Monophthalates with oxidized C5-carbon in the ester chain: A simple synthetic access to two major metabolites of bis-(2-ethylhexyl)-phthalate

Article abstract of DOI:10.1007/s007060200084

The synthesis of two oxidized metabolites of bis-(2-ethylhexyl)-phthalate is described. The target structures were obtained by esterification of the appropriate alcohol carrying a protected hydroxy group with phthalic anhydride, followed by deprotection and further oxidation.

Full text of DOI:10.1007/s007060200084

Monatshefte fuÈr Chemie 133, 1147±1155 ꢀ2002)
Monophthalates with Oxidized C5-Carbon
in the Ester Chain: A Simple Synthetic
Access to Two Major Metabolites
of Bis-!2-ethylhexyl)-phthalate
Hans-Detlev Gilsing1;Ã, JuÈrgen Angerer2, and Dietrich Prescher1
1
Institut fuÈr DuÈnnschichttechnologie und Mikrosensorik, D-14513 Teltow, Germany

Institut und Poliklinik fuÈr Arbeits-, Sozial- und Umweltmedizin der Universitat
2
Erlangen-NuÈrnberg, D-91054 Erlangen, Germany
Summary. The synthesis of two oxidized metabolites of bis-ꢀ2-ethylhexyl)-phthalate is described. The
target structures were obtained by esteri®cation of the appropriate alcohol carrying a protected hydroxy
group with phthalic anhydride, followed by deprotection and further oxidation.
Keywords. Mono-ꢀ2-ethylhexyl)-phthalate; Bis-ꢀ2-ethylhexyl)-phthalate; Metabolites; Alcohols;
Protectinggroups.
Introduction
Bis-ꢀ2-ethylhexyl)-phthalate ꢀDEHP) is the worldwide most frequently used plas-
ticizer for polymer resins [1] and can be found in a variety of consumer products.
Because of its ubiquitous spreading it is important to gain knowledge of the to-
xicology of the parent compound and its metabolites. In the early 1970s it has been
noticed that blood is able to leach DEHP to some extent out of polyvinylchloride
plastics used for medical devices [2], leadingto a signi®cant exposure of patients
undergoing hemodialysis and blood transfusions [3]. The metabolism of DEHP has
been elucidated in animal experiments [4] wherein it was found that in the ®rst step
DEHP is hydrolyzed to mono-ꢀ2-ethylhexyl)-phthalate ꢀMEHP) [5], which is
further oxidized at different positions in the ester chain. The oxidized metabolites
have been isolated from urine samples, separated by chromatographic methods, and
identi®ed by NMR and mass spectroscopy [6]. The major metabolites are com-
pounds 1, 2, and 3 ꢀScheme 1) which result from oxidation at the !- and the ꢀ!-1)-
position.
The same metabolism also occurs in humans [7]. The major oxidative metabo-
lites were found in urine samples of workers who had had contact with DEHP [8].
Investigations concerning their toxicology [9] revealed 2 and mainly 3 as peroxisome
Ã
Corresponding author. E-mail: gilsing@idm-teltow.de

1148
H.-D. Gilsinget al.
Scheme 1
proliferators in rats [10]. Like the phthalates in general, DHEP is also suspected to
cause endocrine effects. In order to estimate the resultinghealth risk it is necessary to
record the dose of the noxious substance taken up [11]. The quantities of noxious
substances and their metabolites in body ¯uids are usually determined by methods
of biological monitoring. In the case of biological monitoring of DEHP [12], the
metabolites 2 and 3 must be accessible as reference materials. Although 2 and 3
have been fully characterized [13] and their synthesis has been claimed several years
ago [14], to our knowledge no preparation procedure has been published until today.
Therefore, we here report a simple synthetic access to these two compounds of
toxicological interest.
Results and Discussion
The retrosynthetic disconnection of the target molecules 2 and 3 leads to phthalic
anhydride and the diol 5 or the hydroxyketone 10a, respectively. The synthesis of 2
was started from the ketoaldehyde 4 [15], which was prepared followinga known
procedure [16] and puri®ed by column chromatography. The diol 5 [17] was ob-
tained in good yields as a diastereomeric mixture from 4 via reduction with sodium
borohydride ꢀScheme 2).
In order to avoid product mixtures duringesteri®cation, the secondary hydroxy
group in 5 had to be protected. The monosilylated alcohol 8 was synthesized
accordingto the method of Black et al. [18] in three steps from 5 via selective
silylation and desilylation of the primary hydroxy group. The reaction of 5 with
tert-butyldimethylsilyl chloride gave the monosilylated diol 6, wherein the secon-
dary hydroxy group was reacted with tert-butyldiphenylsilyl chloride. In the resul-
tingdisilyl ether 7 the primary hydroxy group was deprotected selectively using
pyridinium p-toluenesulfonate ꢀScheme 3).

Synthesis of Metabolites of Bis-ꢀ2-ethylhexyl)-phthalate
1149
Scheme 2
Scheme 3
The selective reduction of the aldehyde group in 4 with zinc borohydride [19],
which is a useful reagent for the reduction of aldehydes in the presence of ketones,
gave only low yields of the expected product 10a. Thin layer chromatography during
the reaction showed several additional spots probably originating from side and
consecutive products of 10a. The reduction of 4 with K-Selectride1 [20] under much

1150
H.-D. Gilsinget al.
Scheme 4
more smoother conditions did not result in better yields of 10a. The selective oxida-
tion of the secondary hydroxy group in diol 5 with sodium bromate [21] or sodium
hypochlorite [22] also lead to complex product mixtures. From H NMR data it is
1
obvious that the product of the selective reduction of the aldehyde group in 4 consists
of equal amounts of the hydroxyketone 10a and the cyclic isomer 10b ꢀScheme 4).
The existence of the hemiketal 10b is indicated by a singlet ꢀꢀ ˆ 1.28 ppm)
belonging to the methyl group at the quarternary carbon and additional signals
ꢀtriplet at 0.91 ppm and multiplet at 3.55 ppm) originating from the terminal methyl
group and the ether protons, respectively. The additional signals are slightly shifted
relative to the appropriate resonances of 10a. The ring-chain tautomerism is typical
for ꢁ-hydroxyketones [23] and has also been observed for other derivatives [24] of
5-oxo-1-hexanol, even in more complex molecules [25].
The synthesis of 2 was performed in high yields by reaction of silyl alcohol 8
and phthalic anhydride in the presence of pyridine [26] and subsequent deprotec-
tion of 9 with tetrabutyl ammonium ¯uoride [27]. 3 was obtained from 2 by
Swern oxidation [28] with dimethyl sulfoxide and oxalic dichloride. An excess
of the oxidizingagent was necessary in order to complete the conversion of 2 to
3 and to suppress the formation of side products ꢀScheme 5).
Scheme 5

Synthesis of Metabolites of Bis-ꢀ2-ethylhexyl)-phthalate
1151
Experimental
IR spectra were recorded on a Perkin-Elmer 1430 spectrophotometer usingthe ®lm technique. NMR
spectra were recorded on a Varian Gemini 300 spectrometer operatingat 300 MHz for 1H and 75 MHz
for 13C. High resolution mass spectra were recorded on a VG 7070 double focusing mass spectrometer
equipped with a FAB ion source or on a Finnigan MAT 95 mass spectrometer. All new compounds
gave satisfactory data of elemental analysis or high resolution mass spectrometry. Puri®cations by
column chromatography were performed on silica gel ꢀMerck 63±200mesh). Compound 4 was pre-
pared accordingto the method described in Ref. [16] and puri®ed by column chromatography ꢀelution
®rst with ethylacetate:heptane ˆ 1:20 and then with ethylacetate:heptane ˆ 1:1). The analytical data of
4 agreed with the published ones.
2-Ethyl-hexane-1,5-diol ꢀ5; C8H18O2)
NaBH4 ꢀ6.4g, 169 mmol) was added in portions to a solution of compound 4 ꢀ23.8 g, 167 mmol)
in 240 cm3 anhydrous EtOH at 0ꢀC. The mixture was stirred at room temperature for 2 h. After
dropwise addition of MeOH:H2O ˆ 1:1 until the evolution of H2 had ceased the solution was poured
in 600 cm3 saturated aqueous NaCl. Diol 5 was extracted with diethyl ether and dried. After
removal of the solvent, the crude product was puri®ed by column chromatography ꢀelution with
ethylacetate:heptaneˆ 1:1).
Colourless oil; 18.8gꢀ77%); 1H NMR ꢀ300MHz, ꢀ, CDCl3): 0.91 ꢀt, 3H, J ˆ 7.2 Hz, CH3CH2CH),
1.21 ꢀd, 3H, J ˆ 6.3 Hz, CH3CHOH), 1.32±1.48 ꢀm, 7H, CH2CH2CHCH2CH3), 3.00 ꢀbr s, 2H, 2 Â
OH), 3.49±3.62 ꢀm, 2H, CH2OH), 3.81 ꢀm, 1H, CHOH) ppm; 13C NMR ꢀ75 MHz, ꢀ, CDCl3): 11.29,
11.30, 23.42, 23.46, 23.57, 23.71, 26.02, 26.50, 35.58, 36.29, 41.57, 42.07, 64.50, 64.82, 67.96,
68.49 ppm; IR ꢀ®lm): ꢂ ˆ 3361, 2963, 2932, 2875, 1461, 1376, 1054cmÀ 1
.
1- tert-Butyldimethylsilyloxy)-2-ethyl-hexane-5-ol ꢀ6; C14H32O2Si)
Imidazole ꢀ23.0 g, 338 mmol) and t-butyldimethylchlorosilane ꢀ25.5g, 169mmol) were added to a
solution of compound 5 ꢀ24.7 g, 169 mmol) in 400cm3 anhydrous DMF at 0ꢀC. The mixture was
stirred at room temperature for 3 h and then diluted with 1500cm3 H2O. Silyl alcohol 6 was extracted
with diethyl ether and dried. After removal of the solvent the crude product was puri®ed by column
chromatography ꢀelution with ethylacetate:heptane ˆ 3:7).
Colourless oil; 29.9gꢀ68%); 1H NMR ꢀ300 MHz, ꢀ, CDCl3): 0.01 ꢀs, 6H, SiMe2), 0.87 ꢀm, 12H,
C4H9, CH2CH3), 1.16 ꢀd, J ˆ 6.0 Hz, 3H, CH3CHOH), 1.22±1.48 ꢀm, 7H, CH2CH2CHCH2), 1.65 ꢀbr s,
1H, OH), 3.48 ꢀm, 2H, CH2OSi), 3.55 ꢀm, 1H, CHOH) ppm; 13C NMR ꢀ75 MHz, ꢀ, CDCl3): À 5.45,
11.17, 11.20, 18.27, 23.33, 23.38, 23.49, 23.61, 25.90, 26.47, 26.62, 36.45, 36.56, 41.83, 41.93, 65.18,
65.20, 68.35, 68.51 ppm; IR ꢀ®lm): ꢂ ˆ 3344, 2958, 2930, 2858, 1095, 836, 774 cmÀ 1; HRMS ꢀESI‡ )
‡
[M±Na] : calcd.: 283.20693, found: 283.20702.
1- tert-Butyldimethylsilyloxy)-2-ethyl-5- tert-butyldiphenylsilyloxy)-
hexane ꢀ7; C30H50O2Si2)
Imidazole ꢀ11.7g, 172 mmol), t-butyldiphenylchlorosilane ꢀ31.8g, 116mmol), and 4-dimethyl-
aminopyridine ꢀ0.1g) were added to a solution of compound 6 ꢀ29.9 g, 115mmol) in 400 cm3 anhy-
drous CH2Cl2. The mixture was stirred at room temperature for 17 h and then ®ltrated. After removal
of the solvent, silyl ether 7 was isolated from the residue by column chromatography ꢀelution with
ethylacetate:heptaneˆ 2:98).
Colourless oil; 50.2gꢀ88%); 1H NMR ꢀ300 MHz, ꢀ, CDCl3): 0.01 ꢀs, 6H, SiMe2), 0.88 ꢀm, 12H,
C4H9, CH2CH3), 1.06 ꢀm, 12H, C4H9, CH3CHOSi), 1.19±1.58 ꢀm, 7H, CH2CH2CHCH2OSi), 3.41 ꢀd,
J ˆ 6.0 Hz, 2H, CH2OSi), 3.80 ꢀm, 1H, CHOSi), 7.36±7.68 ꢀm, 10H, ArH) ppm; 13C NMR ꢀ75 MHz, ꢀ,

1152
H.-D. Gilsinget al.
CDCl3): À 5.40, 11.11, 18.29, 19.26, 23.08, 23.27, 25.80, 25.94, 27.05, 36.53, 41.96, 65.21, 69.95,
‡
127.37, 127.44, 129.34, 129.41, 134.65, 135.00, 135.88ppm; HRMS ꢀESI‡ ) [M±Na] : calcd.:
521.32471, found: 521.32474.
5- tert-Butyldiphenylsilyloxy)-2-ethyl-hexane-1-ol ꢀ8; C24H36O2Si)
Pyridinium p-toluenesulfonate ꢀ8.1g, 33 mmol) was added to a solution of 50.2g ꢀ10.1 mmol) of 7 in
430 cm3 anhydrous EtOH. The mixture was stirred at room temperature for 66h, and the solvent was
evaporated. Silyl alcohol 8 was isolated from the residue by column chromatography ꢀelution with
ethylacetate:heptaneˆ 1:5).
Colourless oil; 29.5 gꢀ76%); 1H NMR ꢀ300 MHz, ꢀ, DMSO-d6): 0.75 ꢀm, 3H, CH2CH3), 0.99 ꢀm,
12H, C4H9, CH3CHOSi), 1.10±1.46 ꢀm, 7H, CH2CH2CHCH2), 3.20 ꢀm, 2H, CH2OH), 3.80 ꢀm, 1H,
CHOSi), 4.22 ꢀm, 1H, OH), 7.37±7.63 ꢀm, 10H, ArH) ppm; 13C NMR ꢀ75 MHz, ꢀ, CDCl3): 10.99,
19.22, 23.17, 25.62, 25.74, 27.02, 36.50, 41.89, 65.08, 69.82, 127.37, 127.44, 129.38, 129.44, 134.58,
‡
134.80, 135.85 ppm; IR ꢀ®lm): ꢂ ˆ 3333, 2930, 2857, 1105, 700 cmÀ 1; HRMS ꢀESI ‡ ) [M±Na] :
calcd.: 407.23823, found: 407.23860.
Mono- 2-ethyl-5- tert-butyldiphenylsilyloxy)-hexyl)-phthalate ꢀ9; C32H40O5Si)
Phthalic acid anhydride ꢀ2.6g, 18 mmol) was added to a solution of 4.0 g ꢀ10.4mmol) of 8 in 200cm3
anhydrous pyridine. The mixture was stirred at room temperature for 72h, and the solvent was
evaporated. The residual oil was diluted with diethyl ether, washed with aqueous HCl and H2O, and
dried. After removal of the solvent the residue was diluted with heptane and ®ltrated in order to remove
phthalic acid. The solvent was evaporated, and 9 was isolated from the residue by column chromato-
graphy ꢀelution with ethylacetate:heptane ˆ 5:1).
Colourless viscous oil; 4.7 gꢀ86%); 1H NMR ꢀ300 MHz, ꢀ, DMSO-d6): 0.81 ꢀm, 3H, CH2CH3),
0.96 ꢀs, 9H, C4H9), 1.01 ꢀd, J ˆ 6.0 Hz, 3H, CH3CHOSi), 1.24±1.58 ꢀm, 7H, CH2CH2CHCH2), 3.80
ꢀm, 1H, CHOSi), 4.04 ꢀd, J ˆ 3.6 Hz, 2H, OCH2CH), 7.41±7.78 ꢀm, 14H, ArH), 13.20 ꢀbr s, 1H,
CO2H) ppm; 13C NMR ꢀ75 MHz, ꢀ, CDCl3): 10.83, 19.20, 23.15, 23.51, 26.05, 27.00, 36.30, 38.69,
65.85, 69.75, 127.37, 127.47, 128.81, 129.39, 129.49, 129.84, 130.36, 130.83, 131.94, 133.20, 134.39,
134.78, 135.84, 168.15, 171.81 ppm; IR ꢀ®lm): ꢂ ˆ 3072, 2961, 2857, 2667, 1728, 1704, 1600, 1581,
1288, 1112, 1076, 740, 703 cmÀ 1; HRMS ꢀESI-) [M±H]À : calcd.: 531.256678, found: 531.255373.
Mono- 2-ethyl-5-hydroxy-hexyl)-phthalate ꢀ2; C16H22O5)
Tetrabutylammonium ¯uoride ꢀ44.5 cm3 of an 1 M solution in THF, 44.5 mmol) was added to a
solution of 4.7 gꢀ8.9mmol) of 9 in 200 cm3 THF. The mixture was stirred at room temperature for
72h and then diluted with 800 cm3 H2O containingconcentrated aqueous HCl ꢀ0.8cm 3, 9.6 mmol). 2
was extracted with diethyl ether and dried over MgSO4. The solvent was evaporated, and the crude
product was puri®ed by column chromatography ꢀelution with ethylacetate:acetic acidˆ 100:1).
Colourless viscous oil; 2.5 gꢀ96%); 1H NMR ꢀ300MHz, ꢀ, DMSO-d6): 0.87 ꢀt, J ˆ 7.2 Hz, 3H,
CH2CH3), 1.03 ꢀd, J ˆ 6.0 Hz, 3H, CH3CHOH), 1.20±1.48 ꢀm, 6H, CH2CH2CHCH2), 1.62 ꢀm, 1H,
CH2CH2CHCH2), 3.58 ꢀm, 1H, CHOH), 4.14 ꢀm, 3H, CO2CH2, OH), 7.61±7.75 ꢀm, 4H, ArH), 13.20 ꢀbr
s, 1H, CO2H) ppm; 13C NMR ꢀ75 MHz, ꢀ, DMSO-d6): 10.77, 23.24, 23.62, 26.31, 35.99, 38.18, 66.03,
67.24, 128.18, 128.78, 131.01, 131.23, 132.25, 132.41, 167.61, 168.07ppm; IR ꢀ®lm): ꢂ ˆ 3444, 2964,
2640, 1718, 1600, 1580, 1292, 1127, 1074, 746cmÀ 1; HRMS ꢀFAB) [M±H]À : calcd.: 293.1345, found:
293.1389.
2-Ethyl-5-oxo-hexane-1-ol=2-Methyl-5-ethyl-tetrahydropyran-2-ol ꢀ10a,b; C8H16O2)
Zinc chloride ꢀ15.4 cm3 of a 0.5M solution in THF, 7.7mmol) was added dropwise to NaBH4 ꢀ0.69 g,
18.2mmol) suspended in 35 cm3 THF. The mixture was stirred overnight at room temperature under an

Synthesis of Metabolites of Bis-ꢀ2-ethylhexyl)-phthalate
1153
atmosphere of Ar and then ®ltrated under Ar. The obtained solution of ZnꢀBH4)2 was added dropwise
at À 10ꢀC to a solution of compound 4 ꢀ1.10 g, 7.7 mmol) in 50 cm3 THF. After additional stirringfor
15min the coolingbath was removed, and the mixture was quenched and diluted with H O. The
2
aqueous phase was saturated with NaCl, and the product was extracted with diethyl ether and dried
over MgSO4. The solvent was evaporated, and the isomeric mixture of 10a and 10b was isolated from
the residue by column chromatography ꢀelution with ethylacetate:heptaneˆ 1:5).
Colourless oil; 0.28gꢀ25%), 1H NMR ꢀ500MHz, ꢀ, CDCl3): 0.88 ꢀt, J ˆ 7.5 Hz, 3H, CH2CH3),
0.91 ꢀt, J ˆ 7.5 Hz, 3H, CH2CH3), 1.20±1.82 ꢀm, 12H, CH2CHCH2, CH2CH2CHCH2), 1.28 ꢀs, 3H,
OCOHCH3), 2.14 ꢀbr s, 2H, 2  OH), 2.15 ꢀs, 3H, COCH3), 2.49 ꢀt, J ˆ 9.0 Hz, 2H, CH2CO), 3.19±
3.33 ꢀm, 2H, CH2O), 3.55 ꢀm, 2H, CH2O) ppm; 13C NMR ꢀ75 MHz, ꢀ, CDCl3): 11.15, 11.20, 24.05,
24.31, 25.18, 25.23, 25.32, 29.83, 30.32, 36.62, 41.51, 41.56, 66.16, 66.31, 97.07, 209.41 ppm; IR
‡
ꢀ®lm): ꢂ ˆ 3428, 2938, 2865, 1720, 1463, 1134, 1052 cmÀ 1; HRMS ꢀFAB) [M±H] : calcd.:
145.1229, found: 145.1225.
Mono- 2-ethyl-5-oxo-hexyl)-phthalate ꢀ3; C16H20O5)
A solution of oxalyl chloride ꢀ0.64 cm3, 7.4 mmol) in 25 cm3 CH2Cl2 was added dropwise to a solution
of DMSO ꢀ1.21 cm3, 17.0mmol) in 15 cm3 CH2Cl2 at À 65ꢀC under an atmosphere of Ar. After 5 min
of stirring, a solution of compound 2 ꢀ0.50 g, 1.7 mmol) in 15cm3 CH2Cl2 was added dropwise at the
same temperature. After additional 30min of stirring, a solution of Et3N ꢀ2.82 cm3, 20.4 mmol) in
10cm3 CH2Cl2 was added dropwise at À 65ꢀC. After additional 5 min of stirringthe coolingbath was
removed, and the mixture was allowed to achieve room temperature. The mixture was poured into
400 cm3 H2O, and 3 was extracted with diethyl ether and dried over MgSO4. The solvent was evapo-
rated, and the crude product was puri®ed by column chromatography ꢀelution with ethylacetate).
Colourless viscous oil; 0.28 gꢀ56%); 1H NMR ꢀ300MHz, ꢀ, DMSO-d6): 0.87 ꢀt, J ˆ 7.8 Hz, 3H,
CH2CH3); 1.20±1.68 ꢀm, 5H, CH2CHCH2), 2.07 ꢀs, 3H, COCH3), 2.45 ꢀt, J ˆ 6.6 Hz, 2H, CH2CO),
4.12 ꢀd, J ˆ 5.4 Hz, 2H, CO2CH2), 7.61±7.75 ꢀm, 4H, ArH), 13.20 ꢀbr s, 1H, CO2H) ppm; 13C NMR
ꢀ75 MHz, ꢀ, DMSO-d6): 10.74, 23.08, 24.00, 29.61, 37.57, 39.71, 66.84, 128.10, 128.71, 130.95,
131.20, 132.05, 132.30, 167.52, 167.94, 208.24ppm; IR ꢀ®lm): ꢂ ˆ 2963, 2638, 2532, 1717, 1600,
‡
1580, 1291, 1128, 1074, 791, 745 cmÀ 1; HRMS ꢀESI ‡ ) [M±Na] : calcd.: 315.12084, found:
315.12037.
Acknowledgements
È
The authors thank Dr. M. Bartoszek, Dr. D. Muller, H. Gehrmann, and G. Seidlitzki, ACA Berlin, for
recordingthe mass and NMR spectra and performingthe elemental analyses. High resolution mass
spectra results were provided by Dr. A. Lehmann, BAM Berlin. GC analyses were conducted by Dr. G.
Czichocki, MPI Golm. Special thanks go to G. Birkhahn, D. Stolle, and E. Tews for skilful technical
assistance. Financial support by the Deutsche Forschungsgemeinschaft under AN107/16-1 is also
gratefully acknowledged.
References

[1] a) Towae FK, Enke W, Jackh R, Bhargava N ꢀ1992) Phthalic Acid and Derivatives. In: Elvers B,
Hawkins S, Schulz G ꢀeds) Ullmann's Encyclopedia of Industrial Chemistry, vol A20. VCH,
Weinheim, p 193; b) Park C-M, Sheehan RJ ꢀ1996) Phthalic Acids. In: Kroschwitz JI ꢀed) Kirk-
Othmer Encyclopedia of Chemical Technology, vol 18. Wiley, New York, p 1004
[2] a) Marcel YL, Noel SP ꢀ1970) Lancet 1: 35; b) Jaeger RJ, Rubin RJ ꢀ1972) N Engl J Med 287:
1114
[3] a) Pollack GM, Buchanan JF, Slaughter RL, Kohli RK, Shen DD ꢀ1985) Toxicol Appl Pharmacol

79: 257; b) SjobergPO, Bondesson UG, Sedin EG, Gustafsson JP ꢀ1985) Transfusion 25: 424;

1154
H.-D. Gilsinget al.

c) SjobergP, Bondesson U, Sedin G, Gustafsson J ꢀ1985) Europ J Clin Invest 15: 430; d) Faouzi
MA, Dine T, Gressier B, Kambia K, Luyckx M, Pagniez D, Brunet C, Cazin M, Belabed A, Cazin
JC ꢀ1999) Int J Pharm 180: 113
[4] a) Daniel JW, Bratt H ꢀ1974) Toxicology 2: 51; b) Carter JE, Roll DB, Petersen RV ꢀ1974) Drug
Metab Dispos 2: 341; c) Chu I, Villeneuve DC, Secours V, Franklin C, Rock G, Viau A ꢀ1978)
DrugMetab Dispos 6: 146; d) Albro PW, Hass JR, Peck CC, Odam DG, Corbett JT, Bailey FJ,
Blatt HE, Barrett BB ꢀ1981) DrugMetab Dispos 9: 223; e) Lhuguenot JC, Mitchell AM, Milner
G, Lock EA, Elcombe CR ꢀ1985) Toxicol Appl Pharmacol 80: 11; f) Barron MG, Albro PW,
Hayton WL ꢀ1995) Environ Toxicol Chem 14: 873
[5] Albro PW, Lavenhar SR ꢀ1989) DrugMetab Rev 21: 13
[6] a) Albro PW, Thomas R, Fishbein L ꢀ1973) J Chromatogr 76: 321; b) Albro PW, Jordan ST,
Schroeder JL, Corbett JT ꢀ1982) J Chromatogr 244: 65; c) Albro PW, Tondeur I, Marbury D,
Jordan S, Schroeder J, Corbett JT ꢀ1983) Biochim Biophys Acta 760: 283
[7] Schmid P, Schlatter C ꢀ1985) Xenobiotica 15: 251
[8] Dirven HAAM, van den Broek PHH, Arends AMM, Nordkamp HH, de Lepper AJGM,
Henderson PT, Jongeneelen FJ ꢀ1993) Int Arch Occup Environ Health 64: 549
[9] a) Gray TJB, Gangolli SD ꢀ1986) Environ Health Perspect 65: 229; b) Lake BG, Gray TJB,

SjobergP, Hodder KD, Beamand JA, Stubber®eld CR, Gangolli SD ꢀ1986) Food Chem Toxicol
24: 573; c) Gray TJB ꢀ1986) Food Chem Toxicol 24: 601; d) Dirven HAAM, van den Broek
PHH, Peeters MCE, Peters JGP, Mennes WC, Blaauboer BJ, Noordhoek J, Jongeneelen FJ
ꢀ1993) Biochem Pharmacol 45: 2425
[10] a) Mitchell AM, Lhuguenot JC, Bridges JW, Elcombe CR ꢀ1985) Toxicol Appl Pharmacol 80:
23; b) Elcombe CR, Mitchell AM ꢀ1986) Environ Health Perspect 70: 211; c) Tugwood JD,
Elcombe CR ꢀ1999) Predictingcarcinogenicity: peroxisome proliferators. In: Kitchin KT ꢀed)
Carcinogenicity. Dekker, New York, p 337
[11] Greim H ꢀ1998) Nachr Chem Tech Lab 46: 63


[12] a) SjobergP, Bondesson U ꢀ1985) J Chromatogr 344: 167; b) Egestad B, SjobergP ꢀ1988)
Biomed Environ Mass Spectrom 16: 151; c) Dirven HAAM, van den Broek PHH, Jongeneelen FJ

ꢀ1993) Int Arch Occup Environ Health 64: 555; d) Egestad B, Green G, SjobergP, Klasson-
Wehler E, Gustafsson J ꢀ1996) J Chromatogr B Biomed Appl 677: 99; e) Blount BC, Milgram
KE, Silva MJ, Malek NA, Reidy JA, Needham LL, Brock JW ꢀ2000) Anal Chem 72: 4127


[13] SjobergP, Bondesson U, Gray TJB, Pl oen L ꢀ1986) Acta Pharmacol Toxicol 58: 225
[14] a) Dirven HAAM, Theuws JLG, Jongeneelen FJ, Bos RP ꢀ1991) Mutat Res 260: 121; b) Grolier
P, Elcombe CR ꢀ1993) Biochem Pharmacol 45: 827
[15] a) Duhamel P, Hennequin L, Poirier JM, Tavel G, Vottero C ꢀ1986) Tetrahedron 42: 4777;
b) Ranu BC, Saha M, Bhar S ꢀ1993) Tetrahedron Lett 34: 1989; c) Ranu BC, Saha M, Bhar S
ꢀ1994) J Chem Soc Perkin Trans I, 2197
[16] Gupta I, Suri HS, Dutta PC ꢀ1971) Ind J Chem 9: 1195
[17] a) Hoffmann B, Seidel H ꢀ1986) Zem Kalk Gips Ed B 39: 269; b) Serve MP, Bombick DD,
Clemens JM, McDonald GA, Hixson CJ, Mattie DR ꢀ1993) Chemosphere 26: 1667; c) Trinh T,
Tordil HB, Wahl EH, Rinker JL, Demeyere HJM, Declercq MJ, Gosselink EP ꢀ1997) WO
9703170; d) Wahl EH, Trinh T, Oler CJ ꢀ1998) WO 9817773
[18] Black GP, Murphy PJ, Thornhill AJ, Walshe NDA, Zanetti C ꢀ1999) Tetrahedron 55: 6547
[19] a) Ranu BC, Chakraborty ꢀ1990) Tetrahedron Lett 31: 7663; b) Ranu BC ꢀ1993) Synlett 885
[20] Pan J, Hanna I, Lallemand J-Y ꢀ1994) Bull Soc Chim Fr 131: 665
[21] Tomika H, Oshima K, Nozaki H ꢀ1982) Tetrahedron Lett 23: 539
[22] Stevens RV, Chapman KT, Stubbs CA, Tam WW, Albizati KF ꢀ1982) Tetrahedron Lett 23: 4647
[23] WhitingJE, Edward JT ꢀ1971) Can J Chem 49: 3799
[24] a) Cartaya-Marin CP, Jackson AC, Snider BB ꢀ1984) J OrgChem 49: 2443; b) Kabalka GW,
Yu S, Li N-S ꢀ1998) Can J Chem 76: 800

Synthesis of Metabolites of Bis-ꢀ2-ethylhexyl)-phthalate
1155
[25] a) Kishi T, Hesse M, Vetter W, Gemenden CW, Taylor WI, Schmid H ꢀ1966) Helv Chim Acta 49:
946; b) Wasserman HH, Amici RM ꢀ1989) J OrgChem 54: 5843
[26] Baldwin JE, Broline BM ꢀ1982) J Am Chem Soc 104: 2857
[27] Hanessian S, Lavallee P ꢀ1975) Can J Chem 53: 2975
[28] Mancuso AJ, Swern D ꢀ1981) Synthesis 165
Received February 26, 2002. Accepted March 6, 2002