Process for the preparation of phenol-3-[[(4,5-dihydro-1h-imidazol-2-YL)methyl]-(4-methylphenyl)amino]-methanesulfonate

Abstract

The present invention refers to three new polymorphic forms of phentolamine mesylate and to the processes for their production.

Description

[0001] P024304WO-01_English text Notarbartolo & Gervasi S.p.A.

[0002] “PROCESS FOR THE PREPARATION OF PHENOL-3-[[(4,5-DIHYDRO-lH-IMIDAZOL- 2- YL METH YL] -(4 -METHYLPHENYL) AMINO] -METHANE SULF ONATE”

[0003] FIELD OF THE INVENTION

[0004] The current invention refers to the field of synthetic processes for the preparation of Active Pharmaceutical Ingredients and, specifically, to a process for the preparation of phenol- 3-[[(4,5-dihydro-lH-imidazol-2-yl)methyl]-(4-methylphenyl)amino]-methanesulfonate, having the structure formula (I) reported here below:

[0005]

[0006] The compound has CAS no. 65-28-1 and is also known, and commonly referred to in the field, with the name phentolamine mesylate, that will be used in the rest of the description and in the claims.

[0007] Phentolamine mesylate is a nonselective alpha adrenergic receptor antagonist approved for use by the Food and Drug Administration (FDA) for reversing soft-tissue anaesthesia. Phentolamine mesylate was also approved by the FDA for use in preventing or controlling hypertensive episodes in patients with pheochromocytoma and for treatment of dermal necrosis following intravenous administration or extravasation of norepinephrine. Phentolamine mesylate continues to be studied for new indications.

[0008] STATE OF THE ART

[0009] Despite having been developed in the 1950’s, the polymorphism of phentolamine mesylate was overlooked until recently, and therefore common knowledge was that this API did not display any polymorphism; the sole form known until recently is hereinafter called “Form A”; this forms exhibits a XRPD pattern (when measured with Cu Ka radiation) comprising peaks at 6.99, 8.64, 11.75, 13.91, 14.81, 15.48, 16.80, 18.61, 18.98, 19.53, 20.42, 20.88, 21.19, 21.45, 21.79, 22.18, 23.36, 23.98, 27.74, 30.03 and 31.98 ± 0.2° 20.

[0010] In 2022 patent US 11566005 B2 by Ocuphire Pharma Inc. disclosed a new polymorph of phentolamine mesylate. Such patent claims a solid form which is different from Form A and is P024304WO-01_English text Notarbartolo & Gervasi S.p.A.

[0011] characterized by the presence of peaks at 6.87, 11.65, 13.15, 18.86, 20.32, 20.85, 21.07, 21.36 ± 0.2° 29 under XRPD analysis using Cu Ka radiation as X-Ray source.

[0012] In 2024 the present Applicant has published the following articles disclosing the three new polymorphic forms of phentolamine mesylate object of the present invention: Research Disclosure RD724005, published on June 25th, 2024; and Research Disclosure RD724133, published on July 22nd, 2024. Both documents are available online at www.researchdisclsure.com or in printed version in the journal Research Disclosure, August 2024 volume.

[0013] SUMMARY OF THE INVENTION

[0014] In its first aspect, the present invention refers to three new solid forms of the a-adrenergic receptor antagonist phentolamine mesylate.

[0015] The first new polymorph of phentolamine mesylate exhibits an XRPD pattern comprising peaks at 8.50, 9.02, 11.25, 11.61, 13.26, 15.89, 16.46, 17.00, 18.56, 18.97, 19.48, 20.18, 20.60, 20.98, 22.33, 23.32, 23.62, 24.22, 24.44, 25.60, 26.42, 27.18, 28.64, 29.52, 30.54, 33.26 and 35.23 ± 0.2° 29; this polymorph is referred to in the rest of the description as “Form B”.

[0016] The second new polymorph of phentolamine mesylate exhibits an XRPD pattern comprising peaks at 8.45, 9.19, 11.49, 13.44, 15.86, 16.86, 19.00, 19.24, 19.88, 20.51, 22.24, 22.76, 23.18, 23.70, 25.37, 25.65, 26.13, 26.86, 27.55, 28.26, 30.16 and 33.80 ± 0.2° 29; this polymorph is referred to in the rest of the description as “Form C”.

[0017] Finally, the third new polymorph of phentolamine mesylate exhibits an XRPD pattern comprising peaks at 7.22, 10.13, 13.29, 13.87, 14.24, 18.01, 19.03, 19.74, 20.38, 21.38, 21.37, 21.71, 22.36, 23.08, 23.33, 24.41, 25.37 and 26.20 ± 0.2° 29; this polymorph is referred to in the rest of the description as “Form D”.

[0018] In the second aspect thereof, the invention provides processes for the preparation of Forms B, C, and D of phentolamine mesylate described above.

[0019] BRIEF DESCRIPTION OF THE FIGURES

[0020] Figure 1 : XRPD diffractograms of Form A (A), Form B (B), Form C (C), Form D (D) of phentolamine mesylate.

[0021] Figure 2: XRPD diffractogram of Pharm. Eur. reference standard phentolamine mesylate. Figure 3: XRPD diffractogram of USP reference standard phentolamine mesylate.

[0022] Figure 4: DSC thermogram of Form A.

[0023] Figure 5: DSC thermogram of Form B.

[0024] Figure 6: DSC thermogram of Form C. P024304WO-01_English text Notarbartolo & Gervasi S.p.A.

[0025] DETAILED DESCRIPTION OF THE INVENTION

[0026] In the subsequent description, the following definitions are adopted:

[0027] - the term “about”, when immediately preceding a numerical value, means ± up to 20% of the numerical value. For example, “about” a numerical value means ± up to 20% of the numerical value, in some embodiments, ± up to 19%, ± up to 18%, ± up to 17%, ± up to 16%, ± up to 15%, ± up to 14%, ± up to 13%, ± up to 12%, ± up to 11%, ± up to 10%, ± up to 9%, ± up to 8%, ± up to 7%, ± up to 6%, ± up to 5%, ± up to 4%, ± up to 3%, ± up to 2%, ± up to 1%, ± up to less than 1%, or any other value or range of values therein;

[0028] - throughout the present specification, numerical ranges are provided for certain quantities. These ranges comprise all subranges therein. Thus, the range “from 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.);

[0029] - the term “substantially the same as”, when used in connection with an XRPD pattern, means that that each peak of the XRPD pattern differs from a respective peak of a stated reference compound by no more than ± 0.2° 29;

[0030] - the term “substantially the same as”, when used in connection with a DSC thermogram, means that that each peak of the DSC thermogram differs from a respective peak of a stated reference compound by no more than ± 3 °C, and in some embodiments no more than ± 2 °C;

[0031] - all XRPD spectra and peaks reported or referred to in this description have been collected using Cu Ka radiation as X-Ray source.

[0032] In its first aspect, the invention is about new solid forms of phentolamine mesylate. Notably, the researchers in the R&D laboratories of the Applicant were able to synthesize in high purity and characterize by XRPD three new solid forms of phentolamine mesylate, that are called hereinafter “Form B”, “Form C”, and “Form D”.

[0033] The present invention provides phentolamine mesylate Form B that exhibits an XRPD pattern comprising peaks at 8.50, 9.02, 11.25, 11.61, 13.26, 15.89, 16.46, 17.00, 18.56, 18.97, 19.48, 20.18, 20.60, 20.98, 22.33, 23.32, 23.62, 24.22, 24.44, 25.60, 26.42, 27.18, 28.64, 29.52, 30.54, 33.26 and 35.23 ± 0.2° 29.

[0034] The present invention provides phentolamine mesylate Form C that exhibits an XRPD pattern comprising peaks at 8.45, 9.19, 11.49, 13.44, 15.86, 16.86, 19.00, 19.24, 19.88, 20.51, 22.24, 22.76, 23.18, 23.70, 25.37, 25.65, 26.13, 26.86, 27.55, 28.26, 30.16 and 33.80 ± 0.2° 29.

[0035] The present invention provides phentolamine mesylate Form D that exhibits an XRPD P024304WO-01_English text Notarbartolo & Gervasi S.p.A.

[0036] pattern comprising peaks at 7.22, 10.13, 13.29, 13.87, 14.24, 18.01, 19.03, 19.74, 20.38, 21.38, 21.37, 21.71, 22.36, 23.08, 23.33, 24.41, 25.37 and 26.20 ± 0.2° 20.

[0037] The table below summarizes the positions of the main XRPD peaks of Forms A (prior art), and Forms B, C and D (invention) of phentolamine mesylate:

[0038]

[0039] The XRPD spectra of Forms A, B, C and D are reproduced in Fig. 1. For comparison, in P024304WO-01_English text Notarbartolo & Gervasi S.p.A.

[0040] Figs. 2 and 3 are reproduced the XRPD spectra of the reference standards of phentolamine mesylate obtained from Pharm. Eur. and USP, respectively.

[0041] Preferably, Form B exhibits an XRPD pattern comprising peaks at 8.50, 9.02, 11.25, 13.26, 15.89, 17.00, 18.56, 18.97, 19.48, 20.60, 20.98, 22.33, 25.60, 26.42 and 27.18 ± 0.2° 20.

[0042] Preferably, Form C exhibits an XRPD pattern comprising peaks at 8.45, 9.19, 11.49, 13.44, 16.86, 19.00, 19.88, 20.51, 22.24 and 27.55 ± 0.2° 20.

[0043] Preferably, Form D exhibits an XRPD pattern comprising a peak at about 7.22, 10.13, 14.24, 18.01, 19.74, 20.38, 21.38, 21.71, 22.36 and 24.41 ± 0.2° 20.

[0044] Form B and Form C have proven to be stable solid forms as they easily survive a drying step, while Form D, despite being sufficiently stable when wet to allow XRPD characterization, is observed to transform into Form C upon drying; this suggests that Form D is likely a solvated form.

[0045] While Form A (the only known form before year 2022) displays at the DSC analysis a single thermal event corresponding to the melting of the solid occurring at 180 °C, Form B and Form C reveal in both cases a more complex behaviour.

[0046] The thermogram obtained by the DSC analysis of Form A is reproduced in Fig. 4.

[0047] The thermogram obtained by the DSC analysis of Form B is reproduced in Fig. 5. This thermogram is characterized by several thermal events consisting in 1) an endothermic transition between about 112 °C and 125 °C with peak at about 120 °C followed by a small exothermic transition; 2) a second endothermic transition between about 128 °C and 135 °C with peak at about 133 °C, most likely a melting transition; 3) the overlapping recrystallization from melt between about 135 °C and 152 °C with peak at about 137-138 °C; and 4) the melting of this recrystallized solid between about 173 °C and 188 °C with peak at about 180 °C, indicating that this final solid consists of Form A.

[0048] The thermogram obtained by the DSC analysis of Form C is reproduced in Fig. 6. This thermogram also displays a series of thermal events consisting in 1) the melting of Form C between about 130 °C and 140 °C with maximum at about 135 °C; 2) an exothermic peak between about 140 °C and 155 °C with a maximum at about 145 °C corresponding to the overlapping recrystallization from melt; and 3) an endothermic peak between 169 °C and 187 °C, with maximum at about 179-180 °C corresponding to the melting of this recrystallized solid, indicating that the latter consists of Form A.

[0049] In its second aspect, the invention is about the processes for preparing the new solid forms of phentolamine mesylate. P024304WO-01_English text Notarbartolo & Gervasi S.p.A.

[0050] In all processes of the invention, Form A of phentolamine mesylate may be used as the starting material.

[0051] Form B may be prepared by suspending and stirring phentolamine mesylate powders in a solvent selected among tetrahydrofuran (THF), dichloromethane (DCM), and acetone, for a time between 8 and 24 h, at a temperature between 10 and 35 °C.

[0052] Preferably Form B is prepared by suspending and stirring phentolamine mesylate powders in acetone for 12-18 h at a temperature between 20 and 30 °C.

[0053] Form C may be prepared by suspending and stirring phentolamine mesylate powders in a solvent selected between tetrahydrofuran (THF) and acetonitrile (ACN) for a time between 8 and 48 h.

[0054] When using acetonitrile, Form C is prepared by suspending and stirring phentolamine mesylate powders for 12-18 h at a temperature between 20 and 30 °C.

[0055] When using THF, Form C is prepared by suspending and stirring phentolamine mesylate powders at a temperature between -15 and -25 °C. Preferably, the suspension is stirred for 12-18 h.

[0056] Form C may also be prepared by slurring a suspension of Form D at room temperature in THF for 1-3 days, collecting the solids and drying them below 1 atmosphere between 40 °C and 50 °C.

[0057] Form D may be prepared by suspending and stirring at reflux phentolamine mesylate powders in tetrahydrofuran (THF) for a time between 30 minutes and 2 h.

[0058] The new solid forms of the invention may be prepared as isolated phentolamine mesylate, filtered phentolamine mesylate, dried phentolamine mesylate, micronized phentolamine mesylate or crystalline phentolamine mesylate.

[0059] The new solid forms of the invention may further be prepared as phentolamine mesylate comprising less than 5% of phentolamine mesylate form A (prior art) by weight.

[0060] Finally, new solid forms of the invention may further be prepared as phentolamine mesylate that comprises less than about 20% of amorphous phentolamine mesylate by weight, preferably less than 10% of amorphous phentolamine mesylate by weight.

[0061] INSTRUMENTS, METHODS AND EXPERIMENTAL CONDITIONS Technical grade solvents and reagents were used if not otherwise specified.

[0062] Phentolamine mesylated was provided as a commercial batch complying with the specifications of the USP and Pharm. Eur. monographies.

[0063] The XRPD analyses were performed using a Bruker® D2 Phaser (2nd ed.) diffractometer P024304WO-01_English text Notarbartolo & Gervasi S.p.A.

[0064] operating in Bragg-Brentano (Theta-Theta) geometry and equipped with a rotating 6 position multisampler. The X-Ray source was a sealed-tube Cu anode operated at 30 KV and 10 mA. The analytical wavelength was the Cu Kai, 2 ( = 1.54184 A). The Kp radiation was filtered using a Ni filter. The X-Ray detector was a LYNXEYE® solid state detector. The samples were loaded as thin powder layer onto a flat zero-background Si sample holder. Measurements were performed in the 4-40° 29 range with 0.016° step size and 1.0 s / step scan speed. The sample holder was rotated at 60 rpm during the analysis. The data were analyzed using the Bruker’s DIFFRAC.EVA software.

[0065] The DSC analyses were performed using a Mettler Toledo’s DSC3 calorimeter operated in nitrogen atmosphere, which had been calibrated using In as standard. The samples were loaded into 40 pL Al pans which were crimped with their Al cap. The cap was pierced just prior to the analysis. The analysis was conducted using a constant heating rate of 10 °C / min. Data were analyzed using Mettler Toledo’s STARe software.

[0066] The starting phentolamine mesylate used was belonging from the internal production of the Applicant, or purchased from the United States Pharmacopoeia (USP shop), or purchased from the European Pharmacopoeia (EDQM), which all correspond to the prior art solid form according to US 11566005 B2 and herein called “Form A”.

[0067] Any pharmaceutical grade phentolamine mesylate whose XRPD diffractogram corresponds to Form A can be used for the purpose of replicating the following experiments.

[0068] EXAMPLE 1

[0069] This example is about a first preparation process of phentolamine mesylate Form B according to the invention.

[0070] 25 mg of phentolamine mesylate Form A were mixed with 1 mL of THF in a closed glass vial and the mixture stirred overnight at 25 ± 5 °C with a magnetic stirrer. The powders were filtered under vacuum and dried for 16 h in a vacuum oven at 45 °C.

[0071] The powders were subjected to XRPD analysis, which resulted in a XRPD pattern substantially the same as diffractogram B in Fig. 1.

[0072] EXAMPLE 2

[0073] This example is about a second preparation process of phentolamine mesylate Form B according to the invention.

[0074] 300 mg of phentolamine mesylate Form A were mixed with 4 mL of THF in a closed glass vial and the mixture stirred overnight at 25 ± 5 °C with a magnetic stirrer. The powders were filtered under vacuum and dried for 16 h in a vacuum oven at 45 °C. P024304WO-01_English text Notarbartolo & Gervasi S.p.A.

[0075] The powders were subjected to XRPD analysis obtaining essentially the same results as in Example 1.

[0076] EXAMPLE 3

[0077] This example is about a third preparation process of phentolamine mesylate Form B according to the invention.

[0078] 25 mg of phentolamine mesylate Form A were mixed with 1 mL of DCM in a closed glass vial and the mixture stirred overnight at 25 ± 5 °C with a magnetic stirrer. The powders were filtered under vacuum and dried for 16 h in a vacuum oven at 45 °C.

[0079] The powders were subjected to XRPD analysis obtaining essentially the same results as in Example 1.

[0080] EXAMPLE 4

[0081] This example is about a fourth preparation process of phentolamine mesylate Form B according to the invention.

[0082] 25 mg of phentolamine mesylate Form A were mixed with 1 mL of acetone in a closed glass vial and the mixture stirred overnight at 25 ± 5 °C with a magnetic stirrer. The powders were filtered under vacuum and dried for 16 h in a vacuum oven at 45 °C.

[0083] The powders were subjected to XRPD analysis obtaining essentially the same results as in Example 1.

[0084] EXAMPLE 5

[0085] This example is about a first preparation process of phentolamine mesylate Form C according to the invention.

[0086] 25 mg of phentolamine mesylate Form A were mixed with 1 mL of acetonitrile in a closed glass vial and the mixture stirred overnight at 25 ± 5 °C with a magnetic stirrer. The powders were filtered under vacuum and dried for 16 h in a vacuum oven at 45 °C.

[0087] The powders were subjected to XRPD analysis, which resulted in a XRPD pattern substantially the same as diffractogram C in Fig. 1.

[0088] EXAMPLE 6

[0089] This example is about a second preparation process of phentolamine mesylate Form C according to the invention.

[0090] 500 mg of phentolamine mesylate Form A were mixed with 4 mL of acetonitrile in a closed glass vial and the mixture stirred overnight at 25 ± 5 °C with a magnetic stirrer. The powders were filtered under vacuum and dried for 16 h in a vacuum oven at 45 °C.

[0091] The powders were subjected to XRPD analysis obtaining essentially the same results as P024304WO-01_English text Notarbartolo & Gervasi S.p.A.

[0092] in Example 5.

[0093] EXAMPLE 7

[0094] This example is about a third preparation process of phentolamine mesylate Form C according to the invention.

[0095] 460 mg of phentolamine mesylate Form D were stirred for 2 days in THF at 25 ± 5 °C until partial conversion into Form C is observed. The solid was filtered under vacuum and then dried for 16 h in a vacuum oven at 45 °C, obtaining 330 mg of Form C.

[0096] The powders were subjected to XRPD analysis obtaining essentially the same results as in Example 5.

[0097] EXAMPLE 8

[0098] This example is about a fourth preparation process of phentolamine mesylate Form C according to the invention.

[0099] 300 mg of phentolamine mesylate Form A were mixed with 4 mL of THF in a closed glass vial and the mixture stirred overnight at -20 ±5 °C with a magnetic stirrer. The powders were filtered under vacuum and dried for 16 h in a vacuum oven at 45 °C.

[0100] The powders were subjected to XRPD analysis obtaining essentially the same results as in Example 5.

[0101] EXAMPLE 9

[0102] This example is about a first preparation process of phentolamine mesylate Form D according to the invention.

[0103] 500 mg of phentolamine mesylate Form A were mixed with 4 mL of THF, heated to reflux, cooled to 25 ± 5 °C and stirred for 24 hours. The solid was filtered under vacuum and dried over the filter.

[0104] The powders were subjected to XRPD analysis, which resulted in a XRPD pattern substantially the same as diffractogram D in Fig. 1.

Claims

P024304WO-01_English text Notarbartolo & Gervasi S.p.A.CLAIMS1. Phentolamine mesylate form B that exhibits an XRPD pattern comprising peaks at 8.50, 9.02, 11.25, 13.26, 15.89, 17.00, 18.56, 18.97, 19.48, 20.60, 20.98, 22.33, 25.60, 26.42 and 27.18 ± 0.2° 20.

2. Phentolamine mesylate form B according to claim 1 that exhibits an XRPD pattern further comprising peaks at 11.61, 16.46, 20.18, 23.32, 23.62, 24.22, 24.44, 28.64, 29.52, 30.54, 33.26 and 35.23 ± 0.2° 20.

3. Phentolamine mesylate form B of claims 1 and 2 that exhibits a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak between about 112 °C and 125 °C, an endothermic peak between about 128 °C and 135 °C, an exothermic peak at about 137 °C, and an endothermic peak between about 173 °C and 188 °C with maximum at about 180 °C.

4. Phentolamine mesylate form C that exhibits an XRPD pattern comprising peaks at 8.45, 9.19, 11.49, 13.44, 16.86, 19.00, 19.88, 20.51, 22.24 and 27.55 ± 0.2° 20.

5. Phentolamine mesylate form C according to claim 4 that exhibits an XRPD pattern further comprising peaks at 15.86, 19.24, 22.76, 23.18, 23.70, 25.37, 25.65, 26.13, 26.86, 28.26, 30.16 and 33.80 ± 0.2° 29.

6. Phentolamine mesylate form C of claims 4 and 5 that exhibits a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak between about 130 °C and 140 °C with maximum at about 135 °C, an exothermic peak between about 140 °C and 155 °C with a maximum at about 145 °C, and an endothermic peak between about 169 °C and 187 °C, with maximum at about 179 °C.

7. Phentolamine mesylate form D that exhibits an XRPD pattern comprising peaks at 7.22, 10.13, 14.24, 18.01, 19.74, 20.38, 21.38, 21.71, 22.36 and 24.41 ± 0.2° 29.

8. Phentolamine mesylate form D according to claim 7 that exhibits an XRPD pattern further comprising peaks at 13.29, 13.87, 19.03, 21.37, 23.08, 23.33, 25.37 and 26.20 ± 0.2° 29.

9. Process for the preparation of phentolamine mesylate Form B of claims 1-3, whichP024304WO-01_English text Notarbartolo & Gervasi S.p.A.comprises suspending and stirring phentolamine mesylate in a solvent selected among tetrahydrofuran, dichloromethane and acetone, for a time between 8 and 24 h, at a temperature between 10 and 35 °C.

10. Process for the preparation of phentolamine mesylate Form C of claims 4-6, which comprises suspending and stirring phentolamine mesylate in a solvent selected between tetrahydrofuran and acetonitrile for a time between 8 and 48 h.

11. Process for the preparation of phentolamine mesylate Form D of claims 7 and 8, which comprises suspending and stirring at reflux phentolamine mesylate in tetrahydrofuran for a time between 30 minutes and 2 h.

12. Process according to any one of claims 9-11, in which the starting phentolamine mesylate is phentolamine mesylate Form A exhibiting an XRPD pattern comprising peaks at 6.99, 8.64, 11.75, 13.91, 14.81, 15.48, 16.80, 18.61, 18.98, 19.53, 20.42, 20.88, 21.19, 21.45, 21.79, 22.18, 23.36, 23.98, 27.74, 30.03 and 31.98 ± 0.2° 20.

13. Phentolamine mesylate Form B, or C or D according to any one of claims 1-8, in the form of isolated phentolamine mesylate, filtered phentolamine mesylate, dried phentolamine mesylate, and micronized phentolamine mesylate.

14. Phentolamine mesylate Form B, or C or D according to any one of claims 1-8, in the form of crystalline phentolamine mesylate.

15. Phentolamine mesylate Form B, or C or D according to any one of claims 1-8, that comprises less than 5% by weight of phentolamine mesylate Form A.

16. Phentolamine mesylate Form B, or C or D according to any one of claims 1-8, that comprises less than about 20% of amorphous phentolamine mesylate by weight, preferably less than 10 % of amorphous phentolamine mesylate by weight.

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