The present invention relates to a novel process for preparing porphyrin derivatives, such as protoporphyrin (IX), and also to intermediates for the synthesis of these compounds.
Certain porphyrins are l98%)

A 2.51 Keller round-bottomed flask equipped with a reflux condenser/distillation head, a thermometer, a dropping funnel and an argon conduit is loaded with a solution of ethyl 4-acetyl-3,5-dimethylpyrrole-2-carboxylate (commercial product, Alpha Aesar, Karlsruhe, Germany/product No. A 17365) (146.00 g, 0.70 mol) in benzyl alcohol (1.001) and heated to 120°C, which results in the azeotropic removal of minor amounts of water. The mixture is then heated to 190°C. The dropping funnel is loaded with a separately prepared solution of sodium (2 g) in benzyl alcohol (20 ml). This solution is added in 5 ml portions, which results in a vigorous reflux of the reaction mixture. The resulting methanol and ethanol are removed semi-continuously by distillation. The conversion is followed by HPLC. The reaction mixture is cooled to 150°C and then

transferred into a mixture of methanol (0.96 I), water (0.66 I) and acetic acid (12 ml). The mixture is cooled to -10°C and again stirred at this temperature for 1.5 h. The precipitated product is isolated by filtration. The product is dried under reduced pressure, to give the compound (VIII.l) (124.40 g, 65%) in the form of an off-white solid.
^H NIVJR (300MHz, CDCI3): 2.34 (s, CH3), 2.40 (s, CH3), 2.52 (s, CH3), 5.23 (s, CH2), 7.85 (m, 5H), 9.55 (broad singlet, NH)

A 2.5 I Keller round-bottomed flask equipped with a reflux condenser, a thermometer, a dropping funnel and an argon conduit is loaded with compound (VIII.l) (66.84 g, 0.25 mol), acetic acid (1.25 1) and sodium acetate (73.90 g, 1.51 mol). In order to obtain a clear solution, the mixture is heated to ~35°C and then cooled to ambient temperature. Sulfuryl chloride (32.4 ml, 0.40 mol) is added in 2 h, while the reaction is carefully controlled toward the end of the addition, in order to minimize by-product formation due to overreaction. Additional amounts of sodium acetate (50.0 g) are added, at ambient temperature, and the mixture is again stirred at ambient temperature overnight. Water (500 ml) Is added, to give a clear solution. After the addition of a 9-1 water-methanol mixture (4.5 I), the reaction mixture is again stirred at ambient temperature for 1 h with precipitation of the product. The product is isolated by filtration and dissolved by refluxlng in ethyl acetate (220 ml). The two-phase mixture is removed from the oil bath and methanol (200 ml) is added with stirring. After further stirring for 1 h at ambient temperature, the product begins to crystallize. Additional amounts of methanol (500 ml) are added and the mixture is stirred and cooled to -10°C. The product is

isolated by filtration. The product is dried under reduced pressure, to give the compound (VI.l) (37.14 g, 45%) in the form of a white solid.
^H NIMR (300MHz, CDCI3): 2.07 (s, CH3), 2.41 (s, CH3), 2.53 (s, CH3), 5.27 (s, CH2), 5.31 (s, CH2), 7.32 (m, 5H), 9.40 (broad singlet, NH).
RP-HPLC:
HP Hypersil BDS-C C18, 125*4 mm, 25°C
Solvents with 0.1% of TFA: acetonitrile (ACN)-water: from 1 to 100% of ACN for 10 min, then 2 min with 100% of ACN
Flow rate: 1 ml/min, detection at 220 nm
Sample: 1 mg/1.5 ml of ACN
Yield: 7.89 min (>94%)

A 2.5 I Keller round-bottomed flask equipped with a reflux condenser, a :hermometer, a dropping funnel and an argon conduit is loaded with glycine [80,00 g, 1.07 mol), benzyl alcohol (700 ml) and p-toluenesulfonic acid Tionohydrate (241 g, 1.27 mol). The thick white mixture is heated to 100°C, A/hich results in the formation of a clear solution, The mixture is again stirred at 100°C for 5 h. The mixture is cooled to ambient temperature. Diethyl ether (4 1) is added slowly, which results in precipitation of the product. The product is isolated 3y filtration, washed with ether (3x0.3 I) and dried under reduced pressure at 50°C. Because the conversion is incomplete, the white solid is taken up, in toluene

(2.3 I), and benzyl alcohol (03 I) and p-toluenesulfonic acid monohydrate (20 g) is added. Tine mixture is refluxed for 4 h, winile tlie water is continuously removed by means of a Dean-Stark apparatus. The mixture is cooled to ambient temperature. Diethyl ether (11) is added slowly and the mixture is cooled to 0°C, which results In precipitation of the product. The product is isolated by filtration, washed with ether (3 x 0.3 I) and dried under reduced pressure at 60°C, to give the compound (9) (303.20 g, 84%) in the form of a white crystalline product.
^H NMR (300MHz, DMSO-De): 2.28 (s, CH3), 3.90 (s, CH^), 5.25 (s, CH2), 7.15 and 7.39 (AB, 4H), 7.37 (mi, 5H).

A 2.5 I Keller round-bottomed flask equipped with a reflux condenser, a thermometer, a dropping funnel and an argon conduit is loaded with methyl formate (700 ml), compound (9) (303.0 g, 898.0 mmol) and triethylamine . (137 ml, 1 mol). The mixture is refluxed for 22 h. The conversion is followed by HPLC. The heterogeneous mixture is concentrated under reduced pressure, to give an oil (429 g). The product is dissolved in dichloromethane (1.5 I), washed with bicarbonate (2x0.5 1) and water (0.5 1). The combined aqueous phase, is - re-extracted with dichloromethane (0.5 I). The combined organic phase is dried (Na2Sd4), filtered and concentrated under reducedpressure (40 mbar, 45°C, 1 h), to give the compound (8) (149.2 g, 86%) in the form of an orangey yellow oil.
,^H NMR (300MHz, CDCI3): 4.12 (d, CH2), 5.19 (s, CH2), 6.33 (broad singlet, NH), 8.23 (s, CHO).

A 2.5 1 Keller round-bottomed flask equipped with a reflux condenser, a

thermometer, a dropping funnel and an argon conduit Is loaded with the compound C8) (129.7 g, 671.3 mmol) and dichloromethane (1 I). The mixture is cooled to 0°C. Triethylamine (234 ml, 1678 mmol) is added to give a yellow solution. POCI3 (102.9 g, 671.3 mmol) is added in 50 min, while the temperature is maintained at between 0 and 5°C. The mixture is stirred for a further 2 h while it is heated to ambient temperature. A solution of k2C03 (134 g) in water (600 ml) is added slowly and carefully in small portions at between 25 and 30°C. After complete addition, the mixture is stirred for a further 1 h. Water (11) is added and the phases are separated. The organic phase is washed with water (0.2 I). The combined aqueous phase is re-extracted with dichloromethane (0.5 I). The combined organic phase is dried (NazSOn), filtered and concentrated under reduced pressure, to give a brown oil (180 g). Chromatography is carried out on silica (500 g), elution being carried out with dichloromethane. The fractions containing the product are combined and concentrated under reduced pressure, to give an orangey-yellow oil. Storage at -10°C allows crystallization of the compound (7) (101.9 g, 87%) so as to form a stable product.
^H NMR (300MHz, CDCI3): 4.22 (s, CH2), 5.23 (s, CH2), 7.38 (s, 5H).

A 4.5 I Keller round-bottomed flask equipped with a reflux condenser, a thermometer, a dropping funnel and an argon conduit is loaded with aluminum trichloride.(297.00 g, 2.23 mol) and dichloromethane (2.3 I).and cooled to 0°C. A solution of trimethylsilylpropyne (250.00 g, 2.23 mol) and acetyl chloride (0.16 I, 2.23 mol) in dichloromethane (0.4 I) was added to the light yellow suspension in 1.5 h, the temperature being maintained at between 0 and 5°C. The brown solution with a certain amount of precipitated salt is heated to ambient temperature. The resulting reddish-brown solution is poured into ice/water (2 I).

The layers are separated and the aqueous phase is extracted with dichloromethane (0.5 I). The combined organic phase is washed with water (0.5 I), dried (Na2S04), filtered and concentrated under reduced pressure, to give a greenish-black liquid (558 g). The product is distilled at 180 mbar, to give a fraction (-160 g) that boils betv»/een 64 and 70*^C. This product is again distilled at 210 mbar, to give the compound (IX.l) (90.30 g, 49%) in the form of a colorless liquid that has a boiling point of between 81 and 85°C.
^H NMR (300MHz, CDCI3): 2.02 (s, CH3), 2.31 (s, CH3).

A 11 Keller round-bottomed flask equipped with a reflux condenser, a thermometer, a dropping funnel and an argon conduit is loaded successively with the compound (7) (101,90 g, 0.58 mmol), dioxane (0.5 I) and the compound IX-1 (52.53 g, 0.64 mol). When methyldiphenylphosphine (38.4 g, 0.19 mol) is added, the reaction becomes highly exothermic.
The reaction mixture becomes dark and is heated at 100°C for 1 h. The conversion is followed by HPLC. The volatile products are removed under reduced pressure. The crude brown oil (209 g) is purified by chromatography on silica (2.1 kg), elution being carried out with a toluene/ethyl acetate (8/1) mixture. The fractions containing the pure product are combined and the volatile products are removed under reduced pressure, to give the compound (VII.l) (73.49 g, 49%) In the form of a light brown syrupy oil.
^H NMR (300MHz, CDCI3): 2.13 (s, CH3), 2.54 (s, CH3), 5.32 (Ss, CH2), 6.68 (d, CH), 7.38 (m, 5H), 9.20 (broad singlet, NH).
RP-HPir-

HP Hypersi! BDS-C C18, 125*4 mm, 25°C
Solvents with 0.1% of TFA: acetonitrile (ACN)-water: from 1 to 100% of ACN for 10 min, then 2 min with 100% of ACN Flow rate: 1 ml/min, detection at 220 nm Sample: 1 mg/1.5 ml of ACN Yield: 7.55 min (>91%)

A 4.5 I Keller round-bottomed flask equipped with a reflux condenser, a :hermpmeter, a dropping funnel and an argon conduit is loaded with the :ompound (3) (52.0 g, 165.0 mmol) and diethyl ether (1.51). A freshly prepared solution of bromine (11.0 ml, 214.0 mmol) in diethyl ether (0.5 I) is added Jropwise in 20 min at ambient temperature, so as to produce an orangey-brown jolution. The conversion is followed by HPLC. If necessary, additional amounts of DrOmine are added. The mixture is again stirred at ambient temfjerature. The /olatile products are removed under reduced pressure and th6 grayish-brown esidue is dissolved in methanol (364 ml). The solution is heated at >^50°G until :omplete conversion is obtained, (determined by HPLC after approximately 11 h). The dark reaction mixture is concentrated under reduced pressure until the )rGduct begins to crystallize. The precipitated product is isolated by filtration and vashed with methanol (0.2 I). The crude product is recrystallized by suspending in Jiethyl ether (0.6 I) and refluxing, while heptane (1.8 I) is added and the heating 3 continued so as to maintain the mixture at reflux for a further 15 min. The nixture is cooled to ambient temperature and the product is isolated by filtration.

The product is dried, to give tj-ie compound (2) (31.70 g, 63%) in ttie form of a light gray powder.
^H NMR (300MHz, CDCI3): 2.21 (s, two CH3), 2.43 (t, two CH2), 2.68 (t, two CH2), 3.50 (s, two CH3), 3.89 (s, CH2), 5.17 (s, two CH2), 7.20 (m, lOH), 9.00 (broad singlet, two NH).

A low-pressure hydrogenation apparatus is loaded with the compound (2) (30.7 g, 49.9 mmol), THF (400 ml) and catalyst Pd/C at 10% (1.5 g, A027). The hydrogenation is carried out at ambient temperature under a hydrogen pressure atmosphere in 3 h. 2N ammonia (0.11) is added to the reaction mixture and the catalyst is removed by filtration. The filtrate is adjusted to pH ~7 by adding acetic acid (60 ml). The solvent is removed under reduced pressure. The precipitated product is isolated by filtration, to give, after drying, the compound (1) (21.7 g, quantitative) in the form of a white powder.
^H NMR (300MH2, DMS0-D6): 2.18 (s, two CH3), 2.20 (t, two CH2), 2.59 (t, two CH2), 3.60 (s, two CH3), 3.82 (s, CH2).


A 1 i Keller round-bottomed flask equipped with a reflux condenser, a thermometer, a dropping funnel and an argon conduit Is loaded with trifluoroacetic acid (190 ml) and cooled to 0°C. The compound (1) (20.0 g, 46.0 mmol) is added in small portions in 10 min at 0°C. The mixture is stirred again at 0°C for 1 h. The conversion is followed by HPLC. Trimethyl ortho-formate (57 ml) is added dropwise in 30 min, while the temperature is maintained at between 0 and 5°C. The reaction mixture is stirred for a further 1 h at 0°C and then poured into water (1.7 I). The mixture is stirred vigorously for 10 min. The precipitated crude product is isolated by filtration, followed by washing with water (0.3 I), in the form of an orange powder. The crude product is triturated In ethanol (0.2 I) and ammonia (0.4 I). The mixture is stirred for 30 min at ambient temperature and the product is Isolated by filtration, followed by washing with water (0.3 I), in the form of a dark yellow powder. The product is refluxed in methanol (0.4 I) for 10 min. The mixture is cooled to ambient temperature and the product is isolated by filtration and washed with cold methanol (0.11). The product is dried under reduced pressure, to give the compound (II.l) (15.30 g, 83%) In the form of a light yellow powder.
^H NMR (300I^Hz, CDCI3): 2.30 (s, two CH3), 2.53 (t, two CH2); 2.81 (t, two CH2), 3.72 (s, two CH3), 4.06 (s, CH2), 9.46 (s, two CHO), 10.43 (broad singlet, twoNH).
RP-HPLC:
HP Hypersil BDS-C C18, 125*4 mm, 25°C
Solvents with 0.1% of TFA: acetonitrile (ACN)-water: from 1 to 100% of ACN for 10 min, then 2 min with 100% of ACN
Flow rate: 1 ml/min, detection at 220 nm
Sample: 1 mg/1.5 ml of ACN
Yield: 6.78 min (>96%)


A 2.5 I Keller round-bottomed flask equipped with a reflux condenser, a thermometer, a dropping funnel and an argon conduit is loaded with the compound (VII.l) (50.0 g, 194.4 mmol), the compound (VI.l) (51.3 g, 155.6 mmol) and dichloroethane (1.11). The mixture is heated to 40°C, to give an orangey-red solution. l-iBF4 etherate (2.35 ml (54%), 9.3 mmol) is added and the mixture is heated rapidly to 90°C. The conversion is followed by HPLC. After 1 h, the mixture is cooled rapidly to ambient temperature and poured into a saturated bicarbonate solution (0.5 I). The layers are separated and the aqueous phase is extracted with, dichloroethane (0,5 I). The combined organic extracts are dried (Na2S04), filtered, stirred with Norrit C (2 g), filtered and completely concentrated under reduced pressure, to give a sticky brown syrup (96.5 g). The crude product is dissolved in methanol (0.3 I), concentrated under reduced pressure and again dissolved in methanol (150 ml). Germination crystals are added and the mixture is left to stand for 15 h at ambient temperature while the product.crystallizes. The supernatant is removed and the crystals (fraction Kl, 34.3 g) are washed with methanol. The combined methanol fractions are completely concentrated under reduced pressure and chromatographed on silica (420 g), elution being carried out with hexane/ethyl acetate (2/1). The fractions containing the product are combined and concentrated under reduced pressure. The product Is recrystallized as above in methanol, to give a fraction K2 (16.7 g). The supernatant Is again chromatographed on silica (400 g), elution being carried out with hexane/ethyl acetate (2/1). The fractions containing the product are combined and concentrated under reduced pressure. The product is recrystallized as above from methanol, to give a fraction K3 (3.7 g). The product fractions (Kl - K3) are

combined, dissolved in toluene and completely concentrated under reduced pressure. After drying under reduced pressure at 50°C for 1 h, the compound (V.l) (54.7 g, 68%) is recovered In tfie form of off-white crystals.
^H NI^R (300MHz, CDCI3): 2.09 (2.09, CH3), 2.49 (s, CH3), 2.50 (s, CH3), 2.58 (s, CH3), 4.04 (s, CH2), 5.27 (s, CH2), 5.29 (s, CH2), 7.35 (m, lOH), 10.5 (broad singlet, NH).

A low-pressure hydrogenation apparatus is loaded with the compound (V.l) [54.3 g, 103.1 mmol), tetrahydrofuran (700 ml), triethylamlne (20.8 g, 206.2 mmol) and catalyst Pd/C at 10% (2.75 g). The hydrogenation is carried out at ambient temperature under a hydrogen pressure atmosphere in 3 h. The catalyst is removed by filtration. The filtrate is concentrated under reduced pressure. After drying under reduced pressure at 45°C for 0.5 h, the compound [IV.l) (54.7 g, quantitative) is recovered in the form of an off-white foam, In the form of a monotrlethylamine salt containing residual amounts of toluene and of THF.
^H NMR (300MHz, DMS0-D6): 1.97 (s, CH3), 2.38 (s, CH3), 2.52 (s, two CH3), 4.14(s, CH2).


A 2.5 I Keller round-bottomed flask equipped with a reflux condenser, a
thermometer, a dropping funnel and an argon conduit is loaded with solid NaHCOs
(55.6 Q, 662.0 mmol), water (900 ml) and ethanol (300 ml). A solution of the
compound (IV.l) (54.3 g, 101.9 mmol) in ethanol (300 ml) Is added. A solution
of iodine (64.7 g, 254.9 mmol) in ethanol (400 ml) Is added, at ambient
temperature, to give a brown heterogeneous mixture. A certain amount of
foaming and a reduced exothermia are observed. The conversion is followed by
HPLC. The reaction mixture is stirred again at ambient temperature for 5 h. The
reaction mixture is diluted with water (0.1 I) and the precipitated product is
isolated by filtration. The precipitate is washed with water (3 x 0.11), ethanol
(2x0.1 I) and ether (2x0.11). After drying of the crystals of product under
reduced pressure at 60°C, the compound (III.a) (48.1 g, 92%) is recovered in
the form of light red crystals.
^H NIVIR (300MHz, DMSO-De): 2.06 (s, CH3), 2.15 (s, CH3), 2.33 (s, CH39, 4.08(s,:CH2).
RP-HPLC:
HP.Hypersll BDS-C CIS, 125*4 mm, 25°C
Solvents with 0.1% of TFA: acetonitrile (ACN)-water: from 1 to 100% of ACN for 10 min, then 2 min with 100% of ACN
Flow rate: 1 ml/min, detection at 220 nm
Sample: 1 mg/1.5 ml of ACN
Yield: 8.13 min (>92%)


A 2.5 I Keller round-bottomed flask equipped with a reflux condenser, a thermometer, a dropping funnel and an argon conduit is loaded with acetic acid anhydride (290 ml), acetic acid (1.8 I) and trifluoromethanesulfonic acid (4.95 ml, 56.77 mmol). A substantially homogeneous solution of the compound (II.l) (12.00 g, 29.82 mmol) and of the compound (Ilia) (14.48 g, 28.40 mmol) in acetic acid (400 ml) is added, at ambient temperature, in 5 min, which produces a blood red solution. No exothermia is observed. The mixture is stirred again at ambient temperature for 1 h, with the formation of a certain precipitate. The conversion is followed by HPLC. A solution of NaOAc (9.4 g) in acetic add (100 ml) is added, to give a dark brown solution. After 10 min, the volatile products are removed under reduced pressure and dried under reduced pressure for 1.5 h at 50°C, The dark residue is taken up in dichloromethane (300 ml) and water (500 ml) without vigorous mixing. The organic layer is separated and the aqueous phase Is extracted with dichloromethane (0.3 1). The combined organic phase is dried (Na2S04), filtered and concentrated, to give a black crystalline product (31.3 g). The mixture is dissolved in dichloromethane and applied to a column of silica gel (1kg) covered with dichloromethane/acetone (95/5). The product is eluted with a gradient of 95/5 to 90/10. The fractions containing the product are combined and completely concentrated under reduced pressure. The compound (la.l) (9,97 g, 55%) is recovered in the form of violet-black crystals. ^H NMR (300MHz, CDCI3): 3.15 (two t, two CH2), 3.17 (s, CH3), 3.25 (s, CH3), 3.39 (s, CH3), 3.50 (s, CH3), 3.60 (s, CH3), 3.64 (s, CH3), 3.65 (s, CH3), 3.71 (s, CH3),

4.22 (two t, two CH2), 9.50 (s, CH), 9.59 (s, CH), 10.43 (s, CH), 10.46 (s, CH).
RP-HPLC:
HP Hypersil BDS-C C18, 125*4 mm, 25°C
Solvents with 0.1% of TFA: acetonitrile (ACN)-water: from 1 to 100% of ACN for 10 min, then 3 min with 100% of ACN
Flow rate: 1 ml/min, detection at 220 nm
Sample: 1 mg/1.5 ml of ACN
Yield: 11.66 min (>93%)

All Keller round-bottomed flask equipped with a reflux condenser, a thermometer, a dropping funnel and an argon conduit is loaded with the compound (la.1) (9.86 g, 15.84 mmol), dichloromethane (500 ml) and methanol (24 ml). NaBH4 (3.00 g, 79.32 mmol) is added portionwise to the reddish-brown mixture. A certain foaming is observed. The reaction is closely followed by HPLC. After 80 min, the mixture is poured into a mixture of water (500 ml) and 4N HCI (80 ml). Gas is seen to be given off. The mixture is neutralized by adding solid NaHCba. The layers are separated and the aqueous phase is extracted with dichloromethane (2 x 300 ml). The combined organic extracts are dried (Na2S04), filtered and concentrated under reduced pressure. After drying under reduced pressure at 50°C for 0.5 h, the compound (Ib.l) in the form of a mixture of two stereoisomers (9.58 g, 96%) is recovered In the form of violet-black crystals.

^H NMR (300MHz, CDCI3): 1.92 (m, 6H, two CH3), 3.16 (m, 4H, two CH2), 3.28, 3.30, 3.33 and 3.35 (4s, 6H, two CH3), 3.43 (s, 6H, two CH3), 3.66 (s, 6H, two CH3), 4.20 (m, 4H, two CH2), 6.05 (m, 2H, two CH), 9.73, 9.74, 9.75, 9.76, 10.00, 10.02, 10.08 and 10.10 (8s, total 4H, four CH).
RP-HPLC:
HP Hypersil BDS-C C18, 125*4 mm, 25°C
Solvents with 0.1% of TFA: acetonitrlle (ACN)-water: from 1 to 100% of ACN for 10 min, then 3 min with 100% of ACN
Flow rate: 1 m!/min, detection at 220 nm
Sample: 1 mg/1.5 ml of ACN
Yield: 7.90 min, 51% and 8.01 min, 49%

All Keller round-bottomed flask equipped with a reflux condenser, a thermometer, a dropping funnel and an argon conduit is loaded with the compound (Ib.l) (9.48 g, 15.12 mmol) and DMF (400 ml) and the mixture is degassed with argon. Benzoyl chloride (45.0 ml, 387.9 mmol) is added and the mixture is rapidly heated to 100°C. The mixture is stirred again at 100°C for 1 h. The conversion is followed by HPLC. The reaction mixture is cooled rapidly and the volatile products are removed under reduced pressure. The residue is dissolved in dichloromethane (0.3 I) and stirred vigorously With a water/methanol (0.3 I) mixture. The layers are separated and the aqueous phase is extracted with

dichloromethane (2 x 0.2 I). The combined organic extracts are washed with bicarbonate (0.3 I), dried (Na2S04) and filtered. The filtrate is treated with silica (20 g) and filtered. I^ethanol (50 ml) is added and the mixture is then concentrated under reduced pressure, while crystallization takes place toward the end, to give a violet-black product (20 g). The product is triturated with methanol at 50°C for 0.5 h. After cooling to ambient temperature, chloroform (2 ml) is added and the product is isolated by filtration. After drying under reduced pressure at 50°C for 15 h, the compound (Ic.l) (6.34 g, 77%) Is recovered in the form of shiny violet-black crystals.
^H NMR (300MHz, CDCI3): 3.23 (t, two CH3), 3.52 (s, CH3), 3.54 (s, CH3), 3.58 (s, CH3), 3.64 (s, CH3), 3.64 (s, CH3), 3.65 (s, CH3), 3.66 (s, CH3), 4.32 (t, two CH2), 6.11-6.34 (m, 4H, two CH2=), 8.10-8.23 (m, 2H, two CH=), 9.85, 9.86, 9.97 and 9.98 (4s, 4CH).
RP-HPLC:
HP Hypersil BDS-C C18, 125*4 mm, 25°C
Solvents with 0.1% of TFA: acetonitrile (ACN)-water: from 1 to 100% of ACN for 10 min, then 6 min with 100% of ACN
Flow rate: 1 ml/min, detection at 220 nm
Sample: 1 mg/1.5 ml of ACN
Yield: 12.43 min (>97%)


A 2.5 I Keller round-bottomed flask equipped with a reflux condenser, a thermometer, a dropping funnel and an argon conduit is loaded with the compound (Ic.l) (6.30 g, 10.67 mmol) and- dichloromethane (200 ml). The product is dissolved by heating to 40°C. At 40°C, methanol (400 ml) followed by 4N NaOH (200 ml) are successively added. The formation of a precipitate is observed. The mixture is refluxed. The conversion is followed by HPLC. The organic volatile products are removed under reduced pressure. The suspension is filtered through a glass fiber filter. The product is washed with water (3 x 0.11), methanol (3 x30 ml) and diethyl ether (2x30 ml). After drying under reduced pressure at 70°C for 2 h, then at 40°C for 15 h, the compound (Ic.2, 2Na) (6.06 g, 94%) isrecovered in the form of a violet-black solid product. ^H NMR (300MHz, TFA-Di): 3.45 (two t, two CH2), 3.82 (s, CH3), 3.85 (s, CH3), 3.88 (s, CH3), 3.91 (s, CH39, 4.73 (tm t, two CH2), 6.43-6.70 (m, 4H, two CH2=), 8.28-8.40 (m, 2H, two CH=), 11.08, 11.11, 11.15, and 11.27 (4s, 4CH).
RP-HPLC:
HP Hypersil BDS-C C18, 125*4 mm, 25°C
Solvents: acetonitrile (ACN) with 0.1% of TFA-water with 0.1% of TFA; from 1 to 100% of ACN for 10 min, then 6 min with 100% of ACN
Flow rate: 1 ml/min, detection at 220 nm , Sample: 0.1 mg/1.5 ml of AcOH/DMF
Yield: 9.85 min (>98%)

Elemental analysis
Theory for C34,.H32.N4.04.Na2 (MW 606.63) Result
"^ 67.32 +/- 0.3% m/m ,64.91% m/m
H 5.32+/-0.3% m/m 5.38% m/m
\J 9.24 +/- 0.3% m/m 8.94% m/m
lA/ater 3.56% m/m
\Ja 7.58 m/m 7.15% m/m
lA/ith measurements adjusted after the addition of 1.24 mol of water (amount of

water measured by Karl-Fisher titration) per mole of product.

Theory for C34.H32..N4.04.Na2.
H2OI.24
(MW 636.54) Result
c 64.93 +1- 0.3% m/m 64.91% m/m
H 5.28 +/- 0.3% m/m " 5.38% m/m
IM 8.91 +/- 0.3% m/m 8.94% m/m
Water 3.56 m/m 3.56% m/m
Na 7.31 m/m 7.15% m/m
H^

1 - A process for preparing a porphyrin of formula (I), optionally In tlie form of a salt:
in which:
- R Is a hydrogen atom or a group selected from: -CH=CH2, -CH2-CH3,
-CH(0H)CH3, -C(0)CH3 and -CHzCHaCOOR'a, with R'a being a hydrogen atom or a
methyl, ethyl, n-propyl or i-propyl group,
- R' is a hydrogen atom or a group R'b selected from methyl, ethyl, n-propyl or
i-propyl,
comprising:
- a step of condensation, in an acidic medium, between a dipyrromethane of
formula (II):
i
i

in which R" is identical to R as defined above for (I) or is a group that is a precursor of R, so as to form the porphyrin of formula (I'):

in which R" and R'b are as defined above for (II) and (III), followed:
- when R" is a group that is a precursor of R, by conversion of the groups R" to R,
- when R'=H, by elimination of the groups R'b so as to form -COOH groups, optionally in the form of a salt.

2 - The process as claimed in claim 1, in which R" is a hydrogen atom or a group selected from: -CH=CH2, -CH2-CH3, -CH(0H)CH3, -C(0)CH3, -CH2CH2OH, -CH2CH2CI and -CH2CH20C(0)CH3 -CH2GH2GOOR'a, with R'a being a hydrogen atom or a methyl, ethyl, n-propyl or i-propyl group.
3 - The process as claimed in claim 1 or 2, characterized in that it is implemented for the preparation of a compound of formula (I) in which R is a hydrogen atom or a group selected from: -CH2-CH3, -CH(0H)CH3, -C(0)CH3 and -CH2CH2COOR'a, with R'a being a hydrogen atom or a methyl, ethyl, n-propyl or i-propyl group.
4 - The process as claimed In claim 1 or 2, characterized in that it is implemented for the preparation of a compound of formula (I) in which R is a -CH=CH2 group, comprising:
a step of condensation, in an acidic medium, between a dipyrromethane of formula (II):


in which R" is a group that is a precursor of R, foiiowed by conversion of the groups R" to R,
and when R'=H, by elimination of the groups R'b so as to obtain -COOH groups, optionally in the form of a salt.
5 - The process as claimed in claim 4, characterized in that R" is a
-CH2CH2OH, -CH2CH2CI, -CH2CH20C(0)CH3, -CH(0H)CH3 or -C(0)CH3 group.
6 - The process as claimed in claim 4 or 5, characterized in that R" is a
■CH(0H)CH3 or-C(0)CH3 group.
7 - The process as claimed in claim 1 or 2, characterized In that it is
mplemented for the preparation of a compound offormula'CIA):

n which R' is as defined for (I), or a salt thereof, by coupling the pyrromethane of
formula (II):


followed, in the case where R' is a hydrogen atom, by a step consisting of elimination of R'b by a hydrolysis reaction so as to give -COOH groups, or, optionally in the case where the compound (lA) to be formed is in the form of a salt, by a saponification step.
8 - The process as claimed in claim 7, characterized in that R'b is a
methyl group.
9 - The process as claimed in claim 1 or 2, characterized in that it is
implemented for the preparation of a compound of formula,(IB):

in which R' is as defined for (I), or a salt thereof, by coupling the pyrromethane of formula (II):


so as to form the compound of formula (la):

in which R'b is as defined for (I),
followed by reduction of the -C(0)CH3 groups to -CH(0H)CH3, :
and, in the case where R' is a hydrogen atom, by a step consisting of elimination
of R'b by a hydrolysis reaction so as to give-COOH groups,
or else, in the case where the compound (IB) to be.formed is in the form of a salt,
by a saponification step.
10- The process as claimed in claim 9, characterized In that the reduction of the -C(0)CH3 groups is carried out in the presence of a hydride.
11 - The process as claimed in claim 9 or 10, characterized in that the
reduction of the -C(0)CH3 groups Is carried out in dichloromethane in the
presence of methanol.
On

12 - The process as claimed in one of claims 1, 2 and 4 to 6, cfiaracterized in that it is implemented for the preparation of the compound of formula (IC):


so as to form the compound of formula (la):

in which R'b is as defined for (I),
followed:
- by reduction of the -C(0)CH3 groups, resulting in the formation of the porphyrin
of formula (lb):

in which R'b Is as defined for (I),
- followed by an elimination reaction that converts the groups -CH(0H)CH3 to -CH=CH2,
- and, in the case where R' is a hydrogen atom, by a step consisting of elimination of R'b by hydrolysis so as to give -COOH groups,
or, in the case where the compound (IC) to be formed is in the form of a salt, by a saponification step.
13 - The process as claimed in claim 12, characterized in that the elimination reaction that converts the groups -CH(0H)CH3 to -CH=CH2 is carried out in the presence of an acid halide.
14 - The process as claimed in claim 12 or 13, characterized in that the

elimination reaction that converts tfie groups -CH(0H)CH3 to -CH=CH2 is carried out in an aprotic polar solvent.
15 - The process as claimed in one of claims 12 to 14, characterized in
that the reduction of the -C(0)CH3 groups is carried out in the presence of a
hydride.
16 - The process as claimed in one of claims 12 to 15, characterized in
that the reduction of the -C(0)CH3 groups is carried out in dichloromethane in the
presence of methanol.
17 - The process as claimed in one of claims 1 to 16, characterized in
that R'b is a methyl group.
18 - The process as claimed in one of claims 12 to 17 for preparing
protoporphyrin (IX) in the form of the sodium salt of formula (IC.2, 2Na):

in which R'b is as defined in claim 1, by the action of sodium hydroxide in the presence of methanol.
19 - The process as claimed in claim 18, characterized in that the

saponification step is carried out in dichloromethane at reflux.
20 - The process as claimed in one of the preceding claims, characterized in that the condensation reaction between the two pyrromethanes (II) and (III) or (Ilia) is carried out in the presence of an add selected from the carboxylic acids, trifluoroacetic acid, hydrochloric acid, trichloromethanesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, tetrafluoroborlc acid, hydrobromic acid and hydriodic acid.
21 - The process as claimed in claim 20, characterized in that the acid is trifluoroacetic acid or trichloromethanesulfonic acid.
22 - The process as claimied in one of claims 1 to 21, characterized in that the condensation reaction between the two pyrromethanes (II) and (III) or 'Ilia) is carried out in the presence of a desiccating agent.
23 - The process as claimed in claim 22, characterized in that the jesiccating agent is selected from anhydrides, molecular sieves and sulfuric acid.
24 - The process as claimed in claim 23, characterized in that the jesiccating agent is acetic anhydride.
25 - The process as claimed in claim 24, characterized in that the acetic anhydride is present in an excess, preferably of at least 10 molar equivalents ■elative to the pyrromethane (II).
26 - The process as claimed in one of claims 1 to 25, characterized in :hat the condensation reaction betv/een the two pyrromethanes (II) and (III) or Ilia) is carried out according to a molar equivalent ratio of between 1 and 1.2.
27 - The process as claimed in one of claims 1 tp 26, characterized in :hat the condensation reaction between the two pyrromethanes (II) and (III) or Ilia) is carried out at a temperature of from 10 to 50°C in a protic solvent.
28 - A process for preparing a metal complex of a porphyrin of formula I), optionally in the form of a salt:
58;


in which:
- R is a hydrogen atom or a group selected from: -CH=CH2, -CH2-CH3,
-CH(0H)CH3, -C(0)CH3 and -CH2CH2COOR'a, with R'a being a hydrogen atom or a
methyl, ethyl, n-propyl or i-propyl group,
- R' is a hydrogen atom or a group R'b selected from methyl, ethyl, n-propyl or
i-propyl,
the process comprising a step of complexation of a porphyrin of formula (I), formed after the step of condensation between the compounds (II) and (III) or (Ilia), with a metal, a metal salt or a metal hydroxide.
29 - The process for preparing a metal complex as claimed in claim 28, according to which the metal, the metal component of the metal salt, or the metal component of the metal hydroxide is selected from iron, gallium, nickel, zinc, palladium, cobalt, calcium or magnesium.
30- The process as claimed in claim 29, characterized in that the complexation step is carried out, in a final step, on the pprphyrin of formula (I), optionally in the form of a salt.
31 - The process as claimed in claim 29 or 30, characterized in that it is implemented for the formation of heme, hemin or hematin.
32 - A pyrromethane of formula (III):


in which R" is a hydrogen atom or a group selected from: -CH=CH2, -CH2-CH3, -CH(0H)CH3, -C(0)CH3 and -CH2CH2COOR'a, with R'a being a hydrogen atom or a methyl, ethyl, n-propyl or i-propyl group.
33 - The pyrromethane as claimed in claim 31, in which R" is a group
that is a precursor of -CH=CH2, selected from: -CH2CH20C(0)CH3, -CH2CH2OH,
-CH2CH2CI, -CH(0H)CH3 and -C(0)CH3.
34 - The pyrromethane as claimed in claim 32 or 33, in which R" is a
-CH(0H)CH3 or -C(0)CH3 group.
35 - A compound selected from the compounds of formulae (Vila), (Va)
and (IVa):



in which R and R' are as defined in claim 1, and also the salts thereof with an alkali metal, that can be obtained according to the process of one of claims 1 to 27.