Convenient syntheses of δ-aminolevulinic acid

Article abstract of DOI:10.1055/s-1999-3452

Two convenient procedures for the synthesis of δ-aminolevulinic acid (5-ALA) are described.

Full text of DOI:10.1055/s-1999-3452

568
SHORT PAPER
Convenient Syntheses of d-Aminolevulinic Acid
Ayelet Nudelman, Abraham Nudelman*
Department of Chemistry, Bar Ilan University, Ramat Gan 52900, Israel
Fax +972(3)535-1250; E-mail: nudelman@mail.biu.ac.il
Received 21 August 1998; revised 6 November 1998
hydrolysis and decarboxylation yielding the desired 5-
ALA.
Abstract: Two convenient procedures for the synthesis of d-ami-
nolevulinic acid (5-ALA) are described.
Key words: oximation, hydrogenation, decarboxylation, hydrolysis
d-Aminolevulinic acid (5-ALA) involved in heme biosyn-
thesis, has been reported to be a precursor for protopor-
phyrin IX and is currently undergoing clinical trials as an
agent for photodynamic therapy (PDT).1–4
Although various synthetic procedures for 5-ALA have
been described in the literature5–21 as well as in patents, it
still is a relatively expensive reagent (see Sigma Catalog).
Based on analogous investigations to those dealing with
the synthesis of the vitamers of biotin,22 we developed the
following two convenient synthetic procedures for 5-
ALA, that neither require expensive reagents nor include
difficult purification steps.
a-Nitro ketone ester 3 (Scheme 1) was prepared by an
analogous procedure to that described earlier.22,23 Selec-
tive reduction of aliphatic nitro groups, in particular in the
presence of other sensitive functionalities, has been re-
ported to be complicated.24 Indeed, our attempts to reduce
the nitro group by transfer-hydrogenation, using
HCO2NH4/10%Pd-C failed.25 However, 3 underwent fac-
ile reduction and concomitant hydrolysis under aqueous
acidic catalytic hydrogenation conditions to give 5-
ALA·HCl 4 in 94% yield.26
Scheme 2
Ethyl 4-(Imidazol-1-yl)-4-oxobutyrate (2)
To a well-stirred solution of ethyl succinyl chloride (1) (98% purity,
1.04 g, 6 mmol) in anhyd THF (15 mL), imidazole (0.82 g, 12
mmol) was added. The solution was stirred at r.t. for 2 h. The pre-
cipitate was filtered and washed with Et2O. The filtrate was evapo-
rated to give the desired imidazole 2 as a white solid; yield: 1.19 g
(quantitative).
1H NMR (200 MHz, CDCl3): d = 1.28 (t, 3H, J = 7.2 Hz, OCH2Me),
2.83 (t, 2H, J = 6.5 Hz, CH2), 3.20 (t, 2H, J = 6.5 Hz, CH2), 4.18 (q,
2H, J = 7.1 Hz, OCH2Me), 7.12 (s, 1H, CH), 7.51 (t, 1H, J = 1.5 Hz,
CH), 8.22 (bs, 1H, CH).
13C NMR (300 MHz CDCl3): d = 14.14 (OCH2Me), 28.06
(CH2CO2Et), 30.21 (CH2CO), 61.16 (OCH2Me), 116.05 (CH),
131.07 (CH), 136.18 (CH), 168.35 (CON), 171.73 (CO2Et).
MS (CI, CH4): m/z (%) = 197 (MH+, 2), 129 (MH+ – C3H3N2, 100),
101 (MH+ – C5H8N2, 62).
HRMS (CI, CH4): calcd for C9H13N2O3 (MH+) 197.0926 found
197.0750.
Scheme 1
Ethyl 5-Nitro-4-oxopentanoate (3)
In the second approach, oximation of the b-keto ester 6,
obtained from succinic acid mono-ester 5, gave 7 as a
mixture of Z and E-isomers. Reduction and in situ acety-
lation of 7 gave amide 827 that underwent acid-catalyzed
To an ice-cold solution of MeNO2 (0.75 g, 12 mmol) in DMSO (10
mL), under N2, t-BuOK (1.13 g, 10 mmol) was added. After stirring
the suspension at 0 °C for a few min, a solution of 2 (1.96 g, 10
mmol) in DMSO (10 mL) was added. The dark-orange mixture was
stirred at r.t. for 48 h. The mixture was poured into water (20 mL)
and was extracted with Et2O (2 x 15 mL). The aqueous layer was
Synthesis 1999, No. 4, 568–570 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Convenient Syntheses of d-Aminolevulinic Acid
569
acidified with concd HCl to pH 4–5, and was extracted with EtOAc
(5 x 25 mL). The organic layer was washed with brine (2 x 20 mL),
dried (MgSO4), filtered and evaporated. The residue was purified by
flash chromatography using hexane/EtOAc 2:1 as eluent (Rf =
0.41). The product 3 was obtained as a yellow oil; yield: 1.14 g
(60%).
1H NMR (200 MHz, CDCl3): d = 1.26 (t, 3H, J = 7.1 Hz, OCH2Me),
2.72, 2.83 (AA'BB' system, 4H, CH2CH2), 4.15 (q, 2H, J = 7.2 Hz,
OCH2Me), 5.39 (s, 2H, CH2NO2).
13C NMR (300 MHz, CDCl3): d = 14.12 (OCH2Me), 28.03
(CH2CO2Et), 34.92 (CH2CO), 61.20 (OCH2Me), 83.30 (CH2NO2),
171.94 (CO2Et), 195.15 (CO).
MS (CI, CH4): m/z (%) = 190 (MH+, 19), 129 (MH+ – CH3NO2,
100).
Dimethyl 2-(Acetylamino)-3-oxohexanedioate (8)
To a solution of 7 (1.30 g, 6 mmol) and Ac2O (3.67 g, 36 mmol) in
glacial AcOH (20 mL), Zn dust (3.12 g, 48 mmol) was added over
a period of 1 h. The mixture was stirred at r.t. and after 24 h, TLC
indicated that the reaction was complete. The mixture was filtered
and the cake was washed with EtOAc (40 mL). The filtrate was
evaporated to give 8 as yellowish oil; yield: 1.47 g (~100%).
1H NMR (300 MHz, CDCl3): d = 2.08 (s, 3H, COMe), 2.66 (m, 2H,
CH2CO2Me), 2.94 (m, 1H, CH2CO), 3.12 (m, 1H, CH2CO), 3.67 (s,
3H, OMe), 3.84 (s, 3H, OMe), 5.33 (d, 1H, J = 6.6 Hz, CH), 6.77
(bd, 1H, J = 6.6 Hz, NH).
13C NMR (300 MHz, CDCl3): d = 22.69 (MeCONH), 27.69
(CH2CO2Me), 35.38 (CH2CO), 51.97 (OMe), 53.42 (OMe), 62.51
(CH), 166.57 (MeCONH), 169.94 (CO2Me), 172.55 (CO2Me),
199.74 (CO).
HRMS (CI, CH4): calcd for C7H12NO5 (MH+) 190.0175 found
190.0750.
+
MS (CI, NH3): m/z (%) = 263 (MNH4 , 89), 246 (MH+, 100).
+
HRMS (DCI, CH4): calcd for C10H16NO6 (MH ) 246.0977 found
Dimethyl 3-Oxohexanedioate (6)28
246.0980.
To a solution of 5 (3.3 g, 25 mmol) in anhyd THF (35 mL) under
N2, CDI (4.86 g, 30 mmol) was added portionwise. After stirring the
mixture at r.t. for 1 h, MgCl2 (2.38 g, 25 mmol) and monomethyl
malonate potassium salt (3.9 g, 25 mmol) were added at once. The
mixture was stirred at 35 °C overnight. The resulting slurry was fil-
tered and the filtrate was evaporated. The residue was dissolved in
EtOAc (20 mL) and 1 N HCl (20 mL). The aqueous phase was ex-
tracted with EtOAc (3 x 20 mL). The organic layers were washed
with 5% NaHCO3 (2 x 20 mL) and brine (20 mL). The organic layer
was dried (MgSO4) and evaporated. The product was purified by
distillation 140 °C/0.5 Torr to give a colorless liquid; yield: 3.10 g
(66%).
5-Amino-4-oxopentanoic Acid Hydrochloride (4)8
Method A: A suspension of 3 (0.37 g, 2 mmol) in 1 N HCl (10 mL),
was hydrogenated at 22 psi over 10% Pd/C (0.19 g) overnight. The
catalyst was filtered and washed with water (15 mL). The solvent
was evaporated to give the desired product 4 as a yellowish solid;
yield: 0.314 g (94%).
Method B: A suspension of 8 (0.49 g, 2 mmol) in 4 N HCl (6 mL)
was refluxed for 4 h. To the resulting dark yellow solution active
charcoal was added and the suspension was filtered. The filtrate was
evaporated to give 4 as a white crystalline material; yield: 0.28 g
(85%).
1H NMR (200 MHz, CDCl3): d = 2.63 (t, 2H, J = 6.5 Hz,
CH2CO2Me), 2.87 (t, 2H, J = 6.5 Hz, CH2CO), 3.52 (s, 2H,
COCH2CO), 3.68 (s, 3H, OMe), 3.75 (s, 3H, OMe).
1H NMR (300 MHz, D O): d = 2.73 (m, 2H, CH CO H), 2.91 (t,
2
2
2
2H, J = 6 Hz, CH CO), 4.14 (s, 2H, CH NH +).
2
2
3
13C NMR (200 MHz, D2O): d = 27.97 (CH2CO2H), 34.92 (CH2CO),
13C NMR (300 MHz, CDCl3): d = 27.70 (CH2CO2Me), 37.42
+
47.65 (CH2NH3 ), 177.33 (CO2H), 204.68 (CO).
(CH2CO), 49.04 (COCH CO), 51.92 (OMe), 52.43 (OMe), 167.43
2
MS (CI, NH3): m/z (%) = 132 (MH+, 17).
HRMS (DCI, CH4): calcd for C5H10NO3 (MH+) 132.0660 found
132.0649.
(CO2Me), 172.85 (CO2Me), 200.93 (CO).
+
MS (CI, NH3): m/z (%) = 206 (MNH4 , 100), 189 (MH+, 44)
HRMS (DCI, CH4): calcd for C8H13O5 (MH+) 189.0763 found
189.0733.
Acknowledgement
Dimethyl 2-(Hydroxyimino)-3-oxohexanedioate (7)
Generous support for this work by the “Marcus Center for Pharma-
ceutical and Medicinal Chemistry” and the Minerva Foundation
Otto Mayerhoff Center for the Study of Drug-Receptor Interactions
at Bar Ilan University is gratefully acknowledged.
To an ice-cold solution of 6 (1.88 g, 10 mmol) in glacial AcOH (5
mL), a solution of NaNO2 (0.83 g, 12 mmol) in water (10 mL) was
added dropwise over a period of 1 h, at such a rate that the temper-
ature did not rise above 10 °C. Additional water (15 mL) was added
and the mixture was allowed to reach r.t., and was stirred overnight.
The solution was extracted with EtOAc (3 x 25 mL). The organic
layer was washed with water (3 x 30 mL), 5% NaHCO3 (3 ´ 25
mL), and brine (3 x 25 mL), dried (MgSO4), filtered and evaporated
to give 7 as a yellowish solid; yield: 1.7 g (78%); mp 84–86 °C.
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Synthesis 1999, No. 4, 568–570 ISSN 0039-7881 © Thieme Stuttgart · New York