CN107879964B - Preparation method of 1- (5- (2-fluorophenyl) -1- (3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine - Google Patents
Preparation method of 1- (5- (2-fluorophenyl) -1- (3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine Download PDFInfo
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Abstract
The invention provides a preparation method of 1- (5- (2-fluorophenyl) -1-3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine on the basis of the prior art, wherein 3- (3-methoxy propoxy) benzenesulfonyl chloride is subjected to reaction steps of sulfonylation amination, reductive amination and the like to obtain 1- (5- (2-fluorophenyl) -1-3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine. The preparation method has short reaction period, avoids highly toxic reagents and simplifies the treatment operation. Is a preparation method for obtaining 1- (5- (2-fluorophenyl) -1-3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine in a large scale with high efficiency and low cost.
Description
Technical Field
The invention relates to a preparation method of a new chemical entity 1- (5- (2-fluorophenyl) -1-3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine.
Background
Since 1988, proton pump inhibitors represented by omeprazole have been widely used clinically for the treatment of peptic ulcer, reflux esophagitis, zollinger-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 (resulting in significant individual differences), and the like.
Potassium-Competitive Acid Blockers (P-CABs) act by competitively inhibiting K + in the H +/K + -ATPase through a direct, reversible process. 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 bind to H +/K + -ATP enzyme in an ionized form, prevent H + transport and acid secretion into the gastric cavity, and rapidly raise the pH value 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 advantage of optimal acid inhibition effect is easily achieved.
The compound 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine (CN 2015094255) shows higher H +/K + -ATPase inhibitory activity in vitro and better drug effect in a histamine-induced gastric acid secretion model of rats; in addition, 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine showed excellent safety in the sub-acute toxicity study. For further study of the compounds, large scale preparation of 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine was required. The research discloses a preparation method of 1- (5- (2-fluorophenyl) -1-3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine, and the preparation method has the advantages of simple post-treatment and high purity of the obtained compound.
Disclosure of Invention
The invention provides a preparation method of a new chemical entity 1- (5- (2-fluorophenyl) -1-3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine. The reaction route shown below, the reaction and post-treatment of steps (1) and (2) are simple, and the HPLC purity of the obtained product is more than 95%.
The technical scheme adopted by the invention is as follows:
a method for preparing 1- (5- (2-fluorophenyl) -1-3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine shown as a compound 3 from 3- (3-methoxy propoxy) benzenesulfonyl chloride shown as the compound 1;
the preparation method comprises the following steps:
(1) Reacting the compound 1 with the compound 1-1 in a tetrahydrofuran solvent in an alkaline environment at-40-50 ℃ under the action of a protic or aprotic organic solvent to obtain a compound 2;
(2) Under the condition of organic solvent and reducing agent at-20-50 deg.c, compound 2 is reductively aminated to produce compound 3;
in the preparation method, the alkaline condition of the step (1) is organic base or inorganic base, preferably NaH, the reaction time is less than 0.5h, the purification method is alcohol stirring to precipitate solid, and the high-purity compound 2 is obtained, wherein the HPLC purity is more than 98%.
In the preparation method, the reaction solvent in the step (2) is a protic or aprotic organic solvent, preferably methanol, and the reducing agent is preferably sodium triacetoxyborohydride.
Drawings
FIG. 1: HPLC spectrogram of 1- (5- (2-fluorophenyl) -1-3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine obtained in the embodiment of the invention.
FIG. 2: the mass spectrum of 1- (5- (2-fluorophenyl) -1-3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine obtained in the invention example is shown.
FIG. 3: nuclear magnetic hydrogen spectrum of 1- (5- (2-fluorophenyl) -1-3- (3-methoxy propoxy) benzene sulfonyl chloride) -1H-pyrrole-3-radical) -N-methyl amine obtained in the invention embodiment.
Detailed Description
The present invention is further illustrated by the following examples, but is not limited thereto.
Example 1: preparation of 5- (2-fluorophenyl) -1- ((3- (3-methoxypropoxy) benzenesulfonyl) -1H-pyrrole-3-carbaldehyde (Compound 2)
In a 10L reaction flask, 60% NaH (300g, 7.62mol) was added to a solution of 1-1 (480 g, 2.54 mol) in THF (200 ml), stirred at-30 ℃ for 25 min, compound 1 (800 g, 3.06 mol) was added dropwise, stirred at-30 ℃ for 10 min, the reaction solution was poured into 5L ice water and extracted with ethyl acetate (2.5Lx3), the combined organic phases were dried, concentrated, added with 1.5 ethanol, stirred for 1h, filtered, and dried under vacuum to give 700g of a pale yellow solid (yield 66%).
Example 2: preparation of 5- (2-fluorophenyl) -1- ((3- (3-methoxypropoxy) benzenesulfonyl) -1H-pyrrole-3-carbaldehyde (Compound 2)
In a 2L reaction flask, compound 1-1 (95g, 0.5 mol) was dissolved in DMF (1000 ml), sodium tert-butoxide (96g, 1mol) was added, stirring was carried out for 25 min, compound 1 (158 g,0.6 mol) was added dropwise, stirring was carried out at 25 ℃ for 1 hour, the reaction mixture was cooled to room temperature, suction filtration was carried out, concentration was carried out under reduced pressure until dryness, and column chromatography was carried out to obtain 80g of a pale yellow solid (yield 38.2%).
Example 3: preparation of 5- (2-fluorophenyl) -1- ((3- (3-methoxypropoxy) benzenesulfonyl) -1H-pyrrole-3-carbaldehyde (Compound 2)
In a 2L reaction flask, compound 1-1 (95g, 0.5 mol) was dissolved in acetonitrile (1000 ml), N-diisopropylethylamine (97g, 0.75mol) was added thereto, and stirred at room temperature for 20 min, compound 1 (158 g,0.6 mol) was added dropwise thereto, stirred at room temperature for 1 hour, the reaction solution was cooled, concentrated under reduced pressure to dryness, and column chromatography was carried out to obtain 68g of a pale yellow solid (yield 32.4%).
Example 4: preparation of 5- (2-fluorophenyl) -1- ((3- (3-methoxypropoxy) benzenesulfonyl) -1H-pyrrole-3-carbaldehyde (Compound 2)
In a 2L reaction flask, compound 1-1 (95g, 0.5 mol) was dissolved in dichloromethane (1000 ml), triethylamine (100g, 1mol) was added, stirring was carried out at normal temperature for 20 min, compound 1 (158 g,0.6 mol) was added dropwise, stirring was carried out at normal temperature for 1 hour, the reaction solution was cooled, then, concentrated to dryness under reduced pressure, and column chromatography was carried out to obtain 75g of a pale yellow solid (yield 35.8%).
Example 5: preparation of 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine (Compound 3)
In a 10L reaction flask, 4 (700 g, 1.68 mol), 33% methylamine methanol solution (630g, 6.71mol) was dissolved in 3.5L methanol, and stirred at room temperature for 0.5h. Cooled to 0 ℃, added with sodium triacetoxyborohydride (882 g, 4.20 mol) and stirred at room temperature for 2h. Quench with 7L of water and extract three times with ethyl acetate (7 Lx 3). The organic phases are combined, concentrated to be dry under reduced pressure, dissolved by adding 12L of water, washed by ethyl acetate for four times (2.5L +1.5L + 1L), the pH of the water phase is adjusted to 9 by 2NNaOH, extracted by dichloromethane for three times (2.5Lx3), the organic phases are combined, washed by water for four times (2.5Lx4), dried by anhydrous sodium sulfate and concentrated to be dry under reduced pressure to obtain 640g of light yellow oily matter (yield 88.2%).
MS（+1）：433
1 HNMR：δ(ppm，DMSO)，12.37 (s，H，COOH)，6.99-7.71 (m，11H，Ar-H)，4.60 (t，2H，CH 2 )，4.60 (t，2H，-OCH 2 )，4.20 (t，2H，-OCH 2 )，1.39 (q，3H，-CH 3 )，1.51 (q，3H，-CH 3 )。
Example 6: preparation of 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine (Compound 3)
Compound 2 (208 g,0.5 mol), 33% methylamine methanol solution (188g, 2mol), and glacial acetic acid (36g, 0.6 mol) were dissolved in 1L methanol in a 2L reaction flask and stirred at room temperature for 0.5h. Sodium triacetoxyborohydride (265 g, 1.25 mol) was added and stirred at room temperature for 2h. Quench with 2L of water and extract three times with ethyl acetate (2 Lx 3). The combined organic phases are concentrated to dryness under reduced pressure, 3L of water is added for dissolution, the mixture is washed four times with ethyl acetate (1L +0.8L +0.5L + 0.3L), the aqueous phase is adjusted to pH 9 with 2NNaOH, dichloromethane is extracted three times (1 Lx 3), the organic phases are combined, washed four times with water (1 Lx 4), dried with anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and 150g of light yellow oil is obtained (yield 69.6%).
Example 7: preparation of 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine (Compound 3)
In a 2L reaction flask, compound 2 (208 g,0.5 mol), 33% methylamine methanol solution (188g, 2mol) was dissolved in 1L methanol and stirred at ambient temperature for 0.5h. Sodium borohydride (57 g, 1.5 mol) was added at 0 ℃ and stirred at ambient temperature for 2h. Quench with 2L water and extract three times with ethyl acetate (2 Lx 3). The combined organic phases are concentrated to dryness under reduced pressure, 3L of water is added for dissolution, the mixture is washed with ethyl acetate four times (1L +0.8L +0.5L + 0.3L), the aqueous phase is adjusted to pH 9 with 2NNaOH, dichloromethane is extracted three times (1 Lx 3), the combined organic phases are washed with water four times (1 Lx 4), dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, and 165g of light yellow oil is obtained (yield 76.5%).
Example 8: preparation of 1- (5- (2-fluorophenyl) -1-3- (3-methoxypropoxy) benzenesulfonyl chloride) -1H-pyrrol-3-yl) -N-methylamine (Compound 3)
In a 2L reaction flask, compound 2 (208 g,0.5 mol), 33% methylamine methanol solution (188g, 2mol) was dissolved in 1L dichloromethane and stirred at ambient temperature for 0.5h. Sodium triacetoxyborohydride (265 g, 1.25 mol) was added and stirred at room temperature for 2h. Quenching with 2L of water, separating, concentrating the organic phase under reduced pressure to dryness, dissolving with 3L of water, washing with ethyl acetate four times (1L +0.8L +0.5L + 0.3L), adjusting the pH of the aqueous phase to 9 with 2NNaOH, extracting with dichloromethane three times (1 Lx 3), combining the organic phases, washing with water four times (1 Lx 4), drying with anhydrous sodium sulfate, concentrating under reduced pressure to dryness to obtain 138g of light yellow oil (yield 64%).
Claims (1)
1. A method for preparing 1- (5- (2-fluorophenyl) -1- (3- (3-methoxy propoxy) benzenesulfonyl chloride) -1H-pyrrole-3-yl) -N-methylamine shown as a compound 3 from 3- (3-methoxy propoxy) benzenesulfonyl chloride shown as the compound 1,
the preparation method is characterized by comprising the following steps:
(1) Under the temperature of minus 30 +/-5 ℃, sodium hydride provides an alkaline environment, and the compound 1-1 react in a tetrahydrofuran solvent to obtain a compound 2; the reaction time is less than 0.5h;
(2) In a 10L reaction bottle, 700g of the compound 2, 630g of 33 percent methylamine methanol solution are dissolved in 3.5L methanol and stirred for 0.5h at normal temperature; cooling to 0 ℃, adding 882g of sodium triacetoxyborohydride, and stirring at normal temperature for 2h; adding 7L of water for quenching, and extracting by using ethyl acetate for three times, namely 7L multiplied by 3 extraction; combining organic phases, concentrating to dryness under reduced pressure, adding 12L of water for dissolving, washing with ethyl acetate for four times by 2.5L +1.5L +1L, adjusting the pH value of a water phase to 9 by 2N NaOH, extracting with dichloromethane for three times by 2.5L x3, combining the organic phases, washing with water for four times by 2.5L x4, drying with anhydrous sodium sulfate, and concentrating to dryness under reduced pressure to obtain 3 640g of a light yellow oily compound;
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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 |
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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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