Preparation of tert-butyl 6-aminopenicillanate and its 6-oxo and 6- diazo derivatives

Article abstract of DOI:10.1039/a808587k

A 1:1 1,4-dioxane-tert-butyl acetate mixture and BF₃ etherate were used for an effective 6-aminopenicillanic acid conversion into the tert-butyl ester (64 ± 3% yield) which could be easily transformed into tert-butyl 6- oxo-and 6-diazo-penicillanates.

Full text of DOI:10.1039/a808587k

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270 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
Preparation of tert-Butyl 6-Aminopenicillanate
and its 6-Oxo and 6-Diazo Derivativesy
1
999, 270^271y
Grigory Veinberg,* Maxim Vorona, Dan Musel, Nora Grigan and
Edmunds Lukevics
Latvian Institute of Organic Synthesis, 21 Aizkraukles Street, Riga, LV 1006, Latvia
A 1:1 1,4-dioxane^tert-butyl acetate mixture and BF3 etherate were used for an effective 6-aminopenicillanic acid
ac no dn v e6 r -s di oi an zo i-n pt oe ni tc hi l el an tae t ret -s b. utyl ester (64 Æ 3% yield) which could be easily transformed into tert-butyl 6-oxo-
O
O
O
6
-Aminopenicillanic acid (6-APA) esters are widely used as
BF3
F3B
O
a)
b)
But +
+
–
starting materials for the preparation of various clinically
useful substances. The chemical lability of the b-lactam ring
dramatically reduces the choice of the carboxyl protective
groups to those which can be introduced and eliminated
under mild conditions. The tert-butyl group is one such,
but in contrast to 7-aminocephalosporanic acid (7-ACA)
and 7-aminodeacetoxycephalosporanic acid (7-ADCA), there
are only few examples of its utilization in the case of 6-APA
But
But
O
Me
Me –BF3
O
Me
2
5
5a
5b
H2N
O
BF3•H2N
O
S
S
BF3
N
N
CO2H
CO2H
a, 5b –AcOH
1
6
(
1) obviously due to the low reactivity of O-tert-butyl-
5
0
1
N,N -dicyclohexyl isourea (10.8%). In a previous report
we have described a simple and highly e¡ective method
for tert-butyl esteri¢cation of 7-aminocephalosporanic acid
using a mixture of tert-butyl acetate (2) and boron tri£uoride
etherate and an attempt to apply these reagents for the prep-
3
BF •H N
2
BF •H N
3
2
S
S
BF3
δ +
N
N
O
O
BF3
CO2But
CO2But
2
aration of tert-butyl APA (3).
8
7
5
a, 5b –CH2 CMe2
H2N
S
t
Ac
NH •BF
But
O
+
Bu OAc
2
3
NH2
N
δ –
O
5a, 5b
O
S
S
CO2H
–2BF3
–Ac2O
1
2
O
HN
O
HN
BF3•Et2O –AcOH
BF3
CO2But
t
2
CO Bu
But
9
4
NH2
H2N
O
O
S
S
+
Scheme 1
N
O
HN
CO2But
CO2But
The optimal 64 Æ 3% yield of pure tert-butyl 6-amino-
penicillanate was reached using a 1:1 dioxane^tert-butyl acet-
ate mixture. Attempts to improve the yield by varying the
ratio failed (Table 1, entries 4 and 5).
Attempts to recover 6-APA by treatment of 3 with
tri£uoroacetic or Lewis acids in dichloromethane according
to procedures published in ref. 4 led to destruction of the
b-lactam ring. However 3 proved to be stable under other
types of chemical transformations.
3
4
It was found that treatment of 6-APA in pure 2, gave target
ester 3 in 21% yield and a side product identi¢ed as the
di-tert-butyl ester of penicic acid (4). Formation of the latter
could be explained by the speci¢c ability of BF3, as a strong
Lewis acid, to convert 2 into the intermediate ions 5a, 5b
(
Scheme 1, reaction a), and to facilitate their addition to
the intermediates 8 and 9 (Scheme 1, sequence b).
Therefore, according to Scheme 1, the yield of 3 could be
increased by inhibition of the reaction sequence at the stage
of monoester 7 by preventing its conversion into the
undesirable intermediate 8. This problem could be solved
by addition to the reaction mixture of solvents capable of
behaving as electron donors and competing with penam
nitrogen for BF3.
It was found that, contrary to the benzhydryl protecting
group, tert-butyl favored the transformation of 3 into
6-oxopenicillanate 10 in the manner described by Hagiwara
et al. Treatment of 3 in dichloromethane with isopropyl
nitrite in the presence of catalytic amounts of tri£uoroacetic
5
Table 1 Effect of solvents on the yield of tert-butyl 6-APA
tert-butylacetate^
The investigation of their e¡ect on the yield and quality of
3
vs. the control (Table 1, entry 1) led to the following results.
Entry Solvent
solvent ratio
t/h
Yield (%)
Diethyl ether, ethyl acetate and acetone did not a¡ect the
esteri¢cation process. Addition of DMF and methanol to
1
tert-Butyl
acetate
Acetonitrile
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
^
6
21a
2
caused a detrimental e¡ect and only acetonitrile and
35b
2
3
4
5
a
1:1
1:1
5:3
3:5
6
3
3
4
1,4-dioxane increased the yield 3 (Table 1).
64 Æ 3
44
48
b
*
To receive any correspondence.
y This is a Short Paper as de¢ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1999, Issue 1]; there is
therefore no corresponding material in J. Chem. Research (M).
Crude product contaminated with 9 (TLC: Rf ˆ 0:53†: Crude
product contaminated with unidentified substance (TLC:
Rf ˆ 0:06†:

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J. CHEM. RESEARCH (S), 1999 271
acid resulted in its almost quantitative conversion into
puri¢ed by column chromatography (ethyl acetate-hexane, 1:1) to
a¡ord tert-butyl 6-aminopenicillanate (3) with 98^99% purity by
HPLC assay.
6
6
-diazopenicillanate 11. Its subsequent transformation into
a-chloropenicillanate 1-oxide 13 serves as an example of
Penicic acid di-tert-butyl ester (4) isolated from reaction mixtures
e¤cient carboxyl deprotection (Scheme 2).
(
Table 1, entry 1) by column chromatography (ethyl acetate^hexane,
1
:1) had mp 84^86 8C, dH (CDCl3)1.42±1.55 (m, 21 H, CH3, 2
1
. 2(CF3SO2)2O, 2Et3N
. Et3N
t
Bu ), 1.61 (s, 3 H, CH3) 2.51 (br s, 2 H, NH2), 3.55 (s, 1 H, 4-H
i
2
PrONO,
N2
O
O
O
thiazolidine), 3.71 (d, 1 H, J ˆ 4 Hz, 2-H thiazolidine), 5.06 (d, 1 H,
S
3. H O+
CF CO H (cat.)
S
3
3
2
J ˆ 4 Hz, 2-CHCO2); IR (®lm): 3300, 2980, 2920, 1730, 1680
3
�
1
79%
>90%
cm . (Found: C, 55.84; H, 8.73; N, 7.64. C
requires C, 56.15; H, 8.90; N, 7.88%).
16 30
H
N O S Á 0:1C H
N
N
2
4
6
12
CO2But
CO2But
tert-Butyl 6-Oxopenicillanate (10) was prepared according to proce-
t
10
11
6
dure of Buynak et al. dH (CDCl3) 1.49 (3 H, s, Me), 1.51 (9 H, s, Bu ),
1
. HCl
1.57 (3 H, s, Me), 4.66 (1H, s, 3-H), 5.77 (1H, s, 5-H). IR (Nujol): 1830,
2
. MCPBA
� 1
179 0, 174 0 c m
.
O
O
tert-Butyl 6-Diazopenicillanate (11) was prepared according to ref. 7.
�
1
Cl
Cl
IR (¢lm): 2980, 2940, 2080, 1770, 1740 cm .
S
S
CF3CO2H
90%
6a-Chloropenicillanate 1-Oxide (13).ötert-Butyl 6a chloro-
penicillanate 1-oxide (12) (800 mg, 2.60 mM) prepared from 11 accord-
ing to ref. 8 was dissolved in tri£uoroacetic acid (3 ml) and stirred
at room temperature for 1h. The reaction mixture was concentrated
in vacuo and the residue puri¢ed by column chromatography (ethyl
N
N
O
O
CO2H
CO2But
13
12
1
acetate) to a¡ord 600 mg (91%) of 13 with H NMR and IR data ident-
ical to published in the literature.9
Scheme 2
The presented data demonstrate the successful application
of a simple and e¡ective transacylation protocol for the syn-
thesis of previously scarcely available tert-butyl 6-APA, simple
and e¤cient removal of the protective group, and its bene¢c-
ial e¡ect on the transformation of this amino ester into 6-oxo
and 6-diazo derivatives.
We are grateful to Taiho Pharmaceutical Co. for generous
gift of 6-APA.
Received, 4th November 1998; Accepted, 20th January 1999
Paper E/9/08587K
References
Experimental
1
2
B. M. Bain and E. P. Tiley, Br. Pat., 1327102, 1970.
N. Grigan, D. Musel, G. A. Veinberg and E. Lukevics, Synth.
Commun., 1996, 26, 1183.
The 1H NMR spectra were recorded on
a Bruker WH-90
spectrometer (90 MHz) using CDCl3 as solvent. Chemical shifts were
registered in ppm relative to TMS. IR spectra were recorded on a Per-
kin-Elmer 580B spectrophotometer. HPLC analyses were performed
on a Dupont Model 8800 chromatograph with a UV detector
3
4
5
6
7
8
P. Proctor, N. P. Gensmantel and M. I. Page, J. Chem. Soc.,
Perkin Trans. 2, 1982, 1185.
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T. J. Blacklock, J. W. Butcher, P. Sohar, T. R. Lamanec and E.
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1494.
(
l ˆ 254nm). Microanalytical data were obtained on a Carlo Erba1108
apparatus. All reactions were monitored byTLC carried out on Merck
Kieselgel plates (ethyl acetate^hexane, 1:1) using ninhydrin as a
visualizing agent. Merck Kieselgel (0.063^0.230 mm) was used for pre-
parative column chromatography.
General Procedure for the tert-Butyl Esteri¢cation of 6-APA.öA sus-
pension of 6-APA (1.0 g, 4.6 mmol) in a mixture of tert-butyl acetate
(
10 ml, 74 mmol), boron tri£uoride diethyl etherate (2.0 ml, 15.8 mmol)
and an equal volume of the tested solvent was stirred at 14^16 8C for
±6 h. On completion of the process, the reaction mixture was
3
quenched with water (50 ml). The aqueous solution was separated,
neutralized with K2CO3, and extracted with ethyl acetate (50 ml).
The organic layer was dried over anhydrous Na2SO4 and con-
centrated in vacuo to give the crude product, which if necessary was
9
L. S. Changov, B. K. Vasileva-Lukanova, N. N. Agapova, M.
M. Tsenkova, D. M. Mondeshka and Z. T. Ivanova, Antibiot.
Khimioterap., 1990, 35, No. 8, 12.