METHOD FOR THE PREPARATION OF SULFONATED TRIARYLMETHANE COMPOUNDS

Description

technical field

[0001] The present invention relates to a new process for synthesizing compounds comprising a triarylmethane structure substituted by sulfonated groups, in particular a new process for synthesizing dyes from the family of sulfonated triarylmethane compounds, especially patent blue. Prior art

[0002] Patent Blue V (salt of 4-[[4-(diethylamino)phenyl]-(4-diethylazaniumylidenecyclohexa-2,5-dien-1-ylidene)methyl]-6-hydroxybenzene-1,3-disulfonate) is a dye with a triarylmethane structure that exists in two forms: the sodium salt [CAS 20262-76-4] and the calcium salt [CAS 3536-49-0]. This dye was first mentioned in 1897 by Ernst Erdmann and Hugo Erdmann, Justus Liebigs Annalen der Chemie, Vol. 294 (3), pp. 376-392. In publications concerning it, there is sometimes confusion between patent blue and isosulfan blue (sodium salt of 2-[[4-(diethylamino)phenyl]-(4-diethylazaniumylidenecyclohexa-2,5-dien-1-ylidene)methyl]benzene-1,4-disulfonate, CAS 68238-36-8 and 748080-29-7), although these molecules have distinct structures.

[0003] Patent Blue V is commercially available, but the products found on the market are characterized by a high impurity content. In particular, they contain significant amounts of monodesethyl compound, which is difficult to separate from Patent Blue V using conventional purification methods. They are also characterized by a significant amount of residual NaCl.

[0004] Patent blue and isosulfan blue are biological tissue dyes used primarily as contrast agents for delineating lymphatic vessels and are particularly useful as cancer diagnostic agents. They are commonly used in a diagnostic procedure called sentinel lymph node mapping. This method complements lymphography by visualizing the lymphatic system draining the injection site. An important application is locating sentinel lymph nodes in patients with breast cancer. Surgical removal of cancerous tissue, guided by patent blue or isosulfan blue, is also performed.

[0005] Few authors have focused on the synthesis of patent blue since the 1897 publication by Ernst and Hugo Erdmann. Among these authors are Hagenbach, "Revue des colorants bleus," Helvetica, Volume 6, Issue 1, 1923, pages 134-186; and Paul Fritsch, Euric, Volume 29, Issue 2, May-August 1896, pages 2290-2301. From the basic reactions taught in these documents, a wide variety of dyes can be produced, including compounds characterized by a sulfonated triarylmethane structure.

[0006] US documents 1531507, US7534911, US8969616, WO2017118882, WO2017218764, WO2018008040 report different processes for the synthesis of isosulfan blue.

[0007] Most prior art synthetic methods for the manufacture of sulfonated triarylmethane dyes include a condensation step of a sulfonated benzaldehyde with the N,N-Diethylaniline, this step involving strong acids and resulting in the formation of a leucobase. This step is generally followed by an oxidation step using known oxidizing agents, some of which are considered dangerous (lead oxide, iron phthalocyanine / oxone), to carry out the conversion to triarylmethane dye.

[0008] Document DE46384 describes a process for synthesizing sulfonated triarylmethane dyes by means of a process involving the sulfonation of a triarylmethane structure by treatment with fuming sulfonic acid, followed by oxidation with lead oxide in the presence of sulfuric acid. Neither the product nor its purity is characterized. It is unknown what substitutions were made on the aromatic rings. The inventors of this application have observed that treatment with fuming sulfonic acid (saturated gaseous SO3 in a concentrated solution of H2SO4) degrades the triarylmethane structure very rapidly. Therefore, the conditions taught in this document do not allow the formation of the intended structure with satisfactory yields and purity.

[0009] The paper AM Montagut et al., Chem. Eur. J. 2017, 23, 3810-3814, describes the synthesis of hydrophobic triarylmethane compounds for textile treatment. After the formation of the triarylmethane structure substituted with long-chain groups, the final step consists of oxidation by a quinone, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The resulting structures are significantly different from conventional dye molecules such as patent blue or isosulfan blue, whose aryl rings are substituted with short-chain groups and which bear sulfonated functional groups.

[0010] Among the impurities that form during the synthesis of these dialkylaminotriarylmethylsulfone compounds, desalkylated derivatives are particularly problematic. In the case of Patent Blue V and Isosulfan Blue, these impurities are designated as desethyl impurities.

[0011] Indeed, these molecules differ from the target molecules only by the absence of one or more alkyl (ethyl) groups on the nitrogen atoms. Because their structure is so similar to the target compounds, they are difficult to remove using conventional purification techniques. Document WO2017 / 118882 claims the synthesis of isosulfan blue with a purity >99.8% and a desethyl impurity <0.15%. However, the described process involves an oxidation step with potassium permanganate, which is likely to lead to manganese contamination. This method, when applied to the synthesis of Patent Blue V, yields a compound with a much higher desethyl content.

[0012] Document RU 2654862 describes a process for purifying diaminotriphenylmethane disulfonated dye compounds. This process is specifically for Patent Blue V. The process described in this document is based on absorption onto a PDMS support and recovery of the Patent Blue V using an aqueous saline solution. The product obtained from this process has a high salt content.

[0013] The document *Journal of Chromatography* A 1499 (2017) 183-189 describes an electrochromatographic separation method applied to dye compounds, including patent blue. The separation is performed with respect to a mixture containing two other dyes of different structures. It is not intended for use in removing the desethyl compound or other components of similar structure.

[0014] Therefore, the need remained for a synthetic process for sulfonated triarylmethane compounds that would yield Patent Blue V, as well as other structures such as isosulfan blue. In particular, the aim was to develop a process that was reproducible, applicable on an industrial scale, offered good yields, and produced products of high purity. Specifically, there was a need for a process that produced a composition in which the target compound was substantially free of dealkylated derivatives, especially desethylated derivatives in the case of Patent Blue V and isosulfan blue, and that did not require the use of heavy metals. There was also a need for a method to prepare Patent Blue V that resulted in a product substantially free of salts.

[0015] Surprisingly, the Applicant has discovered a process that, starting from simple and readily available molecules, provides access to sulfonated triarylmethane compounds via a quinone oxidation step, with high yields and purity. The disclosed process yields products that exhibit both satisfactory organic and metal purity, while also offering good yields. Summary of the invention

[0016] The disclosure relates to a process for preparing a compound corresponding to the formula [Chem I] in which R1, R2, R3 represent, independently of each other, a group chosen from: -H, -OH, -SO3H, -SO3-< , at least one of R1, R2, R3 represents a group chosen from (-SO3H, -SO3-< ), R4, R5, identical or different, represent a group chosen from: a C1-C8 alkyl, a C1-C8 alkenyl, a phenyl, a benzyl, it being understood that two groups R4, R5 on the same nitrogen atom can together form a ring including this nitrogen atom, Y represents an organic or inorganic cation chosen from pharmaceutically acceptable salts; t represents a number, t = 0; 1 / 2;1 , this process being characterized in that it comprises at least one step of oxidation of sulfonated triphenylmethane of formula [Chem V] by a quinone selected from 1,4-benzoquinone, 1,2-benzoquinone, a dialkyl(C 1 -C 4 ) 1,4-benzoquinone, a dialkyl(C 1 -C 4 ) 1,2-benzoquinone, a monoalkyl(C 1 -C 4 ) 1,4-benzoquinone, a monoalkyl(C 1 -C 4 ) 1,2-benzoquinone: ;

[0017] According to a preferred embodiment, quinone is 1,4-benzoquinone.

[0018] According to a preferred embodiment, the treatment is carried out in a nonpolar protic solvent.

[0019] According to a preferred embodiment, the treatment is carried out at a temperature ranging from 40 to 130°C, advantageously at a temperature ranging from 60 to 120°C, even more advantageously from 70 to 110°C.

[0020] According to a preferred embodiment, at the end of the quinone treatment step, the target compound of formula [Chem I] is separated from the reaction medium by precipitation.

[0021] According to a preferred embodiment, the process further comprises a step in which the target compound of formula [Chem I] with t=0 is transformed into a salt of formula [Chem I] with t=1 or t = 1 / 2.

[0022] According to a preferred embodiment, the compound of formula [Chem I] corresponds to formula [Chem IA]

[0023] According to a preferred embodiment, the compound [Chem IA] was obtained by a process comprising at least the following steps: a) the condensation of the benzaldehyde compound of formula [Chem IIA] with dialkylaniline of formula [Chem III] to give triphenylmethane of formula [Chem IVA], b) the treatment of triphenylmethane of formula [Chem IVA] with sulfuric acid to form sulfonated triphenylmethane of formula [Chem VA]

[0024] According to a still preferred embodiment, the compound corresponding to formula [Chem I] is chosen from: Patent Blue V, sodium salt

[0025] Patent Blue V, calcium salt

[0026] Patent Blue V, potassium salt

[0027] According to another variant, the compound corresponding to the formula [Chem I] corresponds to the formula [Chem IB]

[0028] According to a preferred embodiment of this variant, the compound corresponding to the formula [Chem I] is the compound [Chem VIII] Isosulfan Blue

[0029] The disclosure further relates to the use of the process as described above and in detail below, to obtain a composition comprising at least 99.0% of compound meeting the formula [Chem I], the % being measured by high-performance liquid chromatography with detection at 230 nm.

[0030] According to a preferred embodiment, the use is intended to produce a composition in which no impurity other than a monodealkylated derivative is present in an amount greater than 0.1%, the % being measured by high-performance liquid chromatography with detection at 230 nm.

[0031] The invention further relates to a method of manufacturing a drug or a diagnostic product comprising manufacturing the compound corresponding to the formula [Chem I], preferably patent blue, by the method as described above and in detail below and introducing the compound corresponding to the formula [Chem I] into a pharmaceutically acceptable support.

[0032] The invention provides access to a composition comprising at least 99.0% of a compound corresponding to formula [Chem VI] or formula [Chem VII], or formula [Chem X], the % being measured by high-performance liquid chromatography with detection at 230 nm: Patent Blue V, sodium salt

[0033] Patent Blue, calcium salt.

[0034] Patent Blue V, potassium salt

[0035] Advantageously, in this composition, no impurity other than a monodealkylated derivative is present in an amount exceeding 0.1%, the percentage being measured by high-performance liquid chromatography with detection at 230 nm. The disclosure process has the advantage of providing access to a composition substantially free of NaCl, preferably completely free of residual NaCl.

[0036] The invention further relates to a crystalline form of the compound Patent Blue, sodium salt, corresponding to the formula [Chem VI], characterized by the following X-ray powder diffraction pattern, measured on a diffractometer and expressed in terms of interplanar distances d, Bragg angle 2 theta, intensity and relative intensity (expressed as a percentage relative to the most intense line): Angle 2 theta (°) Interreticular distance 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

[0037] It is understood that the intensity (I) and relative intensity (I rel) values ​​of the peaks above are likely to vary by + / -15%.

[0038] Advantageously, the crystal structure is substantially devoid of NaCl, preferably totally devoid of NaCl.

[0039] The invention relates to the crystalline form of the compound Patent Blue, sodium salt, for its use as a medicinal product.

[0040] In particular, it relates to the crystalline form of the compound Patent Blue, sodium salt, for its use in diagnostics, as detailed in the description below.

[0041] The invention further relates to a pharmaceutical composition comprising at least the crystalline form of the compound Patent Blue, sodium salt, corresponding to the formula [Chem VI] as described above and in detail below, in a pharmaceutically acceptable support.

[0042] Surprisingly, it has been found that the disclosure process provides direct access to a crystalline form of Patent Blue, specifically Patent Blue sodium salt, which was not known in the prior art. Obtaining a crystalline form free of residual sodium chloride offers numerous advantages in terms of yield and purity, as well as efficiency and cost-effectiveness for industrial-scale application of the process. The resulting product exhibits crystalline characteristics that ensure good stability. The disclosure process facilitates easier processing because it leads, reproducibly, to a crystalline product with a unique polymorphism, which is necessary in the majority of pharmaceutical formulations (especially dry formulations). The absence of NaCl enhances the solubility of Patent Blue in aqueous solution. Detailed description

[0043] The expression "consists essentially of" followed by one or more characteristics means that components or steps which do not significantly modify the properties and characteristics of the invention may be included in the process or material of the invention, in addition to the components or steps explicitly listed.

[0044] The expression "between X and Y" includes the bounds, unless explicitly stated otherwise. This expression therefore means that the interval in question includes the values ​​X, Y, and all values ​​from X to Y. Compounds obtained by the process of the invention

[0045] This disclosure relates to a process for obtaining compounds conforming to the formula [Chem I] below: in which R1, R2, R3 represent, independently of each other, a group chosen from: -H, -OH, -SO3H, -SO3-< , R4, R5, identical or different, represent a group chosen from: a C1-C8 alkyl, a C1-C8 alkenyl, a phenyl, a benzyl, and two groups R4, R5 on the same nitrogen atom can together form a ring including this nitrogen atom, Y represents an organic or inorganic cation chosen from pharmaceutically acceptable salts; t represents a number, t = 0; 1 / 2; 1; at least one of R1, R2, R3 represents a group chosen from -SO3H, -SO3-< .

[0046] Preferably, at least two of the groups R1, R2, R3 are chosen from -SO3H, -SO3-<.

[0047] Advantageously, in formula [Chem I] two of the groups R1, R2, R3 are chosen from -SO3H, -SO3-< and the third group is different from -SO3H, -SO3-< .

[0048] Preferably, in formula [Chem I]: R1 = -SO3 H or -SO3 -< ; R2 = H; R3 = -SO3 H or -SO3 -<

[0049] Or R1 = -SO 3 H or -SO 3 -<; R2 = -SO 3 H or -SO 3 -<; R3 = -OH.

[0050] Preferably, in formula [Chem I]: R1 = -SO3 H or -SO3 -< ; R2 = -SO3 H or -SO3 -< ; R3 = -OH.

[0051] When two R4, R5 groups on the same nitrogen atom form a ring together, these groups can consist of a single alkyl or alkenyl chain, which forms a ring including the nitrogen atom.

[0052] Advantageously, R4, R5, identical or different, represent a group chosen from: a C1-C6 alkyl, a phenyl, a benzyl and two R4, R5 groups carried by the same nitrogen atom can together form a -(CH2)p- chain, with p an integer, p=2 to 5.

[0053] Even more advantageously, R4 and R5, whether identical or different, represent a group chosen from: a C1-C3 alkyl group, preferably from methyl and ethyl. Preferably, (R4; R5) is chosen from (CH3; CH3), (C2H5; C2H5), (CH3; C2H5).

[0054] According to a preferred embodiment, R4=R5.

[0055] Even more advantageously, (R4; R5) is chosen from (CH3; CH3) and (C2H5; C2H5). According to a preferred variant, (R4; R5) represents (C2H5; C2H5).

[0056] Advantageously, pharmaceutically acceptable salts refer to non-toxic salts in which the cation is chosen from alkali metal ions, alkaline earth metal ions, or an ammonium ion. Even more advantageously, Y represents a group chosen from: Na+, Ca2+, K+, Mg2+, or an ammonium group NH4+.

[0057] In a more preferred way, Y represents a grouping chosen from: Na +< , Ca 2+< .

[0058] According to a preferred variant, the disclosure process involves obtaining compounds corresponding to the formula [Chem IA] below: in which R4, R5, Y and t have the same definition as in formula [Chem I]. The preferences expressed above for the choice of these variables in the context of formula [Chem I] also apply to formula [Chem IA].

[0059] In particular, the invention relates to the following compounds: Patent Blue V, sodium salt

[0060] Patent Blue V, calcium salt

[0061] Patent Blue V, potassium salt

[0062] Preferably, the invention relates to Patent Blue Sodium Salt and Patent Blue Calcium Salt.

[0063] Even more specifically, it concerns Patent Blue, sodium salt.

[0064] Throughout the application, when patent blue is mentioned, it is understood to mean a compound corresponding to formula [Chem VI], formula [Chem VII] or formula [Chem X].

[0065] According to another variant, the disclosure process involves obtaining compounds corresponding to the formula [Chem IB] below: in which R4, R5, Y and t have the same definition as in formula [Chem I]. The preferences expressed above for the choice of these variables in the context of formula [Chem I] also apply to formula [Chem IB].

[0066] In particular, the invention relates to the following compound: Isosulfan Blue

[0067] Throughout the application, when Isosulfan Blue is mentioned, it is understood to be a compound corresponding to the formula [Chem VIII].

[0068] Method for preparing a compound according to the invention - Step c) of treatment with a quinone :

[0069] The disclosure relates to a process for the synthesis of a compound corresponding to the formula [Chem I] as defined above, this process being characterized in that it comprises at least one step c) of oxidation of sulfonated triphenylmethane of formula [Chem V] by a quinone selected from 1,4-benzoquinone, 1,2-benzoquinone, a dialkyl(C1-C4)1,4-benzoquinone, a dialkyl(C1-C4)1,2-benzoquinone, a monoalkyl(C1-C4)1,4-benzoquinone, a monoalkyl(C1-C4)1,2-benzoquinone according to the scheme:

[0070] In formula [Chem V], the variables R1, R2, R3, R4, R5 have the same definition as in formula [Chem I] (with the same preferred variants).

[0071] In this step, sulfonated triphenylmethane of formula [Chem V] is oxidized to the target compound of formula [Chem I] by means of a quinone treatment. At this stage, if the aim is to obtain a high-purity product and high conversion yields, it is important to avoid the degradation of the triarylmethane structure and dealkylation, i.e., the substitution of one or more R4, R5 groups by hydrogen atoms.

[0072] The quinone is chosen from 1,4-benzoquinone, 1,2-benzoquinone, a dialkyl(C1-C4)1,4-benzoquinone, a dialkyl(C1-C4)1,2-benzoquinone, a monoalkyl(C1-C4)1,4-benzoquinone, a monoalkyl(C1-C4)1,2-benzoquinone.

[0073] Dialkyl(C1-C4)-1,4-benzoquinone and dialkyl(C1-C4)-1,2-benzoquinone refer to a quinone bearing two C1-C4 alkyl groups, which may be identical or different, preferably identical, such as 3,5-diterbutyl-1,2-benzoquinone and 2,5-dimethyl-1,4-benzoquinone. Monoalkyl(C1-C4)-1,4-benzoquinone and monoalkyl(C1-C4)-1,2-benzoquinone refer to a quinone bearing one C1-C4 alkyl group, such as 2-methyl-1,4-benzoquinone.

[0074] Preferably, the quinone is 1,4-benzoquinone.

[0075] Surprisingly, it has been found that these quinones give a high conversion rate and low degradation into desalkyl type impurities, particularly desethyl impurities in the case of patent blue.

[0076] Preferably, in step c), the treatment is carried out in a nonpolar protic solvent. For example, the solvent can be chosen from dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), dimethylformamide (DMF).

[0077] Preferably, in step c), the treatment is carried out at a temperature ranging from 40 to 130°C, advantageously at a temperature ranging from 60 to 120°C, even more advantageously from 70 to 110°C.

[0078] Advantageously, at the end of step c) the target compound of formula [Chem I] is separated from the reaction medium by precipitation. Preferably, this precipitation is brought about by the addition of a solvent or a mixture of solvents selected from: alcohols, ethers, water, acetone and mixtures thereof.

[0079] Alternatively, consideration could be given to isolating the compound of formula [Chem I] from the reaction medium by other purification techniques such as solvent extraction or silica column chromatography. Step d) of salification :

[0080] When t is not equal to 0, the process includes, after step c), a salification step d). This step is carried out by introducing the target compound of formula [Chem I] from step c) (t=0) into a solvent with the chosen counter-ion.

[0081] In the specific case of patent blue, the counterion is advantageously chosen from Na+, Ca2+. However, derivatives of patent blue having a different counterion Y, corresponding to the target compound of formula [Chem IA], can be obtained by the disclosure process.

[0082] Optionally, the process can be followed by one or more conventional purification steps such as precipitation, crystallization, solvent extraction, chromatography.

[0083] In the case of compound [Chem IA], the combination of steps c) and d) can be summarized by the diagram below:

[0084] In the case of Patent Blue V (sodium salt), the combination of steps c) and d) can be summarized by the diagram below:

[0085] Surprisingly, it has been found that combining the two steps described above directly yields a crystalline form of Patent Blue, specifically Patent Blue sodium salt, which was unknown in the prior art. Obtaining a crystalline form directly offers numerous advantages in terms of yield and purity, as well as efficiency and cost-effectiveness for industrial-scale application of the process. The resulting product exhibits crystalline characteristics that ensure good stability. Obtaining the compound with formula [Chem V]

[0086] To implement the process described above, a product of formula [Chem V] is used which is oxidized by a quinone in step c).

[0087] In some cases, the product with formula [Chem V] is commercially available, in which case the disclosure process involves a quinone oxidation step and possibly a salification step. This is the case, for example, with Isosulfan Blue, whose precursor [Chem IX] below is commercially available:

[0088] In other cases, the precursor of formula [Chem V] is not available in sufficient quantity or with satisfactory quality, in which case it can be advantageously synthesized by a process as described below.

[0089] The process for preparing the compound of formula [Chem V] advantageously comprises at least the following steps: a) the condensation of the benzaldehyde compound of formula [Chem II] with dialkylaniline of formula [Chem III] to give triphenylmethane of formula [Chem IV], in which R1, R2, R3 represent, independently of each other, a group chosen from: -H, -OH, and at least one of R1, R2, R3 represents H, R4, R5 have the same definition as in formula [Chem I]. b) the treatment of triphenylmethane of formula [Chem IV] with sulfuric acid to form sulfonated triphenylmethane of formula [Chem V]

[0090] In formula [Chem V], the variables R1, R2, R3, R4, R5 have the same definition as in formula [Chem I] (with the same preferred variants).

[0091] The preferences expressed above for the choice of variables R4 and R5 in the context of formula [Chem I] also apply to formulas [Chem II], [Chem III], [Chem IV] and [Chem V].

[0092] The groups R1, R2 and R3 in formulas [Chem II] and [Chem IV] correspond either to R1, R2 and R3 as defined in formulas [Chem I], and [Chem V], or, for one or more of these groups, to a hydrogen atom which is replaced by a SO3 H / SO3-< function during step b). Indeed, step b) performs the substitution of one or more hydrogen atoms among R1, R2, R3 by a SO3 H / SO3-< function. Step a) :

[0093] Step a) consists of condensing the benzaldehyde compound of formula [Chem II] with dialkylaniline of formula [Chem III] to give triphenylmethane of formula [Chem IV]. Preferably, in formulas [Chem II] and [Chem IV], at least two of the groups R1, R2, R3 represent -H.

[0094] Advantageously, two of the groups R1, R2, R3 are chosen from H and the third is chosen from -H and -OH.

[0095] Preferably, in formulas [Chem II] and [Chem IV]: R1 = R2 = H; R3 = -OH.

[0096] Advantageously, in the preparation process defined above, step a) is carried out with 1.95 to 3 molar equivalents of dialkylaniline of formula [Chem III], relative to the amount of benzaldehyde of formula [Chem II].

[0097] Advantageously, in the preparation process defined above, step a) is carried out in the presence of urea and in an acidic medium. Preferably, the reaction medium is acidified with hydrochloric acid. Advantageously further, the reaction medium is acidified with 1.2 to 3 molar equivalents of hydrochloric acid relative to the amount of benzaldehyde of formula [Chem II]. Preferably, step a) is carried out in the presence of 0.25 to 1.5 molar equivalents of urea relative to the amount of benzaldehyde of formula [Chem II]. Advantageously, in the preparation process defined above, step a) is carried out in a solvent selected from protic solvents, in particular alcohols. Preferably, it is carried out in ethanol. Preferably, ethanol is introduced into the reaction medium in an amount ranging from 1 to 6 volumes relative to the mass of aldehyde of formula [Chem II].

[0098] Advantageously, the reaction in step a) is carried out by heating at a temperature ranging from 60°C to 120°C for 5 to 30 hours, even more advantageously at a temperature ranging from 75°C to 100°C for 10 to 25 hours.

[0099] Advantageously, following the condensation reaction in step a), the reaction medium is treated to precipitate the compound of formula [Chem IV]. Preferably, this precipitation is induced by adding a solvent selected from an acidic aqueous solution, acetone, and mixtures thereof to the reaction medium. Advantageously, the compound of formula [Chem IV] is isolated from the reaction medium by filtration and purified by washing. Advantageously, the washing is carried out using a solvent selected from an acidic aqueous solution, acetone, and mixtures thereof.

[0100] Alternatively, consideration could be given to isolating the compound of formula [Chem IV] from the reaction medium by other purification techniques such as solvent extraction or chromatography, in particular silica column chromatography.

[0101] In the case where compound [Chem I] is compound [Chem IA], step a) can be summarized by the diagram below:

[0102] In particular, in the case of Patent Blue, step a) can be summarized by the diagram below: Step b) :

[0103] Advantageously, in the preparation process defined above, step b) is carried out by means of treatment with concentrated sulfuric acid. For example, a sulfuric acid solution with a concentration greater than or equal to 90% by volume is used, preferably a sulfuric acid solution with a concentration greater than or equal to 95% by volume.

[0104] Preferably, the treatment includes adding the compound of formula [Chem IV] to 1 to 5 volumes of sulfuric acid.

[0105] Advantageously, the solution of the compound of formula [Chem IV] in sulfuric acid is heated to a temperature of 60 to 120 °C for a period of 30 minutes to 10 hours, preferably to a temperature of 80 to 100 °C for a period of 1 to 5 hours. Advantageously, at the end of step b), the sulfonated triphenylmethane of formula [Chem V] is separated from the reaction mixture by precipitation. Preferably, this precipitation is brought about by the addition of a solvent or a mixture of solvents selected from: alcohols, ethers, water, acetone and mixtures thereof; even more preferably, by the addition of an alcohol (ethanol, isopropanol, etc.), a water / alcohol mixture, a water / acetone mixture, or an alcohol / ether mixture (isopropanol / isopropyl ether, ethanol / isopropyl ether, etc.).

[0106] Alternatively, consideration could be given to isolating the compound of formula [Chem V] from the reaction medium by other purification techniques such as solvent extraction or chromatography, in particular silica column chromatography.

[0107] Surprisingly, it was found that under the conditions described above, the sulfonation of the aromatic ring bearing the hydroxyl function in the formula [Chem IVa] occurs selectively in ortho and para of the ring when it has a -OH group in meta.

[0108] In the case where compound [Chem I] is compound [Chem IA], step b) can be summarized by the diagram below:

[0109] Step b) is therefore particularly advantageous for the synthesis of compounds corresponding to the formula [Chem IA] defined above. In particular, it allows the production of patent blue with high selectivity for the substitution of the ring bearing the sulfonated functions.

[0110] Moreover, unlike what is observed under other sulfonation conditions, the above treatment results in little formation of side products due to the degradation of the triarylmethane structure or the dealkylation of the alkylamine functions.

[0111] In the case of Patent Blue, step b) can be summarized by the diagram below: Characteristics of the compounds obtained

[0112] The disclosure process provides access to compositions comprising the target compound of formula [Chem I], in particular compounds [Chem IA] and [Chem IB], more particularly compounds of formulas [Chem VI], [Chem VII], [Chem X], and [Chem VIII], with high yields and a very low impurity rate.

[0113] In practice, the mono-dealkylated impurity (where only one alkyl group among R4 and R5 is replaced by a hydrogen atom, the other three being alkyls) is the main impurity observed during the synthesis of compounds with the formula [Chem I]. Other dealkylated impurities, being structurally more distant, have different properties and, if they form, are eliminated during the process.

[0114] In particular, the disclosure process gives access to a composition comprising at least 98.0% of compound corresponding to the formula [Chem I], and less than 1% of monodealkylated impurity (compound of formula [Chem I] in which one of the R4 and R5 groups represents H), the % being measured by high-performance liquid chromatography with detection at 230 nm.

[0115] Even more preferentially, the disclosure process gives access to a composition comprising at least 99.0% of compound corresponding to the formula [Chem I], and less than 0.5% monodealkylated impurity, with no other impurity present in quantities exceeding 0.15%, the % being measured by high-performance liquid chromatography with detection at 230 nm.

[0116] In particular, the disclosure process provides access to a composition comprising at least 98.0% of a compound conforming to the formula [Chem IA] or [Chem IB], and less than 1% of a monodealkylated impurity (a compound in which one of the R4, R5 groups represents H), the percentage being measured by high-performance liquid chromatography with detection at 230 nm. Even more preferably, the disclosure process provides access to a composition comprising at least 99.0% of a compound conforming to the formula [Chem IA] or [Chem IB], and less than 0.5% of a monodealkylated impurity, with no other impurity present in an amount exceeding 0.15%, the percentage being measured by high-performance liquid chromatography with detection at 230 nm.

[0117] Advantageously, the process provides access to a composition in which no impurity other than a monodesalkylated derivative is present in an amount exceeding 0.1%, the percentage being measured by high-performance liquid chromatography with detection at 230 nm. In the case of Patent Blue V, desethyl-type impurities are represented by the formulas below in which Y and t have the same definition as above (in particular Y = Na⁺ and t = 1; Y = Ca²⁺ and t = 1 / 2; Y = K⁺ and t = 1):

[0118] In practice, the mono-desethylated impurity (a single ethyl group replaced by a hydrogen atom) is the main impurity observed during the synthesis of patent blue. Other desethylated impurities, being structurally more distant, have different properties and, if they form, are eliminated during the process.

[0119] In particular, the disclosure process gives access to a composition comprising at least 98.0% of the salt compound 4-[[4-(diethylamino)phenyl]-(4-diethylazaniumylidenecyclohexa-2,5-dien-1-ylidene)methyl]-6-hydroxybenzene-1,3-disulfonate (Patent Blue), and less than 1% of monodesethylated impurity, the % being measured by high-performance liquid chromatography with detection at 230 nm.

[0120] Even more preferentially, the disclosure process gives access to a composition comprising at least 99.0% of the salt compound of 4-[[4-(diethylamino)phenyl]-(4-diethylazaniumylidenecyclohexa-2,5-dien-1-ylidene)methyl]-6-hydroxybenzene-1,3-disulfonate, and less than 0.5% of monodesethylated impurity, with no other impurity present in an amount greater than 0.15%, the % being measured by high-performance liquid chromatography with detection at 230 nm.

[0121] Advantageously, the process provides access to a composition in which no impurity other than the monodesethylated derivative is present in an amount exceeding 0.1%, the percentage being measured by high-performance liquid chromatography with detection at 230 nm. In particular, the disclosure process provides access to a composition comprising at least 98.0% of the sodium salt compound of 2-[[4-(diethylamino)phenyl]-(4-diethylazaniumylidenecyclohexa-2,5-dien-1-ylidene)methyl]benzene-1,4-disulfonate (Isosulfan Blue), and less than 1% of the monodesethylated impurity, the percentage being measured by high-performance liquid chromatography with detection at 230 nm.

[0122] Even more preferentially, the disclosure process gives access to a composition comprising at least 99.0% of the sodium salt compound of N-[4-[[4-(diethyl amino) phenyl](2,5- disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, and less than 0.5% of monodesethylated impurity.

[0123] Advantageously, the disclosure process gives access to a composition in which no impurity other than the monodesethylated derivative is present in an amount greater than 0.1%, the % being measured by high-performance liquid chromatography with detection at 230 nm.

[0124] The disclosure process also provides access to compositions comprising a compound corresponding to formula [Chem I], in particular compounds [Chem IA] and [Chem IB], and more specifically compounds with formulas [Chem VI], [Chem VII], and [Chem VIII], containing few or no metallic impurities. It is understood that alkali and alkaline earth metal salts that may correspond to Y are not considered metallic impurities within the meaning of the invention.

[0125] The disclosure process provides access to compositions comprising a compound conforming to formula [Chem I], in particular compounds [Chem IA] and [Chem IB], and more specifically compounds with formulas [Chem VI], [Chem VII], and [Chem VIII], containing less than 200 ppm of metallic contaminants, advantageously less than 100 ppm of metallic contaminants, even better, less than 50 ppm of metallic contaminants, and even more advantageously, less than 20 ppm of metallic contaminants. The metallic contaminant content refers to the metal content, measured using the ICP / MS (Inductively Coupled Plasma Mass Spectrometry) method.

[0126] Metallic contaminants are defined as all metals in the periodic table of elements, excluding alkali and alkaline earth metals and their organic and inorganic derivatives. More specifically, metallic contaminants include the so-called "heavy" metals, and in particular: Al, As, Cd, Cr, Cu, Fe, Sn, Mn, Hg, Mo, Ni, Pb, Zn, and their organic and inorganic derivatives.

[0127] The disclosure process also provides access to a crystalline form of Patent Blue Sodium salt of formula [Chem VI], characterized by the following X-ray powder diffraction pattern, measured on a diffractometer (copper anode) and expressed in terms of interplanar distances d, Bragg angle 2θ, intensity and relative intensity (expressed as a percentage relative to the most intense line): Angle 2 theta (°) Interreticular distance 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

[0128] It should be understood that the intensity (I) and relative intensity (I rel) values ​​of the peaks above are likely to vary by + / -15%

[0129] In the table above, all lines are assumed to be of order 1 (n=1 in Bragg's law). Medicine :

[0130] The invention also relates to a method of manufacturing a drug or a diagnostic product comprising manufacturing the compound corresponding to formula [Chem I], in particular compounds [Chem IA] and [Chem IB], more particularly compounds of formulas [Chem VI], [Chem VII], [Chem X] and [Chem VIII], preferably of patent blue, sodium salt, or isosulfan blue, by the method described above and introducing the compound corresponding to formula [Chem I] into a pharmaceutically acceptable support.

[0131] The said medicinal product may be in any form suitable for its use in the intended applications.

[0132] In particular, mention may be made of: in tablet or capsule form containing 1 to 500 mg of compound corresponding to the formula [Chem I]; in aqueous solution form containing compound corresponding to the formula [Chem I], preferably patent blue or isosulfan blue, even more preferably patent blue, sodium salt, at a concentration of 0.05% to 2% g / L. In particular, a preferred formulation is an injectable aqueous solution.

[0133] Such compositions include, in addition to the compound corresponding to the formula [Chem I], excipients well known to those skilled in the art, such as, for example, citric acid and / or citrates, a phosphate buffer, polymers, cellulose derivatives, lipids.

[0134] In medical applications, the compound corresponding to the formula [Chem I], preferably patent blue or isosulfan blue, even more preferably patent blue, when obtained by the disclosure process, has the advantage of high purity, which avoids introducing into the body materials that are useless for the application.

[0135] The efficiency of the disclosure process allows access to a high-purity product at reduced costs, easily reproducible and applicable on an industrial scale. Furthermore, the disclosure process yields a product with a crystalline structure, thus exhibiting good stability.

[0136] Such a composition is particularly interesting for use as a contrast agent for locating lymphatic vessels and arterial territories and as a diagnostic agent for cancer. Specifically, the composition of the invention can be used in a diagnostic procedure called "sentinel lymph node mapping." This procedure is particularly relevant to breast cancer, colon cancer, and melanoma. In particular, the composition is especially useful for locating the sentinel lymph node prior to biopsy in patients with operable breast cancer and in intraoperative sentinel lymph node mapping in patients with colon cancer. It is also used in preoperative lymphoscintigraphy for sentinel lymph node biopsy in melanoma.

[0137] The various embodiments, variants, preferences and advantages described above for each of the objects of the invention apply to all the objects of the invention and may be taken separately or in combination.

[0138] The invention is illustrated by the following examples, which are given by way of non-limiting example. Figures

[0139] Figure 1 : there figure 1 This is a graph representing the X-ray diffraction patterns of three samples of Patent Blue Sodium, obtained using the disclosure process (designated Inv1, Inv2, and Inv3). These samples come from three separate production batches. The x-axis represents the angle 2θ in degrees; the y-axis represents the intensity in arbitrary units of intensity. Figure 2 : there figure 2is a graph representing the X-ray diffraction patterns of six commercially available samples of Patent Blue sodium salt (designated C1 to C6). Also shown in this figure are the X-ray diffraction patterns of three samples of Patent Blue sodium salt obtained by the disclosure process (designated Inv1 to Inv3) and illustrated in the figure 1 . On the x-axis: the angle 2 theta in degrees; on the y-axis: the intensity in arbitrary units of intensity. Examples:

[0140] In these examples, parts and percentages are expressed by weight unless otherwise stated. Materials and methods HPLC analysis :

[0141] Column: AGILENT Poroshell 120 SB-C18 150x4.6-2.7µ (ref 683975-902) Mobile Phase A: Ammonium Formate / Formic Acid Buffer 10mM (pH = 4.1±0.1) Mobile Phase B: Acetonitrile Flow Rate: 1 ml / min Temperature: 30°C Injection Volume: 5µL Gradient: Analysis Time 40 min + 7 min post-run stabilization 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 diffraction pattern on powder The X-ray powder diffraction pattern was obtained under the following experimental conditions: X'Pert Pro MPD Panalytical Diffractometer (DY2764), Copper Anode (λ=1.54Å), Voltage: 40 kV, Current: 40 mA, θ-θ Mounting, Measurement Range: 2° to 50°, Increment Between Each Measurement: 0.026°, Measurement Time Per Step: 20.40 s, PIXcel RTMS Detector (PHD 25.5-7%, active length 3.347°) Synthesis of patent blue (according to the invention): Step 1: Preparation of 3-(bis(4-(diethylamino)phenyl)methyl)phenol dihydrochloride:

[0142]

[0143] Add the 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.

[0144] Cool the reaction medium to 0°C and pour in an aqueous solution of 37% HCl (136.5 mL, 1.638 mol, 2.00 eq) while maintaining the medium at a temperature below 20°C.

[0145] Then heat the reaction mixture under reflux for 20 hours.

[0146] Cool the reaction mixture to 60°C and then pour in 800mL of an aqueous 2N HCl solution. Cool the reaction mixture to 0°C and keep it stirred for 5 hours.

[0147] Filter the resulting precipitate and wash the solid with 500 mL of an aqueous 2N (9 / 1) acetone / HCl mixture followed by 500 mL of acetone.

[0148] The solid is dried in a ventilated oven (50°C).

[0149] We obtain 303 g of 3-(bis(4-(diethylamino)phenyl)methyl)phenol dihydrochloride in the form of a white solid. HPLC purity: 97.2% Yield: 78% 1< H NMR (300 MHz, D2O): δ 7.39 (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) 13< C NMR (75 MHz, D2O): δ 156.0, 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:

[0150]

[0151] Add the dihydrochloride of 3-(bis(4-(diethylamino)phenyl)methyl)phenol (150 g, 0.315 mol, 1 eq.) in 600 mL of H 2 SO 4 .

[0152] Heat to 90°C for 3 hours then leave for 16 hours under stirring at room temperature.

[0153] Dilute the reaction medium with 15 L of an ethanol / isopropyl ether mixture (75 / 25) while maintaining a temperature below 20°C.

[0154] Filter the resulting precipitate and wash the solid with 2x600 mL of isopropyl ether.

[0155] The solid is dried in a ventilated oven (50°C).

[0156] 183 g of 4-(bis(4-(diethylamino)phenyl)methyl)-6-hydroxybenzene-1,3-disulfonic acid is obtained in the form of a white solid. HPLC purity: 98.8% Yield: quantitative 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) 13< C NMR (75 MHz, DMSO): δ 153.6, 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: Preparing the Patent Blue:

[0157]

[0158] Add 4-(bis(4-(diethylamino)phenyl)methyl)-6-hydroxybenzene-1,3-disulfonic acid (1.2 kg, 2.1 mol, 1 eq.) into 6 L of N-methylpyrrolidone.

[0159] Heat the reaction mixture to 95°C and pour the 1,4-benzoquinone (346 g, 3.2 mol, 1.5 eq.) in solution in 1.2 L of N-methylpyrrolidone.

[0160] Continue heating for 3 hours then reduce to room temperature.

[0161] Dilute the reaction mixture with 18 L of acetone.

[0162] Filter the resulting precipitate and wash the solid with 2 x 6 L of acetone.

[0163] Resuspend the solid in 6 L of H2O / Methanol mixture (80 / 20).

[0164] Heat for 1 hour at reflux then cool to room temperature.

[0165] Filter the solid and wash with 2 x 6 L of acetone. Resuspend the solid in 15 L of methanol while stirring and pour over a 22% aqueous sodium carbonate solution (256 mL).

[0166] Leave under agitation for 3 hours then concentrate.

[0167] Resume in 10 L of isopropanol.

[0168] Recover the solid by filtration and wash with 2 x 4 L of acetone

[0169] The solid is dried in a ventilated oven (50°C).

[0170] 766 g of sodium salt of 4-[[4-(diethylamino)phenyl]-(4-diethylazaniumylidenecyclohexa-2,5-dien-1-ylidene)methyl]-6-hydroxybenzene-1,3-disulfonate (Patent Blue) is obtained in the form of a purple solid. Purity HPLC: 99.3% Yield: 61% 1< H NMR (300 MHz, D2O): δ 8.29 (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) 13< C NMR (75 MHz, D2O): δ 170.1, 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):

[0171] Steps 1 and 2 were carried out as described above. For step 3, the protocol described above was followed, varying the oxidizing compound. This oxidizing compound could be another quinone or another oxidizing reagent.

[0172] The results obtained are reported in Tables 2 and 3 below. Table 2 Quinone Conversion rate step 3 (*) Mono-desethylated compound % (*) 1,4-benzoquinone (a) 93% <1% 3,5-Diterbutyl-1,2-benzoquinone (a) 93% 2,6% 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-benzoquinone (b) 31% 2,4% 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

[0173] It has been observed that some quinones provide high conversion rates while resulting in a product with low levels of monodesethylated impurities. Other quinones give either very low yields or a high content of monodesethylated compounds, which are difficult to separate. Table 3 Oxidizing agent (comparative) Conversion rate step 3 (*) Mono-desethylated compound % (*) KMnO 4 95% 5% NaMnO 4 78% 7% Ammonium Cerium (IV) Nitrate 41% 4% MnO2 38% 5% FeCl 3 - - (*) measured according to the HPLC method described above

[0174] It has been observed that only a few oxidizing reagents other than quinones can transform compound (V) into Patent Blue V. Few of these reagents allow for a desethyl content below 5%, or with a low conversion rate. Furthermore, these reagents are based on heavy metals, the use of which is strongly discouraged, both for environmental reasons and to avoid contamination of the final product. X-ray diffractogram on powder:

[0175] The X-ray diffraction profile of the powder (diffraction angles) of Patent Blue Sodium Salt obtained in Example 3 is given by the significant lines reported in Table 4 with their intensity and relative intensity (expressed as a percentage of the most intense line). The measurement was carried out on three separate batches, all of which exhibit essentially the same profile as shown in the table. figure 1 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 consistent after the preparation process. It also confirms the absence of NaCl (see characteristic peaks on the figure 2 ). Table 4 Angle 2 theta (°) Interreticular distance 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 commercially available Patent Blue V product, sodium salt :

[0176] The commercial products of the following producers (Table 5) were analyzed using the same X-ray diffraction method: Table 5: Patent Blue V, commercial sodium salt Producer Commercial reference Reference on the figure 2 ACROS 339330050 C1 Santa Cruz Biotechnology SC250653 C2 TCI A1242 C3 Combi Blocks HA8936 C4 Biosynth FC1571 C5 Colorey FG18191327 C6

[0177] The results are reported on the figure 2 It is observed that most of the peaks do not correspond to those of Patent Blue V, sodium salt, of the invention, which are reported in Table 4 and on the figure 1 This observation leads to the conclusion that Patent Blue V, sodium salt, of the invention is a new crystalline form compared to previously known crystalline forms. On the figure 2We also observe the presence of characteristic NaCl peaks, in particular the peaks at angles 2 theta = 32 and 45.5, which allows us to note the presence of NaCl in all samples of commercial Patent Blue, but not in Patent Blue sodium salt according to the invention.

Claims

1. A composition comprising at least 98 % patent blue sodium salt and less than 1 % mono-desethyl impurities, the percentage being measured by high performance liquid chromatography with detection at 230 nm, characterised in that the patent blue sodium salt is in crystalline form.

2. The composition according to claim 1, wherein the crystalline form of the patent blue sodium salt is characterised by an X-ray powder diffraction pattern having the following peaks: 2Theta angle (°)5.66.29.410.911.512.114.415.616.517.618.219.420.022.924.

73. The composition according to claim 2, wherein the X-ray powder diffraction pattern is additionally characterised by the following inter-reticular distances d, intensities and relative intensities: 2Theta angle (°)Inter-reticular distance d (Å)I (counts)rel I (%)5.615.8050061.56.214.2937546.29.49.39187.523.110.98.1262.57.711.57.7112515.412.17.33156.2519.214.46.14343.7542.315.65.6825030.816.55.3837546.217.65.02187.523.118.24.8637546.219.44.57812.5100.020.04.4350061.522.93.87187.523.124.73.6025030.8 The values of intensity (I) and relative intensity (rel I) of the peaks being likely to vary by ±15 %4. The composition according to any of claims 1 to 3, comprising at least 99 % patent blue sodium salt and less than 0.5 % mono-desethyl impurities, the percentage being measured by high performance liquid chromatography with detection at 230 nm.

5. The composition according to any of claims 1 to 4, wherein no impurity other than the mono-desethyl impurities is contained in an amount higher than 0.15 %, the percentage being measured by high performance liquid chromatography with detection at 230 nm.

6. The composition according to claim 5, wherein no impurity other than the mono-desethyl impurities is contained in an amount higher than 0.1 %, the percentage being measured by high performance liquid chromatography with detection at 230 nm.

7. The composition according to any of claims 1 to 6, comprising less than 200 ppm of metal contaminants, advantageously less than 100 ppm of metal contaminants, better still less than 50 ppm of metal contaminants, and further advantageously less than 20 ppm of metal contaminants.

8. The composition according to any of claims 1 to 7 that is free of NaCl.

9. The composition according to any of claims 1 to 8 for use thereof as medicinal product.

10. The composition according to any of claims 1 to 8 for use thereof as diagnosis product.

11. The composition according to any of claims 1 to 8 for use thereof as contrast agent for the detection of lymphatic vessels and arterial territories and / or as diagnosis agent for cancer.

12. The composition according to any of claims 1 to 8 for use thereof according to claim 11 for the detection of the sentinel lymph node before biopsy in patients suffering from operable breast cancer, or for intra-operative mapping of the sentinel lymph nodes in patients suffering from cancer of the colon.

13. A method for producing a medicinal product or diagnosis product comprising the manufacture of the composition according to any of claims 1 to 8, and the insertion of said composition in a pharmaceutically acceptable carrier.

14. A composition in tablet or capsule form comprising from 1 to 500 mg of a composition according to any of claims 1 to 8 in a pharmaceutically acceptable carrier.