Process for preparing fluorescein quinoid
阅读说明：本技术 制备荧光素醌型的方法 (Process for preparing fluorescein quinoid ) 是由 尼古拉斯·泰森 爱德华·布甘 娜代日达·斯帕索娃 于 2019-07-31 设计创作，主要内容包括：本发明涉及制备荧光素醌型的方法。本发明特别地涉及制备式(I)的荧光素醌型的方法、荧光素甲磺酸盐或共晶体、通过用水或水和水溶性有机溶剂的混合物处理从荧光素甲磺酸盐或共晶体杂质纯化式(I)的荧光素醌型的方法、通过用水或水和水溶性有机溶剂的混合物洗涤从荧光素甲磺酸盐或共晶体中除去可能的游离甲磺酸的方法及其制备方法、以及荧光素甲磺酸盐或共晶体用于合成式(I)的荧光素醌型的用途。<Image he="574" wi="650" file="DDA0002150704910000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention relates to a process for preparing a fluorescein quinoid. The invention relates in particular to a process for preparing a fluorescein quinoid of formula (I), fluorescein methanesulfonate or co-crystal, a process for purifying a fluorescein quinoid of formula (I) from fluorescein methanesulfonate or co-crystal impurities by treatment with water or a mixture of water and a water-soluble organic solvent, a process for preparing a fluorescein quinoid of formula (I) by treatment with water or a mixture of water and a water-soluble organic solvent, a method for preparing a fluorescein quinoid of formula (I) from fluorescein methanesulfonate or co-crystal impuritiesA method for removing possible free methanesulfonic acid from fluorescein methanesulfonate or co-crystal by washing the compound, a process for its preparation, and the use of fluorescein methanesulfonate or co-crystal for synthesizing a fluorescein quinoid of formula (I).)
1. A process for the preparation of a fluorescein quinoid of formula (I),
the method comprises the following steps:
a) preparing fluorescein mesylate or a co-crystal;
b) converting the fluorescein methanesulfonate salt or co-crystal to the fluorescein quinoid of formula (I) by treatment with water or a mixture of water and a water-soluble organic solvent.
2. The method of claim 1, wherein the water-soluble organic solvent is C1-C3An alkyl alcohol.
3. The method of any one of claims 1-2, wherein C is1-C3The alkyl alcohol is methanol or ethanol.
4. The method according to any one of claims 1 to 3, wherein the fluorescein quinoid has a particle size distribution with a d (0.9) of from 30 μm to 100 μm.
5. The process according to any one of claims 1 to 4, wherein in step b) when a mixture of water and water-soluble organic solvent is used, the water-soluble organic solvent is added after or before treatment with water.
6. The method of any one of claims 1 to 5, wherein the fluorescein mesylate salt or co-crystal has a molar ratio of fluorescein to methanesulfonic acid of 1: 1.
7. The method according to any one of claims 1 to 6, wherein the fluorescein mesylate salt or co-crystal has a DSC onset of 285 ± 1 ℃ and/or a DSC peak of 289 ± 1 ℃.
8. The method according to any one of claims 1 to 7, wherein the fluorescein mesylate salt or co-crystal has a characteristic X-ray powder diffraction pattern having characteristic peaks expressed in terms of 2 θ at 8.3 ± 0.2, 15.0 ± 0.2, 24.1 ± 0.2, 28.6 ± 0.2.
9. The method of any one of claims 1 to 8, wherein the fluorescein mesylate salt or co-crystal is isolated.
10. The method according to any one of claims 1 to 9, wherein the preparation of the fluorescein mesylate salt or co-crystal in step a) is carried out by converting fluorescein to fluorescein mesylate in the presence of methanesulfonic acid or by reacting resorcinol and phthalic anhydride in methanesulfonic acid.
11. The method according to any one of claims 1 to 8, further comprising step a'): removing possible free methanesulfonic acid from the fluorescein methanesulfonate salt or co-crystal prepared in step a) by washing with water or a mixture of water and a water-soluble organic solvent.
12. A fluorescein mesylate salt or co-crystal.
13. Fluorescein mesylate salt or co-crystal according to claim 12, wherein the fluorescein mesylate salt or co-crystal is as defined in any one of the preceding claims 6 to 9.
14. A process for the purification of a fluorescein quinoid of formula (I) from fluorescein methanesulfonate or co-crystal impurities by treatment with water or a mixture of water and a water-soluble organic solvent,
15. a process for removing possible free methanesulfonic acid from fluorescein methanesulfonate or co-crystal prepared in step a) as claimed in claims 1, 6 to 9 by washing with water or a mixture of water and a water-soluble organic solvent.
16. Use of fluorescein methanesulfonate or a co-crystal for the synthesis of a fluorescein quinoid of formula (I):
Technical Field
The invention relates to a method for preparing a fluorescein quinoid (abbreviated as FlsQ) of formula (I):
furthermore, the present invention relates to novel solid fluorescein forms and methods for their preparation. The invention also relates to the use of the novel solid fluorescein form in the synthesis of fluorescein quinoids.
Background
Fluorescein (abbreviated Fls) is an artificial organic compound and dye that is widely used as a fluorescent tracer for many applications. Fls exist in several tautomeric forms and in some solid forms.
Among the various crystalline forms disclosed in the prior art, particular reference is made to the specific solvated and unsolvated forms.
In particular, FlsQ, known as a quinoid (which is in the unsolvated form, also known as the red form; also characterized by Angew. chem. int. Ed. Engl. (German applied chemistry), 1997,36(7), 770-772), has the following formula (I):
the Fls Z form, which is referred to as the zwitterionic form (which is the unsolvated form, also referred to as the yellow form; see chem. Eur. J. (J. Eur.) 2016,22,2-20) has the formula:
the Fls L form, referred to as the lactone form, has the formula:
currently, Fls L exists only in solvated form.
WO 2017/082430 discloses a method for purifying sodium fluorescein by crystallizing it with 2-propanol or 2-butanol.
Disclosure of Invention
The problem addressed by the present invention is therefore to provide a method capable of enhancing the filtration behavior of the Fls Q form and improving the purity of the Fls Q form finally obtained.
This problem is solved by a specific method of preparation of Fls Q, which involves the formation of a specific solid form of fluorescein.
The invention specifically relates to the following:
the method comprises the following steps:
a) preparing fluorescein mesylate or a co-crystal;
b) converting the fluorescein methanesulfonate salt or co-crystal to the fluorescein quinoid of formula (I) by treatment with water or a mixture of water and a water-soluble organic solvent.
Item 3. the method of any one of
Item 7. the method of any one of
Item 9. the method of any one of
Item 11. the method of any one of
Item 13. the fluorescein mesylate salt or co-crystal of
further characteristics and advantages of the preparation process and of the particular fluorescein solid form according to the invention will become apparent from the description of preferred embodiments given below by way of non-limiting example.
Drawings
FIGS. 1A and 1B show XPRD diffractograms of fluorescein mesylate or co-crystal (abbreviated Fls A).
FIG. 2 shows the XPRD diffractogram of Fls Q.
Fig. 3A and 3B show the PSDs (particle size distributions) of Fls a and Fls Q, respectively.
FIG. 4 shows DSC of Fls A.
Fig. 5A and 5B show DSC of Fls Q.
Detailed Description
According to a first aspect, the present invention relates to a process for the preparation of a fluorescein quinoid (Fls Q) of formula (I):
the method comprises the following steps:
a) preparing fluorescein mesylate or a co-crystal;
b) converting the fluorescein methanesulfonate salt or co-crystal to the fluorescein quinoid of formula (I) by treatment with water or a mixture of water and a water-soluble organic solvent.
Advantageously, the applicant has surprisingly found that by the process of the invention involving the preparation of fluorescein mesylate or co-crystal (abbreviated Fls a) and subsequent conversion to a fluorescein quinoid (Fls Q), an enhanced FlsQ filtration, in particular avoiding filtration problems, can be obtained, especially on an industrial scale.
As a further advantage, fluorescein quinoid (FLs Q) has improved purity.
The fluorescein mesylate salt or co-crystal prepared in step a) may have the following formulae (IIa) and (IIb), respectively:
the preparation of the fluorescein mesylate or co-crystal of step a) can be carried out as follows: fluorescein, in particular fluorescein quinoid (Fls Q), is converted into fluorescein methanesulfonate in the presence of methanesulfonic acid (MsOH) or resorcinol and phthalic anhydride are reacted in methanesulfonic acid. Preferably, the fluorescein mesylate salt or co-crystal of step a) is in isolated form. The term isolated form refers to a wet or dry solid that is separated by a solvent.
According to a preferred embodiment, the fluorescein mesylate or co-crystal has a DSC onset of 285 ± 1 ℃ and/or a DSC peak of 289 ± 1 ℃.
According to another preferred aspect, the fluorescein mesylate salt or co-crystal has a characteristic X-ray powder diffraction pattern with at least one characteristic peak expressed in terms of a 2 θ value (2 θ) at 8.3 ± 0.2, 15.0 ± 0.2, 24.1 ± 0.2, 28.6 ± 0.2 of the characteristic X-ray powder diffraction pattern. Preferably, the characteristic X-ray powder diffraction pattern of fluorescein methanesulfonate or co-crystal consists of characteristic peaks expressed in 2 θ values (2 θ) of 8.3. + -. 0.2, 15.0. + -. 0.2, 24.1. + -. 0.2, 28.6. + -. 0.2.
According to another preferred aspect, the characteristic X-ray powder diffraction pattern of the fluorescein methanesulfonate salt or co-crystal further has at least one characteristic peak expressed in 2 θ values (2 θ) of 10.7 ± 0.2, 11.9 ± 0.2, 13.4 ± 0.2, 16.8 ± 0.2, 26.5 ± 0.2, 27.8 ± 0.2.
The fluorescein mesylate or co-crystal has a molar ratio of fluorescein to methanesulfonic acid of 1: 1.
According to a preferred embodiment, the above process further comprises a step a'), after step a) and before step b), by usingWashing with water or a mixture of water and a water-soluble organic solvent removes possible free methanesulfonic acid (abbreviated as MsOH) from the fluorescein methanesulfonate or cocrystal prepared in step a). Preferably by washing or slurrying, e.g. by washing with or slurrying in a solvent, e.g. water, C1-C3Alcohol or mixtures thereof, removing possible free methanesulfonic acid. Alternatively, possible free methanesulfonic acid may be removed by recrystallization, for example by pH change mediated crystallization. As intended herein, the term free methanesulfonic acid (MSA) refers to MSA that is not part of the mesylate salt or co-crystal, but rather an impurity thereof.
As intended herein, the term C1-C3The alcohol refers to methanol (MetOH), ethanol (EtOH), isopropanol, and n-propanol, respectively.
Without being bound by any theory, experimental evidence suggests that in the absence of methanesulfonic acid, the fluorescein mesylate or co-crystal is converted to Fls Q, which is reversible. Thus, step a') above is particularly advantageous to avoid the presence of methanesulfonic acid residues, which prevents complete conversion of fluorescein mesylate or the co-crystal to the Fls Q form (see experimental evidence in example 6). Incomplete conversion of Fls a to Fls Q can create serious filtration problems.
According to a preferred embodiment, when a mixture of water and a water-soluble organic solvent is used in step b), the water-soluble organic solvent is C1-C3An alkyl alcohol, preferably methanol or ethanol, even more preferably ethanol.
As intended herein, the term volume refers to the volume of solvent per unit of product, thus, for example, 1 volume is 1 liter/1 kg, or 1 ml/1 g, or 1 μ l/1 mg. Thus, a volume of 10 means, for example, 10 liters per 1 kilogram of material. As for the mixture of water and the water-soluble organic solvent described above, water and a water-soluble organic solvent are used in the mixture used in step b).
The volume of each water-soluble solvent and water used in the mixture of solvent and water used in step b) is preferably in the range of 1 to 10 volumes, more preferably 2 to 7 volumes, more preferably 3 to 5 volumes.
Furthermore, when a mixture of water and a water-soluble organic solvent is used in step b), the water-soluble organic solvent may be added after or before the treatment with water, preferably after, because the conversion is faster. Alternatively, water and the water-soluble organic solvent may be added simultaneously or as a mixture thereof.
According to a preferred embodiment, the treatment with water or a mixture of water and a water-soluble organic solvent of step b) is carried out at a temperature of from 20 ℃ to 60 ℃, preferably from 30 ℃ to 50 ℃, even more preferably from 35 to 45 ℃. According to a particularly preferred embodiment, the temperature is about 40 ℃.
According to a preferred embodiment, the treatment with water or a mixture of water and a water-soluble organic solvent of step b) is carried out for a period of time ranging from 10 minutes to 20 hours, preferably from 15 minutes to 10 hours, more preferably from 20 minutes to 5 hours, even more preferably from 30 minutes to 2 hours. According to a particularly preferred embodiment, said period of time is between 15 minutes and 2 hours.
According to a particularly preferred embodiment, the treatment with water or a mixture of water and a water-soluble organic solvent of step b) is carried out at a temperature of from 35 to 45 ℃ for a period of from 15 minutes to 2 hours.
However, it is generally expected that the larger the amount of water in the mixture of water and water-soluble organic solvent of step b), the smaller the time period and temperature values for completing the conversion of step b).
Thus, for example, when only water is present, the conversion of step (b) lasts only 20 minutes at 40 ℃.
In terms of Particle Size Distribution (PSD), the fluorescein quinoid has a PSD with a d (0.9) in the range of 30 μm to 100 μm.
Another aspect is fluorescein mesylate or a co-crystal. Some possible forms and/or characteristics of the fluorescein mesylate salt or co-crystal are as defined above.
Another aspect is a method for the synthesis of fluorescein methanesulfonate or co-crystal, comprising the step of treating a fluorescein of formula (I), in particular a fluorescein quinoid, with methanesulfonic acid.
Another aspect is a process for removing possible free methanesulfonic acid from the fluorescein methanesulfonate salt or co-crystal prepared in step a) as defined above, by washing with water or a mixture of water and a water-soluble organic solvent.
Preferably, the amount of possible free methanesulfonic acid to be removed in the fluorescein mesylate salt or cocrystal ranges from 0.1 to 10% by weight, relative to the total weight of the fluorescein mesylate salt or cocrystal.
Another aspect is a method for purifying fluorescein quinoid (Fls Q) from fluorescein mesylate or co-crystal impurities by treating Fls Q with water or a mixture of water and a water-soluble organic solvent. The water-soluble organic solvent is as defined above.
Advantageously, said step of purifying the fluorescein quinoid from fluorescein methanesulfonate or cocrystal (abbreviated as Fls A) is important, since Fls Q may contain fluorescein methanesulfonate or cocrystal as an impurity, and therefore such purification can be used to remove said impurity. Furthermore, it facilitates rapid filtration of Fls Q. In fact, the presence of Fls a as impurities of Fls Q presents serious filtration problems to the Fls Q suspension. Said Fls Q treatment may also be advantageously applied to FlsQ prepared according to the method of the invention, for example, as a further step after step b) if step b) is incomplete, i.e. if it provides Fls Q containing Fls a as an impurity.
Another aspect is the use of fluorescein mesylate or a co-crystal for the synthesis of a fluorescein quinoid (FLs Q) of formula (I):
Detailed Description
Experimental part
All starting materials are commercially available, for example from Sigma-Aldrich.