CN107814758B - Preparation of pyrrole sulfonic acid compound salt - Google Patents
Preparation of pyrrole sulfonic acid compound salt Download PDFInfo
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Abstract
The invention provides a 1- (5- (2-fluorophenyl) -1-3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine salt type, which comprises an organic acid salt or an inorganic acid salt. The invention mainly screens various organic acids and inorganic acids to obtain 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine hydrochloride and 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine fumarate which have higher purity and better stability, and can be used for treating erosive esophagitis, gastric ulcer, duodenal ulcer and helicobacter pylori eradication indication and treating related diseases caused by gastric acid excess.
Description
Technical Field
The invention belongs to the field of compounds, and particularly relates to 1- (5- (2-fluorophenyl) -1-3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine salt and a preparation method thereof.
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.
Since 1988, proton pump inhibitors represented by omeprazole have been widely used clinically for the treatment of peptic ulcer, reflux esophagitis, zollingia-ellison syndrome, and the like, by inhibiting gastric acid secretion. The long-term clinical application shows that the existing proton pump inhibitor has limitations in the aspects of pharmacokinetics and pharmacodynamics. Such as: the effect of the time of administration on the efficacy of the drug; acid breakthrough at night takes effect slowly; unstable under acidic conditions (required to be formulated into an enteric formulation); dependence on CYP450 enzymes (leading to significant individual differences), and the like.
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) + K in ATPase) + The medicine has the functions of obviously reducing the occurrence of acid rebound at night clinically, and the medicine comprises the following components: TAK438, revaprazan (Revaprazan), and the like.
Potassium-Competitive Acid Blockers (P-CABs) competitively by a direct, reversible processInhibition of H + /K + K in ATPase + Thereby producing an effect. Compared with the traditional proton pump inhibitor, the P-CABs have the characteristics of lipophilicity, alkalescence, high dissociation constant and stability under the condition of low pH. Under acidic environment, P-CABs are ionized with H + /K + ATP-enzyme binding, blocking H + Transport and acid secretion into the gastric lumen, rapidly raising the pH in the stomach. Animal experiments and clinical studies show that: the P-CABs have quick response and can achieve the maximum treatment effect within 1 hour; the blood concentration is linearly related to the oral administration dosage, and the optimal acid inhibition effect is easily achieved.
Although a series of potassium competitive acid retarders have been disclosed so far, there is still a need to develop compounds with more abundant structural types, new compounds that may have better druggability, and through continuous efforts, the present invention designs compounds having a structure represented by the general formula and finds that compounds having such a structure exhibit excellent effects and actions.
Disclosure of Invention
The invention aims to provide a novel gastric acid secretion inhibitor which has better stability and bioactivity on the basis of the prior art. The salt form of the compound is mainly researched, various organic acids and inorganic acids are screened, and the salt form with higher purity and better stability is obtained. The 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine hydrochloride has higher purity and stability in a series of compounds, and provides support for later formulation research, so that the gastric acid related diseases are more effectively treated, and different clinical medication requirements are met.
The technical scheme of the invention is as follows: disclosed is an organic acid salt or an inorganic acid salt of 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine having the following general formula.
The organic acid is: fumaric acid, oxalic acid, succinic acid, lactic acid, methanesulfonic acid, L-malic acid and citric acid.
The organic acid is preferably: fumaric acid.
The inorganic acid is as follows: nitric acid, hydrobromic acid, hydrochloric acid, phosphoric acid, sulfuric acid.
The inorganic acid is preferably: hydrochloric acid.
The invention provides a preparation method of the organic acid salt or the inorganic acid salt, which comprises the following steps:
method one (acid is liquid): dissolving 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine in an organic solvent under stirring (generally 4-8 mL per gram of free amine), dropwise adding the corresponding acid (the molar ratio of the free amine to the corresponding acid is 1.05) into the reaction system at room temperature, stirring for 2 hours, filtering the obtained solid, washing the solid with the organic solvent for 2 times (generally 5-6 mL per gram of free amine), and drying the obtained solid in a vacuum oven (35 ℃) for 4 hours to obtain the related salt.
Method two (acid as solid): 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine is mixed with an organic solvent and dissolved under stirring (typically 4-8 mL per gram of free amine), the corresponding acid (typically 3-5 mL per gram of free amine and 1.05 mole ratio of free amine to corresponding acid) is added to the reaction system at room temperature, the mixture is stirred under heating for 1 hour, the resulting solid is filtered, the solid is washed 2 times with the organic solvent (typically 5-6 mL per gram of free amine), and the resulting solid is dried in a vacuum oven (35 ℃) for 4 hours to obtain the relevant salt.
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:
nuclear magnetic resonance apparatus: BRUKER 500MHZ, germany
High performance liquid chromatograph: agilent 1260
An electronic balance: mettler XS105
Vacuum baking oven: vacuum drying oven DZF6021 by Shanghai Soxhlet apparatus
Constant temperature and humidity test chamber:
example 1
1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine fumarate
In a 100 mL single-neck flask, 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine (5.0 g,11.6 mmol) and ethyl acetate (25 mL) were added and dissolved with stirring at room temperature (25 ℃), fumaric acid (1.6 g,15.20 mmol) was added to the reaction system, heating was carried out with stirring to 50 ℃ and stirring was carried out at that temperature for 2 hours, a solid precipitated, the solid was filtered and washed with ethyl acetate (10 mL x 2 times), and the resulting solid was dried in a vacuum oven (35 ℃) for 4 hours to give an off-white solid (4.8 g, yield 73%).
1 HNMR(DMSO-d6; 500 MHZ) δ (ppm) 7.6 (s, 1H), 7.48 (m, 2H), 7.28 (m, 1H), 7.20 (m, 2H), 7.09 (m, 2H), 6.83 (s, 1H), 6.58 (s, 2H), 6.38 (s, 1H), 3.96 (m, 2H), 3.76 (s, 2H), 3.45 (m, 2H), 3.26 (s, 3H)，2.39 (s, 3H)，1.92 (m, 2H)。
Example 2
1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylaminomethanesulfonate
In a 100 mL single-neck flask, 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine (5.0 g,11.6 mmol) and ethyl acetate (25 mL) were added and dissolved with stirring at room temperature (25 ℃), methanesulfonic acid (1.3 g,13.9 mml) was added dropwise to the reaction system, and stirred at that temperature for 2H, a solid precipitated, which was filtered off and washed with ethyl acetate (8 mL × 2 times), and the resulting solid was dried in a vacuum oven (35 ℃) for 4H to give 2.8 g of an off-white solid in 45.9% yield.
1 HNMR(DMSO-d6; 500 MHZ) δ (ppm) 7.60 (s, 1H), 7.43 (m, 2H), 7.24 (m, 1H), 7.21 (m, 2H), 7.05 (m, 2H), 6.81 (s, 1H), 6.35 (s, 1H), 3.86 (m, 2H), 3.70 (s, 2H), 3.45 (m, 2H), 3.23 (s, 3H)，2.82 (s, 3H)，2.38 (s, 3H)，1.91 (m, 2H)。
Example 3
1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine hydrochloride
1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine (5.0 g,11.6 mmol) and ethyl acetate (30 mL) were added to a 100 mL single-neck flask, and dissolved with stirring at room temperature (25 ℃), a solution of hydrochloric acid in ethyl acetate (2M) was added dropwise to the reaction system, and stirred at that temperature for 2 hours until no solid precipitated, the solvent was removed by drying under reduced pressure to give a solid, the resultant was dispersed in ethyl acetate (10 mL), stirred at room temperature for 1 hour, filtered with suction, and washed with ethyl acetate (4mL 2), and the resultant was dried in a vacuum oven (35 ℃) for 4 hours to give 4.8 g of an off-white solid in a yield of 89.1%.
1 HNMR(DMSO-d6; 500 MHZ) δ (ppm) 7.63 (s, 1H), 7.58 (m, 2H), 7.38 (m, 1H), 7.32 (m, 2H), 7.19 (m, 2H), 6.93 (s, 1H), 6.48 (s, 1H), 3.96 (m, 2H), 3.86 (s, 2H), 3.55 (m, 2H), 3.36 (s, 3H)，2.30 (s, 3H)，1.91 (m, 2H)。
Example 4
1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylaminonitrate
1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine (5.0 g,11.6 mmol) and ethyl acetate (25 mL) were added to a 100 mL single-necked flask, and dissolved with stirring at room temperature (25 ℃), nitric acid (0.8 g,13.9 mmol) was added dropwise to the reaction system, and stirred at that temperature for 2H to precipitate a solid, which was filtered off and washed with ethyl acetate (8 mL × 2 times), and the resulting solid was dried in a vacuum oven (35 ℃) for 4 hours to give 4.8 g of an off-white solid in 84.2% yield.
1 HNMR(DMSO-d6; 500 MHZ) δ (ppm) 7.59 (s, 1H), 7.44 (m, 2H), 7.34 (m, 1H), 7.28 (m, 2H), 7.15 (m, 2H), 6.81 (s, 1H), 6.55 (s, 1H), 3.84 (m, 2H), 3.72 (s, 2H), 3.41 (m, 2H), 3.22 (s, 3H)，2.38 (s, 3H)，1.93 (m, 2H)。
Example 5
1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylaminohydrobromide
In a 100 mL three-necked flask, 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine (5.0 g,11.6 mmol) and methanol (25 mL) were added and dissolved with stirring at room temperature (25 ℃), hydrobromic acid (3.7 g,13.9 mmol, 30%) was added, stirring at that temperature for 2H, a solid precipitated, the solid was filtered and washed with ethyl acetate (6 mL x 2 times), and the resulting solid was dried in a vacuum oven (35 ℃) for 4H to give 1.3g as a yellow solid in 22% yield.
1 HNMR(DMSO-d6; 500 MHZ) δ (ppm) 7.62 (s, 1H), 7.56 (m, 2H), 7.38 (m, 1H), 7.35 (m, 2H), 7.19 (m, 2H), 6.93 (s, 1H), 6.49 (s, 1H), 3.96 (m, 2H), 3.83 (s, 2H), 3.55 (m, 2H), 3.36 (s, 3H)，2.30 (s, 3H)，1.98 (m, 2H)。
Example 6
1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylaminosuccinate
In a 100 mL three-necked flask, 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine (5.0 g,11.6 mmol) and methanol (25 mL) were added and dissolved with stirring at room temperature (25 ℃), the reaction system was heated to 50 ℃, succinic acid (1.6 g,13.9 mmol) was added, stirring was carried out at that temperature for 2H, then the temperature was lowered to room temperature (25 ℃) and stirring was carried out for 10 minutes, a solid was precipitated, the solid was filtered and washed with methanol (6 mL × 2 times), and the resulting solid was dried in a vacuum oven (35 ℃) for 4 hours to give a white solid of 4.1 g in 65% yield.
1 HNMR(DMSO-d6; 500 MHZ) δ (ppm) 7.68 (s, 1H), 7.58 (m, 2H), 7.35 (m, 1H), 7.31 (m, 2H), 7.16 (m, 2H), 6.98 (s, 1H), 6.49 (s, 1H), 3.96 (m, 2H), 3.80 (s, 2H), 3.57 (m, 2H), 3.36 (s, 3H)，2.58 (m, 4H)，2.30 (s, 3H)，1.93 (m, 2H) 。
Example 7
1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylaminooxalate
In a 100 mL three-necked flask, 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine (5.0 g,11.6 mmol) and methanol (30 mL) were added and dissolved with stirring at room temperature (25 ℃), after which the temperature was raised to 50 ℃, oxalic acid (1.2 g,13.9 mmol) was added and stirred for 2H, with solids separating out, the solids were filtered and washed with methanol (10 mL x 2 times), and the resulting solids were dried in a vacuum oven (35 ℃) for 4H to give 5.0 g of an off-white solid in yield: 83 percent.
1 HNMR(DMSO-d6; 500 MHZ) δ (ppm) 7.56 (s, 1H), 7.41 (m, 2H), 7.34 (m, 1H), 7.28 (m, 2H), 7.16 (m, 2H), 6.81 (s, 1H), 6.65 (s, 1H), 3.84 (m, 2H), 3.72 (s, 2H), 3.41 (m, 2H), 3.22 (s, 3H)，2.38 (s, 3H)，1.92 (m, 2H)。
Stability test of the Compound of the present invention
1. Influence factor experiment: wherein 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine fumarate, 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine methanesulfonate, 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine hydrochloride, 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine hydrobromide, 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine nitrate, 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl) -1H-pyrrol-3-yl) -N-methylamine succinate, 1- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl) -1H-pyrrol-3-yl) -N-methylamine hydrochloride, 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine oxalate was subjected to influential factor experiments, respectively:
samples were taken at high temperature (60 ℃) on day 5 and day 10, respectively, and properties (color and solubility) of the compounds were examined, and substances and contents thereof were detected by high performance liquid chromatography.
Samples were taken at 5 th and 10 th days under high humidity (92.5% RH), and properties (color and solubility) of the compound were examined, and substances and contents thereof were detected by high performance liquid chromatography.
Samples were taken on day 5 and day 10 under illumination (4500 lx), and properties of the compounds (color, solubility) were examined and the substances and contents were determined by HPLC.
Through the relevant stability examination, the following results are found: 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine hydrochloride and 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine fumarate have better stability and can be used as compounds for further study.
TABLE 1 salt type stability Experimental Table
The analysis on the data measured by the compound shows that the compound has deepened color and unchanged solubility in high-temperature, high-humidity and illumination experiments (30 days) of influencing factors, and other salt forms except hydrochloride are obviously increased on related substances; in these 30 days, new impurities were produced and some were measured to be only 87.6%, and among these tests, 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine hydrochloride and 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine fumarate exhibited higher stability.
Claims (5)
1.1- (5- (2-fluorophenyl) -1- (3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine organic acid salt or inorganic acid salt,
wherein n is 1, HA is an organic acid or an inorganic acid; wherein standThe organic acid is fumaric acid; the inorganic acid is hydrochloric acid.
2. The organic or inorganic acid salt of 1- (5- (2-fluorophenyl) -1- (3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine as claimed in claim 1, which is prepared by the following method:
(1) Dissolving 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine in an organic solvent,
(2) Adding organic acid or inorganic acid into a reaction bottle,
(3) Stirring the mixture for 2 hours at the corresponding reaction temperature,
(4) And (5) carrying out suction filtration, and carrying out vacuum drying on a filter cake.
3. The method of claim 2, wherein the organic or inorganic acid salt of 1- (5- (2-fluorophenyl) -1- (3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine is selected from ethyl acetate, methanol, acetone, acetonitrile, tetrahydrofuran.
4. The method of claim 2, wherein the organic or inorganic acid salt of 1- (5- (2-fluorophenyl) -1- (3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine is prepared at a reaction temperature of 0 ℃ to 50 ℃.
5. Use of the organic or inorganic acid salt of 1- (5- (2-fluorophenyl) -1- (3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine as claimed in any one of claims 1-4 for the preparation of a medicament for the treatment of erosive esophagitis, gastric ulcer, duodenal ulcer, helicobacter pylori eradication indications, and for the treatment of diseases associated with gastric hyperacidity.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101300229A (en) * | 2005-08-30 | 2008-11-05 | 武田药品工业株式会社 | 1-heterocyclylsulfonyl, 2-aminomethyl, 5- (hetero-) aryl substituted 1-h-pyrrole derivatives as acid secretion inhibitors |
| WO2014075575A1 (en) * | 2012-11-19 | 2014-05-22 | 江苏豪森药业股份有限公司 | Pyrrole sulfonamide derivative, preparation method for same, and medical application thereof |
| CN105693693A (en) * | 2014-11-27 | 2016-06-22 | 江苏柯菲平医药股份有限公司 | Preparation of pyrrole gastric acid secretion inhibitor compound salt |
| WO2016119505A1 (en) * | 2015-01-27 | 2016-08-04 | 江苏柯菲平医药股份有限公司 | Pyrrole sulfonyl derivative, and preparation method and medical use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101300229A (en) * | 2005-08-30 | 2008-11-05 | 武田药品工业株式会社 | 1-heterocyclylsulfonyl, 2-aminomethyl, 5- (hetero-) aryl substituted 1-h-pyrrole derivatives as acid secretion inhibitors |
| WO2014075575A1 (en) * | 2012-11-19 | 2014-05-22 | 江苏豪森药业股份有限公司 | Pyrrole sulfonamide derivative, preparation method for same, and medical application thereof |
| CN105693693A (en) * | 2014-11-27 | 2016-06-22 | 江苏柯菲平医药股份有限公司 | Preparation of pyrrole gastric acid secretion inhibitor compound salt |
| WO2016119505A1 (en) * | 2015-01-27 | 2016-08-04 | 江苏柯菲平医药股份有限公司 | Pyrrole sulfonyl derivative, and preparation method and medical use thereof |
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