WO2019112483A1

WO2019112483A1 - Crystal nobazit having orthorhombic crystal system and method for producing same

Info

Publication number: WO2019112483A1
Application number: PCT/RU2018/000802
Authority: WO
Inventors: Денис Владимирович РЕМЕНЯКО; Елена Васильевна Ткаченко; Юрий Андреевич КРЮКОВ; Алла Ивановна РОГОВА; Сергей Викторович СЫСОЛЯТИН
Original assignee: Открытое акционерное общество "Авексима"
Priority date: 2017-12-06
Filing date: 2018-12-05
Publication date: 2019-06-13
Also published as: EA201792455A1

Abstract

This invention relates to new crystalline form of enisamium iodide (also known as carbabenzpyride), represented by the formula (I), particularly, to rhombic crystal system in space group of symmetry Р2 1 2 1 2 1 , with the following elementary cell parameters: a = 9.2867(2) Å; b = 10.8741(2) Å; c = 14.3038(3) Å; V =1444.46(5) Å3; Z = 4; it also relates to a method for production of this crystalline form. Said form can be used as a substance for preparing medicinal products to be used for viral infections treatment and prevention.

Description

Crystalline nobazite in the form of a rhombic syngony and method for producing it

The technical field to which the invention relates.

The present invention relates to a novel crystalline form of nobazite (1M-methyl-4-benzylcarbamidopyridinium iodide), namely, the rhombic syngony in the space symmetry group P1 _\ 2 {1 _\ with the following unit cell parameters: a = 9.2867 (2) A b = 10.8741 (2) A; c = 14.3038 (3) A; V = 1444.46 (5) A ³ ; Z = 4, used for the treatment and prevention of viral infections, characterized by the formula I:

and how to obtain it.

The level of technology

Nobazite (K-methyl-4-benzylcarbamidopyridinium iodide, enisamium iodide) is an active drug substance and has pharmacological properties in terms of its ability to treat and prevent viral infections.

For pharmaceutical applications, medicinal substances with a high degree of purity and properties suitable for the subsequent manufacture of dosage forms are of particular interest. For these

one

SUBSTITUTE SHEET (RULE 26) goals need to have a scalable, easily reproducible production process.

The invention SU 583612 (1975) describes the synthesis of nobazite for pharmaceutical use, but there is no description of the reproducibility of the preparation of the substance.

The objective of the claimed invention is to develop a method of obtaining nobazita in the form of a rhombic syngony, which would provide a substance with a high degree of purity that meets the requirements for subsequent pharmaceutical use.

Summary of Invention

The present invention relates to a novel crystalline form of nobazite in the form of a rhombic syngony and a method for producing it. The following characteristics, inherent in x-ray diffraction and X-ray phase analysis methods, are inherent in the nobazitu ristastic in the form of a rhombic syngony. The nobazite obtained by the proposed method crystallizes in the rhombic syngony in the space group of symmetry R2] 2i2 ₁ with the following unit cell parameters: a = 9.2867 (2) A b = 10.8741 (2) A; c = 14.3038 (3) A; V = 1444.46 (5) A ³ ; Z = 4.

The Cambridge database has searched for crystal structures of compounds containing a cation similar to the cation of the claimed substance (CSD, version 5.38, November 2016 [Groom, S. R., Bruno, IJ, Lightfoot, M. R. & Ward, S. S. Acta Cryst, 2016, B72, 171-179.]). Crystal structures containing the cation [MeC ₅ H ₄ NCONHCH2C6H5] ⁺ were not found, which confirms the scientific novelty of the claimed invention.

The crystalline nobazite in the form of a rhombic system is obtained by a method which, in accordance with the present invention, consists of the following stages:

2

SUBSTITUTE SHEET (RULE 26) (a) Interaction of 4-pyridinecarboxylic acid with benzylamine at elevated temperatures;

(b) Interaction of 4-carbamidobenzpyridine obtained in stage (a) with methyl iodide;

(c) recrystallization of nobasite raw, obtained in stage (b) from a mixture of solvents.

In one embodiment of the invention, the solvent is selected from the group consisting of dimethyl sulfoxide, water, methanol, acetonitrile, acetone, dimethylformamide, ethanol and isopropanol, as well as mixtures thereof.

Detailed Description of the Invention

In accordance with the claimed method, a new crystal structure of nobazite in the form of a rhombic syngony was obtained, which has a high degree of purity. Nobazite crystal in the form of a rhombic syngony has the following parameters, determined using X-ray diffraction and X-ray phase analysis methods. The crystal structure of nobazite is determined. The compound crystallizes in the rhombic syngony in the space symmetry group of P2 ₁ 2 ₁ 2 ₁ , the unit cell parameters: a = 9.2867 (2) A; B = 10.8741 (2) A c = 14.3038 (3) A; V = 1444.46 (5) A ³ ; Z = 4.

As shown in the experimental part, α-methyl-4-benzylcarbamidopyridinium iodide obtained in accordance with the present invention has a purity of at least 99.7% and preferably at least 99.9%, as determined by HPLC.

Experiments to determine the crystal structure of the obtained compound were carried out on a Gemini R Ultra single crystal diffractometer from Rigaku Oxford diffraction and on a Stadi MP powder diffractometer from Stoe (Germany).

s

SUBSTITUTE SHEET (RULE 26) Table 1. Some details of the experiment

The data were collected and processed using the CrysAlis PRO 1.171.38.43 diffractometer control program [Rigaku Oxford Diffraction, CrysAlis PRO, 2015, Agilent Technologies Inc., Santa Clara, CA, USA.]. The quality of data collection is indicated by the parameter R _int , which is calculated from the intensities of equivalent reflexes. If there are no other components in the sample or a twin, it should be less than 10% in order for the crystal structure to be reliably determined from the collected data. In our experiment R _ml

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SUBSTITUTE SHEET (RULE 26) is 3.3% (Table 1). Other data acquisition parameters (absorption coefficients, diffraction angles, number of collected and strong reflexes), shown in Table 1, also meet the standards for the qualitative determination of the structure.

Nobazite crystallizes in the rhombic syngony in the chiral space symmetry group (PGS) of P2 {1 {1 _\ . Since this CGM does not have an inversion center, the absolute structure was determined from experimental data based on the calculation of the Flefactor of the absolute structure [Parsons S., Flack N. D., Wagner T. Acta Cryst., 2013, V69, 249-259 ]. It is determined by anomalous scattering and must be equal to 0 for the correct structure and 1 for the inverted structure. In our experiment, taking into account the standard deviation, this factor is almost equal to 0, which corresponds to the correct definition of the absolute structure.

The decryption of the crystal structure by the direct method was carried out in the SHELXS program, the refinement by the full-matrix least squares method in the SHELXL2014 / 6 program [Sheldrick, G.M. Acta Cryst., 2015, C71, 3-8]. All non-hydrogen atoms were refined in the anisotropic approximation. The position of the hydrogen of the amide group involved in the hydrogen bond was found from the difference Fourier synthesis, and it was refined in the isotropic approximation. All other hydrogen atoms are placed in geometrically calculated positions and refined in the “rider” model in the isotropic approximation (distance C – H = 0.96 A, £ ₀ (H) = l, 2– t / _e q (C)). After clarification, the final R-factors (R [F ² >

wR (F ² ), the formulas by which they are defined, see the SHELXL program manual) indicate the good quality of the determination of the crystal structure, the reliability of which is beyond doubt that it is also affected by the factor S and the values of the residual electron density (A /? _max , A /? _tt ) (see instructions for the SHELXL program).

The independent part of the unit cell contains one cation of the organic molecule and one anion of iodine (Fig. 1). Cation and anion form

five

SUBSTITUTE SHEET (RULE 26) strong hydrogen bonded ion pair

Thermal ellipsoids are shown at a 50% probability level. Hydrogen atoms are depicted with an arbitrary radius. The hydrogen bond is shown by a dashed blue line.

Table 2 shows the coordinates of the atoms in the independent part of the unit cell in fractions of the parameters of the unit cell and the equivalent or isotropic thermal parameters. The thermal parameters of non-hydrogen atoms in the anisotropic approximation are presented in Table 3.

Table 2. Atomic coordinates in the independent part of the nobazite unit cell

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SUBSTITUTE SHEET (RULE 26)

Table 3. Parameters of thermal ellipsoids of non-hydrogen atoms of nobasite

All bond lengths and valent angles, taking into account standard deviations, do not exceed the limits of the norm (Tables 4, 5). Table 6 gives some torsion angles. The parameters of hydrogen bonds are given in table 7.

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SUBSTITUTE SHEET (RULE 26) Table 4. The lengths of nobazit bonds

Table 5. Nobazit bond angles

Table 6. Some torsion angles of nobasite

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SUBSTITUTE SHEET (RULE 26)

Table 7. Parameters of hydrogen bonds

Symmetry codes: (i) x + 1/2, -y + 1/2, -z + 1; (ii) x + 1, y, z.

The central part of the nobazite molecule obtained by the claimed method and the pyridine ring lie almost in the same plane (the exit of atoms from the N2-C8-O1-C9-C10-C11-N1-C12-C13 plane is on average 0.015 A, the maximum is 0.025 (3 ) BUT). The iodine anion is located close to this plane (the distance to the N2 – C8 – O1 – C9 – C10 – C11 – N1 – C12 – C13 – 0.504 (3) A) plane. The dihedral angle between the planes of the pyridine and benzene rings is 117.2 (1) ° (Fig. 2), or 62.8 (1) ° from a formal point of view.

In addition to the strong hydrogen bond N – H ... I, two weak C – H bonds can be distinguished in the structure of the claimed compound. (Table 7, Fig. 3). Ion pairs through the binding of these weak hydrogen bonds form infinite tapes along the direction of the crystallographic axis a (Fig. 3). There are no hydrogen bonds between ribbons.

The Cambridge database has searched for crystal structures of compounds containing a cation similar to the cation of the claimed substance (CSD, version 5.38, November 2016 [Groom, S. R., Bruno, IJ, Lightfoot, M. R. & Ward, S. S. Acta Cryst, 2016, B72, 171-179.]). Crystal structures containing a cation [MeS _b U Sh SOMNSN _b RU ^

9

SUBSTITUTE SHEET (RULE 26) It was not found, which confirms the scientific novelty of the claimed invention.

To check the possible polymorphism, an X-ray phase analysis of nobazite samples recrystallized by the claimed method using different solvents (numbers 1-8, Table 8) was carried out. Large nobazite crystals (Sample No. 9, Table 8) were previously ground in an agate mortar and examined using X-ray phase analysis. The essence of the method is as follows: a powder sample is placed on a diffractometer and an integral diffraction pattern is obtained (intensity dependence on the reflection angle 2Q), which contains information about all the crystalline phases present in the sample. Each crystalline phase corresponds to its own set of reflections (peaks). For already known structures there are cards in the powder database (PDF), or they can be calculated theoretically from the crystal structure obtained in a single crystal experiment.

The diffraction patterns of the studied samples were recorded on a STOE STADI-MP powder diffractometer (CuK _a1 radiation, curved Ge monochromator, measurement for lumen). Analysis of diffraction patterns was carried out in the program WinXPOW. The calculation of the theoretical diffraction pattern of the structure deciphered by us was also carried out in the WinXPOW program. Figures 4-11 show the initial diffraction patterns of the samples in comparison with the theoretically calculated ones.

The results of powder diffractometry showed that all samples of nobasite have the same crystal structure, which was determined by single crystal data, and do not have impurities of any other crystalline phases (within the accuracy of the XRF method). For clarity, the diffraction patterns of all samples (without background) are presented in one figure (Fig. 12). FIG. Figure 13 shows the diffraction pattern from large crystals worn into powder (sample in Table 8).

Yu

SUBSTITUTE SHEET (RULE 26) During the recrystallization of nobasite from the stated solvents, no other polymorphic forms were detected. Additionally, this is evidenced by the data of IR spectroscopy (Fig. 14-21) and differential scanning calorimetry (hereinafter - DSC, Fig. 22-29).

As shown in the experimental section, the nobasite obtained in accordance with the present invention has a purity of at least 99.7% and preferably at least 99.9%, as determined by HPLC. Such a high degree of purity could not be obtained according to the prior art. This was made possible by using a method in accordance with the present invention to significantly reduce the intermediate substance in the final product.

Nobazite crystalline in the form of a rhombic syngony is obtained by a method which, in accordance with the present invention, consists of the following stages:

(a) Interaction of 4-pyridinecarboxylic acid with benzylamine at elevated temperatures from 220 ° C to 230 ° C with the formation of 4-carbamidobenzpyridine;

(b) Interaction of 4-carbamidobenzpyridine obtained in stage (a) with methyl iodide to form nobazite;

(c) recrystallization of nobasite raw, obtained in stage (b), from a mixture of solvents.

This method is illustrated in the diagram:

The interaction of 4-pyridinecarboxylic acid with benzylamine occurs at elevated temperatures, i.e. ranging from 220 ° C to 230 ° C. and

SUBSTITUTE SHEET (RULE 26) The molar ratio of 4-pyridinecarboxylic acid and benzylamine is in the range of 1: (1 D-1,2).

As a result of the reaction of 4-pyridinecarboxylic acid and benzylamine, water is formed, which is removed by distillation with an excess of benzylamine.

The product of the reaction, namely 4-carbamidobenzpyridine, is released from the reaction mixture by the addition of toluene. The reaction mixture is dissolved in toluene, filtered from unreacted 4-pyridinecarboxylic acid, cooled, and 4-carbamide-benzpyridine is filtered off.

The high purity of 4-carbamidobenzpyridine allows the use of methyl iodide in a molar ratio of 1: (1.1-1.2). 1-methyl-4-benzylcarbamidopyridinium raw iodide is isolated with filtration.

T4-methyl-4-benzylcarbamidopyridinium iodide crystallizes in rhombic syngony using a wide range of solvents listed in Table 8:

Table 8. The list of samples of K-methyl-4-benzylcarbamidopyridinium iodide, obtained by the claimed method

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SUBSTITUTE SHEET (RULE 26) List of figures, drawings and other materials

FIG. 1. Molecular structure of nobasite with numbering of non-hydrogen atoms

FIG. 2. Type of nobazite molecule with planes of aromatic rings

FIG. 3. Fragments of the crystal structure of nobazite in a projection along the crystallographic axis b (a) and axis a (b). Hydrogen bonds are shown by a dotted line.

FIG. 4. Diffractogram of sample l of nobazite (Table 8). Crystallization from DMSO

FIG. 5. Diffraction pattern of sample M2 of nobazite (Table 8). Water crystallization

FIG. 6 The diffractogram of sample M3 of nobazite (Table 8). Crystallization from methanol

FIG. 7. Diffraction pattern of sample M4 of nobazite (Table 8). Crystallization from acetonitrile

FIG. 8 The diffractogram of sample No5 Basitum (Table 8). Crystallization from 90% acetone

FIG. 9. Diffractogram of sample MB of nobazite (Table 8). Crystallization from DMF

FIG. 10. Diffractogram of sample M7 of nobazite (Table 8).

Crystallization from 90% ethanol

FIG. 11. Diffraction pattern of sample M8 nobazite (Table 8).

Isopropyl Alcohol Crystallization

FIG. 12. Diffractograms without background: a - theoretical, bs - samples

Ml -8

FIG. 13. Diffraction pattern of sample M9 nobazita (tab. 8). The theoretically calculated diffractogram is shown in red.

FIG. 14. IR spectra of sample Nobasite Ml (Table 8)

FIG. 15. IR spectra of sample No2 basitas (Table 8)

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SUBSTITUTE SHEET (RULE 26) FIG. 16. IR spectra of sample 1 ^ 3 nobasite (tab. 8)

FIG. 17. IR spectra of sample no. 4 of nobasite (Table 8)

FIG. 18. IR spectra of sample no. 5 of nobazite (Table 8)

FIG. 19. IR spectra of sample Nobasite JV26 (Table 8)

FIG. 20. IR spectra of sample Ni »7 nobasite (tab. 8)

FIG. 21. IR spectra of sample no. 8 of nobazite (Table 8)

FIG. 22. DSC diagram of sample no. 1 of nobazite (Table 8)

FIG. 23. DSC diagram of sample N22 of nobazite (Table 8)

FIG. 24. DSC diagram of sample N "3 nobasite (Table 8)

FIG. 25. DSC-diagram of sample J ®4 nobasite (tab. 8)

FIG. 26. DSC-diagram of sample No5 nobasite (Table 8)

FIG. 27. DSC diagram of sample N "6 nobasite (Table 8)

FIG. 28. DSC diagram of sample e7 nobazite (Table 8)

FIG. 29. DSC diagram of sample no. 8 of nobazite (Table 8)

FIG. 30. PMR spectrum of nobasite

FIG. 31 ¹³ C NMR spectrum of nobasite

Information confirming the possibility of implementation

inventions

Getting 4-carbamide-benzpyridine

4-Pyridinecarboxylic acid 1,231 kg (10 mol) for 1 h load with stirring in 1,286 kg (12 mol) of benzylamine heated to 140 ° C. At the end of the dosage, the reaction mixture is gradually heated to 220-230 ° C. After the distillation of water and an excess of benzylamine, the mass is cooled to 100-110 ° C and poured into 10 liters of toluene with stirring. The hot solution is filtered and cooled to 15 ° C. After cooling, the precipitated product is filtered off, washed on the filter with 0.2 l of toluene and dried in air at room temperature. 1.857 kg (8.75 mol; 87.5%) of 4-urea-benzpyridine are obtained.

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SUBSTITUTE SHEET (RULE 26) Getting nobasite

In 11 liters of acetone, 1.857 kg (8.75 mol) of 4-carbamidobenzpyridine are loaded with stirring. After complete dissolution, 1.49 kg (10.5 mol) of methyl iodide are added and kept at 50 ° C for 5 hours. The reaction mass is cooled to 10-15 ° C and filtered. The precipitate is washed on the filter with 50 ml of acetone and dried in air. The yield of nobasite is 2.465 kg (6.96 mol; 79.5%). 99.7% purity by HPLC using standards.

Calculated for C ^^ NiOI: C, 47.46; H, 4.21; N, 7.91; Oh, 4.52. Found C, 47.31; H, 4.13; N, 7.62; Oh, 4.35.

T _pl. 190.78-193.31.

IR spectrum (cm): 611.27, 631.44, 703.72, 777.41, 759.32, 860.4, 920.77, 960.85, 1020.8, 1078.2, 1147.6, 1187.8, 1618.8, 1285.4, 1329.8, 1416.4, 1452.5, 1505.1, 1541.1, 1571.6, 1629.8, 1616.4, 1452.5, 1505.1, 1516.4, 1452.5, 1505.1, 1541.4, 1452.5, 1505.1, 1516.4, 1452.5, 1509.1, 1516.4, 1452.5, 1505.1, 1541.4, 1452.5, 1505.1, 1516.4, 1452.5, 1505.1, 1516.4, 1452.5, 1505.1, 1516.4 , 1828.1, 1950.9, 2828.6, 2936.6, 3040.4, 3237.6.

dmso-d ₆ , ppm): d = 4.40 [s, 3N, CH ₃ ], 4.55 [d, 2H, CH ₂ ], 7.22-7.45 [m, 5H, Ar], 8.44 [d, 2H, Py], 9.19 [d, 2H, Ru] (Fig. 30).

¹³ O- {Ή} NMR (100 MHz, dmso-de, ppm): d = 43.89 (CH2), 49.00 (SN3), 125.95, 147.06, 148.20 (Ru), 127.65, 128.01, 128.92, 139.18 (Ar), 162.63 (C = 0) (Fig. 31).

Crystallization from DMSO

5.0 kg (14 mol) of nobasite raw material was dissolved in 20 liters of dimethyl sulfoxide (DMSO) at 80 C. After dissolution and hot filtration, the solution was cooled to 10 ° C. The precipitate was filtered and washed on the filter with 10 l of acetone. Received nobasite substance 2.83 kg (8 mol, 56.6%). 99.9% purity by HPLC using standards.

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SUBSTITUTE SHEET (RULE 26) Water crystallization

5.0 kg (14 mol) of nobasite raw was dissolved in 6 l of water at 90 ° C. Added 0.15 kg (3.0%) of coal. After complete dissolution, the solution was cooled to 10 ° C. After stirring for 1 h, the precipitate was filtered, washed with 10 l of acetone and dried at 100 ° C. Received nobazita substance 4.71 kg (13, Zmol; 94.3%). 99.9% purity by HPLC using standards.

Crystallization from methanol

5.0 kg (14 mol) of nobasite raw was dissolved in 25 liters of methanol at the boil. After dissolution and hot filtration, the solution was cooled to 10 ° C. The precipitate was filtered and washed on the filter with 10 ml of acetone. Received nobazita substance 3.2 kg (9.1 mol; 65%). 99.9% purity by HPLC using standards.

Crystallization from acetonitrile

5.0 kg (14 mol) of nobasite raw was dissolved in 25 l of acetonitrile at boiling. After dissolution and hot filtration, the solution was cooled to 10 ° C. The precipitate was filtered and washed on the filter with 10 l of acetone. Received nobasite substance 4.8 kg (6.7 mol; 48%). 99.9% purity by HPLC using standards.

Crystallization from 90% acetone (10% water)

5.0 kg (14 mol) of nobasite raw was dissolved in 10 liters of a mixture of 90% acetone and 10% water at boiling. After complete dissolution and hot filtration, the solution was cooled to 10 ° C. The precipitate was filtered, washed with 10 l of cold acetone and dried at 100 ° C. Received nobazita substance 4.41 kg (1.25 mol; 89%). 99.9% purity by HPLC using standards.

sixteen

SUBSTITUTE SHEET (RULE 26) Crystallization from DMF

5.0 kg (014 mol) of nobasite raw was dissolved in 8 l of dimethylformamide (DMF) at 70 ° C. The hot solution was filtered, cooled to 10 ° C and the precipitate was filtered through a filter. The filter cake was washed with 10 l of cold acetone and dried at 100 ° C. Received nobasite substance 2.41 kg (6.8 mol; 48.3%). 99.9% purity by HPLC using standards.

Crystallization from 90% ethanol (10% water)

5.0 kg (14 mol) of nobasite raw was dissolved in 15 liters of a mixture of 90% ethanol and 10% water at boiling. Added 0.15 kg (3.0%) of coal. After 30 min, the hot solution was filtered, cooled to 10 ° C and the precipitate was filtered. The precipitate was washed on the filter with 10 l of cold acetone and dried at 100 ° C. Nobazite-substance was obtained 4.14 kg (1.17 mol; 83.9%). 99.9% purity by HPLC using standards.

Isopropyl Alcohol Crystallization

5.0 kg (14 mol) of nobasite raw was dissolved in 25 liters of a mixture of 90% isopropyl alcohol and 10% water at boiling. The hot solution was filtered, cooled to 10 ° C and the precipitate was filtered. The filter cake was washed with 10 l of cold acetone and dried at 100 ° C. Received nobasite substance 4,07 kg (1.15 mol; 81.9%). 99.9% purity by HPLC using standards.

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SUBSTITUTE SHEET (RULE 26)

Claims

Claim

1. Nobazite crystalline in the form of a rhombic syngony of the formula I

which has the following parameters defined by the methods of X-ray structural and X-ray phase analysis, namely the spatial symmetry group P2 _\ 2 _\ 2 _\ parameters of the unit cell: a = 9.2867 (2) A; b = 10.8741 (2) A; c = 14.3038 (3) A; V = 1444.46 (5) A ³ ; Z = 4; the coordinates of the atoms in the independent part of the unit cell according to the table below:

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SUBSTITUTE SHEET (RULE 26)

2. The crystalline form of nobasite according to claim 1, characterized by a degree of purity of at least 99.7% by HPLC.

3. The crystalline form of nobasite according to claim 2, characterized by a degree of purity of not less than 99.9% by HPLC.

4. The method of obtaining crystalline nobazite in the form of a rhombic syngony, comprising the following stages:

(a) Interaction of 4-pyridinecarboxylic acid with benzylamine at elevated temperatures;

(c) recrystallization of M-methyl-4-benzylcarbamidopyridinium raw iodide, obtained in step (b), from a suitable solvent.

5. The method according to claim 4, characterized in that a solvent selected from the group consisting of dimethyl sulfoxide, water, methanol, acetonitrile, acetone, dimethylformamide, ethanol and isopropanol, as well as mixtures thereof, is used.

nineteen

SUBSTITUTE SHEET (RULE 26)