PROCESS FOR SYNTHESIZING SULFONATED TRIARYL METHANE COMPOUNDS

Abstract

A process for preparing a compound of formula

##STR00001##

including oxidizing the triphenylmethane sulfone of formula (V) with a quinone chosen from 1,4-benzoquinone, 1,2-benzoquinone, a di(C.sub.1-C.sub.4)alkyl-1,4-benzoquinone, a di(C.sub.1-C.sub.4)alkyl-1,2-benzoquinone, a mono(C.sub.1-C.sub.4)alkyl-1,4-benzoquinone and a mono(C.sub.1-C.sub.4)alkyl-1,2-benzoquinone. A crystalline form of patent blue, sodium salt, can be achieved.

Claims

1. A process for preparing a compound of formula (I), the process comprising: oxidizing triphenylmethane sulfone of formula (V) with a quinone comprising 1,4-benzoquinone, 1,2-benzoquinone, a di(C.sub.1-C.sub.4)alkyl-1,4-benzoquinone, a di(C.sub.1-C.sub.4)alkyl-1,2-benzoquinone, a mono(C.sub.1-C.sub.4)alkyl-1,4-benzoquinone, or a mono(C.sub.1-C.sub.4 alkyl-1,2-benzoquinone: ##STR00037## wherein, in the compound of formula (I) ##STR00038## R1, R2, and R3 are independently H, —OH, —SO.sub.3H, and —SO.sub.3.sub.−, at least one of R1, R2 and R3 is —SO.sub.3H or —SO.sub.3.sub.−, R4 and R5, are independently a C.sub.1-C.sub.8 alkyl, a C.sub.1-C.sub.8 alkenyl, a phenyl or a benzyl, wherein two groups R4 and R5 bone by the same nitrogen atom optionally together form a ring including the nitrogen atom, Y is an organic or inorganic cation, which is pharmaceutically acceptable, t is 0, ½ or 1.

2. The process of claim 1, wherein the quinone is 1,4-benzoquinone.

3. The process of claim 1, wherein the oxidizing is performed in an apolar protic solvent.

4. The process of claim 1, wherein the oxidizing is performed at a temperature in a range of from 40 to 130° C.

5. The process of claim 1, further comprising, on conclusion of the oxidizing: separating the compound of formula from a reaction medium by precipitation.

6. The process of claim 1, further comprising: converting the compound of formula (I), wherein t is 0 into a salt of formula (I), wherein t is ½ or 1.

7. The process of claim 1, wherein the compound of formula (I) has a formula (IA) ##STR00039##

8. The process of claim 7, further comprising: (a) condensing a benzaldehyde compound of formula (IIA) with a dialkylaniline of formula (III) to give a triphenylmethane of formula (IVA) ##STR00040## b) treating the triphenylmethane of formula (IVA) with sulfuric acid to form a triphenylmethane sulfone of formula (VA) ##STR00041##

9. The process of claim 1, wherein the compound of formula (I) is of formula (VI) or (VII): ##STR00042##

10. The process of claim 1, wherein the compound of formula (I) has formula (IB): ##STR00043##

11. The process of claim 10, wherein the compound of formula (I) has formula (VIII): ##STR00044##

12. A crystalline form of the compound of formula (VI): ##STR00045## wherein the crystalline form has an X-ray powder diffraction diagram, measured on a diffractometer and expressed in terms of interplanar spacing d, 2 theta Bragg angle, intensity, and relative intensity, expressed as a percentage relative to the most intense line: TABLE-US-00008 Interplanar 2 theta angle (°) spacing d (Å) I (counts) I rel (%} 5.6 15.80 500 61.5, 6.2 14.29 375 46.2, 9.4 9.39 187.5 23.1, 10.9 8.12 62.5  7.7, 11.5 7.71 125 15.4, 12.1 7.33 156.25 19.2, 14.4 6.14 343.75 42.3, 15.6 5.68 250 30.8, 16.5 5.38 375 46.2, 17.6 5.02 187.5 23.1, 18.2 4.86 375 46.2, 19.4 4.57 812.5 100.0,  20.0 4.43 500 61.5, 22.9 3.87 187.5 23.1, and 24.7 3.60 250 30.8, wherein values of the intensity (I) and the relative intensity (I rel) can vary by ±15%.

13. A pharmaceutical composition, comprising: a pharmaceutically acceptable support; and the crystalline form of claim 12 in the pharmaceutically acceptable support.

14. The process of claim 1, wherein the quinone comprises 1,4-benzoquinone.

15. The process of claim 1, wherein the quinone comprises 1,4-benzoquinone, and wherein the oxidizing is performed in an apolar protic solvent.

16. The process of claim 1, wherein the oxidizing is performed at a temperature in a range of from 60 to 120° C.

17. The process of claim 1, wherein the oxidizing is performed at a temperature in a range of from 70 to 110° C.

Description

FIGURES

[0140] FIG. 1: FIG. 1 is a graph representing the X-ray diffraction diagrams of three samples of patent blue, sodium salt, obtained according to the process of the invention (designated Inv1, Inv2 and Inv3). These are samples from three different production batches. On the x-axis: the 2 theta angle in degrees; on the y-axis: the intensity in arbitrary intensity units.

[0141] FIG. 2: FIG. 2 is a graph representing the X-ray diffraction diagrams of six commercially available samples of patent blue, sodium salt (designated C.sub.1 to C.sub.6). Also plotted on this figure are the X-ray diffraction diagrams of three samples of patent blue, sodium salt obtained according to the process of the invention (designated Inv1 to Inv3) and shown in FIG. 1. On the x-axis: the 2 theta angle in degrees; on the y-axis: the intensity in arbitrary intensity units.

EXAMPLES

[0142] In these Examples, the parts and percentages are expressed on a weight basis, unless otherwise indicated.

[0143] Materials and Methods

HPLC analysis:

Column: Agilent Poroshell 120 SB-C18 150×4.6-2.7μ (ref. 683975-902)

[0144] Mobile phase A: 10 mM ammonium formate/formic acid buffer (pH=4.1±0.1)
Mobile phase B: Acetonitrile
Flow rate: 1 ml/mn

Temperature: 30° C.

[0145] Injection volume: 5 μL
Gradient: Analysis time 40 min+7 min post-run stabilization

TABLE-US-00003 TABLE 1 Time A % B % 0.0 90 10 4.0 90 10 12 85 15 30 10 90 40.0 10 90 40.1 90 10 47.0 90 10
Detector: UV-Vis 230 nm and MS Electrospray (negative mode)
X-ray powder diffractogram: The X-ray powder diffraction diagram was produced under the following experimental conditions: [0146] X'Pert Pro MPD Panalytical diffractometer (DY2764), [0147] Copper anode (λ=1.54 Å), voltage: 40 kV, current 40 mA [0148] Mounting θ-θ [0149] Measuring range: 2° to 500 [0150] Increment between each measurement: 0.026° [0151] Measurement time per step: 20.40 s, [0152] PIXcel RTMS detector (PHD 25.5-7%, active length 3.3470

Synthesis of Patent Blue (According to the Invention)

Step 1: Preparation of 3-(bis(4-(diethylamino)phenyl)methyl)phenol dihydrochloride

[0153] ##STR00034##

Add N,N-diethylaniline (254.0 mL, 1.597 mol, 1.95 eq) to a mixture of 3-hydroxybenzaldehyde (100 g, 0.819 mol, 1.00 eq) and urea (24.6 g, 0.409 mol, 0.50 eq) in 100 mL of ethanol.
Cool the reaction medium to 0° C. and pour in aqueous 37% HCl solution (136.5 mL, 1.638 mol, 2.00 eq), while keeping the medium at a temperature below 20° C.
Next, reflux the reaction medium for 20 hours.
Cool the reaction medium to 60° C. and then pour in 800 mL of aqueous 2N HCl solution.
Cool the reaction medium to 0° C. and continue stirring for 5 hours.
Filter off the precipitate obtained and wash the solid with 500 mL of a 2N aqueous acetone/HCl mixture (9/1) and then 500 mL of acetone.
The solid is dried in a ventilated oven (50° C.). 303 g of 3-(bis(4-(diethylamino)phenyl)methyl)phenol dihydrochloride are obtained in the form of a white solid.
HPLC purity: 97.2%

Yield: 78%

[0154] .sup.1H NMR (300 MHz, D2O) δ7.39 (4H, dd, J=8.7 Hz), 7.33 (4H, dd, J=8.7 Hz), 7.22 (1H, t, J=7.9 Hz), 6.80 (1H, ddd), 6.71 (1H, dd, J=7.8 Hz), 6.67 (1H, t, J=2.0 Hz), 5.67 (1H, s), 3.60 (8H, q, J=6.9 Hz), 1.06 (12H, t, J=7.2 Hz) .sup.13C NMR (75 MHz, D20): δ156.0, 145.5, 144.3, 135.1, 131.2, 130.3, 122.4, 121.4, 116.2, 114.0, 54.9, 53.7, 9.7

Step 2: Preparation of 4-(bis(4-(diethylamino)phenyl)methyl)-6-hydroxybenzene-1,3-disulfonic acid

[0155] ##STR00035##

Add 3-(bis(4-(diethylamino)phenyl)methyl)phenol dihydrochloride (150 g, 0.315 mol, 1 eq.) to 600 mL H.sub.2SO.sub.4.
Heat at 90° C. for 3 hours and then leave stirring for 16 hours at room temperature.
Dilute the reaction medium with 15 L of an ethanol/isopropyl ether mixture (75/25) while keeping the temperature below 20° C.
Filter off the precipitate obtained and wash the solid with 2×600 mL of isopropyl ether.
The solid is dried in a ventilated oven (50° C.). 183 g of 4-(bis(4-(diethylamino)phenyl)methyl)-6-hydroxybenzene-1,3-disulfonic acid are obtained in the form of a white solid.
HPLC purity: 98.8%
Yield: quantitative

.SUP.1.H NMR (300 MHz, DMSO) δ 10.91 (2H, br s), 8.08 (1H, s), 7.52 (4H, dd, J=8.5 Hz), 7.38 (4H, dd, J=8.6 Hz), 6.95 (1H, s), 6.54 (1H, s), 4.75 (1H, br s), 3.54 (8H, q, J=7.1 Hz), 0.92 (12H, t, J=6.7 Hz)

.SUP.13.C NMR (75 MHz, DMSO) δ153.6, 145.2, 143.0, 137.1, 135.5, 130.8, 128.0, 126.7, 122.3, 118.4, 52.5, 49.2, 10.1

Step 3: Preparation of Patent Blue

[0156] ##STR00036##

Add 4-(bis(4-(diethylamino)phenyl)methyl)-6-hydroxybenzene-1,3-disulfonic acid (1.2 kg. 2.1 mol. 1 eq.) to 6 L of N-methylpyrrolidone.
Heat the reaction medium to 95° C. and pour in 1,4-benzoquinone (346 g, 3.2 mol, 1.5 eq.) dissolved in 1.2 L of N-methylpyrrolidone.
Continue heating for 3 hours and then cool to room temperature.
Dilute the reaction medium with 18 L of acetone.
Filter off the precipitate obtained and wash the solid with 2×6 L of acetone.
Take up the solid in 6 L of an H.sub.2O/methanol mixture (80/20).
Reflux for 1 hour and then cool to room temperature.
Filter off the solid and wash with 2×6 L of acetone. Take up the solid in 15 L of methanol with stirring and pour into aqueous 22% sodium carbonate solution (256 mL).
Leave stirring for 3 hours and then concentrate.
Take up in 10 L of isopropanol.
Recover the solid by filtration and wash with 2×4 L of acetone.
The solid is dried in a ventilated oven (50° C.).
766 g of 4-[[4-(diethylamino)phenyl]-(4-diethylazaniumylidenecyclohexa-2,5-dien-1-ylidene)methyl]-6-hydroxybenzene-1,3-disulfonate sodium salt (patent blue) are obtained in the form of a purple solid.
HPLC purity: 99.3%

Yield: 61%

.SUP.1.H NMR (300 MHz, D20) δ8.29 (1H, s), 7.24 (4H, dd, J=8.8 Hz), 6.72 (4H, dd, J=8.9 Hz), 6.41 (1H, s), 3.49 (8H, q, J=5.8 Hz), 1.12 (12H, t, J=5.9 Hz)

.SUP.13.C NMR (75 MHz, D20): δ170.1, 156.6, 154.9, 141.6, 139.7, 133.2, 128.9, 128.2, 125.6, 121.2, 113.5, 45.8, 12.2

Synthesis of patent blue (comparative)

[0157] The process was performed as described above for steps 1 and 2. For step 3, the protocol described above was followed, the oxidizing compound being varied. This oxidizing compound could be another quinone or another oxidizing reagent.

TABLE-US-00004 TABLE 2 Degree of conversion Mono-de-ethylated Quinone step 3 (*) compound % (*) 1,4-Benzoquinone (a) 93%  <1% 3,5-Di-tert-butyl-1,2-benzoquinone 93% 2.6% (a) 2,5-Dimethyl-1,4-benzoquinone (a) 70% 1.7% 2-Methyl-1,4-benzoquinone (a) 52% 2.1% 2,3-Dichloro-5,6-dicyano-1,4- 31% 2.4% benzoquinone (b) Tetrachloro-1,4-benzoquinone (b) 90% 6.8% Tetrachloro-1,2-benzoquinone (b) 65%   4% 2-Chloro-1,4-benzoquinone (b) 92% 3.7% (*) measured according to the HPLC method described above (a) according to the invention (b) comparative

[0158] It is found that some quinones afford access to high degrees of conversion while leading to a product having little mono-de-ethylated impurity. Other quinones give either very low yields or a high content of mono-de-ethylated compound, which is difficult to separate out.

TABLE-US-00005 TABLE 3 Degree of conversion Mono-de-ethylated Oxidizing agent (comparative) step 3 (*) compound % (*) KMnO.sub.4 95% 5% NaMnO.sub.4 78% 7% Ammonium cerium (IV) nitrate 41% 4% MnO.sub.2 38% 5% FeCl.sub.3 — — (*) measured according to the HPLC method described above

[0159] It is seen that only a few oxidizing reagents other than quinones make it possible to convert compound (V) into patent blue. Few of them are able to afford a de-ethyl content of less than 5%, or with a low degree of conversion. In addition, these reagents are based on heavy metals, the use of which is not recommended, both for ecological reasons and if it is desired to avoid contamination of the final product.

X-Ray Powder Diffractogram:

[0160] The X-ray powder diffraction profile (diffraction angles) of the patent blue sodium salt obtained in Example 3 is given by the significant lines reported in Table 4 with their intensity and their relative intensity (expressed as a percentage relative to the most intense line). The measurement was performed on three different batches which all have substantially the same profile as shown in FIG. 1. The batches Inv 1, Inv 2 and Inv 3 were prepared on a pilot scale (3 to 6 kg prepared). This measurement confirms that the crystalline characteristics of the product are constant on conclusion of the preparation process. It also confirms the absence of NaCl (see the characteristic peaks in FIG. 2).

TABLE-US-00006 TABLE 4 Interplanar 2 theta angle (°) spacing d (Å) I (counts) I rel (%) 5.6 15.80 500 61.5 6.2 14.29 375 46.2 9.4 9.39 187.5 23.1 10.9 8.12 62.5 7.7 11.5 7.71 125 15.4 12.1 7.33 156.25 19.2 14.4 6.14 343.75 42.3 15.6 5.68 250 30.8 16.5 5.38 375 46.2 17.6 5.02 187.5 23.1 18.2 4.86 375 46.2 19.4 4.57 812.5 100.0 20.0 4.43 500 61.5 22.9 3.87 187.5 23.1 24.7 3.60 250 30.8
Comparison with Commercial Patent Blue, Sodium Salt Products:

[0161] Commercial products from the following producers (Table 5) were analysed by the same X-ray diffraction method:

TABLE-US-00007 TABLE 5 Commercial patent blue, sodium salt Producer Commercial reference Reference on FIG. 2 Acros 339330050 C1 Santa Cruz SC250653 C2 Biotechnology TCI A1242 C3 Combi Blocks HA8936 C4 Biosynth FC1571 C5 Colorey FG18191327 C6

[0162] The results are collated in FIG. 2. It is seen that most of the peaks do not correspond to those of the patent blue, sodium salt of the invention which are reported in Table 4 and in FIG. 1. This observation leads to the conclusion that the patent blue, sodium salt of the invention is a new crystalline form relative to the crystalline forms already known. In FIG. 2, the presence of peaks characteristic of NaCl is also observed, notably the peaks at the 2 theta angles=32 and 45.5, which makes it possible to note the presence of NaCl in all the commercial patent blue samples, but not in the patent blue sodium salt according to the invention.