Synthesis of optical active 2-arylpropionic acids

Article abstract of DOI:10.1081/SCC-100103535

(S)-2-(6′-methoxyl-α-naphthyl)propionic acid ((S)-Naprofen, ee%=99) has been prepared by starting from (6-methoxyl-α-naphthyl)propan-1-one and D-sorbitol under ZnCl₂ catalysis.

Full text of DOI:10.1081/SCC-100103535

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SYNTHESIS OF OPTICAL
ACTIVE 2-ARYLPROPIONIC
ACIDS
B. Wang a & H.-Zh. Ma a
a Department of Chemistry , Northwest
University , Xi'An, 710068, P.R. China
Published online: 09 Nov 2006.
To cite this article: B. Wang & H.-Zh. Ma (2001) SYNTHESIS OF OPTICAL ACTIVE
2-ARYLPROPIONIC ACIDS, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 31:7, 1047-1051, DOI:
10.1081/SCC-100103535
To link to this article: http://dx.doi.org/10.1081/SCC-100103535
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SYNTHETIC COMMUNICATIONS, 31(7), 1047–1051 (2001)
SYNTHESIS OF OPTICAL ACTIVE
2-ARYLPROPIONIC ACIDS
B. Wang* and H.-Zh. Ma
Department of Chemistry, Northwest University, 710068,
Xi’An, P.R. China
ABSTRACT
(S)-2-(60-methoxyl-ꢀ-naphthyl)propionic
acid
((S)-
Naprofen, ee% ¼ 99) has been prepared by starting from
(6-methoxyl-ꢀ-naphthyl)propan-1-one and D-sorbitol under
ZnCl2 catalysis.
2-Arylpropionic acid and its derivatives are pharmaceutically and
agriculturally useful products,1,2 specifically the optical isomer possesses
an extra biological or pharmaceutical activity. A well-known example is
2-(60-methoxyl-ꢀ-naphthyl) propionic acid, whose S isomer (Naproxen) is
3,4
28 times as active as the Risomer as an antiflammatory agent.
For the
preparation of optically active 2-arylalkanoic acids, many different synthetic
strategies have been reported: the use of racemates resolving by optically
active bases; asymmetric hydrogenation of prochiral unsaturated 2-aryl
carboxylic acids; asymmetric carboalkoxylation of aryl alkotones; asym-
metric carbonylation of benzyl halides; and asymmetric cross-coupling
reactions of organometallic reagents either with aryl and vinyl halides or
with allylic derivatives.3–5 Among these routes is the Castaldi et al.6
* Corresponding author.
1047
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1048
WANG AND MA
procedure, as shown in Scheme 1, where the stereospecific rearrangement
of optically active acetals to esters is the key step, and depending on the
nature of X group, basic or acidic catalysts are used to catalyze this step.
This procedure has been applied to prepare (S)-(þ)-Naproxen commercially
by the Zambon Company of Italy, but the yield is relatively low (80%),
the procedure is long, the chiral auxilliary is expensive and can be reused,
which make production costly.
Scheme 1.
Another industrial method is the Monsanto procedure,7 as shown in
Scheme 2, which applies an electrochemical process that can get high-yield
product (95%) with ee% ¼ 98.5, but the catalyst turnover is only 215 and
the reaction must be performed under 13.5 Mpa, which leads to difficult
production.
Here we report a very practical one-step method of (S)-(þ)-Naproxen
preparation involving the cheap chiral auxiliary, D-sorbitol, and ZnCl2
catalyst, synthesis of optically active acetals, and stereospecific rearrange-
ment. The route can be summarized as Scheme 3 shows. Compared with
Scheme 1, the procedure has been simplified, the yield increased upto 87%,
ee%¼99, and it is easily industrialized.
In theory, D-sorbitol reaction with (6-methoxyl-ꢀ-naphthyl)propan-
1-one under ZnCl2 catalyst, two types of 1,2-(S)-O-(6-methyhoxyl-ꢀ-
naphthyl)propylidene-D-sorbitol and 1,2,5,6-O-diketal (Scheme 3) formed
in polar solvent (DMF), existing kinetically and thermal controlled

2-ARYLPROPIONIC ACIDS
1049
Scheme 2.
intermediate. But in polar solvent, the rearrangement of acetal is difficult, so
the mixture solvent of DMF and trimethoxyl orthoformate was used. The
periodate oxidation results indicate that 1 mol intermediate acetal produces
2.2 mmol formaldehyde (calc. 2 mmol) and 3.8 mmol (calc., 4 mmol) of
formic acid. 1,2-(S)-O-(6-Methoxyl-ꢀ-naphthyl)propylidene-D-sorbitol is
the main intermediate.
Scheme 3.
EXPERIMENTAL
All 1H NMRspectra were recorded at 400 MHz, all 13C NMRspectra
at 100 MHz in D4-methanol. MS, IR(KBr pellets) and m.p. tested.

1050
WANG AND MA
Synthesis of 1
A mixture of 1 mmol D-sorbitol (1.82 g), 1 mmol (6-methoxyl-ꢀ-
naphthyl)propan-1-one (2.2 g), and 0.01 mol, ZnCl2 (1.3 g) in 10 cm3 DMF
and 30 cm3 trimethoxyl orthoformate was heated 3 h to 130ꢀ–140ꢀC in air.
Then the solvent was evaporated by reduced pressure. The residue was
crystallized in methanol (20 cm3Â3) and chromatographed on silica
column (CH2Cl2 : MeOH ¼ 70 : 30). A pale yellow product was obtained
20
and analyzed. M.p. 84ꢀ–86ꢀC. ½ꢀꢁD ¼ þ 126ꢀ (cl.8, CHCl3), yield 90%,
ee% ¼ 92.
Elemental analysis: Found: C 60.4%, H 7.4%; Calculated: C 60.4%,
H 7.4%.
MS(m/e): 397(M-1þ, 20), 398(Mþ, 14), 105(105).
IR(KBr): 3450br, 2900, 1726, 1604, 1540, 1445, 1320, 1225, 1110,
1030, 985, 780, 685 cmꢂ1
.
1H NMR( ꢁ, ppm, DMF-d7) 7.4(m, naphthyl, H1–8), 4.0(s, OMe),
1.2(d, CH3), 3.5(q, CH), 4.7(d, H13), 4.5(dd, H14), 3.9(dd, 3.7(dd, H16),
4.1(dd, H17), 4.3(dd, H18), 5.1(-OH), 13C NMR(ꢁ, ppm, DMF-d7),
170(CO), 129(C1), 127(C2), 124(C3), 128(C4), 129(C5), 126(C6), 125(C7),
130(C8), 131(C9), 132(C10), 39.5(C11), 21(C12), 81(C13), 78(C14), 76(C15),
74(C16), 76(C17), 78(C18), 55(s, OMe).
Hydrolysis of 1
The solid was dissolved in 40 cm3 methanol and 10 cm3 hydroxyl
chlorite was added and refluxed 2 h, then the solvent was evaporated by
reduced pressure. The residue was dissolved in 1 M NaOH solution (50 cm3),
extracted by CHCl3, and chromatographed on silica column (CH2Cl2:
MeOH¼70:30). A white product was obtained (2 g, yield 87%) and
20
analyzed. M.p. 154ꢀ–156ꢀC. ½ꢀꢁD ¼ þ 63.2ꢀ (cl.8. CHCl3), ee% ¼ 99, ref 3,4
20
m.p. 154ꢀ–156ꢀC. ½ꢀꢁD ¼ þ 63.5ꢀ (cl.8. CHCl3).

2-ARYLPROPIONIC ACIDS
1051
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Accepted May 8, 2000