield of 16%. Furthermore, this synthesis illustrates a new route
to 3-aminopyrrolidines from aminoacids by organometallic
condensation. Further applications of this synthetic strategy are
currently under investigation.
1
pure for the next reaction: yield 93% (106 mg); H NMR (360
MHz, CDCl3) δ 1.10 (3H, d, J ) 7 Hz), 1.45 (1H, m), 1.78 (2H,
br s, exchange with D2O), 2.03 (1H, m), 2.13 (1H, m), 2.35 (1H,
m), 2.91 (1H, m), 3.13 (1H, d, J ) 13 Hz), 3.25 (1H, m), 3.98
(1H, d, J ) 13 Hz), 7.13-7.32 (5H, br s); 13C NMR (62.5 MHz,
CDCl3) δ 13.5, 32.8, 51.7, 54.4, 57.8, 62.9, 126.8, 128.1, 128.8,
139.3; HRMS (EI) calcd for C12H18N2 190.1465; found 190.1465.
HPLC analysis: Chiralpack AD column (hexane/EtOH 9/1 with
0.1% Et2NH), 1 mL/min, λ ) 254 nm; retention times ) 9.69 min
(R,R enantiomer), 11.07 min (S,S enantiomer).
Experimental Section
General Methods: Unless otherwise stated, all reactions were
performed under argon atmosphere. All commercially available
reagents were used without further purification. Triethylamine and
dichloromethane were distilled from CaH2 under argon. THF was
distilled from benzophenone ketyl under argon prior to use. Reagent
grade acetone was used from a freshly opened bottle. Column
chromatography was performed using silica gel (230-400 mesh).
NMR spectra were recorded with 250 or 360 MHz spectrometers.
Chemical shifts (δ) are reported in parts per million downfield from
tetramethylsilane. Coupling constants (J values) are reported in
hertz. IR spectra were recorder on a FT-IR spectrometer. MS and
HRMS experiments were performed on a high/low-resolution
magnetic sector mass spectrometer. Optical rotations were per-
formed on a precision automated polarimeter. HPLC experiments
were performed using a diode array detector.
(4R,5R)-4-Amino-1-benzyl-5-methyl-2-pyrrolidone hydro-
chloride (6). A solution of the urea 45 (150 mg, 6 mmol) in 3 M
hydrochloric acid solution (10 mL) was heated at reflux (oil bath
temperature ) 140 °C) for 120 h. After cooling to rt, the volatiles
were removed in vacuo to give the pyrrolidone hydrochloride 6 as
a yellow foam: yield 99% (144 mg); 1H NMR (360 MHz, D2O) δ
1.16 (3H, d, J ) 7 Hz), 2.59 (1H, dd, J ) 4.4 Hz, 17.5 Hz), 2.89
(1H, dd, J ) 7.9 Hz, 17.5 Hz), 3.83 (1H, m), 4.0 (1H, m), 4.02
(1H, d, J ) 15.8 Hz), 4.70 (1H, d, J ) 15.8 Hz), 7.14-7.3 (5H, br
s); 13C NMR (90, MHz, D2O) δ 12.0, 35.0, 43.8, 47.5, 54.8, 127.7,
128.0, 129.0, 135.3, 173.3; IR (NaCl) ν (cm-1) 3395, 1683, 1645;
HRMS (ESI) calcd for C12H17N2O (MH+) 205.1346; found
205.1353; [R]D ) -17 (c ) 0.4, H2O).
5-Chloro-2-methoxy-4-methylamino benzoic acid sulfate (9).
A solution of ester 8 (300 mg, 1.16 mmol) and potassium hydroxide
(196 mg, 3.5 mmol) in acetone (4 mL) was stirred at rt for 20 min.
Dimethylsulfate (0.33 mL, 3.5 mmol) was then added, and the
mixture was stirred at reflux for 90 min. After cooling to rt, the
volatiles were removed in vacuo. The residue was redissolved in
water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The
combined organic layer was dried (MgSO4), filtered, and concen-
trated in vacuo. The crude residue was dissolved in water (0.5 mL)
and concentrated sulfuric acid (1 mL), and the resulting solution
was stirred for 15 min at 80 °C. After cooling to 0 °C, water
(2 mL) was added, giving an white precipitate, which was filtered,
washed with cold water, and dried under vacuum: yield 51% (158
1
mg); H NMR (250 MHz, CDCl3) δ 3.02 (3H, s), 4.09 (3H, s),
5.02 (1H, br s), 6.15 (1H, s), 8.07 (1H, s), 10.2 (1H, br s); 13C
NMR (62.5 MHz, CDCl3) δ 30.1, 56.7, 92.5, 105.7, 112.2, 133.5,
149.9, 158.9, 165.0; HRMS (ESI) calcd for C9H10NClO3Na (M +
Na - H2SO4) 238.0241; found 238.0237.
(+)-Nemonapride (1). Triethylamine (0.24 mL, 1.74 mmol) and
ethyl chloroformate (65 µL, 0.65 mmol) were added to a cooled
(0 °C) solution of acid 9 (140 mg, 0.65 mmol) in anhydrous CH2-
Cl2 (1 mL). The reaction was stirred for 30 min, and a solution of
aminopyrrolidine 7 (82 mg, 0.43 mmol) in dry CH2Cl2 (1 mL) was
added. The mixture was stirred at 0 °C for 2 h, then quenched with
water (3 mL) and extracted with EtOAc (3 × 4 mL). The combined
organic layer was washed with water (5 mL) and brine and dried
(Na2SO4), filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography (heptane/EtOAc 1/1 followed
by EtOAc/MeOH 9/1) to give nemonapride 1 as a colorless solid:
(2R,3R)-3-Amino-1-benzyl-2-methyl pyrrolidine (7). LiAlH4
(67 mg, 1.76 mmol) was added portionwise to a solution of
pyrrolidone 6 (120 mg, 0.59 mmol) in anhydrous THF (5 mL).
The solution was stirred at reflux for 4 h, then cooled to rt and
treated with MeOH (5 mL). The solvents were removed in vacuo
(8) Since there is a slight difference in the optical rotation of synthetic
nemonapride 1 and literature data, the enantiomeric purity of 1 was checked
by HPLC analysis on a chiral column with comparison to a racemic standard
(prepared according to the same synthetic sequence from racemic alanine)
and was found to be >99%.
1
yield 74% (124 mg); H NMR (250 MHz, CDCl3) δ 1.17 (3H, d,
J ) 6.3 Hz), 1.69 (1H, m), 2.22 (2H, m), 2.68 (1H, m), 2.97 (3H,
d, J ) 5.1 Hz), 3.04 (1H, m), 3.24 (1H, d, J ) 13.3 Hz), 4.01 (3H,
J. Org. Chem, Vol. 73, No. 3, 2008 1163

s), 4.08 (1H, d, J ) 13.3 Hz), 4.72 (2H, m), 6.15 (1H, s), 7.25-
7.43 (5H, br s), 8.06 (1H, d, J ) 8.8 Hz), 8.13 (1H, s); 13C NMR
(90 MHz, CDCl3) δ 13.9, 30.2, 31.1, 51.7, 52.2, 56.1, 57.5, 61.9,
93.2, 110.6, 111.4, 127.0, 128.3, 132.3, 139.6, 148.1, 158.2, 164.3;
IR (NaCl) ν (cm-1) 3389, 1634, 1603, 1520, 1282; HRMS (ESI)
calcd for C21H27ClN3O2 (MH+) 388.1786; found 388.1788; [R]D
) +2.3 (c ) 0.6, CHCl3); lit.4 [R]D ) +4 (c ) 0.6, CHCl3). HPLC
analysis: Chiralpack AD column (hexane/EtOH 9/1), 1 mL/min,
λ ) 278 nm; retention times ) 17.28 min (R,R enantiomer), 26.41
min (S,S enantiomer).
Acknowledgment. This research was supported by Univer-
site´ de Paris-Sud and CNRS (doctoral grant to C.T.H). We thank
Mr. Didier Gori for HPLC analysis.
Supporting Information Available: Copies of NMR spectra
for compounds 6, 7, 9, and 1. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO702278K
1164 J. Org. Chem., Vol. 73, No. 3, 2008