Preparation of the key intermediate in a novel synthesis of ZD9063P: The chemical component of ADEPT, a targeted cytotoxic therapy

Article abstract of DOI:10.1021/op000016+

A novel regioselective opening of the cyclic anhydride of a urethane derivative of glutamic acid using 4-(dimethylamino)-pyridine (DMAP) as the catalyst has greatly simplified the synthesis of the target compound, ZD9063P, 5-(N-[(S)-N-{N,N-bis(2-chloroeth

Full text of DOI:10.1021/op000016+

Organic Process Research & Development 2000, 4, 259−263
Preparation of the Key Intermediate in a Novel Synthesis of ZD9063P: The
Chemical Component of ADEPT, a Targeted Cytotoxic Therapy
David M. G. Martin* and Pawel S. Siedlecki
Process Research and DeVelopment Department, AstraZeneca, Silk Road Business Park, Charter Way,
Macclesfield, Cheshire SK10 2NA, U.K.
Abstract:
A novel regioselective opening of the cyclic anhydride of a
urethane derivative of glutamic acid using 4-(dimethylamino)-
pyridine (DMAP) as the catalyst has greatly simplified the
synthesis of the target compound, ZD9063P, 5-(N-[(S)-N-{N,N-
bis(2-chloroethyl)amino}phenoxycarbonyl)-γ-glutamyl]amino)-
isophthalic acid.
Introduction
The use of cytotoxic drugs is limited by their general
toxicity and a highly desirable aim is the targeted delivery
Figure 1.
of the active cytotoxic agent. A novel approach under
development is the dosing of the patient with an anti-body/
enzyme complex which binds specifically at the site of the
tumour. Subsequent treatment with a synthetic compound,
the pro-drug, which bears a masked cytotoxic entity and has
been specifically designed to be cleaved by the enzyme,
delivers the cytotoxic agent, the drug, at the site of the
tumour.
Scheme 1. Initial route to ZD9063P
AstraZeneca has an anti-body directed enzyme pro-drug
therapy (ADEPT) program in progress, and this contribution
describes improvements made in the synthesis of the pro-
drug, ZD9063P (Figure 1).
Background
The original synthesis of ZD9063P involved the coupling
of a differentially substituted derivative of (S)-glutamic acid
1 with the dibenzylester of 5-aminoisophthalic acid 2 to give
the corresponding amide 3.1 Deprotection of the R-amino
group and its subsequent activation with triphosgene gave
4. This was condensed with 5 under phase transfer conditions
to give 6 which was chlorinated to give 7. This product, 7,
was hydrogenated and ZD9063P isolated as an amorphous
solid (Scheme 1).
This synthetic approach was not ideal even though it was
used to manufacture a kilogram of ZD9063P. The route
involved the use of a capricious method for the construction
of the key urethane linkage in 6, and subsequent chlorination
of the hydroxyl groups gave 7 which possessed physical
properties offering little scope for purification via standard
crystallisation techniques. Indeed, the product required
chromatographic purification to remove impurities generated
during formation of the urethane linkage.
reaction as this compound, a nitrogen mustard, is the actual
cytotoxic agent and would pose very significant containment
problems if used on a manufacturing scale.
Proposed Approach for a New Synthetic Route
Significant quantities of a related molecule 8, possessing
the same basic aryl urethane derivative of (S)-glutamic acid
as ZD9063P, were available and it seemed opportune to
reinvestigate the choice of synthetic route to ZD9063P
(Scheme 2).
The incorporation of the dichloro analogue of 5 is not a
practical option in avoiding the late-stage chlorination
The two key transformations required are the conversion
of the hydroxyl groups to chloro groups and the regioselec-
(1) Lee, S. A. Personal communication.
10.1021/op000016+ CCC: $19.00 © 2000 American Chemical Society and The Royal Society of Chemistry
Published on Web 05/23/2000
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259

Scheme 2. Original synthesis of the related derivative of
(S)-glutamic acid
suggested that a dichloro derivative should be chosen as the
key starting material for coupling with the dibenzyl ester of
5-aminoisophthalic acid 2. In addition, approaches based on
the opening of the corresponding cyclic anhydride were
considered to be more selective than activation of the acyclic
system with, for example, a chloroformate ester.
Control of the regioselective opening of anhydrides of
glutamic acid derivatives by methanol in the presence of
triethylamine containing varying amounts of DMAP (4-
dimethylaminopyridine) has been described. The ratio of
regioisomers is reversed from about 1:7 to about 7:1 R/γ by
the addition of DMAP.3
Scheme 3. Options for the key transformations
Regioselective opening of the anhydrides of phthaloyl
derivatives of glutamic acid with amines has been described
leading to the γ-isomer, and specific reference was made to
the opening of the anhydrides of urethane derivatives of the
anhydride of glutamic acid with ammonia leading to
predominantly the R-isomer.4 The regioselectivity of reaction
with amines has also been controlled in urethane derivatives
of glutamic and aspartic acid anhydrides by the choice of
reaction solvent.5-7 No examples in which DMAP affected
the regioselectivity of nucleophilic attack by amines on
derivatives of the cyclic anhydrides of glutamic acid have
been found.
Model Studies
Derivatives of glutamic acid were used as mechanistic
probes to investigate the reaction of anhydrides with the
dibenzylester of 5-aminoisophthalic acid 2.
CBZ-glutamic acid was converted by 1,3-dicyclohexyl-
carbodiimide to its cyclic anhydride 13 which was reacted
with the p-toluenesulphonate salt of the dibenzylester of
5-aminoisophthalic acid 2 in the presence of an excess of a
tertiary amine. Two products were seen in the reactions
involving triethylamine and 4-methylmorpholine, whereas
completely unexpectedly, a single product resulted when
DMAP was used as the base. The compounds were isolated
and shown to be 11 and 12, the regioisomers from the
opening of the anhydride ring system8 (Scheme 4).
The single compound formed in the DMAP-catalysed
reaction corresponded to the more polar regioisomer 12
which possesses the ZD9063P substitution pattern. This key
observation means that the basic carbon skeleton of ZD9063P
can be assembled without the need for an expensive,
differentially protected, glutamic acid derivative.
tive coupling of the dibenzyl ester of 5-aminoisophthalic acid
with the glutamic acid residue giving a compound 9 which
can be converted to ZD9063P by catalytic hydrogenation.
The key decision is the order in which the chlorination
reaction and the introduction of the dibenzyl ester of
5-aminoisophthalic acid moiety are carried out (Scheme 3).
Initially, the partial hydrolyses of 8 and of its dichloro-
analogue 10 were investigated to provide differentially
protected derivatives of glutamic acid. Trifluoroacetic acid
selectively cleaved the less hindered ester group, but it was
not possible to obtain solution yields of the desired regio-
isomer of greater than about 50% because further de-
esterification continually occurred.2
Racemisation of the chiral centre of the glutamic acid
residue is a possible problem with the base-catalysed opening
of the anhydride ring. The proposed reaction was modelled
(3) Jouin, P.; Castro, B.; Zeggaf, C.; Pantaloni, A.; Senet, J. P.; Lecolier, S.;
Sennyey, G. Tetrahedron Lett. 1987, 28, 1665.
The physical characteristics of the chlorinated species as
well as the desire to avoid the conversion of the hydroxyl
group to the chloro group at a late stage in the synthesis
(4) Sheehan, J. C.; Bolhofer, W. A. J. Am. Chem. Soc. 1950, 72, 2469.
(5) Cristea, I.; Mager, S.; Batiu, C.; Ple´, G. ReV. Roum. Chim. 1994, 39(12),
1435.
(6) Huang, X.; Luo, X.; Roupioz, Y.; Keillor, J. W. J. Org. Chem. 1997, 62,
8821.
(2) The structure of the major regioisomer of the mixture was assigned by
comparison of the chemical shifts in the NMR spectra of the protons adjacent
to the carbonyl groups in the glutamic acid residue in the acid and salt
forms of the product. Formation of the ammonium salt resulted in an upfield
shift of approximately 0.2 ppm in the position of the methylene protons,
thus showing them to be adjacent to a carboxylic acid group and not an
ester function.
(7) Ksander, G. M.; Yuan, A. M.; Diefenbacher, C. G.; Stanton, J. L. J. Med.
Chem. 1985, 28, 1606.
(8) The key feature of the structural assignment was a comparison of the NMR
spectra with that of CBZ-glutamic acid. The chemical shift of the methine
proton in the less polar compound was significantly different from the
methine proton in CBZ-glutamic acid, whereas in the more polar compound
the significant difference was in the methylene protons.
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Scheme 4. Initial experiment with CBZ-glutamic acid
generated in the system, about 2 BarG, is entirely consistent
with operation in a standard production plant.
The de-esterification of 10 could be readily achieved by
the extended reaction of trifluoroacetic acid, but a significant
practical problem encountered was the complete removal of
the excess trifluoroacetic acid prior to the activation step. A
large excess of trifluoroacetic acid is required to displace
the equilibrium set up between its tert-butyl ester and the
corresponding tert-butyl ester of the substrate. Complete
reaction is normally only achieved by multiple treatments
removing volatile substances by distillation, a time-consum-
ing procedure for large scale operation. The tert-butyl ester
of methanesulphonic acid is unstable, and thus the corre-
sponding equilibrium can be displaced by the formation of
isobutylene which escapes from the system.11 In this way,
complete deprotection of 10 to 14 is achieved using only
0.75 mol equiv of methane sulphonic acid (18 h at 40
°C). Practical problems arose because the product precipi-
tated as an oily solid in the presence of methane sul-
phonic acid. However, neutralisation of the added methane
sulphonic acid with an equivalent of DMAP successfully
overcame the problem giving a solution with a pH suitable
for cyclisation to the anhydride with 1,3-dicyclohexylcar-
bodiimide.
using the (-)-menthyloxycarbonyl derivative of (R)-glutamic
acid because an enantiomeric analytical method for 9 was
not initially available. The corresponding anhydride was
reacted with the dibenzylester of 5-aminoisophthalic acid in
the presence of various tertiary amines and the following
results obtained9,10, (Table 1).
The results demonstrate that a highly nucleophilic but
weakly basic amine possesses the desired catalytic activity
for the desired regioselective opening of the cyclic anhydride
of a glutamic acid derivative by the dibenzyl ester of
5-aminoisophthalic acid 2.
The corresponding anhydride 15 reacts at -30 °C with
the dibenzylester of 5-aminoisophthalic acid 2 in the presence
of one equivalent of DMAP. The reaction is largely complete
within 2 h.12
Development of the Ultimate Manufacturing Route
With the information from the modelling studies, the
conversion of 8 to the desired cyclic anhydride was then
reinvestigated with a high degree of confidence that the
approach would ultimately lead to a practical manufacturing
process for ZD9063P (Scheme 5).
Although it is possible to isolate the free acid form of 9
from the reaction mixture after work-up by crystallisation
of the evaporated residue from an ethyl acetate/cyclohexane
solvent mixture, it was simpler to isolate the salt 16 formed
with (S)-R-methylbenzylamine directly from a mixture of
methylene chloride and acetonitrile. Formation of the salt
gave considerable purification as well as an opportunity for
any necessary subsequent enantiomeric enrichment.13
Currently the desired physical form of ZD9063P, a tri-
acid, has not been defined, but the structure of 16 has been
correlated with ZD9063P by conversion to the corresponding
free acid followed by removal of the benzyl groups by
catalytic hydrogenation. The resulting tri-acid was identical
The readily available starting material 8 reacts with
methanesulphonyl chloride/N,N-diisopropylethylamine in
methylene chloride solution to give an essentially quantitative
yield of the corresponding dimesylate. The mesylate groups
are displaced by the chloride ion present to give 10, but the
reaction is very slow even at reflux. An alternative solvent
is not an attractive option as methylene chloride is the most
suitable solvent for obtaining an initial solution of 8, a
necessary requisite for a high chemical conversion to the
dimesylate. The solvent used must be compatible with the
strongly acidic reaction conditions required for removal of
the tert-butyl groups as the isolation of 10 as a crystalline
solid is not easy and it is more convenient to proceed directly
with the deprotection stage. In addition, both 10 and 14
contain the nitrogen mustard system, albeit in a less activated
form, and handling of such intermediates would cause
concern on a production scale.
1
to an authentic sample of ZD9063P by H and 13C NMR
and HPLC.14
(11) King, J. F.; du Manoir, J. R. J. Am. Chem. Soc. 1975, 97, 2566.
(12) Two minor by-products are observed.
The problem of the slow rate of the displacement reaction
at reflux in methylene chloride solution (40 °C) was
overcome, without introducing a change to a higher boiling
solvent, by operating the reaction under pressure. Complete
exchange occurs after 18 h at 75 °C, and the pressure
(13) A crystalline product was also obtained in about the same isolated yield
with (R)-R-methylbenzylamine. It was noticed that the two diastereomeric
salts did crystallise at significantly different rates from the same solvent
mixture, but it is not known which salt would be more useful in further
work on enhancing the purity of the derived ZD9063P.
(14) A sample of the regioisomeric dibenzyl ester was isolated by chromatography
and its structure confirmed by NMR. Removal of the benzyl ester groups
gave a compound very closely related to, but clearly different from,
ZD9063P by HPLC and NMR analysis.
(9) It was not possible to analyse (HPLC or NMR) the anhydride for the
presence of the diastereomer to demonstrate the absence of racemisation
during the 1,3-dicyclohexylcarbodiimide-mediated ring closure reaction.
(10) The anhydride of menthyloxycarbonyl-(S)-glutamic acid was subjected to
a similar series of reactions. Comparison with the similar products from
the enantiomeric acid allowed the four possible products to be assigned
unambiguously on the HPLC trace.
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Table 1. Results of opening anhydride 13 under various conditions (% yields)
desired
product
glutamic acid enantiomer
of desired product
glutamic acid enantiomer
of regioisomer
base
regioisomer
4-methylmorpholine
pyridine
triethylamine
no additional base
4-pyrrolidinopyridine
DMAP (at + 20 °C)
DMAP (at - 30 °C)
50
50
25
15
82
88
96
0
0
25
0
16
8
2
50
50
25
85
2
4
2
0
0
25
0
0
0
corresponding dimesylate after 2h.15 The solution was
transferred to an autoclave, methylene chloride (460 mL)
was added, and the solution was agitated and heated in a
sealed vessel for 18 h (jacket temperature 75 °C, pressure
generated 1.6 BarG). Analysis by HPLC showed a 97% AN
conversion to 10. A sample was isolated by chromatography
for characterisation.
Scheme 5. Manufacturing route to ZD9063P
1H NMR 7.95 (d, J ) 10 Hz, 1H), 6.94, (d, J ) 10 Hz,
2H), 6.72 (d, J ) 10 Hz, 2H), 4.0-3.9, (m, 1H), 3.73 (s,
8H), 2.4-2.3 (m, 2H), 2.0-1.9 (m, 1H), 1.9-1.75 (m, 1H),
1.42 (s, 18H)
The cooled reaction mixture was washed with water (570
mL), aqueous citric acid solution (570 mL of 20% w/v), and
water (570 mL). The final two separations emulsified slightly.
The solution was passed through Whatman 1PS filter paper
to remove extraneous water. Methanesulphonic acid (57.7
g, 38.9 mL, 0.60 mol) was added, the solution was stirred
and distilled, and 1.0 L of distillate was collected. Methylene
chloride (1.0 L) was added, the mixture was heated, and 1.0
L of distillate was collected. Further methylene chloride (0.7
L) was added, and the mixture was heated at reflux for 18
h to give an oily mixture. Analysis of the supernatant solution
showed the absence of significant quantities of 10 and any
intermediate mono esters. A solution of DMAP (70.8 g, 0.58
mol) in methylene chloride (200 mL) was added slowly. The
oil dissolved to give a dark solution, and analysis by HPLC
showed >95% AN conversion to the desired product, 14,
present as a salt with DMAP.
The methylene chloride solution of 14 was inerted by a
stream of nitrogen, and a solution of 1,3-dicyclohexylcar-
bodiimide (88.3 g, 0.428 mol) in methylene chloride (220
mL) was added over about 1 h, maintaining a temperature
of 5-10 °C. After a further hour, analysis by HPLC showed
essentially complete conversion of 14 to the corresponding
anhydride 15. The solution was cooled to -50 °C, and a
solution of DMAP (48.8 g, 0.40 mol in methylene chloride
200 mL) was added followed by a solution of the dibenzyl-
ester of 5-aminoisophthalic acid (144 g, 0.40 mol) in
methylene chloride (800 mL), the temperature being main-
tained throughout at -50 °C. Periodic analysis of the reaction
mixture showed the reaction to be essentially complete after
3 h, and the mixture was allowed to reach ambient temper-
ature overnight. Water (2.5 L) was added, and the mixture
was stirred for 1 h and filtered to remove precipitated N,N1-
dicyclohexylurea, and the phases were separated. The organic
phase was washed with aqueous citric acid (2 L of 10% w/v)
Conclusions
In conclusion, we have developed a new, efficient, and
convergent route to ZD9063P by converting a readily
available starting material to a key intermediate suitable for
both chemical and enantiomeric purification. The success
of the synthetic approach arose from the use of a catalyst to
obtain regiospecific opening of an anhydride ring, incorpora-
tion of a reaction at an elevated pressure to avoid a solvent
exchange, and the development of an improved practical
procedure for the deprotection of tert-butyl esters
Experimental Section
Reagents were purchased from standard suppliers.
NMR spectra were run at 270 MHz (proton) and at 67.7
MHz (carbon) in d6-DMSO or d6-DMSO/TFA solution and
are reported in parts per million downfield from internal
TMS. The signals assigned to TFA (159.0, q, J ) 60.9 Hz,
115.3, q, J ) 440 Hz) are omitted from the description of
the 13C spectrum for each compound.
HPLC analyses were conducted using a HiChrome RPB
column, solvent system acetonitrile/water/TFA 640/360/1 (v/
v/v), flow rate 1 or 2 mL/min and detection at 254λ
(S)-(r)-Methylbenzylamine Salt of the Dibenzyl
Ester of 5-(N-[(S)-N-{N,N-Bis(2-chloroethyl)amino}phe-
noxycarbonyl)-γ-glutamyl]amino)isophthalic Acid (16). A
solution of 8 (193 g, 0.40 mole) and N,N-diisopropylethyl-
amine (124 g, 167 mL, 0.96 mole) in dichloromethane (1.5
L) was protected from atmospheric moisture and stirred at
0 °C. Methane sulphonyl chloride (101 g, 68 mL, 0.878 mol)
was added at such a rate so that the reaction temperature
remained between 0 and 5 °C. A wash of methylene chloride
(200 mL) was added via the dropping funnel. Analysis by
HPLC showed greater than 97% AN conversion to the
(15) AN-area normalised.
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and water (2 L). The organic solution was filtered through
Whatman 1PS filter paper to remove adventitious water and
divided into two portions of 1.38 L each.
citric acid (50 mL of 20% w/v) followed by water (3 × 50
mL). The organic phase was filtered through Whatman 1PS
filter paper and the solvent removed under reduced pressure
to give the desired product 9 as an amorphous foam. Yield
4.0 g, 5.34 mmol (93% yield).
1H NMR 10.5, (s, 1H), 8.60, (s, 2H), 8.28 (s, 1H), 8.00
(d, J ) 10 Hz, 1H), 7.5-7.3 (m, 10H), 6.94, (d, J ) 10 Hz,
2H), 6.72 (J ) 10 Hz, 2H), 5.38 (s, 4H), 4.2-4.1, (m, 1H),
3.73 (s, 8H), 2.68-2.50 (m, coincides with signal from d6-
DMSO) 2.62-2.50 (m, 2H), 2.32-2.15 (m, 1H), 2.1-1.9
(m, 1H)
13C NMR 173.9, 171.8, 165.1, 155.5, 144.1, 142.5, 140.8,
136.1, 131.2, 128.8, 128.5, 128.2, 124.7, 124.4, 123.0, 112.6,
67.0, 53.8, 53.0, 41.6, 33.0, 27.0
One portion was distilled to half of the volume at
atmospheric pressure, diluted with acetonitrile (1.3 L), and
stirred at 40 °C whilst a solution of (S)-R-methyl benzyl-
amine (24.2 g, 0.20 mol) in acetonitrile (80 mL) was added.
Crystallisation commenced quickly, and the slurry was
allowed to cool to ambient temperature over 2-3 h. The
product was filtered, washed with 2 × 100 mL methylene
chloride/acetonitrile, 1/2 v/v, and dried at 30 °C.
The weight of product 16 was 134 g, 0.154 mol (76.9%
yield from 8).
Recrystallisation of the (r)-Methylbenzylamine Salt of
the Dibenzyl Ester of 5-(N-[(S)-N-{N,N-Bis(2-chloroethyl)-
amino}phenoxycarbonyl)-γ-glutamyl]amino)isophthalic
Acid (16). The salt 16 (20.0 g, 22.9 mmol) was dissolved in
acetonitrile (700 mL) at reflux and cooled to 20 °C. The
crystalline product was filtered, washed with acetonitrile (100
mL), and dried at 50 °C. Yield 14.6 g, 16.7 mmol (73.0%
yield).
Analysis showed the presence of less than 1% of the (R)-
enantiomer.16
5-(N-[(S)-N-{N,N-Bis(2-chloroethyl)amino}phenoxy-
carbonyl)-γ-glutamyl]amino)isophthalic Acid (ZD9063P).
A sample of 10% palladium/carbon (200 mg) was slurry-
washed with redistilled THF (20 mL) and transferred to a
flask. A solution of 9 (0.30 g, 0.4 mmol) in redistilled THF
(50 mL) was added. The slurry was hydrogenated at ambient
temperature and pressure. After 18 h, when removal of the
protecting groups was complete, the slurry was diluted with
redistilled THF (10 mL) and the catalyst removed by
filtration. The solvents were removed under vacuum to leave
the product as an amorphous solid. Yield 0.18 g, 0.315 mmol
(78.9% yield).
1H NMR 10.68 (s, 1H), 8.54 (s, 2H), 8.18 (s, 1H), 7.90
(d, J ) 10 Hz, 1H), 7.52-7.23 (m, 15H), 6.90 (d, J ) 10
Hz, 2H), 6.68 (d, J ) 10 Hz, 2H), 5.38 (s, 4H), 4.28 (q, J )
10 Hz, 1H), 3.85-3.75 (m, 1H), 3.70 (s, 8H), 2.48-2.37
(m, 2H), 2.20-2.00 (m, 1H), 2.00-1.98 (m, 1H), 1.44 (d, J
) 10 Hz, 3H)
13C 173.8, 171.5, 165.1, 155.2, 144.1, 142.5, 140.6, 139.5,
136.2, 130.8, 129.0, 128.9, 128.8, 128.5, 128.4, 127.0, 124.5,
124.0, 122.9, 67.0, 53.8, 52.8, 50.5, 41.2, 33.1, 26.7, 20.8
Calcd for C46H48N4O9Cl2: C, 63.37; H, 5.55; N, 6.43,
Cl, 8.13. Found: C, 63.34; H, 5.52; N, 6.41; Cl, 8.13.
Quantitative analysis by 1H NMR showed the strength to
be 100% relative to an internal standard of maleic acid.
Additionally, although quantitative analysis by HPLC showed
that recrystallisation increased the strength of the product
1H NMR17 10.40, (s, 1H), 8.50, (s, 2H), 8.20, (s, 1H),
8.00 (d, J ) 10 Hz, 1H), 7.00 (d, J ) 10 Hz, 2H), 6.75 (d,
J ) 10 Hz, 2H), 4.23-4.08 (m, 1H), 3.73, (s, 8H), 2.65-
2.52 (m) overlaps with the d6-DMSO signal, 2.35, (m, 1H),
2.10-1.95, (m,1H)
13C NMR 173.9, 171.2, 167.2, 155.3, 144.1, 142.6, 140.2,
132.2, 125.2, 124.2, 122.8, 113.0, 54.2, 53.3, 41.7, 33.2, 27.2
Acknowledgment
Simon D. Broady is thanked for helpful comments during
the preparation of the manuscript.
1
by only 1-2%, comparison of the H spectra showed that
low levels of structurally unrelated aliphatic components had
been removed.
Dibenzyl Ester of 5-(N-[(S)-N-{N,N-Bis(2-chloroethyl)-
amino}phenoxycarbonyl)-γ-glutamyl]amino)isophthalic
Acid (9). The above salt 16 (5.0 g, 5.74 mmol) was
partitioned between ethyl acetate (150 mL) and an aqueous
solution of citric acid (100 mL of 20% w/v). The resulting
organic phase was re-washed with an aqueous solution of
Received for review February 16, 2000.
OP000016+
(16) Analysis by chiral HPLC using a CHI-DMB column, solvent system
isohexane/2-propanol/TFA (75/25/0.1), flow 1 mL/min and detection at 254
λ. The authors are grateful to Miss Fiona J Bell for this result.
(17) Residual toluene and THF were detected in both spectra.
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