CN113861030A - Glycopyrronium bromide intermediate and preparation method and application thereof - Google Patents
Glycopyrronium bromide intermediate and preparation method and application thereof Download PDFInfo
- Publication number
- CN113861030A CN113861030A CN202010612143.3A CN202010612143A CN113861030A CN 113861030 A CN113861030 A CN 113861030A CN 202010612143 A CN202010612143 A CN 202010612143A CN 113861030 A CN113861030 A CN 113861030A
- Authority
- CN
- China
- Prior art keywords
- glycopyrronium bromide
- compound
- preparation
- reaction
- base catalyst
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/03—Preparation of carboxylic acid esters by reacting an ester group with a hydroxy group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
Abstract
The invention provides a glycopyrronium bromide intermediate, a preparation method and application thereof, and relates to the technical field of chemical synthesis. The preparation method of the glycopyrronium bromide intermediate comprises the following steps: taking alpha-cyclopentyl methyl mandelate as a raw material, and carrying out ester exchange reaction with 1, 4-dibromo-2-butanol under the action of a first base catalyst to obtain a glycopyrronium bromide intermediate, namely a compound 2. The preparation method of glycopyrronium bromide comprises the following steps: and carrying out quaternization reaction on the compound 2 and dimethylamine under the action of a second base catalyst to obtain the glycopyrronium bromide. The method has the advantages of cheap and easily-obtained raw materials, avoidance of the use of a toxic gas, namely methyl bromide, which is commonly used in the prior art, small environmental pollution, environmental friendliness, mild reaction conditions, easiness in operation and control of the reaction process, avoidance of the use of metallic sodium, safety in operation, high safety coefficient, great reduction of reaction steps, production cost saving, high yield and high purity of the obtained product, and provision of a process route capable of industrially producing the product with higher quality.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a glycopyrronium bromide intermediate and a preparation method and application thereof.
Background
Glycopyrronium Bromide (Glyco), the chemical name of which is 3-hydroxy-1, 1-dimethylpyrrolidine-alpha-cyclopentyl mandelate Bromide, is a quaternary ammonium muscarinic receptor antagonist, has the effects of inhibiting gastric secretion and regulating gastrointestinal peristalsis, is an early preparation for treating gastric and duodenal ulcer, chronic gastritis, hyperacidity and the like, and is available in the forms of tablets, injections, oral liquids and the like. Later research shows that glycopyrronium bromide is opposite to choline M3The receptor has high selectivity. Nowa Switzerland company GlogongAmmonium bromide was developed as an inhalation powder aerosol, which was introduced to the market in 2012 and used for long-term relief of symptoms of adult Chronic Obstructive Pulmonary Disease (COPD). The epidemiological survey result of chronic obstructive pulmonary disease in China released in 2018 shows that the prevalence rate of chronic obstructive pulmonary disease accounts for 13.7% of people over 40 years old.
In recent years, the clinical demand for glycopyrronium bromide in China has become increasingly prominent. Therefore, the development of a process synthetic route of glycopyrronium bromide with high reaction yield, mild reaction conditions, less environmental pollution and higher industrial production quality is very important.
The synthesis methods of glycopyrronium bromide reported in the literature at present mainly comprise the following methods:
1. US2009005577 uses alpha-cyclopentyl mandelic acid as initial material, and makes it produce esterification reaction with methanol, then uses metal sodium or sodium hydride as alkali in n-heptane solvent, and makes it implement ester exchange with 1-methyl-3-pyrrolidinol, and the product is purified, then makes it implement quaterisation with methyl bromide in ethyl acetate so as to obtain glycopyrronium bromide crude product, then makes it undergo the process of recrystallization with mixed solvent of butanone and ethyl acetate so as to obtain the invented product. The method uses sodium metal, is flammable and explosive, cannot ensure safe production, and simultaneously, the intermediate of the method is easy to generate reversible reaction, thereby causing exogenous mental diseases. The purification has high operation requirement, high safety risk and low yield, and is not beneficial to industrialization.
2. Styrene is used as an initial raw material, oxidized by potassium permanganate, esterified with methanol under the catalysis of sulfuric acid, substituted by cyclopentadiene and methyl magnesium bromide Grignard reagent, reduced by hydrogen under the catalysis of active nickel, subjected to ester exchange by 1-methyl-3-pyrrolidinol under the catalysis of sodium, and finally subjected to quaternization with methyl bromide to prepare a crude product of glycopyrronium bromide. The process is an early production process and has the defects of more reaction steps, low yield and the like. Meanwhile, the potential safety hazard brought by using metal nickel for hydrogenation reduction and using metal sodium as a strong base reagent for ester exchange exists, and the method is not suitable for industrial production. (1974 of the pharmaceutical industry of the literature, No. 3P 8-10 and handbooks for organic Synthesis P810-812)
3. Chinese patent CN 102627595A uses cyclopentyl mandelic acid as raw material, reacts with 4-chloro-2, 6-dimethoxy triazine in toluene, adds 1-methyl-3-pyrrolidinol dropwise for ester exchange, adds organic solution of methyl bromide dropwise to obtain crude product, and enriches to obtain pure glycopyrronium bromide. The synthesis process uses toxic gas methyl bromide and 4-chloro-2, 6-dimethoxytriazine which is possibly carcinogenic, has potential safety hazard, and the 4-chloro-2, 6-dimethoxytriazine is not easy to obtain.
4. Chinese patent CN 103819384a uses alpha-cyclopentyl methyl mandelate as a starting material, and performs esterification reaction with 1-methyl-3-pyrrolidinol in the presence of CDI condensing agent to obtain an intermediate product, after purification, performs quaternization reaction with methyl bromide in toluene solvent to obtain a crude product of glycopyrronium bromide, and then performs recrystallization with an organic solvent to obtain a refined product of glycopyrronium bromide. Although the method has short steps, the yield of the intermediate is low, the cost of using reaction reagents such as CDI and the like is high, impurities are easily introduced in the post-treatment, and the method is not beneficial to industrial production.
5. The preparation of glycopyrronium bromide is disclosed in international patent application WO2018154597a1 by two routes. Respectively taking a compound 1 and a compound 2 as raw materials, reacting with 1-methyl-3-pyrrolidinol, reacting the generated product with a cyclopentyl format reagent or a phenyl format reagent in diethyl ether to obtain an intermediate, and then continuously carrying out quaternization reaction with methyl bromide to obtain glycopyrronium bromide. The method uses a Grignard reagent, requires low-temperature reaction, and is complicated to operate. And the reaction in ether has certain danger, which is not beneficial to industrial production.
Y is selected from H, OH, OMe, Cl
In the five routes, the final step is to perform quaternization reaction on the intermediate and the toxic gas methyl bromide to obtain a final product. Methyl bromide is a low boiling point solvent and is a substance which is easy to consume the ozone layer. And methyl bromide belongs to class 3 carcinogens. In addition, the synthesis route of the routes is long, and the yield is low; some of the products need to use metal sodium, so the safety is poor; some reagents are few in commercial manufacturers, and raw materials are not easy to obtain; some reaction reagents are expensive, easy to introduce impurities and lack of economy.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The main object of the present invention is to provide a glycopyrronium bromide intermediate, a process for its preparation and its use, which are intended to at least partially solve at least one of the above mentioned technical problems.
As a first aspect of the present invention, the present invention provides a glycopyrronium bromide intermediate, compound 2, having the following structure:
the intermediate of glycopyrronium bromide, namely the compound 2, provided by the invention provides a new intermediate for effectively preparing glycopyrronium bromide, so that the reaction steps for preparing glycopyrronium bromide are greatly reduced, the production cost is saved, the obtained product has high yield and high purity, the quality is easy to control, and the preparation of glycopyrronium bromide is facilitated.
As a second aspect of the present invention, the present invention also provides a process for the preparation of the above glycopyrronium bromide intermediate, comprising the steps of:
(a) reacting the compound 1 with 1, 4-dibromo-2-butanol under the action of a first base catalyst to obtain a compound 2, wherein the reaction formula is as follows:
the preparation method of the glycopyrronium bromide intermediate provided by the invention takes alpha-cyclopentyl methyl mandelate as a raw material to perform ester exchange reaction with 1, 4-dibromo-2-butanol under the action of a first base catalyst to obtain a new glycopyrronium bromide intermediate, namely a compound 2. Provides a new idea for effectively preparing the glycopyrronium bromide, greatly reduces the reaction steps for preparing the glycopyrronium bromide, saves the production cost, has high yield and purity of the obtained product, is easy to control the quality, and is beneficial to the preparation of the glycopyrronium bromide.
Further, the method comprises the following steps:
(a) adding the compound 1, 4-dibromo-2-butanol and a first base catalyst into a first solvent, and reacting at 70-100 ℃ to obtain a compound 2.
In the present invention, typical but non-limiting temperatures of the reaction in the step (a) may be, for example, 70 ℃, 72 ℃, 74 ℃, 76 ℃, 78 ℃, 80 ℃, 82 ℃, 84 ℃, 86 ℃, 88 ℃, 90 ℃, 92 ℃, 94 ℃, 96 ℃ or 100 ℃.
Further, in the step (a), the first base catalyst is selected from an organic base or an inorganic base.
Further, in the step (a), the organic base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide.
Further, in the step (a), the inorganic base is selected from sodium hydroxide or potassium hydroxide.
Further, in the step (a), the first solvent is selected from one or a combination of several of n-heptane, n-hexane, isopropanol or butanone.
Further, in the step (a), the molar ratio of the first base catalyst, 1, 4-dibromo-2-butanol to the compound 1 is (0.1 to 0.2): (1.0-2.0): 1.
in the present invention, in said step (a), a typical but non-limiting molar ratio of the first base catalyst, 1, 4-dibromo-2-butanol, to the compound 1 may be, for example, 0.1: 1.0: 1. 0.1: 1.2: 1. 0.1: 1.4: 1. 0.1: 1.6: 1. 0.1: 1.8: 1. 0.1: 2.0: 1. 0.13: 1.0: 1. 0.13: 1.2: 1. 0.13: 1.4: 1. 0.13: 1.6: 1. 0.13: 1.8: 1. 0.13: 2.0: 1. 0.15: 1.0: 1. 0.15: 1.2: 1. 0.15: 1.4: 1. 0.15: 1.6: 1. 0.15: 1.8: 1. 0.15: 2.0: 1. 0.18: 1.0: 1. 0.18: 1.2: 1. 0.18: 1.4: 1. 0.18: 1.6: 1. 0.18: 1.8: 1. 0.18: 2.0: 1. 0.2: 1.0: 1. 0.2: 1.2: 1. 0.2: 1.4: 1. 0.2: 1.6: 1. 0.2: 1.8: 1 or 0.2: 2.0: 1.
further, in the step (a), the reaction temperature is 80-100 ℃.
As a third aspect of the invention, the invention also provides the application of the glycopyrronium bromide intermediate or the glycopyrronium bromide intermediate prepared by the preparation method in the preparation of glycopyrronium bromide.
Further, the preparation method of the glycopyrronium bromide comprises the following steps:
(b) reacting the compound 2 with dimethylamine under the action of a second base catalyst to obtain glycopyrronium bromide; the reaction formula is as follows:
according to the preparation method of glycopyrronium bromide, the compound 2 and dimethylamine are subjected to quaternization reaction under the action of a second base catalyst to obtain the glycopyrronium bromide. The method has the advantages of cheap and easily-obtained raw materials, avoidance of the use of a toxic gas, namely methyl bromide, which is commonly used in the prior art, small environmental pollution, environmental friendliness, mild reaction conditions, easiness in operation and control of the reaction process, avoidance of the use of metallic sodium, safety in operation, high safety coefficient, great reduction of reaction steps, production cost saving, high yield and high purity of the obtained product, and provision of a process route capable of industrially producing the product with higher quality.
Further, the preparation method of glycopyrronium bromide comprises the following steps:
(b) and adding the compound 2, dimethylamine and a second base catalyst into a second solvent, and reacting at 65-100 ℃ to obtain glycopyrronium bromide.
In the present invention, a typical but non-limiting temperature of the reaction in the step (b) may be, for example, 65 ℃, 67 ℃, 69 ℃, 70 ℃, 72 ℃, 74 ℃, 76 ℃, 78 ℃, 80 ℃, 82 ℃, 84 ℃, 86 ℃, 88 ℃, 90 ℃, 92 ℃, 94 ℃, 96 ℃ or 100 ℃.
Further, in the step (b), the second alkali reagent is selected from an organic alkali or an inorganic alkali.
Further, in the step (b), the inorganic base is selected from potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.
Further, in the step (b), the organic base is selected from diisopropylethylamine, 4-dimethylaminopyridine or triethylamine.
Further, in the step (b), the second solvent is selected from a C1-C3 alcohol solvent or N-methyl pyrrolidone.
Further, in the step (b), the alcohol solvent of C1-C3 is selected from methanol, ethanol or isopropanol.
Further, in the step (b), the molar ratio of the second base catalyst, dimethylamine and compound 2 is (1.0-2.0): (1.0-2.0): 1.
in the present invention, in the step (b), a typical but non-limiting molar ratio of the second base catalyst, dimethylamine, to compound 2, for example, can be 1.0: 1.0: 1. 1.0: 1.2: 1. 1.0: 1.4: 1. 1.0: 1.6: 1. 1.0: 1.8: 1. 1.0: 2.0: 1. 1.2: 1.0: 1. 1.2: 1.2: 1. 1.2: 1.4: 1. 1.2: 1.6: 1. 1.2: 1.8: 1. 1.2: 2.0: 1. 1.4: 1.0: 1. 1.4: 1.2: 1. 1.4: 1.4: 1. 1.4: 1.6: 1. 1.4: 1.8: 1. 1.4: 2.0: 1. 1.6: 1.0: 1. 1.6: 1.2: 1. 1.6: 1.4: 1. 1.6: 1.6: 1. 1.6: 1.8: 1. 1.6: 2.0: 1. 1.8: 1.0: 1. 1.8: 1.2: 1. 1.8: 1.4: 1. 1.8: 1.6: 1. 1.8: 1.8: 1. 1.8: 2.0: 1. 2.0: 1.0: 1. 2.0: 1.2: 1. 2.0: 1.4: 1. 2.0: 1.6: 1. 2.0: 1.8: 1 or 2.0: 2.0: 1.
further, in the step (b), the reaction temperature is 65-80 ℃.
Compared with the prior art, the invention has the following beneficial effects:
the intermediate of glycopyrronium bromide, namely the compound 2, provided by the invention provides a new intermediate for effectively preparing glycopyrronium bromide, so that the reaction steps for preparing glycopyrronium bromide are greatly reduced, the production cost is saved, the obtained product has high yield and purity, the quality is easy to control, and the preparation of glycopyrronium bromide is facilitated.
The preparation method of the glycopyrronium bromide intermediate provided by the invention takes alpha-cyclopentyl methyl mandelate as a raw material to perform ester exchange reaction with 1, 4-dibromo-2-butanol under the action of a first base catalyst to obtain a new glycopyrronium bromide intermediate, namely a compound 2. Provides a new idea for effectively preparing the glycopyrronium bromide, greatly reduces the reaction steps for preparing the glycopyrronium bromide, saves the production cost, has high yield and purity of the obtained product, is easy to control the quality, and is beneficial to the preparation of the glycopyrronium bromide.
According to the preparation method of glycopyrronium bromide, the compound 2 and dimethylamine are subjected to quaternization reaction under the action of a second base catalyst to obtain the glycopyrronium bromide. The method has the advantages of cheap and easily-obtained raw materials, avoidance of the use of a toxic gas, namely methyl bromide, which is commonly used in the prior art, small environmental pollution, environmental friendliness, mild reaction conditions, easiness in operation and control of the reaction process, avoidance of the use of metallic sodium, safety in operation, high safety coefficient, great reduction of reaction steps, production cost saving, high yield and high purity of the obtained product, and provision of a process route capable of industrially producing the product with higher quality.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples were carried out under the conventional conditions, unless otherwise specified. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
In order to facilitate a clearer understanding of the present invention, the following will further describe the technical solutions of the present invention with reference to examples.
EXAMPLE 1 preparation of Compound 2
Examples 1 to 1
Under the protection of nitrogen, 115g of compound, 11.3mL of 1, 4-dibromo-2-butanol and 0.5g of sodium methoxide were added to 150mL of n-heptane, and the mixture was stirred and warmed to 100 ℃ and monitored by TLC until no compound 1 was present. And after the reaction is finished, cooling to room temperature, cooling to below 10 ℃, dropwise adding 10mL of 3mol/L hydrochloric acid, adding n-heptane to separate an aqueous phase, adjusting the pH of the aqueous phase to 8-9 by using 10% sodium carbonate aqueous solution, extracting twice by using n-heptane, combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to constant weight to obtain 223.6g of an oily liquid compound, wherein the yield is 85.2%, and the HPLC purity is 98.3%.
Examples 1 to 2
Under the protection of nitrogen, 115g of compound, 7.5mL of 1, 4-dibromo-2-butanol and 0.4g of sodium ethoxide were added to 150mL of n-hexane, the temperature was raised to 70 ℃ with stirring, and TLC was performed until no compound 1 was detected. And after the reaction is finished, cooling to room temperature, cooling to below 10 ℃, dropwise adding 10mL of 3mol/L hydrochloric acid, adding n-heptane to separate an aqueous phase, adjusting the pH of the aqueous phase to 8-9 by using 10% sodium hydroxide aqueous solution, extracting twice by using n-heptane, combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to constant weight to obtain 220.6g of an oily liquid compound, wherein the yield is 74.4%, and the HPLC purity is 97.6%.
Examples 1 to 3
Under the protection of nitrogen, 115g of compound, 9.0mL of 1, 4-dibromo-2-butanol and 0.3g of sodium hydroxide were added to 150mL of butanone, the mixture was stirred and heated to 80 ℃, and TLC was used to detect the absence of compound 1. And after the reaction is finished, cooling to room temperature, cooling to below 10 ℃, dropwise adding 10mL of 3mol/L hydrochloric acid, adding n-heptane to separate an aqueous phase, adjusting the pH of the aqueous phase to 8-9 by using 10% potassium carbonate aqueous solution, extracting twice by using n-heptane, combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to constant weight to obtain 221.7g of an oily liquid compound, wherein the yield is 78.3% and the HPLC purity is 97.5%.
Examples 1 to 4
Under the protection of nitrogen, 115g of compound, 15mL of 1, 4-dibromo-2-butanol and 0.7g of potassium hydroxide were added to 150mL of isopropanol, the mixture was stirred and heated to 85 ℃, and TLC was performed until no compound 1 was present. And after the reaction is finished, cooling to room temperature, cooling to below 10 ℃, dropwise adding 10mL of 3mol/L hydrochloric acid, adding n-heptane to separate an aqueous phase, adjusting the pH of the aqueous phase to 8-9 by using 10% potassium hydroxide aqueous solution, extracting twice by using n-heptane, combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to constant weight to obtain 222.1g of an oily liquid compound, wherein the yield is 79.8%, and the HPLC purity is 97.9%.
Examples 1 to 5
Under the protection of nitrogen, 115g of compound, 12mL of 1, 4-dibromo-2-butanol and 1g of sodium tert-butoxide are added to 150mL of isopropanol, stirred and heated to 85 ℃, and TLC is used for monitoring until no compound 1 exists. And after the reaction is finished, cooling to room temperature, cooling to below 10 ℃, dropwise adding 10mL of 3mol/L hydrochloric acid, adding n-heptane to separate an aqueous phase, adjusting the pH of the aqueous phase to 8-9 by using 10% potassium hydroxide aqueous solution, extracting twice by using n-heptane, combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to constant weight to obtain 222.0g of an oily liquid compound, wherein the yield is 79.6%, and the HPLC purity is 97.5%.
Examples 1 to 6
Under the protection of nitrogen, 115g of compound, 13.5mL of 1, 4-dibromo-2-butanol and 1.3g of potassium tert-butoxide were added to 150mL of isopropanol, and the mixture was stirred to raise the temperature to 85 ℃ and monitored by TLC until no compound 1 was present. And after the reaction is finished, cooling to room temperature, cooling to below 10 ℃, dropwise adding 10mL of 3mol/L hydrochloric acid, adding n-heptane to separate an aqueous phase, adjusting the pH of the aqueous phase to 8-9 by using 10% potassium hydroxide aqueous solution, extracting twice by using n-heptane, combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to constant weight to obtain 221.3g of an oily liquid compound, wherein the yield is 77.0%, and the HPLC purity is 97.8%.
Examples 1 to 7
This example differs from example 1-1 in that the reaction temperature in this example was 80 ℃ and the conditions were otherwise the same, giving 223.2g of the compound as an oily liquid in 84.0% yield and 98.1% HPLC purity.
Examples 1 to 8
This example differs from example 1-1 in that the reaction temperature in this example was 90 ℃ and the conditions were otherwise the same, giving 223.4g of the compound as an oily liquid in 84.5% yield and 98.2% HPLC purity.
Examples 1 to 9
This example differs from example 1-1 in that the reaction temperature was 70 ℃ and the conditions were the same, resulting in 220.8g of the oily liquid compound, 75.1% yield and 97.3% HPLC purity.
EXAMPLE 2 preparation of glycopyrronium bromide
Example 2-1
Example 2-1
Mixing 210g of compound with K2CO34.3g was added to 50mL of methanol, the temperature was raised to 65 ℃ with stirring, then 10mL of a methanol solution containing 1.0g of dimethylamine was slowly added dropwise, and TLC was monitored as the absence of Compound 2. After the reaction, the reaction solution was filtered to remove the residual inorganic salts, and the supernatant was poured into an excess amount of ether to precipitate 6.9g of glycopyrronium bromide as a white solid with a yield of 75.0% and a HPLC purity of 98.1%.
Examples 2 to 2
Mixing 210g of compound with Na2CO33.7g was added to 50mL of ethanol, the temperature was raised to 80 ℃ with stirring, and then 13mL of an ethanol solution containing 1.3g of dimethylamine was slowly added dropwise, and TLC was monitored until no Compound 2 was present. After the reaction, the reaction solution was filtered to remove the residual inorganic salts, and the supernatant was poured into an excess of diethyl ether to precipitate 7.0g of glycopyrronium bromide as a white solid, with a yield of 76.1% and a HPLC purity of 98.1%.
Examples 2 to 3
210g of compound and 4.6mL of diisopropylethylamine were added to 50mL of N-methylpyrrolidone, the mixture was stirred and warmed to 100 ℃, and then 14mL of N-methylpyrrolidone solution containing 1.4g of dimethylamine was slowly added dropwise, and TLC was carried out until no compound 2 was present. After the reaction, the reaction solution was filtered to remove the residual inorganic salts, and the supernatant was poured into an excess of diethyl ether to precipitate 6.2g of glycopyrronium bromide as a white solid, with a yield of 67.4% and a HPLC purity of 97.8%.
Examples 2 to 4
Compound 210g and 4-dimethylaminopyridine 2.8g were added to 50mL of isopropanol, stirred to 85 ℃ and then 17mL of an ethanol solution containing 1.7g dimethylamine was added dropwise slowly, monitored by TLC as the absence of Compound 2. After the reaction, the reaction solution was filtered to remove the residual inorganic salts, and the supernatant was poured into excess ether to precipitate 6.5g of glycopyrronium bromide as a white solid with a yield of 70.7% and a HPLC purity of 97.9%.
Examples 2 to 5
Compound 210g and sodium bicarbonate 3.9g were added to 50mL isopropanol, stirred to 85 ℃, then 19mL isopropanol solution containing 1.9g dimethylamine was slowly added dropwise, monitored by TLC to be free of compound 2. After the reaction, the reaction solution was filtered to remove the residual inorganic salts, and the supernatant was poured into an excess of diethyl ether to precipitate 6.3g of glycopyrronium bromide as a white solid with a yield of 68.5% and a HPLC purity of 98.1%.
Examples 2 to 6
210g of compound (2) and 1.7g of sodium hydroxide were added to 50mL of methanol, the mixture was stirred and warmed to 65 ℃, then 21mL of a methanol solution containing 2.1g of dimethylamine was slowly added dropwise, and TLC was used to detect the absence of compound (2). After the reaction, the reaction solution was filtered to remove the residual inorganic salts, and the supernatant was poured into an excess of ether to precipitate 6.8g of glycopyrronium bromide as a white solid, with a yield of 73.9% and an HPLC purity of 98.2%.
Examples 2 to 7
210g of compound (2) and 2.8g of triethylamine are added to 50mL of methanol, the mixture is stirred and heated to 65 ℃, then 21mL of a methanol solution containing 2.1g of dimethylamine is slowly added dropwise, and TLC monitors that no compound (2) exists. After the reaction, the reaction solution was filtered to remove the residual inorganic salts, and the supernatant was poured into excess ether to precipitate 6.6g of glycopyrronium bromide as a white solid with a yield of 71.7% and a HPLC purity of 97.5%.
Examples 2 to 8
This example differs from example 2-3 in that the reaction temperature in this example was 65 ℃ and the conditions were otherwise the same, and 6.8g of glycopyrronium bromide was precipitated as a white solid in 73.9% yield and 98.2% HPLC purity.
Examples 2 to 9
This example differs from examples 2-3 in that in this example, the reaction temperature was 80 ℃ and the conditions were otherwise the same, and 6.9g of glycopyrronium bromide was precipitated as a white solid in a yield of 75.0% and a HPLC purity of 98.3%.
Examples 2 to 10
This example differs from examples 2-3 in that in this example, the reaction temperature was 90 ℃ and the conditions were otherwise the same, and 6.3g of glycopyrronium bromide was precipitated as a white solid in 68.5% yield and 98.1% HPLC purity.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. A glycopyrronium bromide intermediate, characterized in that compound 2 has the following structure:
2. a process for preparing the glycopyrronium bromide intermediate of claim 1, comprising the steps of:
(a) reacting the compound 1 with 1, 4-dibromo-2-butanol under the action of a first base catalyst to obtain a compound 2, wherein the reaction formula is as follows:
3. the process for the preparation of glycopyrronium bromide intermediates as claimed in claim 2, characterized in that it comprises the following steps:
(a) adding the compound 1, 4-dibromo-2-butanol and a first base catalyst into a first solvent, and reacting at 70-100 ℃ to obtain a compound 2.
4. A process for the preparation of a glycopyrronium bromide intermediate as claimed in claim 3, characterized in that in step (a) the first base catalyst is selected from the group consisting of organic or inorganic bases;
the organic base is selected from sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium tert-butoxide;
the inorganic base is selected from sodium hydroxide or potassium hydroxide;
and/or the first solvent is selected from one or a combination of several of n-heptane, n-hexane, isopropanol or butanone.
5. The process for the preparation of glycopyrronium bromide intermediate as claimed in any one of claims 2 to 4, characterized in that in step (a) the molar ratio of the first base catalyst, 1, 4-dibromo-2-butanol to compound 1 is (0.1 to 0.2): (1.0-2.0): 1.
6. use of a glycopyrronium bromide intermediate according to claim 1 or prepared by a method according to any one of claims 2 to 5 for the preparation of glycopyrronium bromide.
7. Use according to claim 6, characterized in that the process for the preparation of glycopyrronium bromide comprises the following steps:
(b) reacting the compound 2 with dimethylamine under the action of a second base catalyst to obtain glycopyrronium bromide; the reaction formula is as follows:
8. use according to claim 7, characterized in that the process for the preparation of glycopyrronium bromide comprises the following steps:
(b) and adding the compound 2, dimethylamine and a second base catalyst into a second solvent, and reacting at 65-100 ℃ to obtain glycopyrronium bromide.
9. Use according to claim 8, wherein in step (b) the second basic agent is selected from an organic or inorganic base;
the inorganic base is selected from potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide;
the organic base is selected from diisopropylethylamine, 4-dimethylaminopyridine or triethylamine;
and/or the second solvent is selected from C1-C3 alcohol solvents or N-methyl pyrrolidone.
10. The process for the preparation of glycopyrronium bromide as claimed in claim 9, characterized in that in step (b) the molar ratio of the second base catalyst, dimethylamine to compound 2 is (1.0-2.0): (1.0-2.0): 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010612143.3A CN113861030A (en) | 2020-06-30 | 2020-06-30 | Glycopyrronium bromide intermediate and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010612143.3A CN113861030A (en) | 2020-06-30 | 2020-06-30 | Glycopyrronium bromide intermediate and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113861030A true CN113861030A (en) | 2021-12-31 |
Family
ID=78981138
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010612143.3A Pending CN113861030A (en) | 2020-06-30 | 2020-06-30 | Glycopyrronium bromide intermediate and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113861030A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113461585A (en) * | 2021-07-12 | 2021-10-01 | 安徽普利药业有限公司 | Synthesis process of glycopyrronium bromide |
-
2020
- 2020-06-30 CN CN202010612143.3A patent/CN113861030A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113461585A (en) * | 2021-07-12 | 2021-10-01 | 安徽普利药业有限公司 | Synthesis process of glycopyrronium bromide |
| CN113461585B (en) * | 2021-07-12 | 2023-10-31 | 安徽普利药业有限公司 | Synthesis process of glycopyrronium bromide |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110950765A (en) | Preparation method of terbutaline sulfate | |
| KR20110004528A (en) | Process for preparing tricyclic derivatives | |
| CN113861030A (en) | Glycopyrronium bromide intermediate and preparation method and application thereof | |
| CN101914052A (en) | Oxiracetam compound and new method thereof | |
| CN106674084A (en) | Preparation method of 2-isopropoxy-5-methyl-4-(piperidine-4-yl) aniline dihydrochloride | |
| CN101007800A (en) | Compound for preparing nifeviroc and its preparing process | |
| JP4568398B2 (en) | Hexahydroisoindoline acid addition salt and method of use thereof | |
| CN107652226B (en) | Preparation method of N-Boc-4-piperidine formaldehyde | |
| CN102887826B (en) | Synthesis method of (-)-chicoric acid | |
| CN109824520B (en) | Preparation method of cis-4-methylcyclohexylamine | |
| WO2021020998A1 (en) | Method for producing roxadustat | |
| CN112250586A (en) | Preparation method of terbutaline sulfate and B crystal form thereof | |
| CN111620802A (en) | Preparation method of cefditoren intermediate (R) -1-benzyl-3-aminopyrrolidine | |
| CN101898998A (en) | Method for preparing tirofiban hydrochloride intermediate | |
| CN101781288B (en) | Preparation method of Pranlukast intermediate | |
| CN101550107B (en) | Method for preparing telmisartan | |
| CN101384564A (en) | Process for the preparation of 2-(4-hydroxy-3-morfolynil)-2-cyclohexenone | |
| WO2015012271A1 (en) | Method for producing heterocyclic compound | |
| CN101088999A (en) | Process of synthesizing 3-amino quinine dihydrochloride | |
| CN109232222A (en) | A kind of preparation method of (E)-octyl- 4- alkene -1,8- diacid | |
| JP3869530B2 (en) | Production method of biphenyl derivatives | |
| CN112079712B (en) | Preparation method of p-vinyl salicylic acid | |
| CN113735693B (en) | Synthesis method of resveratrol dimethyl ether | |
| CN111423319B (en) | Preparation method of loxoprofen | |
| CN104098556A (en) | Novel synthetic process for rivaroxaban |
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 |