Convenient synthesis of 2-(2-phenylethyl)benzoic acid: A key intermediate in the synthesis of dibenzosuberone

Article abstract of DOI:10.1081/SCC-100105118

A convenient and improved synthesis of 2-(2-phenylethyl) benzoicacid, a key intermediate in the synthesis of dibenzosuberone is described.

Full text of DOI:10.1081/SCC-100105118

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CONVENIENT SYNTHESIS OF 2-(2-
PHENYLETHYL)BENZOIC ACID: A KEY INTERMEDIATE
IN THE SYNTHESIS OF DIBENZOSUBERONE
A. R. Ramesha a b & Anjan K. Roy b
a National Institutes of Health, NIDDK, Bldg 8, Rm 1A-05, Bethesda, Maryland, MD,
20851, USA
b Ray Chemicals Pvt. Ltd, 41, KHB, Yelahanka Industrial Area, Bangalore, 560 064, India
Version of record first published: 09 Nov 2006.
To cite this article: A. R. Ramesha & Anjan K. Roy (2001): CONVENIENT SYNTHESIS OF 2-(2-PHENYLETHYL)BENZOIC ACID:
A KEY INTERMEDIATE IN THE SYNTHESIS OF DIBENZOSUBERONE, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 31:16, 2419-2422
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SYNTHETIC COMMUNICATIONS, 31(16), 2419–2422 (2001)
CONVENIENT SYNTHESIS OF
2-(2-PHENYLETHYL)BENZOIC ACID:
A KEY INTERMEDIATE IN THE
SYNTHESIS OF DIBENZOSUBERONE
A. R. Ramesha* and Anjan K. Roy
41, KHB, Ray Chemicals Pvt. Ltd, Yelahanka Industrial Area,
Bangalore, India, Pin 560 064
ABSTRACT
A convenient and improved synthesis of 2-(2-phenylethyl)
benzoicacid, a key intermediate in the synthesis of dibenzo-
suberone is described.
Dibenzosuberone is one of the key intermediates in the synthesis of
1
several life savingdrugs like Amitriptyline or Cyproheptadine2 (Figure 1).
It is also used in the synthesis of suberenyl chloride which is an interesting
protecting group and also a modulator for anti-cancer drugs.3 Because of its
importance as a key intermediate in the synthesis of several pharmaceutical
products, there are several patents and procedures in the literature which
describes the synthesis of dibenzosuberone.4 The key step in the synthesis of
dibenzosuberone involves synthesis of the 2-(2-phenylethyl)benzoic acid 2
which on cyclization with either PPA4 or with SOCl2-AlCl35 affords the
product.
*Correspondingauthor. NIDDK, Bldg8, Rm 1A-05, National Institutes of Health,
Bethesda, Maryland MD 20851, USA.
2419
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
2420
RAMESHA AND ROY
Figure 1.
2-(2-Phenylethyl)benzoic acid 2, is made by reducingbenzphthalide by
several known methods involvingHI-P 6, H2-Pd-C7, H2-Ra-Ni8 systems.
While the former process involves handlingof HI under reflux and the
later ones are very voluminous reaction involves risk of handlinghydrogen.
Also, both the process have their own disadvantages while scaling up the
reaction. We have encountered a mild explosion while scaling-up the HI-P
reaction and also have faced major problems in recyclingPd-C in the later
process.
In our continuous effort to develop new methods for the synthesis of
dibenzosuberone, we have found that the transfer hydrogenation9 works
extremely well for the synthesis of 2-(2-phenylethyl)benzoic acid, 2. In the
procedure described herein we have made use of a commercially available and
cheap dipentene as the hydrogen source which makes this process commer-
cially very attractive (Figure 2). This procedure works equally well with other
hydrogen donors like limonene and terpeniol. Also, this process is highly
volume effective compared to other known procedures and involves minimal

ORDER
REPRINTS
2-(2-PHENYLETHYL)BENZOIC ACID
2421
Figure 2.
work-up. In a representative experiment, benzphthalide9 (200 g) was refluxed
with dipentene (300 mL) and 10% Pd-C (20 g) for 3 h and the mixture was
cooled, diluted with acetone (1000 mL) and filtered. Concentration of the
filtrate gave 2-(2-phenylethyl)benzoic acid 2 as the major product.
Cyclization of 2 afforded dibenzosuberone 3 as the only product.
Thus the new method for the synthesis of dibenzosuberone is
highly efficient and convenient for the synthesis of 2-(2-phenylethyl) benzoic
acid 2, which is a key intermediate in the synthesis of many pharmaceutical
products.
EXPERIMENTAL
Commercially available dipentene, limonene and acetone were distilled
prior to use. m.p/b.p are uncorrected. 1H NMR: Brucker AM 400, chemical
shifts are in d values downfield from TMS. IR: Perkin Elmer 1710.
2-(2-phenylethyl)benzoic acid (2): To a 1-L four necked flask carryinga
mechanical stirrer, Dean-stark apparatus (to remove traces of moisture in
dipentene), nitrogen inlet, thermometer pocket and an addition flask, 10%
Pd-C (20 g) was charged under nitrogen atmosphere followed by benzphtha-
lide 1 (200 g, 0.9 mol). Under a slow stream of nitrogen, the temperature of
the mixture was raised to 170–180ꢀC. Once the temperature reaches 175ꢀC,
dipentene (or limonene) (300 g, 2.2 mol) was added slowly over a period of
1 h under reflux. After the complete addition of dipentene (or limonene),
reflux was continued for 2 h. The reaction mass was cooled to 50–60ꢀC and
the solid was dissolved in acetone (1000 mL) and the reaction mixture was
filtered under nitrogen. The filter cake containing the Pd-C catalyst was
washed with acetone (50 mL). The combined filtrates were mixed and con-
centrated under reduced pressure. The residue was cooled to 10ꢀC, filtered
and washed with a cold mixture of toluene: petroleum ether (3:7, 300 mL)
to gave 2 as a white crystalline solid. 175 g(86%), m.p: 129–131 ꢀC,
lit. 129–131ꢀC.5,7

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2422
RAMESHA AND ROY
Dibenzosuberone (3): 2 was cyclised to dibenzosuberone 3 according
to the reference 5 to get 3 as a pale yellow liquid. 141 g(85%),
bp: 190–195ꢀC/6 mm, lit. 148/0.3 mm,5b NMR, IR, MS of 2, 3 were identical
with the reported data.8,4
REFERENCES
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Received in the USA November 6, 2000

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