CN114890997A - Preparation process of anticholinergic drug tiaogelium bromide - Google Patents
Preparation process of anticholinergic drug tiaogelium bromide Download PDFInfo
- Publication number
- CN114890997A CN114890997A CN202210417844.0A CN202210417844A CN114890997A CN 114890997 A CN114890997 A CN 114890997A CN 202210417844 A CN202210417844 A CN 202210417844A CN 114890997 A CN114890997 A CN 114890997A
- Authority
- CN
- China
- Prior art keywords
- bromide
- ammonium bromide
- reaction
- crude product
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention provides a preparation process of an anticholinergic drug, namely thiagerium bromide, which comprises the following steps: s1, ester exchange reaction: taking R-1-methyl-3-hydroxypyrrolidine and 2, 2-dithienyl methyl glycolate as starting materials to generate an intermediate under an alkaline condition; s2, bromomethylation reaction: the intermediate obtained in the S1 reacts with methyl bromide to generate a crude product of the Tiger ammonium bromide; s3, refining: and (5) decoloring and recrystallizing the crude product of the tiager ammonium bromide obtained in the S2 to obtain a finished product of the tiager ammonium bromide. According to the invention, the safe and easily removable solid alkalis are used in the ester exchange reaction to replace sodium, sodium hydride and other strong bases used in the previous reports, and ethers are used for recrystallization purification of the intermediate product crude product, so that the operation steps are simplified, and the yield is higher; the crude product of the tiager ammonium bromide is decolorized and recrystallized by active carbon, and a finished product of the tiager ammonium bromide with better properties and higher purity can be obtained.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to a preparation process of an anticholinergic drug, namely thiagerium bromide.
Background
Chronic Obstructive Pulmonary Disease (COPD) is a common and frequent progressive respiratory disease, including chronic bronchitis, asthma, bronchiectasis, cystic fibrosis, etc., which has a high prevalence and mortality rate and is the third leading cause of death worldwide (global health assessment, WHO, 2020). COPD is characterized by persistent airway inflammation, has a cascade reaction of inflammation and inflammatory mediators, and patients often have dyspnea symptoms due to limited airflow during expiration and inspiration caused by lung lesion or airway stenosis in the lung. The drug treatment of COPD includes the use of anti-inflammatory drugs such as glucocorticoids and leukotrienes, as well as the use of anticholinergics and adrenal beta 2 Bronchodilatory drugs such as receptor agonists are the main drugs, and if necessary, drug-based dual or triple therapy (GOLD 2022report) is used.
Anticholinergic drugs are drugs for the treatment of COPD that have been developed more rapidly in recent years. Muscarinic Acetylcholine receptors (mAChRs) are important neurotransmitter receptors widely distributed in both central and peripheral parasympathetic nerves and can be classified as M 1 -M 5 Five receptor subtypes. In which M is distributed in bronchial smooth muscle 3 Subtype is the main target of action of COPD therapeutic drug, M 3 Type is the major acetylcholine receptor subtype that mediates bronchial and tracheal smooth muscle contraction and is involved in mucus secretion and vasodilation of vascular smooth muscle cells. Anticholinergic agents by blocking M on smooth muscle 3 The receptor type relaxes airway smooth muscle and inhibits mucus secretion, thereby realizing comprehensive control of symptoms. M 1 Receptors are distributed predominantly in the parasympathetic ganglia, which connect the respiratory tract, inhibiting M 1 Type receptors can also achieve the effect of relaxing bronchial smooth muscle by cutting off central nerve conduction. M 2 Receptor type receptors located at the anterior of the ganglion in cholinergic nerve endings act as autoreceptors, mediate feedback inhibition of acetylcholine release from nerves, and antagonize acetylcholine. Ideal anticholinergic agents for COPD should antagonize M 1 Type and M 3 Type receptor, pair M 2 Receptor typeHas a lower affinity.
Currently, anticholinergic drugs for COPD treatment include ipratropium bromide (Boehringer Ingelheim, 1986by FDA), tiotropium bromide (Boehringer Ingelheim, 2004byFDA), oxitropium bromide (Boehringer Ingelheim), glycopyrronium bromide (Novartis, 2012 EMA), aclidinum bromide (alamiral Prodesfarma & fort Laboratories Inc, 2012by FDA), etc., wherein ipratropium bromide and oxitropium bromide belong to Short-acting cholinergic receptor inhibitors (SAMAs), tiotropium bromide, glycopyrronium bromide, aclidinum bromide belong to Long-acting cholinergic receptor inhibitors (Long-acting cholinergic agonists, LAMAs).
Ipratropium bromide inhalation formulations were the earliest SAMAs on the market. Ipratropium bromide can be reacted with M 1 Type, M 2 Type and M 3 The type choline receptor is combined, but the dissociation and decomposition are rapid, the common dosage is 3 to 4 times of daily inhalation, each time is 20 to 40 mu g, and the half life is 1.6 to 3.6 h. SAMAs are currently being replaced clinically by LAMAs.
Tiotropium bromide is a representative drug in LAMAs. The tiotropium bromide is obtained by deriving an ipratropium bromide structure, and a disubstituted thiophene structural fragment is introduced into a molecule, so that the hydrophobicity of the tiotropium bromide is enhanced, and the pharmacokinetic property is improved. Tiotropium bromide can inhibit M 1 -M 3 Type receptor, but with M 1 Type and M 3 The type receptor is combined for a longer residence time, so that the drug effect is more durable, and a common inhalation preparation is taken 1 time a day, 18 mu g each time, and the half life is as long as 5-6 days. In addition, tiotropium bromide can improve dyspnea symptoms, improve exercise tolerance, reduce hyperventilation, and relieve acute episodes in moderately severe COPD patients, however, tiotropium bromide has metabolic stability and resistance to M 2 Inhibition of type receptors leads to the susceptibility to adverse reactions such as mouth feel, urinary retention, constipation, and even tachycardia (exp. opin. invest. drugs.2001, 10, 733).
Glycopyrrolate pair M 1 Type and M 3 The receptor type has selective binding and can be used for treating COPD, but most of the biological activity exists in [3S,2R ]]Among the configurational optical isomers, their pairs M 3 The activity of the receptor type is [3R,2S ] thereof]100 times of configurational optical isomer. Grid (C)The molecular structure of the ammonium bromide contains two chiral centers and is a pair of racemic enantiomer mixtures ([3S, 2R)]：[3R,2S]1: 1) and has inhibitory effects on various subtypes of M receptors to different degrees, and has wide anticholinergic effects and miscellaneous pharmacological activities. Currently, glycopyrronium bromide is rarely used alone clinically, and is often used together with an adrenobeta 2 receptor agonist such as formoterol and indacaterol as a mixed inhalation preparation for treating COPD (j. pharmacol. exp. ther.2012, 343,520).
The aclidinium bromide is obtained by further structural modification of the medicines, compared with tiotropium bromide, the aclidinium bromide has better M1 and M3 receptor selectivity, but the half-life period in vivo is only 2.4min, and although the side effect is greatly reduced, daily administration needs to be carried out twice a day, and the dosage is up to 400 mu g.
Ticagnium bromide is a highly selective M discovered in recent years 3 A cholinergic receptor inhibitor. Thigeum bromide, white crystals or powder, chemical name: 3R-1, 1-dimethyl-3- (2-hydroxy-2, 2-dithien-2-ylacetoxy) pyrrolidine bromide, formula: c 16 H 20 BrNO 3 S 2 The structural formula is shown as formula I. According to the report of Zuo et al, the tiager ammonium bromide molecule contains the dominant structural fragment of the quaternary ammonium bromide based COPD therapeutic drug, and simultaneously overcomes the potential pharmacokinetic property defect of the tiager ammonium bromide on the market. In CHO cell experiments, compared to aclidinium bromide (K) i ＝0.11nM,IC 50 0.68nM) and glycopyrronium bromide (K) i ＝0.25nM,IC 50 0.65nM) and exhibits comparable binding capacity and superior inhibitory activity (K) i ＝0.16nM,IC 50 0.38nM) with moderate plasma stability (t) 1/2 9.34min) is a potential candidate COPD therapeutic drug (chemmedcem 2017,12,1173).
Chinese patent CN103965178 discloses a preparation and synthesis route of milligram-grade thiage ammonium bromide, which is specifically shown in formula ii:
the route is characterized by short route, convenient operation and easy obtaining of a small amount of finished product of the Tiger ammonium bromide in short time, but the reaction conditions for mass preparation or mass production have obvious defects: 1) a large amount of dangerous strong base sodium hydride is used in the ester exchange reaction, hydrogen is released at high temperature in the projection, obvious safety risk exists in the process of amplifying feeding, danger is easy to occur in the processes of large-scale transportation, use and post-treatment, and meanwhile, the requirement of the reaction condition of strong base heating on production equipment is high; 2) the post-treatment process of the generated intermediate involves complicated operation steps such as quenching, acid washing, alkalifying and extracting, and the yield is only 30-40%; 3) a large amount of methyl bromide solution and 2-butanone solvent are not easily available on the market, so that large-scale production is limited; 4) the appearance, properties and purity of the finished product of the Tiger ammonium bromide obtained by the reported route do not meet the quality control requirements. Therefore, reasonable improvement is carried out on the synthesis conditions and operation steps of the tiager ammonium bromide, a process route which is suitable for pilot plant test and industrial production is found to prepare the tiager ammonium bromide in large quantity, and the problem which needs to be solved is supported for drug research and development.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, provides a preparation method of an anticholinergic drug, namely thiage ammonium bromide, and realizes gram-grade and kilogram-grade preparation of the thiage ammonium bromide in an efficient and safe mode.
In order to solve the technical problems, the invention adopts the technical scheme that: a preparation process of an anticholinergic drug of Tiger ammonium bromide comprises the following specific preparation route:
the method comprises the following steps:
s1, ester exchange reaction: taking R-1-methyl-3-hydroxypyrrolidine and 2, 2-dithienyl methyl glycolate as starting materials to generate an intermediate under an alkaline condition;
s2, bromomethylation reaction: the intermediate obtained in the S1 reacts with methyl bromide to generate a crude product of the Tiger ammonium bromide;
s3, refining: and (5) decoloring and recrystallizing the crude product of the tiager ammonium bromide obtained in the S2 to obtain a finished product of the tiager ammonium bromide.
Further, the transesterification reaction is specifically as follows: dissolving the starting material in a solvent, and adding solid alkali in batches in the dissolving process to the reaction liquid to complete the reaction;
the solvent is any one of benzene, toluene, xylene and N, N-dimethylformamide;
the solid alkali is any one of cesium carbonate, sodium carbonate, potassium carbonate and lithium carbonate;
the equivalent ratio of the R-1-methyl-3-hydroxypyrrolidine to the 2, 2-dithienylmethyl glycolate is 0.8-1.2: 1;
the reaction time is 1-8h, and the reaction temperature is 50-150 ℃.
Further, after the transesterification reaction is completed, a recrystallization process is also included, in the recrystallization process, the intermediate crude product obtained in the S1 is dissolved by an ether solvent, and the ether solvent is any one of ethyl ether, isopropyl ether and methyl tert-butyl ether.
Further, the bromomethylation reaction process is specifically as follows: dissolving the intermediate in a solvent, introducing sufficient methyl bromide gas into the reaction solution at low temperature, and continuously stirring at room temperature after the reaction is finished to separate out a crude product of the Tiger ammonium bromide;
the solvent is acetone, dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, N-dimethylformamide, methanol, ethanol and isopropanol; the reaction temperature is-20-20 ℃.
Further, the refining process is specifically as follows: dissolving the crude product of the tiager ammonium bromide in a refined solvent, adding activated carbon into the mixed solution for decolorization, and completing the subsequent crystallization process to obtain a finished product of the tiager ammonium bromide;
the refined solvent is one or the combination of two of methanol, ethanol, isopropanol, 95% ethanol, acetonitrile, tetrahydrofuran, acetone and dichloromethane;
the mass ratio of the active carbon to the crude product of the Tiger ammonium bromide is 0.05-0.3: 1.
Further, the thiager ammonium bromide prepared by the preparation process of the anticholinergic drug thiager ammonium bromide is white crystal or solid, and the purity of the thiager ammonium bromide is not less than 98%.
Compared with the prior art, the invention has the beneficial effects that:
1) the safe and easily removable solid alkalis are used for replacing sodium, sodium hydride and other strong bases used in the previous reports in the ester exchange reaction, and ethers are used for recrystallizing and purifying the intermediate product crude product, so that the operation steps are simplified, and the yield is higher; active carbon decoloration and recrystallization are carried out on the crude product of the tiager ammonium bromide, so that a finished product of the tiager ammonium bromide with better properties and higher purity can be obtained;
2) the raw materials, reagents and solvents can be obtained in a large scale through the market, the whole process route is safer and more efficient, and the method is suitable for gram-grade and above large-scale preparation and industrial production and can obtain high-quality products.
Drawings
The disclosure of the present invention is illustrated with reference to the accompanying drawings. It is to be understood that the drawings are designed solely for the purposes of illustration and not as a definition of the limits of the invention. In the drawings, like reference numerals are used to refer to like parts. Wherein:
FIG. 1 is a graphic representation of an intermediate prepared using the procedure of example 1 of the present invention 1 An H-NMR spectrum;
FIG. 2 is a graphic representation of an intermediate prepared using the procedure of example 1 of the present invention 13 A C-NMR spectrum;
FIG. 3 is a graph of Saigo ammonium bromide prepared using the method of example 1 of the present invention 1 An H-NMR spectrum;
FIG. 4 is a graph of Saigo ammonium bromide prepared using the method of example 1 of the present invention 13 A C-NMR spectrum;
FIG. 5 is the elemental analysis results of Tiger ammonium bromide prepared using the method of example 1 of the present invention;
FIG. 6 is a differential scanning calorimetry analysis of Tiger's ammonium bromide prepared using the method of example 1 of the present invention;
FIG. 7 is a thermogravimetric analysis of thigeum bromide prepared using the method of example 1 of the present invention;
FIG. 8 is an infrared spectrum of thigeum bromide prepared using the method of example 1 of the present invention;
FIG. 9 is the X-ray powder diffraction results of Sage ammonium bromide prepared using the method of example 1 of the present invention;
FIG. 10 is the X-ray powder diffraction results of Sage ammonium bromide prepared using the method of example 4 of the present invention.
Detailed Description
It is easily understood that, according to the technical solution of the present invention, a person skilled in the art can propose various alternative structural modes and implementation modes without changing the spirit of the present invention. Therefore, the following detailed description and the accompanying drawings are merely illustrative of the technical aspects of the present invention, and should not be construed as all of the present invention or as limitations or limitations on the technical aspects of the present invention.
A preparation process of an anticholinergic drug, namely thiagerium bromide, comprises the following preparation route:
the method comprises the following steps:
s1, ester exchange reaction: taking R-1-methyl-3-hydroxypyrrolidine and 2, 2-dithienyl methyl glycolate as starting materials to generate an intermediate under an alkaline condition;
s2, bromomethylation reaction: the intermediate obtained in the S1 reacts with methyl bromide to generate a crude product of the Tiger ammonium bromide;
s3, refining: and (5) decoloring and recrystallizing the crude product of the tiager ammonium bromide obtained in the S2 to obtain a finished product of the tiager ammonium bromide.
The starting materials in S1 comprise a starting material 1 and a starting material 2, wherein the starting material 1 is (R) -1-methyl-3-hydroxypyrrolidine, the starting material 2 is 2, 2-dithienyl methyl glycolate, the intermediate is (R) -1-methylpyrrolidin-3-yl-2-hydroxy-2, 2-di (thiophene-2-yl) acetate, the crude product is a thiger ammonium bromide product which contains a large amount of impurities and has properties and purity which do not reach the properties and purity of the thiger ammonium bromide product which can be used as a raw material medicine, and the fine product is the thiger ammonium bromide product which reaches the quality standard.
A process for preparing the thiager ammonium bromide as anticholinergic medicine includes preparing intermediate by ester exchange reaction, synthesizing coarse thiager ammonium bromide by bromomethylation reaction and refining coarse thiager ammonium bromide. Specifically, one starting material is dissolved in the reaction solvent for later use. The other starting material was mixed with the reaction solvent, completely dissolved and the base was added in portions. Heating the system to be stable, dropwise adding the standby initial material liquid in batches, refluxing out part of reaction solvent, after the reaction is finished, removing insoluble solid by suction filtration, concentrating to obtain an intermediate crude product, and adding an ether solvent for recrystallization. And adding dichloromethane into the intermediate until the intermediate is dissolved clearly, continuously introducing sufficient bromomethane gas at low temperature, and after the reaction is finished, continuously stirring at room temperature to separate out a crude product. And washing the crude product with cold dichloromethane, and drying to obtain the crude product of the Tiger ammonium bromide. And adding a refined solvent into the crude product of the tiaog ammonium bromide for reflux dissolution, adding activated carbon for decolorization, performing suction filtration, heating and refluxing the filtrate again, cooling to 0-10 ℃ to separate out a product, washing the product by using a cold solvent, and drying to obtain a finished product of the tiaog ammonium bromide.
In the step of preparing the intermediate by transesterification in the preparation method, the base is selected from inorganic solid bases such as cesium carbonate, sodium carbonate, potassium carbonate and lithium carbonate, wherein cesium carbonate is preferred; selecting benzene, toluene, xylene and N, N-dimethylformamide by adopting a solvent, and preferably selecting the toluene; the ratio of the volume (L) of the solvent to the 2(g) of the starting material is 20-72: 1, preferably in a ratio of 25-36: 1; the charging sequence selected may be that starting material 1 and starting material 2 are mixed in the reactor at the same time or that starting material 1 solution is dropped into starting material 2 solution or that starting material 2 solution is dropped into starting material 1 solution, preferably that starting material 2 solution is dropped into starting material 1 solution; reaction mass equivalent is starting material 1 (eq): starting material 2(eq) ═ 0.8-1.2:1, preferably in a ratio of 1: 1; the reaction time is 1-8 hours, preferably 1-4 hours; the reaction temperature is 50-150 ℃, and preferably 100-120 ℃; the solvent for recrystallization of the product is selected from diethyl ether, isopropyl ether and methyl tert-butyl ether, preferably isopropyl ether and methyl tert-butyl ether.
In the intermediate bromomethylation reaction step of the preparation method, the bromomethylation reagent is methyl bromide gas, and the reaction time is 0.5-4 hours, preferably 1-1.5 hours; the equivalent reaction solvent using methyl bromide is acetone, dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, N-dimethylformamide, methanol, ethanol, isopropanol, wherein dichloromethane is preferred; the reaction temperature is-20 to 20 ℃, and preferably-10 to 10 ℃.
In the step of refining the crude product of the Tiger's ammonium bromide in the preparation method, the refining solvent selected is one or a combination of two solvents of methanol, ethanol, isopropanol, 95% ethanol, acetonitrile, tetrahydrofuran, acetone and dichloromethane, preferably ethanol and 95% ethanol; the selected active carbon proportion is active carbon (g): crude product (g) is 0.05-0.3:1, preferably in a ratio of 0.1-0.15: 1. if the properties and purity of the pure product can not meet the requirements, the refining operation can be continued, and the product meeting the quality requirements can be obtained by generally refining for 1-2 times.
The gram-scale preparation process of the present application is further illustrated below with reference to the examples.
EXAMPLE 1 Synthesis preparation of Sagittarium Bromide
Preparation of intermediates
Starting material 1(23g,90.4mmol) was dissolved in toluene (500mL) and starting material 2(10.7g, 105.8mmol), N, was added 2 Under protection, the temperature is raised to 110 ℃ and 120 ℃, cesium carbonate powder (79.55g, 146.5mmol) is added in portions, and the reaction is continued for 2.5 h. Detecting the residual 5% of the starting material 1 by TLC (PE: EA ═ 3:1), filtering to remove alkaline solids, cooling with ice water to below 20 ℃, pouring the filtrate into water (500mL), stirring, standing for liquid separation, adding anhydrous sodium sulfate for drying, filtering, and concentrating to dryness by reduced pressure distillation at 50 ℃ to obtain a crude intermediate brown oily liquid. Adding 150ml of methyl tert-butyl ether, heating and refluxing, cooling to 0-10 ℃ without dissolving, and stirring for 1 h. The filtrate was washed with 15ml of frozen methyl t-butyl ether and dried to give 30.9g of a light brown solid (yield: 45)% HPLC purity: 83%,). Can be directly used for the next step or be used for subsequent pulping purification.
And (3) purification process: 10g of the crude intermediate product is added into 10ml of dichloromethane, stirred at room temperature and filtered, the obtained solid is suspended in 10ml of ethyl acetate, filtered and dried, and 8.1g of white solid is obtained (yield: 81%, HPLC purity: 98.2%).
And (3) confirming the structure of the intermediate and performing pattern characterization:
hydrogen spectrum: 1 HNMR(400MHz,DMSO-d 6 ) δ 7.46-7.40(m,1H),7.27(s,1H),7.09-7.02(m,2H),6.99-6.91(m,2H),5.18-5.09(m,1H),2.68-2.53(m,2H),2.52-2.43(m,2H),2.28-2.19(m,1H),2.17(s,3H),2.16-2.09(m,1H),1.71-1.59(m,1H) see FIG. 1.
Carbon spectrum: 13 CNMR(101MHz,DMSO-d 6 ) Delta 171.38,147.85,127.11,126.53,125.88,77.04,76.77,61.62,54.86,42.11 and 32.36, see figure 2.
m/z:324.2[Μ+H] + .
Preparation of crude Tiger's ammonium bromide
Adding 240mL of dichloromethane into the crude intermediate (30g) until the mixture is dissolved, cooling to-5-5 ℃, continuously introducing methyl bromide gas, stopping introducing the gas after 1h, removing the cooling, continuing stirring for 30min, and filtering. The filter cake was washed with 30mL of cold dichloromethane and dried by forced air drying at 40 ℃ for 2 hours to obtain a pink powder (31.1g, yield: 104%, purity: 98.6%).
Refining of crude Tiger ammonium bromide
Adding 2.4L 95% ethanol into the crude product of Tiger's ammonium bromide (30g), heating and refluxing to dissolve, adding active carbon (10g), stirring for 30min, filtering while hot, naturally cooling to room temperature after the filtrate is refluxed and dissolved, further cooling to 0-10 ℃, keeping the temperature and stirring for 1h, filtering, washing the filter cake with 30ml absolute ethanol, and drying the filter cake by air blast at 40 ℃ for 3h to obtain white crystals (23.8g, yield: 78%, HPLC purity: 99.5%).
The structure confirmation and the spectrum characterization of the Tiger ammonium bromide fine product are as follows:
hydrogen spectrum: 1 HNMR(400MHz,DMSO-d 6 )δ7.92-7.76(m,3H),7.49-7.38(m,2H),7.35-7.25(m,2H),5.94-5.74(m,1H),4.28-418(m,1H),4.05-3.98(m,2H),3.95-3.83(m,1H),3.52(s,3H),3.36-3.31(m,3H),3.12-2.95(m,1H),2.53-2.36(m,1H) see figure 3.
Carbon spectrum: 13 CNMR(101MHz,DMSO-d 6 ) δ 171.28,147.56,127.65,127.20,126.70,126.65,77.17,74.79,69.98,64.84,53.54,30.67, see fig. 4.
Mass spectrum: m/z 338.1[ mu-Br ]] + .
Specific optical rotation: [ alpha ] to] d 20 ＝-8.5(c＝0.1,MeOH)
Melting point: decomposing at 200 deg.C or higher.
Elemental Analysis (EA): measured value: c, 46.17; h4.84%; n3.07; s,15.34 theoretical value: c, 45.94; h, 4.82; n, 3.35; s,15.33, see figure 5.
Differential Scanning Calorimetry (DSC): a strong heat absorption peak is generated in a temperature range of 198.2-200.4 ℃, and the enthalpy change is 97.31J/g. See figure 6.
Thermogravimetric analysis (TGA): weight loss began to occur at 187.5 ℃ and 73.4% of the mass was lost until 345.8 ℃. See fig. 7.
Characteristic peak (sigma, cm) of infrared spectrum -1 ): 3201, 1746, 1475, 1223, 1089, 765, 743, 611. See figure 8.
X-ray powder diffraction: the diffraction pattern and diffraction peak data are shown in figure 9.
EXAMPLE 2 Synthesis preparation of Sagittarium Bromide
Preparation of intermediates
5g of the starting material 2 are weighed, 200ml of toluene are added, the mixture is stirred at room temperature to dissolve, 16g of cesium carbonate powder are added, and the mixture is warmed up to slight reflux. Dropwise adding a toluene solution of the starting material 1(12.5g), wherein the total time of dropping is 30min, fractionating the refluxed liquid, supplementing an equal amount of toluene solvent, and dropwise adding the toluene solvent into the reaction system; after dropping, the reaction is refluxed for 1 h. TLC (PE: EA is 3:1) is used for monitoring the reaction, ice water is cooled to below 20 ℃, the reaction solution is filtered, water is added for washing, the organic phase is concentrated, 25ml of isopropyl ether is added after the concentration is finished, the temperature is increased for reflux, the temperature is reduced to 0-10 ℃, and the reaction solution is stirred for 1 h. The filtration was washed with 5ml of frozen methyl t-butyl ether and blown at 40 ℃ for 2 hours to obtain 8g of an intermediate light brown powder (yield: 50%, HPLC purity: 95.3%).
Preparation of crude Tiger's ammonium bromide
5.0g of the intermediate was taken and 25ml of dichloromethane was added, and the mixture was stirred to dissolve. And (3) cooling, slowly introducing bromomethane when the temperature is reduced to-5-5 ℃, stopping introducing the bromomethane after stirring for 10min, stirring for 30min at the temperature of-5-5 ℃, removing the ice bath, stirring for 1h at room temperature, filtering, washing with 5ml of dichloromethane, and drying a filter cake by blowing at 40 ℃ for 2 h. This gave 6.5g of crude tioxaglammonium bromide as an off-white powder (yield: 100%, HPLC purity: 97.1%).
Refining of crude Tiger's ammonium bromide
The purification process was carried out twice in the same manner as in example 1 to obtain 5.3g of fine white crystals of Saigo ammonium bromide (yield: 82%, HPLC purity: 99.3%).
The preparation and the process route used in the invention are equally applicable to the chiral enantiomers of thiagerium bromide: (S) -Tiger' S ammonium bromide, i.e., 3S-1, 1-dimethyl-3- (2-hydroxy-2, 2-dithien-2-ylacetoxy) pyrrolidine bromide; when preparing (S) -thiagernium bromide according to the technical scheme of the invention, the starting material 2 used is (S) -1-methyl-3-hydroxypyrrolidine. The following examples are specifically described below.
EXAMPLE 3 Synthesis preparation of (S) -Thioglutammonium Bromide
Starting material 2(6g, 59.32mmol) was weighed, toluene (240mL) was added, the solution stirred at room temperature, cesium carbonate solid (19.33g, 59.32mmol) was added portionwise and the mixture warmed to slight reflux. Starting material 1(15g, 59.32mol) was weighed out and dissolved in toluene (200mL) in a 10L three-necked flask, and the mixture was warmed to vigorous reflux at 40-60 ℃. The starting material 1 solution was added dropwise in portions, and the refluxed toluene solution was separated out. The dropwise addition is finished about 1 hour, and the reaction is carried out for 1 hour. TLC (PE: EA: 3:1) detection reaction, heating is removed, the temperature is reduced to below 20 ℃ by ice water, cesium carbonate solid is removed by suction filtration, 50mL of water is used for washing filtrate, stirring is carried out for 10min, standing is carried out for 10min for liquid separation, an organic phase is concentrated until no fraction is generated, an oily crude product is obtained, 30mL of methyl tert-butyl ether is added, heating reflux is carried out, cooling crystallization is carried out, crystallization is carried out at 0-10 ℃ for 1h, suction filtration is carried out, 5mL of cold methyl tert-butyl ether is added for washing, air blowing drying is carried out at 40 ℃ is carried out, and 5.3g of (S) -intermediate is obtained, and light red solid powder is obtained (yield: 35%, HPLC purity: 72%).
The intermediate (5.3g) was added to methylene chloride with stirringStirring, cooling to-5-5 deg.C, slowly introducing bromomethane gas, TLC (MeOH: CH) 2 Cl 2 1:16), stopping ventilation after 0.5h, keeping the temperature and stirring for 30min, stirring for 1h at room temperature, and filtering. After washing the filter cake with 6ml of cold dichloromethane, the filter cake was dried by forced air at 40 ℃ for 2h to give 6.5g of an off-white powder.
Dissolving the crude product with hot 95% ethanol, heating to boil, adding 50mg active carbon, and stirring for 30 min. And (3) carrying out suction filtration, heating the filtrate to be completely dissolved, cooling to 0-5 ℃ to separate out a product, carrying out suction filtration, and drying to obtain a finished product of (S) -thiagerium bromide, wherein the white crystal is 6.4g (the yield is 93%, and the HPLC purity is 98.6%). [ alpha ] to] d 20 ＝7(c＝0.1,MeOH)。
The kilogram-scale preparation process of the invention is described in detail below with reference to the examples.
EXAMPLE 4 Synthesis preparation of Sagittarium Bromide
Preparation of intermediates
A50L glass reactor weighed starting material 2(500g, 4.94mol), added toluene (20L), mechanically stirred at room temperature to clear, added cesium carbonate powder (1610g, 4.94mol) in portions, and steam jacketed to warm to slight reflux. Starting material 1(1256g, 4.94mol) was weighed out in a 20L reactor and dissolved in toluene (16L) and cleared at room temperature. The 50L reaction system is heated to be violently refluxed, the 20L dropping funnel is added with the feed liquid of the starting material 1 in batches, and the toluene solution which flows back is separated out. After about 3 hours of dripping, 2L of new toluene is dripped, and the reaction is carried out for 1.5 hours at constant temperature and stirring speed. TLC (PE: EA ═ 3:1) detects that about 25% of the starting material 1 remains, the temperature of a brine bath is reduced to below 20 ℃, 5L of filtrate is washed by water, after standing and liquid separation, the organic phase is concentrated to obtain oil, 600ml of isopropyl ether is added and heated to reflux and clear, the product is cooled and separated out, crystallization is carried out at 0-10 ℃ for 1h, and solid is filtered out by suction, thus obtaining 490g of light gray solid powder (yield: 39%, HPLC purity: 85%).
Synthesis of crude Tiger's ammonium bromide
Adding the intermediate (490g) into 4L dichloromethane in a 10L reaction kettle until it is clear, cooling the saline interlayer to-5-5 deg.C, continuously introducing bromomethane gas (about 2kg), stopping introducing gas after 1h, removing cooling, stirring for 30min, and filtering. The filter cake was washed with 600mL of dichloromethane and then dried by oven blowing at 40 ℃ to obtain 572g of an off-white powder (yield: 90%, HPLC purity: 97.6%).
Refining of finished product of Tiger ammonium bromide
The crude Tiger's ammonium bromide (570g) was added to 2.5L of 95% ethanol in a 5L glass reactor, the system was refluxed and dissolved to dryness by heating with a hot steam jacket, and activated carbon (50g) was added and mechanically stirred for 30 min. The mixture is filtered when the mixture is hot, the filtrate enters a 5L glass reaction kettle again for refluxing and dissolving, the mixture is naturally cooled to room temperature, and is further cooled to 0-10 ℃ by a brine bath, and the mixture is stirred for 1 hour under the condition of heat preservation to fully separate out the product. The mixture is filtered, the filter cake is washed by 500mL of absolute ethyl alcohol and then enters an oven for forced air drying at 50 ℃ to obtain 550g of finished product white crystals of the Tiger ammonium bromide (yield: 78%, HPLC purity: 99.4%, analytical result shown in figure 10)
The technical scope of the present invention is not limited to the above description, and those skilled in the art can make various changes and modifications to the above embodiments without departing from the technical spirit of the present invention, and such changes and modifications should fall within the protective scope of the present invention.
Claims (6)
1. A preparation process of an anticholinergic drug tiaogegan ammonium bromide is characterized in that the preparation route is as follows:
the method comprises the following steps:
s1, ester exchange reaction: taking R-1-methyl-3-hydroxypyrrolidine and 2, 2-dithienyl methyl glycolate as starting materials to generate an intermediate under an alkaline condition;
s2, bromomethylation reaction: the intermediate obtained in the S1 reacts with methyl bromide to generate a crude product of the Tiger ammonium bromide;
s3, refining: and (5) decoloring and recrystallizing the crude product of the tiager ammonium bromide obtained in the S2 to obtain a finished product of the tiager ammonium bromide.
2. The process for preparing the anticholinergic drug thiager ammonium bromide according to claim 1, wherein the transesterification reaction is specifically as follows: dissolving the starting material in a solvent, and adding solid alkali in batches in the dissolving process to the reaction liquid to complete the reaction;
the solvent is any one of benzene, toluene, xylene and N, N-dimethylformamide;
the solid alkali is any one of cesium carbonate, sodium carbonate, potassium carbonate and lithium carbonate;
the equivalent ratio of the R-1-methyl-3-hydroxypyrrolidine to the 2, 2-dithienylmethyl glycolate is 0.8-1.2: 1;
the reaction time is 1-8h, and the reaction temperature is 50-150 ℃.
3. The process of claim 2, wherein the transesterification reaction is completed, and the process further comprises a recrystallization step, wherein the crude intermediate obtained from S1 is dissolved in an ether solvent, wherein the ether solvent is any one of diethyl ether, isopropyl ether and methyl tert-butyl ether.
4. The process for preparing the anticholinergic drug thiager ammonium bromide according to claim 1, wherein the bromomethylation reaction process is as follows: dissolving the intermediate in a solvent, introducing sufficient methyl bromide gas into the reaction solution at low temperature, and continuously stirring at room temperature after the reaction is finished to separate out a crude product of the Tiger ammonium bromide;
the solvent is acetone, dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, N-dimethylformamide, methanol, ethanol and isopropanol; the reaction temperature is-20-20 ℃.
5. The process for preparing the anticholinergic drug thiaglium bromide of claim 1, wherein the refining process is as follows: dissolving the crude product of the tiager ammonium bromide in a refined solvent, adding activated carbon into the mixed solution for decolorization, and completing the subsequent crystallization process to obtain a finished product of the tiager ammonium bromide;
the refined solvent is one or the combination of two of methanol, ethanol, isopropanol, 95% ethanol, acetonitrile, tetrahydrofuran, acetone and dichloromethane;
the mass ratio of the active carbon to the crude product of the Tiger ammonium bromide is 0.05-0.3: 1.
6. The process for the preparation of the anticholinergic agent thiageminium bromide according to any one of claims 1-5, wherein said thiageminium bromide is a white crystal or solid and has a purity of not less than 98%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210417844.0A CN114890997A (en) | 2022-04-20 | 2022-04-20 | Preparation process of anticholinergic drug tiaogelium bromide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210417844.0A CN114890997A (en) | 2022-04-20 | 2022-04-20 | Preparation process of anticholinergic drug tiaogelium bromide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114890997A true CN114890997A (en) | 2022-08-12 |
Family
ID=82717721
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210417844.0A Pending CN114890997A (en) | 2022-04-20 | 2022-04-20 | Preparation process of anticholinergic drug tiaogelium bromide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114890997A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115487180A (en) * | 2022-09-01 | 2022-12-20 | 江苏联环药业股份有限公司 | A pharmaceutical composition for the treatment of allergic rhinitis |
Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080051582A1 (en) * | 2006-07-10 | 2008-02-28 | Sicor Inc. | Process for the preparation of tiotropium bromide |
| CN101863885A (en) * | 2010-06-03 | 2010-10-20 | 南京金丹呈医药技术有限公司 | Method for preparing tiotropium bromide |
| US20130030182A1 (en) * | 2010-04-01 | 2013-01-31 | Mahmut Bilgic | Methods for the synthesis of tiotropium bromide |
| CN103012231A (en) * | 2012-12-14 | 2013-04-03 | 沈阳药科大学 | Preparation method and application of glycopyrronium bromide chiral antipode |
| WO2013046138A1 (en) * | 2011-09-27 | 2013-04-04 | Lusochimica S.P.A. | Process for the preparation of scopine esters |
| CN103819384A (en) * | 2013-12-05 | 2014-05-28 | 广东嘉博制药有限公司 | Preparation method of glycopyrronium bromide |
| CN103965178A (en) * | 2013-02-06 | 2014-08-06 | 中国药科大学 | Pyridinium derivative used as M3 muscarinic receptor antagonist and application of pyridinium derivative to pharmacy |
| CN104098560A (en) * | 2013-04-08 | 2014-10-15 | 百福微生物有限公司 | Crystalline form of tiotropium bromide |
| CN104144928A (en) * | 2012-02-10 | 2014-11-12 | 好利安国际有限公司 | Process for preparing tiotropium bromide |
| CN107879962A (en) * | 2017-12-22 | 2018-04-06 | 安徽德信佳生物医药有限公司 | A kind of preparation method of glycopyrronium bromide |
| US20180105517A1 (en) * | 2015-03-30 | 2018-04-19 | Hovione Scientia Limited | Process for the Preparation of Aclidinium Bromide |
| CN108586450A (en) * | 2017-12-15 | 2018-09-28 | 上海方予健康医药科技有限公司 | A kind of recrystallization purifying method of choline m receptor anticaking agent |
| CN113234003A (en) * | 2021-04-23 | 2021-08-10 | 广东嘉博制药有限公司 | Glycopyrronium bromide and preparation method thereof |
-
2022
- 2022-04-20 CN CN202210417844.0A patent/CN114890997A/en active Pending
Patent Citations (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080051582A1 (en) * | 2006-07-10 | 2008-02-28 | Sicor Inc. | Process for the preparation of tiotropium bromide |
| US20130030182A1 (en) * | 2010-04-01 | 2013-01-31 | Mahmut Bilgic | Methods for the synthesis of tiotropium bromide |
| CN101863885A (en) * | 2010-06-03 | 2010-10-20 | 南京金丹呈医药技术有限公司 | Method for preparing tiotropium bromide |
| WO2013046138A1 (en) * | 2011-09-27 | 2013-04-04 | Lusochimica S.P.A. | Process for the preparation of scopine esters |
| CN104144928A (en) * | 2012-02-10 | 2014-11-12 | 好利安国际有限公司 | Process for preparing tiotropium bromide |
| CN103012231A (en) * | 2012-12-14 | 2013-04-03 | 沈阳药科大学 | Preparation method and application of glycopyrronium bromide chiral antipode |
| CN103965178A (en) * | 2013-02-06 | 2014-08-06 | 中国药科大学 | Pyridinium derivative used as M3 muscarinic receptor antagonist and application of pyridinium derivative to pharmacy |
| CN103965179A (en) * | 2013-02-06 | 2014-08-06 | 中国药科大学 | Polymorphic substance of pyridinium derivative used as M3 muscarinic receptor antagonist as well as preparation method and medicine composition of polymorphic substance |
| CN104098560A (en) * | 2013-04-08 | 2014-10-15 | 百福微生物有限公司 | Crystalline form of tiotropium bromide |
| CN103819384A (en) * | 2013-12-05 | 2014-05-28 | 广东嘉博制药有限公司 | Preparation method of glycopyrronium bromide |
| US20180105517A1 (en) * | 2015-03-30 | 2018-04-19 | Hovione Scientia Limited | Process for the Preparation of Aclidinium Bromide |
| CN108586450A (en) * | 2017-12-15 | 2018-09-28 | 上海方予健康医药科技有限公司 | A kind of recrystallization purifying method of choline m receptor anticaking agent |
| CN107879962A (en) * | 2017-12-22 | 2018-04-06 | 安徽德信佳生物医药有限公司 | A kind of preparation method of glycopyrronium bromide |
| CN113234003A (en) * | 2021-04-23 | 2021-08-10 | 广东嘉博制药有限公司 | Glycopyrronium bromide and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| ZUOJUAN XIANG ET AL.: ""Discovery of Novel Potent Muscarinic M3 Receptor Antagonists with Proper Plasma Stability by Structural Recombination of Marketed M3 Antagonists"", 《CHEMMEDCHEM》, vol. 12, pages 1173 - 1182, XP072420353, DOI: 10.1002/cmdc.201700189 * |
| 王钝;侯利珂;吴丽容;于鑫;: "格隆溴铵合成方法的改进", 《沈阳药科大学学报》, vol. 29, no. 2, pages 113 - 115 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115487180A (en) * | 2022-09-01 | 2022-12-20 | 江苏联环药业股份有限公司 | A pharmaceutical composition for the treatment of allergic rhinitis |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0253711B1 (en) | 1H,3H-pyrrolo[1,2-c]thiazole derivatives, their preparation and pharmaceutical compositions containing them | |
| WO2014028343A1 (en) | Solid forms of an antiviral compound | |
| BR112016010788B1 (en) | PROCESS FOR THE LARGE-SCALE PRODUCTION OF 1-[(2-BROMOPHENYL)SULFONYL]-5-METHOXY-3-[(4-METHYL-1-PIPERAZINYL)METHYL]-1H-INDOLE | |
| WO1998024788A1 (en) | Tropane derivatives and method for their synthesis | |
| CN102702067A (en) | Novel intermediate for synthesizing silodosin as well as preparation method and purpose of novel intermediate | |
| JP2024503753A (en) | Urolithin derivatives and their usage | |
| KR101545068B1 (en) | Polymorphs of cddo ethyl ester and uses thereof | |
| CN114890997A (en) | Preparation process of anticholinergic drug tiaogelium bromide | |
| SK165795A3 (en) | 3-phenylizoquinoline-1(2h)-one derivatives, preparation method and pharmaceutical compounds containing these derivatives | |
| CN106905319B (en) | Preparation method of substituted benzenesulfonyl kuhseng butane or hydrochloride thereof | |
| RU2695524C2 (en) | 3,4-dihydro-2h-isoquinoline-1-one and 2,3-dihydro-isoindol-1-one derivatives useful as aldosterone synthase inhibitor | |
| EP0343050A1 (en) | 6-Phenyl-3-piperazinylalkyl 1H,3H-pyrimidinedione-2,4 derivatives, their preparation and their use in therapy | |
| EP0564650B1 (en) | Quinoline derivative | |
| CN108947989B (en) | Deuterated optical isomer and medical application thereof | |
| JPS60197687A (en) | Indolophenantridines | |
| SK317290A3 (en) | Thienopyrane derivatives, method of their production and their use | |
| US20080299215A1 (en) | Deuterium-enriched lestaurtinib | |
| JPH0559117B2 (en) | ||
| IE883136L (en) | Ó(2)-adreno receptor antagonists | |
| CN116621828A (en) | Crystal forms of oxazolidinone derivative, preparation method and application thereof | |
| US5962486A (en) | Indole derivatives as prodrugs of 5-HT1 -like receptor agonists | |
| US20080312318A1 (en) | Deuterium-enriched escitalopram | |
| CN115572294B (en) | Deuterated aza-indole dipyrazole compound, pharmaceutical composition and application | |
| WO2022057826A1 (en) | Crystal form of pyrazol [3,4-c] pyridine compound, and preparation method therefor and use thereof | |
| EP0120832B1 (en) | 4-alkylindolonaphthyridines and pharmaceutical compositions containing them |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |