Convenient and high-yielding preparations of mono(5-carboxy-2-ethylpentyl) phthalate and its ring-deuterated isomer - The "third" major metabolite of bis(2-ethylhexyl) phthalate

Article abstract of DOI:10.1007/s00706-004-0267-6

The synthesis of an oxidative major metabolite of bis(2-ethylhexyl) phthalate is described. The target molecule and its ring-deuterated isomer were obtained via acylation of the appropriate ω-hydroxy benzyl ester or the corresponding carboxylate with phthalic anhydride or phthalic anhydride-d ₄. All transformation steps proceed with high yields. Springer-Verlag 2005.

Full text of DOI:10.1007/s00706-004-0267-6

Monatshefte f€ur Chemie 136, 795–801 (2005)
DOI 10.1007/s00706-004-0267-6
Convenient and High-Yielding Preparations
of Mono(5-carboxy-2-ethylpentyl)
Phthalate and its Ring-Deuterated
Isomer – The ‘‘Third’’ Major Metabolite
of Bis(2-ethylhexyl) Phthalate
Hans-Detlev Gilsing1;ꢀ, Ju¨rgen Angerer2, and Dietrich Prescher1
1
€
Institut fur Dunnschichttechnologie und Mikrosensorik e.V., D-14513 Teltow, Germany
Institut und Poliklinik f€ur Arbeits-, Sozial- und Umweltmedizin der Universitat
€
2
€
Erlangen-N€urnberg, D-91054 Erlangen, Germany
Received September 7, 2004; accepted September 20, 2004
Published online January 18, 2005 # Springer-Verlag 2005
Summary. The synthesis of an oxidative major metabolite of bis(2-ethylhexyl) phthalate is described.
The target molecule and its ring-deuterated isomer were obtained via acylation of the appropriate
!-hydroxy benzyl ester or the corresponding carboxylate with phthalic anhydride or phthalic anhy-
dride-d4. All transformation steps proceed with high yields.
Keywords. Bis(2-ethylhexyl) phthalate; Oxidative metabolites; Carboxylic acids; Protecting groups;
Ozonolysis.
Introduction
Due to their use as additives in many products of every day life phthalates can be
found as ubiquitous contaminants in the environment [1]. Recently human expo-
sure to phthalates has been proven unequivocally [2]. Several phthalates cause
hepatic peroxisome proliferation [3] and testicular damage [4] in animal experi-
ments. The relevance of these results with regard to human health is still debated
controversially [5] so that further toxicological investigations must reveal poten-
tially existing risks. The metabolism of bis(2-ethylhexyl) phthalate (DEHP) has
been elucidated [6] and compounds 1, 2, and 3 have been identified as major
metabolites (Scheme 1).
The major metabolites are formed by different !- and (!-1)-oxidation steps
proceeding consecutively from mono(2-ethylhexyl) phthalate (MEHP) which is the
ꢀ
Corresponding author. E-mail: gilsing@idm-teltow.de

796
H.-D. Gilsing et al.
Scheme 1
primary metabolite of DEHP. Compound 3 is metabolized further by degradation
[7] with loss of a two-carbon fragment. The concentration of 3 detected in rats has
been found to be time dependent and strongly related to the amount of DEHP or
MEHP administered [8].
A new powerful method [9] of biological monitoring allows the measurement
of exposure to DEHP by determination of its oxidative metabolites 1 and 2 in
urine. This method needs the original compounds and their isotopically labelled
analogues as reference materials. In the past it has been necessary to gain ref-
erence material from animal experiments until a synthetic access to 1 and 2 and
their deuterated isomers has been developed [10]. We now report our efforts in
the synthesis of 3 [11] and its deuterated isomer 10, which may also serve as
biomarkers.
Results and Discussion
The retrosynthetic disconnection of the target molecule 3 leads to phthalic anhy-
dride and 5 [12], which is a derivative of 6-hydroxycaproic acid. The introduction
of the ethyl group was achieved by copper catalyzed conjugate addition [13] of the
appropriate Grignard reagent to 2-cyclohexenone in the presence of chlorotri-
methylsilane and ozonolytic cleavage [14] of the resulting silyl enol ether 4 [15].
These steps yielded 5 with very good overall yield (Scheme 2).
In order to investigate if direct acylation of 5 is possible some screening experi-
ments with commercial 6-hydroxycaproic acid were done. Whereas the acylation
of this compound with acetic anhydride is known [16] the reaction with phthalic
anhydride showed only low conversion. Using pyridine as solvent gave 6 as single
Scheme 2

The ‘‘Third’’ Metabolite of Bis(2-ethylhexyl) Phthalate
797
Scheme 3
product, which is formed by intermolecular esterification and was identified by
comparison of its NMR spectra with published data [17] of similar structures
(Scheme 3). Attempted acylation in chloroform with 4-(dimethylamino)pyridine
as catalyst [18] was not successful.
As a conclusion of these results the benzyl group was choosen for the protec-
tion [19] of the carboxylic group of 5 because it can be removed easily in the
presence of another ester group. The benzylation of 5 via the tetrabutylammonium
salt [20] gave the hydroxy benzyl ester 7. The target molecule 3 was obtained in
high overall yield by acylation of 7 using an excess of phthalic anhydride and
subjecting the resulting monophthalate 8 to hydrogenolysis [21] with Pd=C as
catalyst (Scheme 4).
This reaction sequence provides an easy access to the target structure. In the
view of the expensive deuterated anhydride, however, it is desired to avoid iso-
topically labelled intermediates. Therefore we checked the acylation [22] of !-
hydroxycarboxylate 9. Although it was necessary to increase the temperature
slightly in order to dissolve the salt and the solution remained thick during the
reaction acidic work-up gave 10 with 69% yield (Scheme 5).
Scheme 4
Scheme 5

798
H.-D. Gilsing et al.
Experimental
IR spectra were recorded on a Perkin-Elmer 1430 spectrophotometer using the film technique. NMR
spectra were recorded on a Varian Mercury plus-BB=4-nuc spectrometer operating at 400 MHz for
1H and 100 MHz for 13C. High resolution mass spectra were recorded on a VG 7070 double focusing
mass spectrometer using the CI and the NCI mode. Elemental analyses were carried out using a
CE Instruments CHNS-Elemental Analyzer EA 1110. All new compounds gave satisfactory data of
elemental analysis or high resolution mass spectrometry. All reactions except the neutralization of 5
were carried out under an atmosphere of Ar. 6-Hydroxycaproic acid and phthalic anhydride-d4 (99.4%)
were purchased from Aldrich and used as received. Purifications by column chromatography were
performed on silica gel (Merck 63-200 mesh).
3-(Ethylcyclohex-1-enyloxy)trimethylsilane (4)
To a solution of ethylmagnesium bromide, prepared from 1.70 g of Mg turnings (70.0mmol) and
5.23cm3 of ethyl bromide (70.0mmol) in 100 cm3 of anhydrous THF was added 0.51g of CuBr ꢁ Me2S
(2.5mmol) at ꢂ78ꢃC. A solution of 20.88 cm3 of HMPT (120.0mmol) in 100 cm3 of THF was then
added dropwise. The mixture was stirred for 15min, a solution of 3.85 cm3 of 2-cyclohexenone
(39.8mmol) and 12.68 cm3 of chlorotrimethylsilane (100.0 mmol) in 20cm3 of THF was then added
dropwise. The reaction mixture was stirred for 3 h at ꢂ78ꢃC, and a solution of 14.05 cm3 of triethyl-
amine (100.0mmol) in 20 cm3 of THF was added. The mixture was stirred for additional 30min,
warmed up to room temperature, hydrolyzed with a saturated aqueous solution of NaHCO3 and
diluted with 100 cm3 of diethyl ether:heptane ¼ 1:1. The mixture was filtered and the filter cake was
washed with 5 ꢄ 30cm3 of heptane. The filtrate was washed with 10ꢄ 20 cm3 of a saturated aqueous
solution of NaHCO3 and dried (Na2SO4). The drying agent was filtered off, the solvent was evapo-
rated under reduced pressure, and the product was isolated from the residue by Kugelrohr distillation.
Yield 6.57 g (83%); colourless liquid; the analytical data agreed with the published ones [15].
5-(Hydroxymethyl)heptanoic acid (5)
A solution of 5.25g of 4 (26.5mmol) in 20cm3 of anhydrous MeOH and 5 cm3 of CH2Cl2 was treated
with O3 at ꢂ78ꢃC until a blue colour persisted. 1.00g of sodium borohydride (26.5 mmol) was added
in portions and the mixture was stirred for 1 h. Additional portions of 1.00g of sodium borohydride
(26.5mmol) were then added, the mixture was warmed up to room temperature, and poured into
200 cm3 of a saturated aqueous solution of NaHCO3. The organic layer was discarded and the aqueous
layer was extracted with 3 ꢄ 20cm3 of diethyl ether. The aqueous phase was then acidified with
400 cm3 of a 5% aqueous HCl, saturated with NaCl and extracted with 4 ꢄ 100 cm3 of CHCl3. The
combined extracts were dried (MgSO4). The drying agent was filtered off and the solvent was evap-
1
orated under reduced pressure. Yield 4.04g (96%); colourless oil; H NMR (400 MHz, DMSO-d6):
ꢀ ¼ 0.81–0.86 (m, CHCH2CH3), 1.10–1.65 (m, HOCH2CH–(CH2CH3)CH2CH2CH2CO2H), 2.11–2.22
(m, CH2CO2H), 3.17–3.42 (m, CH2OH), 4.25 (s, br, OH), 11.94 (s, br, CO2H) ppm; 13C NMR
(100 MHz, DMSO-d6): ꢀ ¼ 10.9, 22.0, 22.9, 29.7, 34.1, 41.3, 62.9, 174.4 ppm; IR (film): ꢁꢀ¼ 3500–
2400, 2932, 2876, 1704, 1461, 1410, 1235, 1171, 1027, 755cmꢂ1; HRMS (NH3–CI) [Mþ H]þ:
calcd.: 161.1178, found: 161.1182.
Phthalic acid mono[5-(5-carboxy-pentyloxycarbonyl)-pentyl]ester (6, C20H26O8)
A solution of 1.90g of phthalic anhydride (12.8 mmol) and 0.95 g of 6-hydroxycaproic acid (7.2mmol)
in 100 cm3 of anhydrous pyridin was refluxed for 11 h, cooled, and stirred at room temperature for
additional 40h. The solvent was evaporated under reduced pressure and the residue was diluted with
50cm3 of CHCl3, washed with 2ꢄ 20cm3 of a 1 M aqueous HCl and 2 ꢄ 20cm3 of H2O and dried

The ‘‘Third’’ Metabolite of Bis(2-ethylhexyl) Phthalate
799
(MgSO4). The drying agent was filtered off and the solvent was evaporated under reduced pressure.
The product was isolated from the residue by column chromatography using ethylacetate:heptane¼
1
1:1 as eluent. Yield 0.14 g (10%); pale yellow waxy solid; H NMR (400MHz, DMSO-d6): ꢀ ¼
1.23–1.68 (m, OCH2CH2CH2CH2CH2CO2CH2CH2CH2CH2CH2CO2H), 2.17–2.32 (m, 2 CH2CO2),
4.00–4.04 (m, OCH2), 4.18–4.27 (m, OCH2), 7.60–7.63 (m, 3H, Ar), 7.72–7.76 (m, 1H, Ar), 12.54 (s,
br, 2 CO2H) ppm; 13C NMR (100MHz, DMSO-d6): ꢀ ¼ 24.1, 24.9, 27.5, 27.6, 27.7, 27.8, 33.3, 33.5,
63.4, 64.8, 127.9, 128.5, 130.7, 131.0, 131.9, 132.2, 167.2, 167.7, 172.5, 174.0 ppm; IR (film):
ꢁꢀ¼ 3500–2500, 2940, 2868, 1721, 1699, 1600, 1579, 1284, 1259, 1125, 1072, 743 cmꢂ1
.
5-(Hydroxymethyl)heptanoic acid benzyl ester (7, C15H22O3)
A mixture of 1.64cm3 of an 40% aqueous solution of tetrabutylammonium hydroxide (2.5mmol) and
0.40g of 5 (2.5mmol) was stirred at 65ꢃC until a clear solution appeared. The solvent was removed
under reduced pressure and the residual oil was dried under high vacuum. 1.00 g of oil (2.5mmol) was
dissolved in 15 cm3 of anhydrous DMF and 0.32cm3 of benzylchloride (2.8mmol) were added and the
mixture was stirred at room temperature for 24h. The reaction mixture was poured into 150 cm3 of
H2O and was extracted with 3 ꢄ 50 cm3 of diethyl ether. The combined extracts were dried (Na2SO4).
The drying agent was filtered off and the solvent was evaporated under reduced pressure. The product
was isolated from the residue by column chromatography using ethylacetate:heptane ¼ 2:3 as eluent.
Yield 0.50 g (81%); colourless oil; 1H NMR (400MHz, DMSO-d6): ꢀ ¼ 0.81 (t, J ¼ 7.3 Hz,
CHCH2CH3), 1.19–1.31 (m, HOCH2CH(CH2CH3)CH2), 1.54 (t, J ¼ 7.3 Hz, CH2CH2CO2CH2Ar),
2.33 (t, J ¼ 7.3 Hz, CH2CO2CH2Ar), 3.26–3.30 (m, CH2OH), 4.28 (t, J ¼ 5.3 Hz, OH), 5.08 (s,
OCH2Ar), 7.31–7.37 (m, 5H, Ar) ppm; 13C NMR (100MHz, DMSO-d6): ꢀ ¼ 10.9, 21.9, 22.9, 29.5,
33.9, 41.2, 62.9, 65.2, 127.8, 127.9, 128.4, 136.3, 172.7 ppm; IR (film): ꢁꢀ¼ 3450, 2959, 2931, 2875,
1733, 1456, 1158, 1029, 736, 696 cmꢂ1; HRMS (NH3–NCI) [M ꢂ H]ꢂ: calcd.: 249.1491, found:
249.1495.
Phthalic acid mono(5-benzyloxycarbonyl-2-ethylpentyl)ester (8, C23H26O6)
A solution of 1.07 g of phthalic anhydride (7.2mmol) and 0.72 g of 7 (2.9mmol) in 50 cm3 of
anhydrous pyridine was stirred at room temperature for 72 h. The mixture was evaporated under
reduced pressure and the residue was diluted with 100 cm3 of diethyl ether. The solution was washed
with 3 ꢄ 20 cm3 of a 10% aqueous HCl, dried (Na2SO4), and evaporated. The product was isolated
from the residue by column chromatography using ethylacetate:heptane¼ 5:1 as eluent. Yield 0.94 g
(82%); colourless oil; 1H NMR (400 MHz, DMSO-d6): ꢀ ¼ 0.86 (t, J ¼ 7.3 Hz, CHCH2CH3), 1.24–1.39
(m, OCH2CH(CH2CH3)CH2CH2CH2CO2CH2Ar), 1.55–1.67 (m, OCH2CH(CH2CH3)CH2CH2CH2–
CO2CH2Ar), 2.33–2.38 (m, CH2CO2CH2Ar), 4.09–4.16 (m, OCH2CH), 5.08 (s, OCH2Ar),
7.29–7.38 (m, 5H, Ar), 7.60–7.65 (m, 3H, Ar), 7.71–7.76 (m, 1H, Ar), 13.18 (s, br, CO2H) ppm;
13C NMR (100 MHz, DMSO-d6): ꢀ ¼ 10.7, 21.7, 23.1, 29.5, 33.6, 37.8, 65.2, 67.0, 127.9, 128.1, 128.3,
128.7, 130.9, 131.1, 132.3, 136.2, 167.5, 168.0, 172.6ppm; IR (film): ꢁꢀ¼ 3400–2500, 3034, 2961,
2877, 1725, 1698, 1600, 1580, 1456, 1383, 1285, 1259, 1123, 1072, 742, 697, 639cmꢂ1; HRMS
(NH3–NCI) [M]ꢂ: calcd.: 398.1729, found: 398.1743.
Phthalic acid mono(5-carboxy-2-ethylpentyl)ester (3, C16H20O6)
To a solution of 0.30 g of 8 (0.8mmol) in 25 cm3 of anhydrous MeOH was added 0.03g of Pd=C (10%
Pd). Hydrogen was passed through at room temperature for 8 h and the reaction mixture was stirred
under 1 atm of hydrogen for additional 16h. The mixture was filtered and the filtrate was evaporated
under reduced pressure. The residue was diluted with 100 cm3 of diethyl ether and the solution was
washed with 2 ꢄ 100 cm3 of a saturated aqueous solution of NaHCO3. The organic layer was discarded

800
H.-D. Gilsing et al.
and the aqueous layer was acidified, saturated with NaCl, and extracted with 3 ꢄ 100 cm3 of CHCl3.
The combined extracts were dried (Na2SO4) and evaporated to give the pure product. Yield 0.18g
(78%); colourless oil; 1H NMR (400 MHz, DMSO-d6): ꢀ ¼ 0.88 (t, J ¼ 7.3 Hz, CHCH2CH3), 1.23–1.40
(m, OCH2CH(CH2CH3)CH2CH2CH2CO2H), 1.41–1.58 (m, OCH2CH(CH2CH3)CH2CH2CH2CO2H),
1.60–1.69 (m, OCH2CH(CH2CH3)), 2.15–2.23 (m, CH2CO2H), 4.09–4.17 (m, OCH2CH), 7.60–7.66
(m, 3H, Ar), 7.72–7.76 (m, 1H, Ar), 12.56 (s, br, 2 CO2H) ppm; 13C NMR (100MHz, DMSO-d6):
ꢀ ¼ 10.7, 21.7, 23.1, 29.6, 33.8, 37.9, 67.0, 128.1, 128.7, 130.9, 131.1, 132.2, 132.3, 167.5, 168.0,
174.3ppm; IR (film): ꢁꢀ¼ 3400–2500, 2961, 2877, 2665, 1721, 1698, 1600, 1580, 1412, 1383, 1284,
1259, 1124, 1073, 742, 705, 675, 640 cmꢂ1; HRMS (NH3–NCI) [Mꢂ H]ꢂ: calcd.: 307.1182, found:
307.1168.
Sodium 5-(hydroxymethyl)heptanoate (9, C8H15NaO3)
To a solution of 0.13 g of NaOH (3.1mmol) in 15cm3 of distilled H2O was added 0.50g of 5 (3.1mmol)
and the mixture was stirred at 65ꢃC until a homogenous phase appeared. The solvent was evaporated
and the residue solidified upon drying under high vacuum. Yield 0.57g (100%); colourless solid; mp
93–94ꢃC; IR (film): ꢁꢀ¼ 3170, 2959, 2935, 2874, 1571, 1459, 1379, 1062, 883, 739 cmꢂ1
.
Preparation of 3 via Acylation of 9
To a solution of 0.46g of phthalic anhydride (3.1mmol) in 25cm3 of anhydrous pyridine was added
0.57g of 9 (3.1mmol), the mixture was stirred at 35ꢃC for 1 h to give a thick solution which was stirred
at room temperature for additional 72 h. The solution was poured into 250 cm3 of a 10% aqueous HCl.
The aqueous solution was saturated with NaCl and extracted with 3 ꢄ 100 cm3 of CHCl3. The com-
bined extracts were dried (Na2SO4). The drying agent was filtered off and the solvent was evaporated
under reduced pressure. The residue was partitionated between 200 cm3 of a saturated aqueous solution
of NaHCO3 and 100 cm3 of diethyl ether and the organic layer was discarded. The aqueous layer was
acidified, saturated with NaCl, and extracted with 3 ꢄ 100 cm3 of CHCl3. The combined extracts were
dried and evaporated to give the pure product. Yield 0.63g (66%).
Phthalic acid (3,4,5,6-2H4) mono(5-carboxy-2-ethylpentyl)ester (10, C16H16D4O6)
To a solution of 0.42 g of phthalic anhydride-d4 (2.7mmol) in 35cm3 of anhydrous pyridine was added
0.50g of 9 (2.7mmol), the mixture was stirred at 35ꢃC for 1 h to give a thick solution which was stirred
at room temperature for additional 72 h. After work-up as described above the pure product was
1
obtained. Yield 0.59g (69%); colorless oil; H NMR (400MHz, DMSO-d6): ꢀ ¼ 0.88 (t, J ¼ 7.3 Hz,
CHCH2CH3), 1.24–1.42 (m, OCH2CH(CH2CH3)CH2CH2CH2–CO2H), 1.50–1.58 (m, OCH2CH
(CH2CH3)CH2CH2CH2CO2H), 1.60–1.68 (m, OCH2CH(CH2CH3)), 2.19–2.23 (m, CH2CO2H),
4.11–4.13 (m, OCH2CH), 12.61 (s, br, 2 CO2H) ppm; 13C NMR (100 MHz, DMSO-d6): ꢀ ¼ 10.7,
21.7, 23.1, 29.6, 33.9, 37.9, 67.0, 132.2, 132.3, 167.6, 168.0, 174.4 ppm; IR (film): ꢁꢀ¼ 3400–2500,
2962, 2936, 1697, 1557, 1432, 1235, 1077, 941, 751, 666 cmꢂ1; HRMS (NH3–NCI) [Mꢂ H]ꢂ: calcd.:
311.1433, found: 311.1436.
Acknowledgements
The authors thank Dr. K. Seiler, ASCA Berlin, for recording the NMR spectra, Dr. M. Bartoszek, ACA
Berlin, for providing the HRMS data, Dr. U. Gross, Humboldt University Berlin, for performing the
elemental analyses, Dr. F. Theil, ASCA Berlin, for his help during the ozonolysis, and E. Tews and
D. Stolle for conducting the preparative work. Financial support by the Deutsche Forschungsgemein-
schaft under AN107=16-1 is gratefully acknowledged. H.-D. Gilsing dedicates this article to the
memory of his beloved mother.

The ‘‘Third’’ Metabolite of Bis(2-ethylhexyl) Phthalate
801
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