CN108069891B

CN108069891B - A crystal form of methyl methylamine hydrochloride, preparation and application thereof

Info

Publication number: CN108069891B
Application number: CN201611008732.0A
Authority: CN
Inventors: 金秋; 刘飞; 苏梅
Original assignee: Jiangsu Carephar Pharmaceutical Co ltd
Current assignee: Jiangsu Carephar Pharmaceutical Co ltd
Priority date: 2016-11-16
Filing date: 2016-11-16
Publication date: 2022-09-20
Anticipated expiration: 2036-11-16
Also published as: CN108069891A

Abstract

The invention relates to a crystal form A of 1- (5- (2-fluorophenyl) -1- ((3- (3-methoxypropoxy) phenyl) sulfonyl) -1H-pyrrole-3-yl) -N-methyl methylamine hydrochloride shown as a formula I, a preparation method thereof and application thereof in treating erosive esophagitis, gastric ulcer, duodenal ulcer and helicobacter pylori eradication indication and treating related diseases caused by excessive gastric acid.

Description

A crystal form of methyl methylamine hydrochloride, preparation and application thereof

Technical Field

The invention relates to a potassium ion competitive acid retarder, in particular to a crystal form A of 1- (5- (2-fluorophenyl) -1- ((3- (3-methoxy propoxy) phenyl) sulfonyl) -1H-pyrrole-3-yl) -N-methyl methylamine hydrochloride.

Background

Gastric acid related diseases are the most common diseases in digestive system diseases, and refer to a general term of digestive tract diseases caused by excessive gastric acid secretion or particular sensitivity to gastric acid, and the common digestive system diseases are gastroesophageal reflux disease, peptic ulcer, Zollinger-Ellison syndrome and non-steroidal anti-inflammatory drugs. PPI is a class of drugs with the strongest acid inhibition effect at present, such as omeprazole, lansoprazole, pantoprazole, rabeprazole and the like. PPI has a phenomenon of acid rebound at night, so that the treatment effect is influenced. The advent of potassium competitive acid blocker (P-CAB) class of drugs addressed this problem well by the competitive inhibitor proton pump (H) ⁺ ATPase) K ⁺ And the occurrence of acid rebound at night can be obviously reduced clinically.

1- (5- (2-fluorophenyl) -1- ((3- (3-methoxypropoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methyl methylamine is a potassium ion competitive acid blocker (P-CAB), and in vitro and in vivo experimental studies show that the compound can effectively inhibit gastric acid secretion and has the advantage of long duration.

In organic compounds, many substances often have the same chemical composition and form different crystal structures under different thermodynamic conditions (temperature, pressure, pH, etc.), which we refer to as polymorphism. These different crystalline forms are referred to as "polymorphs". Different polymorphs of a substance have different lattice energies, and thus exhibit different chemical and physical properties in the solid state, including chemical stability, apparent solubility, dissolution rate, melting point, and the like, which can directly affect the handling and production of drug substances and formulations, and can affect the stability, solubility, and bioavailability of drug substances and formulations. For the present invention, there is a need in the art for: the polymorphism with excellent physical and chemical properties suitable for application is obtained.

Drawings

FIG. 1: the XRPD spectrogram of the crystal form A compound of the invention;

FIG. 2: TG/DSC spectrogram of the crystal form A compound of the invention;

FIG. 3: the invention relates to an infrared spectrogram of a crystal form A compound.

Disclosure of Invention

On the basis of researching the prior art, 1- (5- (2-fluorophenyl) -1- ((3- (3-methoxy propoxy) phenyl) sulfonyl) -1H-pyrrole-3-yl) -N-methyl methylamine hydrochloride with good stability and high purity is developed, and meanwhile, crystal form A and amorphous form are researched, so that support is provided for later formulation research, and therefore gastric acid related diseases are more effectively treated, and different clinical medication requirements are met.

The invention provides a crystal form A of 1- (5- (2-fluorophenyl) -1- ((3- (3-methoxypropoxy) phenyl) sulfonyl) -1H-pyrrole-3-yl) -N-methyl methylamine hydrochloride shown as a formula I.

According to the invention, the crystal form A of the compound shown in the formula I is radiated by using Cu-Ka = 1.5406A, and the 2 theta value of a characteristic peak in an X-ray powder diffraction spectrogram is as follows: 11.78, 14.40, 18.23, 21.67 and 24.35, with a 2 theta diffraction angle error of 0.2 deg..

Further, the crystalline form of compound a of formula I described herein is irradiated using Cu-K α λ =1.5406 a, having the X-ray powder diffraction spectrum as depicted in fig. 1.

The crystal form A of the compound shown in the formula I has DSC endothermic transition at 140 +/-2 ℃.

Further, a crystal form TG/DSC spectrogram of the compound A shown in the formula I is shown in figure 2.

The infrared absorption spectrum of the crystal form A of the compound A shown in the formula I is 589, 619, 679, 699, 763, 1077, 1184, 1248, 1375, 1470, 1586 and 2707cm ^-1 Has an absorption peak.

Further, the crystal form A of the compound shown in the formula I has an infrared absorption spectrum shown in figure 3.

The invention also reports a method for preparing the crystal form A of the compound shown in the formula I, which is characterized in that:

(1) dissolving 1- (5- (2-fluorophenyl) -1-3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine in an organic solvent, stirring,

(2) dropwise adding concentrated hydrochloric acid, stirring for 0.5 h after dropwise adding, precipitating white solid under stirring, continuously stirring for 1h,

(3) after filtration, the filter cake was dried in vacuo to give a sample of crystalline form a of 1- (5- (2-fluorophenyl) -1- ((3- (3-methoxypropoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine hydrochloride.

Further, the organic solvent in the preparation method comprises methanol, ethanol, acetone, acetonitrile or a mixture thereof.

Finally, the invention reports the use of the compound of crystal form a for the manufacture of a medicament for the treatment of indications of erosive esophagitis, gastric ulcer, duodenal ulcer, helicobacter pylori eradication, and the treatment of related diseases due to gastric hyperacidity.

Detailed Description

The following examples are intended to illustrate the invention but are not intended to limit it.

In the following reference examples, the apparatus used:

high performance liquid chromatograph: agilent 1260

An electronic balance: mettler XS105

Vacuum oven: DZF6021 Shanghai Soxhlet spectrometer Ltd

Constant temperature and humidity test box: SHH-500SD-2T Shanghai immortal experimental instrument factory

X-ray diffractometer: bruker D8 advanced X-ray diffractometer

Example 1

Crystal form A

In a 100mL single-neck flask, 1- (5- (2-fluorophenyl) -1- ((3- (3-methoxypropoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine (10.0 g, 23.15 mmol, 1 eq) and acetone (50 mL) were added, and dissolved with stirring at 25 ℃, concentrated hydrochloric acid (2.3 mL, 27.8mmol, 1.1 eq) was added dropwise to the reaction system, and stirring was continued for 0.5 hour after the end of the addition, whereupon a white solid precipitated, and after stirring for 1 hour, filtration was performed, the filter cake was washed with acetone (20 mL × 2 times), dried under vacuum (40 ℃) for 12 hours, to give 9.8 g of an off-white solid with a yield of 90%, HPLC: 99.5 percent.

Example 2

Crystal form A

1- (5- (2-fluorophenyl) -1- ((3- (3-methoxypropoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine (10.0 g, 23.15 mmol, 1 eq) and methanol (50 mL) were added to a 100mL single-neck flask, stirred at 25 ℃ to dissolve, concentrated hydrochloric acid (1.5 mL, 18.52mmol, 0.8 eq) was added dropwise to the reaction system, the mixture was cooled to 10 ℃ and stirred for 0.5 hour, a white solid precipitated, stirring was continued for 1 hour, the solid was filtered and washed with ethyl acetate (20 mL × 2 times), and the filter cake was dried in a vacuum oven (40 ℃) for 12 hours to give 8.2 g of an off-white solid with a yield of 75.6%.

Example 3

Crystal form A

1- (5- (2-fluorophenyl) -1- ((3- (3-methoxypropoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine (10.0 g, 23.15 mmol, 1 eq) and acetone (100 mL) were added to a 100mL single-neck flask and dissolved with stirring at 25 ℃, concentrated hydrochloric acid (3.86 mL, 46.3mmol, 2 eq) was added dropwise to the reaction system, the mixture was heated to 30 ℃ and stirred for 0.5 hour, a white solid precipitated, stirring was continued for 1 hour, the solid was filtered and washed with acetone (20 mL x 2 times), and the filter cake was dried in a vacuum oven (40 ℃) for 12 hours to give an off-white solid 8.9g with a yield of 82.1%.

Example 4

Crystal form A

In a 100mL single neck flask, 1- (5- (2-fluorophenyl) -1- ((3- (3-methoxypropoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine (10.0 g, 23.15 mmol, 1 eq) and acetonitrile (10 mL) were added and dissolved with stirring at 25 ℃, concentrated hydrochloric acid (9.6 mL, 115.8mmol, 5 eq) was added dropwise to the reaction system, stirring was carried out at this temperature for 0.5 hour, white solid precipitated, stirring was continued for 1 hour, the solid was filtered off and washed with acetonitrile (20 mL x 2 times), the filter cake was dried in a vacuum oven (40 ℃) for 12 hours to give 8.3g of off-white solid in 76.5% yield.

Example 5

Crystal form A

1- (5- (2-fluorophenyl) -1- ((3- (3-methoxypropoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine (10.0 g, 23.15 mmol, 1 eq) and methanol (50 mL) were added to a 100mL single-neck flask and dissolved with stirring at room temperature (20 ℃), concentrated hydrochloric acid (5.8 mL, 69.45mmol, 3 eq) was added dropwise to the reaction system and stirred at that temperature for 0.5 hour, a white solid precipitated, stirring was continued for 1 hour, the solid was filtered off and washed with acetonitrile (20 mL x 2 times), and the filter cake was dried in a vacuum oven (40 ℃) for 12 hours to give 8.8g of an off-white solid in 81.1% yield.

Example 6

Crystal form B

In a 100mL single-necked flask, 1- (5- (2-fluorophenyl) -1- ((3- (3-methoxypropoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine (5.0 g, 11.6 mmol) and ethyl acetate (30 mL) were added, and dissolved by stirring at room temperature (25 ℃ C.), about 7ml of an ethyl acetate solution (2M) of hydrochloric acid was added dropwise to the reaction system, stirring at the temperature for 2h to remove solid, drying under reduced pressure to remove solvent to obtain solid, dispersing the obtained solid in ethyl acetate (10 ml), stirring at room temperature for 1h, filtering, and washed with ethyl acetate (4 ml x 2) and the resulting solid was dried in a vacuum oven (35 ℃) for 4 hours to give 4.8 g of an off-white solid with a yield of 89.1%.

Example 7

Influence factor experiment:

samples were taken at high temperature (60 ℃) on day 5, and properties (color, solubility) of the compounds were examined and the substances and contents thereof were measured by high performance liquid chromatography.

Samples were taken at high humidity (92.5% RH) on day 5, and properties (color, solubility) of the compounds were examined, and substances and contents thereof were measured by high performance liquid chromatography.

Samples were taken on day 5 under light (4500 lx) and the properties of the compounds (color, solubility) were examined by hplc to determine the maximum single impurity and content.

Example 8

Accelerated testing:

samples were taken at high temperature (60 ℃) in months 1, 3 and 6, and properties of the compound (color, solubility) were examined and the maximum single impurity and content were determined by HPLC.

Through analyzing the data measured by the compound, the compound has no obvious change in the properties and the content of the crystal form A in an influencing factor experiment and an accelerated experiment, and the maximum single impurity is hardly increased.

Claims

1. A crystal form A compound of 1- (5- (2-fluorophenyl) -1- ((3- (3-methoxypropoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine hydrochloride shown as a formula I, wherein the 2 theta value of a characteristic peak in an X-ray powder diffraction spectrogram of the crystal form A compound is as follows: 11.78, 14.40, 18.23, 21.67 and 24.35, with a 2 θ diffraction angle error of 0.2;

2. crystalline form a compound according to claim 1, characterized in that it is used

Radiation having an X-ray powder diffraction spectrum as shown in FIG. 1.

3. The crystalline form a compound of claim 1, characterized by a DSC endothermic transition at 140 ± 2 ℃.

4. The compound of crystal form a according to claim 3, characterized by a TG/DSC profile as shown in figure 2.

5. The compound of claim 1, having an infrared absorption spectrum at 589, 619, 679, 699, 763, 1077, 1184, 1248, 1375, 1470, 1586, 2707cm ^-1 Has an absorption peak.

6. The compound of crystalline form a according to claim 5, characterized by an infrared absorption spectrum as shown in figure 3.

7. A process for preparing the compound of form a according to any one of claims 1 to 6, characterized in that:

(1) dissolving 1- (5- (2-fluorophenyl) -1- ((3- (3-methoxypropoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanamine in an organic solvent, stirring,

(3) after filtration, the filter cake was dried in vacuo to give a sample of form a of 1- (5- (2-fluorophenyl) -1- ((3- (3-methoxypropoxy) phenyl) sulfonyl) -1H-pyrrol-3-yl) -N-methylmethanemethylamine hydrochloride.

8. The process for preparing a compound of form a according to claim 7, wherein the organic solvent is selected from methanol, ethanol, acetone, acetonitrile or mixtures thereof.

9. Use of the compound of crystalline form a according to claim 1 for the manufacture of a medicament for the treatment of indications for erosive esophagitis, gastric ulcer, duodenal ulcer, helicobacter pylori eradication, and for the treatment of associated diseases due to gastric hyperacidity.