Total synthesis of hematoporphyrin and protoporphyrin; A conceptually new approach

Article abstract of DOI:10.2533/chimia.2013.204

The total synthesis of protoporphyrin IX and its disodium salt using a new alternative method to the classical MacDonald condensation is reported. The key step is the reaction of the new unsymmetrical diiodo dipyrrylmethane 1 with the known dipyrrylmethane 2. Coupling of the two fragments leads directly to porphyrin 3 without the need of an oxidizing agent. The new methodology is well suited for the synthesis of protoporphyrin IX derivatives on a multi-100 g scale in good quality without the need for chromatography. Furthermore, these preparations are completely free of any contaminant of animal origin, which represents a real improvement in the manufacturing of protoporphyrin IX derivatives. Schweizerische Chemische Gesellschaft.

Full text of DOI:10.2533/chimia.2013.204

204 CHIMIA 2013, 67, Nr. 4
Laureates: awards and Honors, sCs FaLL Meeting 2012
doi:10.2533/chimia.2013.204
Chimia 67 (2013) 204–206 © Schweizerische Chemische Gesellschaft
Total Synthesis of Hematoporphyrin and
Protoporphyrin; a Conceptually New
Approach
Pierre Martin*, Markus Müller, Dietmar Flubacher, Andreas Boudier, and Dirk Spielvogel
Winners of the Sandmeyer Award sponsored by KPMG 2012
In memoriam Prof. Dr. H. Prinzbach
Abstract: The total synthesis of protoporphyrin IX and its disodium salt using a new alternative method to the
classical MacDonald condensation is reported. The key step is the reaction of the new unsymmetrical diiodo
dipyrrylmethane 1 with the known dipyrrylmethane 2. Coupling of the two fragments leads directly to porphyrin
3
without the need of an oxidizing agent. The new methodology is well suited for the synthesis of protoporphyrin
IX derivatives on a multi-100 g scale in good quality without the need for chromatography. Furthermore, these
preparations are completely free of any contaminant of animal origin, which represents a real improvement in the
manufacturing of protoporphyrin IX derivatives.
Keywords: Development & scale-up · Novel porphyrin cyclization method · Process research ·
Protoporphyrin IX · Total synthesis
Introduction
dipyrrylmethane 1 with the known dipyr- is quite unstable and not easy to detect.
rylmethane 2 (Scheme 1).[ Th e two frag-
4]
Furthermore, the reduced quinone is dif-
Protoporphyrin IX (Fig. 1) is most com- ments are coupled without the presence ficult to remove from the reaction mixture
monly prepared by semisynthesis starting of a metal leading directly to porphyrin requiring a chromatographic separation.
from hemin, which in turn is isolated from 3 without the need of an oxidizing agent. For these reasons, scale up problems are
ox or pork blood.[ For medical applica- Th e new methodology is well suited for
unavoidable and, indeed, literature prepa-
1,2]
tions, e.g. in cell culture media, this poses the synthesis of protoporphyrin IX on a rations are usually described in the mg
the problem of impurities of animal origin multi-100 g scale in good quality without range.
that may be present, in particular of agents the need for chromatography.
in connection with transmissible spongi-
We reasoned that in order to avoid the
formation of the dihydroporphin, one of
the two dipyrrylmethanes should either be
in a higher oxidation state or carry a nu-
cleofuge which can be eliminated to form
form encephalopathy. In order to meet the
[
3]
guidelines of the regulatory agencies, it Synthetic Concept
was necessary to provide a completely syn-
thetic preparation process for the prepara-
tion of protoporphyrin IX that uses only tion where a dipyrrylmethane unit is re- We decided to prepare the diiodo deriva-
products of synthetic origin.
acted with a dipyrrylmethane dialdehyde tive 1 and to react it under MacDonald con-
Th e classical MacDonald condensa- the required additional C=C double bond.
Here, we describe the total synthesis has been widely applied for the preparation ditions with dipyrrylmethane dialdehyde 2
of protoporphyrin IX and its disodium salt of a variety of unsymmetrically substituted (Scheme 1). To our delight and surprise,
[
5]
using a novel variant of the MacDonald porphyrins. Th e primary product is a di-
condensation method. Th e key step is the
hydroporphin which must then be oxidized 3 in good yields. We postulate that the pri-
reaction of the new unsymmetrical diiodo- to obtain the corresponding porphyrin us- mary condensation product is intermediate
we directly obtained the desired porphyrin
[
5]
[6]
ing either air or a quinone such as DDQ.
A which spontaneously eliminates water
In many cases, the oxidation step is rath- as well as one mol of HI to give the iodin-
er problematic since the dihydroporphin ated porphyrin B which then is reduced by
the HI formed in the first step to give 3 and
[7]
I . We consider the elimination of 2 mol
2
of HI improbable since a rather thermody-
namically unfavourable dehydroporphyrin
would be formed.
C
O H
2
NH
N
protoporphyrin IX
N
HN
CO H
2
Synthetic Details[8]
*
Correspondence: Dr. P. Martin
Solvias AG
Römerpark 2, CH-4303 Kaiseraugst
E-mail: pierre.martin@solvias.com
Th e synthesis of the new diiodo dipyr-
rylmethane 1 was carried out as depicted
Fig. 1.

Laureates: awards and Honors, sCs FaLL Meeting 2012
CHIMIA 2013, 67, Nr. 4 205
in Scheme 2. Th e partially optimized
O
O
OH
synthesis which delivered the desired in-
termediate in an acceptable over-all yield,
starts with the silylated propyne 4 which
is reacted with acetyl chloride in presence
I
OH
C
C
O Me
2
CO Me
2
I
NH
N
H
N
N
N
H
H
N
H
N
CO Me
HN
CO Me
2
of AlCl to give 3-pentyne-2-one (5). Th e
2
I
3
I
phosphine-catalyzed reaction of 5 with
OHC
O
benzyl isocyanoacetate gave the first pyr-
role unit 6 which was obtained in pure
form after chromatography in moderate
OH
O
1
2
A (not isolated)
yield. Th e second pyrrole moiety 9 was
AcOH/Ac O/CF SO H, rt
- 2H O
2
2
3
3
prepared starting from the commercially
available pyrrole ethyl ester 7 which was
first transformed to the corresponding ben-
zyl ester 8 with Na/BnOH at 190 °C and
then acetoxylated in presence of sulfuryl
-HI
O
O
C
O Me
CO Me
2
2
N
H
N
HI
N
N
chloride to give 9 in moderate yield. Th e
-
I
condensation of the two pyrrolo units 6
N
HN
2
N
HN
C
O Me
CO Me
2
I
2
and 9 catalyzed by HBF gave the desired
4
dipyrrylmethane 10 in an acceptable yield
of 68%.After removal of the benzyl groups
via hydrogenolysis with Pd/C to give the
diacid 11, the novel diiodo dipyrrylmeth-
ane 1 was obtained in excellent yield and
high purity as light red crystals.
O
O
3 (76%)
B (not isolated)
Scheme 1.
Th e synthesis of the second dipyrryl-
O
methane moiety 2 was carried out as de-
picted in Scheme 3. Commercially avail-
able 12 was brominated selectively and
C
H C
O
Cl, AlCl , CH Cl
O C
NCH CO Bn, PMe(Ph) 2
2 2
3
3
0°C to rt
(49%)
2
2
Si Me 3
CO Bn
2
dioxane, 100°C
49%)
N
H
5
then condensed with the loss of a C unit
4
1
(
6
to give dipyrrylmethane 13 in good yield.
Dialdehyde 2 was then obtained in excel-
lent yield via debenzylation with Pd/C to
give 14, followed by reduction with tri-
methyl orthoformate in presence of trifluo-
roacetic acid.
O
O
O
1) BnOH, 120°C
) Na/BnOH, 190°C
SO Cl
2
2
2
O Et
C
O Bn
N
2
C
H C
O
O
H, NaOAc, rt
CO Bn
2
C
3
N
N
H
2
H
AcO
O
H
(65%)
(
45%)
With the two dipyrrylmethane moieties
and 2 in hand, the condensation reaction
8
9
7
1
O
O
was carried out in a mixture of acetic acid,
acetic anhydride and trifluoromethyl sul-
C
O Bn
C
O H
I
2
2
.
Pd/C, THF
I ,NaHCO
2 3
HBF Et O
4
2
NH
NH
NH
fonic acid (Scheme 1). Th e desired por-
phyrin 3 was indeed obtained in excellent
6
+ 9
H
NEt
,1 bar, rt
H
H
D
CE, 90°C
3
H O/EtOH, rt
2
N
N
N
7
6% yield. Th e target protoporphyrin IX
C
O Bn
C
O H
I
2
2
(
16) and its disodium salt 17 were obtained
(68%)
(100%)
(92%)
as shown in Scheme 4 via reduction of the
O
O
O
two acetyl groups with NaBH to give the
4
1
10
11
hematoporphyrin ester 15, followed by
elimination of the intermediately formed
dibenzoates in good to excellent yields.
While 16 was obtained as violet-black
crystals of high purity, the disodium salt
was isolated as an amorphous powder.
As can be seen from the detailed exper-
imental part, the synthesis of 17 was first
carried out on a 6 g scale. While most inter-
mediates could be isolated via distillation
or crystallization some compounds had to
be purified by column chromatography. In
an intensive process development, all of
these chromatographic steps could be cir-
cumvented by relatively small variations of
Scheme 2.
C
O Me
2
BnO C
R
2
C
O Me 1) Pd/C, THF
CO Me
2
2
1) Br , TBME, rt to 50°C
N
H
1 bar, rt
N
2
H
2) HCl/MeOH, 50°C
2) CH(OMe) 3
HN
CO Me
H
N
CO Me
2
N
H
2
CF COOH, 0°C
3
BnO C
BnO
C
2
2
R
(63%)
(83%)
12
13
1
2
4 R= CO H
2
R=CHO
Scheme 3.
the experimental conditions. Th e improved
procedure was then applied to the prepa- Conclusions
ration of protoporphyrin IX derivatives on
rials via a modified MacDonald procedure.
Th e key step is the condensation reaction
a 100 g scale with an overall yield in the
range of 40% starting from 1 and 2.
Protoporphyrin IX dimethyl ester 16 of the diiodo dipyrrylmethane 1 with the
and its disodium salt 17 can be prepared dialdehyde 2 which directly furnishes the
from commercially available starting mate- porphyrin 3 without the need of oxidation

206 CHIMIA 2013, 67, Nr. 4
Laureates: awards and Honors, sCs FaLL Meeting 2012
O
HO
C
O Me
CO Me
2
2
NH
N
NaBH , MeOH
NH
N
4
N
HN
C
H
2
Cl
2
,rt
N
HN
C
O Me
CO Me
2
2
O
HO
(96%)
3
15
(77%)
BzCl, DMF, 100°C
C
O Na
CO Me
2
2
NH
N
NH
N
CH Cl , MeOH; NaOH 40°C
2 2
N
HN
N
HN
C
O Na
CO Me
2
2
(94%)
17
16
Scheme 4.
[
2] A. H. Jackson, K. R. Rao, M. Wilkins, J. Chem.
Soc., Perkin Trans. 1 1987, 307; W. Chen, H.
Yang, D. Xu Zhnongguo Yiyao Gongye Zazhi
of a dihydroporphyrin intermediate. Both
dipyrrylmethane units can be prepared
on multi-100 g scale in excellent purity
2
000, 31, 293. CAN 134: 193262.
and satisfactory yield without the need of [3] Official J. Europ. Union, C24, 28.1.2004, p. 6.
chromatography.
[4] R. Chong, P. S. Clezy, A. J. Liepa, A. W. Nichol,
Austr. J. Chem. 1969, 22, 229; A. H. Jackson, R.
K. Pandey, J. Chem. Soc., Perkin Trans. 1 1987,
2
99.
Acknowledgements
[
5] G. P. Arenault, E. Bullock, S. F. MacDonald,
J. Am. Chem. Soc. 1960, 82, 4384; M.
Chakrabarty, J. Ind. Chem. Soc. 2001, 78, 761;
P. S. Clezy, V. Diakiw, Austr. J. Chem. 1975, 28,
We thank Sanofi-Pasteur for the fruitful
collaboration and the permission to publish our
results.
2
703.
[
6] C.-H. Lee, F. Li, K. Iwamoto, J. Dadok, A. A.
Received: October 8, 2012
Bothner-By, J. S. Lindsay, Tetrahedron 1995,
5
1, 11645.
[
1] Th e original procedure was first reported by
[
7] Indeed, I could be observed when the reaction
2
M. Schalfejew, Hoppe Seylers Zeitschrift 1900,
solution was heated in the rotovap. Furthermore,
small amounts of
isolated via chromatography which showed the
appropriate mass corresponding to intermediate
B and reacted to give 3 in presence of HI.
3
0, 390 (see also Ullmann, Encyklopädie der
a compound could be
technischen Chemie, IV edition, 1976, Vol. 11,
p. 129). An improved procedure is described by
H. Schulze, US-Pat. 4761472 (1988, assigned
to BASF). About 3-4 g of heme are obtained
from 1 l of oxblood.
[
8] For experimental details see P. Martin, M.
Müller, D. Flubacher, A. Boudier, H. U. Blaser,
D. Spielvogel, Org. Process Res. Devel. 2010,
1
4, 799.