Glycopyrrolate intermediate and its preparation method and application

Abstract

The present invention provides a glycopyrronium bromide intermediate and its preparation method and application, and relates to the technical field of chemical synthesis. The preparation method of glycopyrronium bromide intermediate comprises the following steps: using α-cyclopentylmandelic acid methyl ester as raw material, and 1,4-dibromo-2-butanol undergoes ester exchange reaction under the action of a first base catalyst to obtain a glycopyrronium bromide intermediate, i.e., compound 2. The preparation method of glycopyrronium bromide comprises the following steps: compound 2 undergoes quaternization reaction with dimethylamine under the action of a second base catalyst to obtain glycopyrronium bromide. The raw materials of the present invention are cheap and easy to obtain, and the use of toxic gas methyl bromide commonly used in the prior art is avoided, the environmental pollution is small, the green environmental protection, the reaction conditions are mild, the reaction process is easy to control, the use of metallic sodium is avoided, the operation is safe, the safety factor is high, and the reaction steps are greatly reduced, the production cost is saved, the product yield obtained is high, the purity is high, and a process route for industrial production of higher quality products is provided.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a glycopyrrolate intermediate and a preparation method and application thereof. Background Art

[0002] Glycopyrronium Bromide (Glyco), chemically known as 3-hydroxy-1,1-dimethylpyrrolidinyl-α-cyclopentylmandelate bromide, is a quaternary ammonium muscarinic receptor antagonist that inhibits gastric juice secretion and regulates gastrointestinal motility. Early preparations were used to treat gastric and duodenal ulcers, chronic gastritis, excessive gastric acid secretion, etc. The marketed dosage forms include tablets, injections, oral solutions, etc. Later studies found that glycopyrrolate is highly selective for choline M3 receptors. Novartis of Switzerland developed glycopyrrolate into an inhalation powder spray and launched it in 2012 for long-term relief of symptoms of chronic obstructive pulmonary disease (COPD) in adults. The results of the epidemiological survey on COPD in my country released in 2018 showed that the prevalence of COPD accounted for 13.7% of people over 40 years old.

[0003] In recent years, the clinical demand for glycopyrrolate has become increasingly prominent in China. Therefore, it is very important to develop a process synthesis route for glycopyrrolate with high reaction yield, mild reaction conditions, less environmental pollution and higher industrial production quality.

[0004] The synthesis methods of glycopyrrolate reported in the literature are mainly the following:

[0005] 1. U.S. Patent US2009005577 uses α-cyclopentylmandelic acid as the starting material, first reacts with methanol for esterification, then uses sodium metal or sodium hydride as a base in n-heptane solvent to transesterify with 1-methyl-3-pyrrolidinol, and the product is purified and quaternized with methyl bromide in ethyl acetate to obtain crude glycopyrrolate, which is then recrystallized from a mixed solvent of butanone and ethyl acetate to obtain the finished product. This method uses sodium metal, which is flammable and explosive, and cannot guarantee safe production. At the same time, the intermediates of this method are prone to reversible reactions, leading to exogenous mental illness. The purification operation requires high requirements, has high safety risks, and has a low yield, which is not conducive to industrialization.

[0006]

[0007] 2. Using styrene as the starting material, it is oxidized with potassium permanganate, esterified with methanol under sulfuric acid catalysis, cyclopentadiene is replaced with methylmagnesium bromide Grignard reagent, reduced with hydrogen under active nickel catalysis, 1-methyl-3-pyrrolidinol is transesterified under sodium catalysis, and finally reacted with methyl bromide to obtain crude glycopyrrolate. This process is an early production process, and has the disadvantages of many reaction steps and low yield. At the same time, there are safety hazards caused by the use of metal nickel hydrogenation reduction and the use of metal sodium as a strong base reagent for transesterification, which is not suitable for industrial production. (Literature Pharmaceutical Industry 1974 Issue 3 P 8-10 and Organic Synthesis Handbook P810-812)

[0008]

[0009] 3. Chinese patent CN 102627595A uses cyclopentylmandelic acid as a raw material, reacts with 4-chloro-2,6-dimethoxytriazine in toluene, drips 1-methyl-3-pyrrolidone for ester exchange, and then drips an organic solution of methyl bromide to obtain a crude product, which is enriched to obtain pure glycopyrrolate. This synthesis process uses toxic gas methyl bromide and 4-chloro-2,6-dimethoxytriazine, which may be carcinogenic, and there are safety hazards. In addition, the raw material of 4-chloro-2,6-dimethoxytriazine is not easy to obtain.

[0010]

[0011] 4. Chinese patent CN 103819384A, using α-cyclopentyl mandelate as the starting material, in the presence of CDI condensing agent, esterification reaction with 1-methyl-3-pyrrolidinol, to obtain an intermediate product, after purification, quaternization reaction with methyl bromide in toluene solvent, to obtain crude glycopyrrolate, and then recrystallization from an organic solvent to obtain refined glycopyrrolate. Although the method has a short step, the intermediate yield is low, and the cost of using reaction reagents such as CDI is high, and impurities are easily introduced in post-processing, which is not conducive to industrial production.

[0012]

[0013] 5. Two routes for preparing glycopyrrolate are disclosed in international patent application WO2018154597A1. Compound 1 and compound 2 are used as raw materials, respectively, and reacted with 1-methyl-3-pyrrolidinol, and the resulting product is reacted with a cyclopentyl Grignard reagent or a phenyl Grignard reagent in ether, and after obtaining an intermediate, it is further quaternized with methyl bromide to obtain glycopyrrolate. This method uses a Grignard reagent, requires low-temperature reaction, and the operation is more complicated. And the reaction in ether is dangerous and not conducive to industrial production.

[0014]

[0015] Y is selected from H, OH, OMe, Cl

[0016] The last step of the above five routes is to obtain the final product by quaternization reaction of the intermediate with the toxic gas methyl bromide. Methyl bromide is a low-boiling point solvent that easily depletes the ozone layer. And methyl bromide belongs to Class 3 carcinogens. In addition, some of the above routes have long synthetic routes and low yields; some require the use of metallic sodium, which has poor safety; some reagents have few commercial manufacturers and raw materials are not easy to obtain; some reaction reagents are expensive and easily introduce impurities, which lacks economy.

[0017] In view of this, the present invention is proposed. Summary of the invention

[0018] The main purpose of the present invention is to provide a glycopyrrolate intermediate and a preparation method and application thereof, in order to at least partially solve at least one of the above-mentioned technical problems.

[0019] As a first aspect of the present invention, the present invention provides a glycopyrrolate intermediate, that is, compound 2 has the following structure:

[0020]

[0021] The glycopyrrolate intermediate provided by the present invention, i.e., compound 2, provides a new intermediate for effectively preparing glycopyrrolate, greatly reduces the reaction steps for preparing glycopyrrolate, saves production costs, and obtains a product with high yield and high purity, and is easy to control quality, which is conducive to the preparation of glycopyrrolate.

[0022] As a second aspect of the present invention, the present invention also provides a method for preparing the above-mentioned glycopyrrolate intermediate, comprising the following steps:

[0023] (a) Compound 1 reacts with 1,4-dibromo-2-butanol in the presence of a first base catalyst to obtain compound 2, as shown in the following reaction formula:

[0024]

[0025] The preparation method of the glycopyrrolate intermediate provided by the present invention uses α-cyclopentylmandelic acid methyl ester as a raw material, and undergoes an ester exchange reaction with 1,4-dibromo-2-butanol under the action of a first base catalyst to obtain a new glycopyrrolate intermediate, namely compound 2. A new idea is provided for the effective preparation of glycopyrrolate, the reaction steps for preparing glycopyrrolate are greatly reduced, the production cost is saved, the obtained product has high yield and high purity, and the quality is easy to control, which is conducive to the preparation of glycopyrrolate.

[0026] Further, the following steps are included:

[0027] (a) Compound 1, 1,4-dibromo-2-butanol and a first base catalyst are added to a first solvent and reacted at 70-100° C. to obtain Compound 2.

[0028] In the present invention, in the step (a), the typical but non-limiting reaction temperature can be, for example, 70°C, 72°C, 74°C, 76°C, 78°C, 80°C, 82°C, 84°C, 86°C, 88°C, 90°C, 92°C, 94°C, 96°C or 100°C.

[0029] Furthermore, in step (a), the first base catalyst is selected from an organic base or an inorganic base.

[0030] Furthermore, in step (a), the organic base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide.

[0031] Furthermore, in step (a), the inorganic base is selected from sodium hydroxide or potassium hydroxide.

[0032] Furthermore, in step (a), the first solvent is selected from one or a combination of n-heptane, n-hexane, isopropanol or butanone.

[0033] Furthermore, in the step (a), the molar ratio of the first base catalyst, 1,4-dibromo-2-butanol and compound 1 is (0.1-0.2):(1.0-2.0):1.

[0034] In the present invention, in the step (a), a typical but non-limiting molar ratio of the first base catalyst, 1,4-dibromo-2-butanol and compound 1 can 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.

[0035] Furthermore, in the step (a), the reaction temperature is 80-100°C.

[0036] As a third aspect of the present invention, the present invention also provides use of the above-mentioned glycopyrrolate intermediate or the glycopyrrolate intermediate prepared by the above-mentioned preparation method in the preparation of glycopyrrolate.

[0037] Furthermore, the preparation method of glycopyrrolate comprises the following steps:

[0038] (b) Compound 2 reacts with dimethylamine in the presence of a second base catalyst to obtain glycopyrrolate; the reaction formula is as follows:

[0039]

[0040] The preparation method of glycopyrrolate provided by the present invention comprises the following steps: compound 2 and dimethylamine are subjected to a quaternization reaction under the action of a second base catalyst to obtain glycopyrrolate. The raw materials of the present invention are cheap and readily available, and the use of methyl bromide, a toxic gas commonly used in the prior art, is avoided, the environmental pollution is small, the process is green and environmentally friendly, the reaction conditions are mild, the reaction process is easy to control, the use of metallic sodium is avoided, the operation is safe, the safety factor is high, and the reaction steps are greatly reduced, the production cost is saved, the product yield obtained is high, the purity is high, and a process route for industrially producing a product with higher quality is provided.

[0041] Furthermore, the preparation method of glycopyrrolate comprises the following steps:

[0042] (b) adding compound 2, dimethylamine and a second base catalyst into a second solvent and reacting at 65-100° C. to obtain glycopyrrolate.

[0043] In the present invention, in the step (b), the typical but non-limiting temperature of the reaction can be, for example, 65°C, 67°C, 69°C, 70°C, 72°C, 74°C, 76°C, 78°C, 80°C, 82°C, 84°C, 86°C, 88°C, 90°C, 92°C, 94°C, 96°C or 100°C.

[0044] Furthermore, in the step (b), the second alkaline reagent is selected from an organic base or an inorganic base.

[0045] Furthermore, in the step (b), the inorganic base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.

[0046] Furthermore, in the step (b), the organic base is selected from diisopropylethylamine, 4-dimethylaminopyridine or triethylamine.

[0047] Furthermore, in step (b), the second solvent is selected from a C1-C3 alcohol solvent or N-methylpyrrolidone.

[0048] Furthermore, in step (b), the C1-C3 alcohol solvent is selected from methanol, ethanol or isopropanol.

[0049] Furthermore, 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.

[0050] In the present invention, in the step (b), a typical but non-limiting molar ratio of the second base catalyst, dimethylamine and compound 2 can be, for example, 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. 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.

[0051] Furthermore, in the step (b), the reaction temperature is 65-80°C.

[0052] Compared with the prior art, the present invention has the following beneficial effects:

[0053] The glycopyrrolate intermediate provided by the present invention, namely compound 2, provides a new intermediate for effectively preparing glycopyrrolate, greatly reduces the reaction steps for preparing glycopyrrolate, saves production costs, and obtains a product with high yield and high purity, and is easy to control quality, which is conducive to the preparation of glycopyrrolate.

[0054] The preparation method of the glycopyrrolate intermediate provided by the present invention uses α-cyclopentylmandelic acid methyl ester as a raw material, and undergoes an ester exchange reaction with 1,4-dibromo-2-butanol under the action of a first base catalyst to obtain a new glycopyrrolate intermediate, namely compound 2. A new idea is provided for the effective preparation of glycopyrrolate, the reaction steps for preparing glycopyrrolate are greatly reduced, the production cost is saved, the obtained product has high yield and high purity, and the quality is easy to control, which is conducive to the preparation of glycopyrrolate.

[0055] The preparation method of glycopyrrolate provided by the present invention comprises the following steps: compound 2 and dimethylamine are subjected to a quaternization reaction under the action of a second base catalyst to obtain glycopyrrolate. The raw materials of the present invention are cheap and readily available, and the use of methyl bromide, a toxic gas commonly used in the prior art, is avoided, the environmental pollution is small, the process is green and environmentally friendly, the reaction conditions are mild, the reaction process is easy to control, the use of metallic sodium is avoided, the operation is safe, the safety factor is high, and the reaction steps are greatly reduced, the production cost is saved, the product yield obtained is high, the purity is high, and a process route for industrially producing a product with higher quality is provided. DETAILED DESCRIPTION

[0056] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, conventional conditions are used. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0057] In order to help to more clearly understand the present invention, the technical solution of the present invention will be further described below in conjunction with embodiments.

[0058] Example 1 Preparation of Compound 2

[0059]

[0060] Example 1-1

[0061] Under nitrogen protection, compound 115g, 1,4-dibromo-2-butanol 11.3mL and sodium methoxide 0.5g were added to 150mL n-heptane, stirred and heated to 100°C, and TLC was monitored until there was no compound 1. After the reaction was completed, the temperature was lowered to room temperature, cooled to below 10°C, 3mol / L hydrochloric acid 10mL was added dropwise, n-heptane was added to separate the aqueous phase, the aqueous phase was adjusted to pH 8-9 with 10% sodium carbonate aqueous solution, and extracted twice with n-heptane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to constant weight to obtain 223.6g of oily liquid compound, with a yield of 85.2% and a HPLC purity of 98.3%.

[0062] Example 1-2

[0063] Under nitrogen protection, compound 115g, 1,4-dibromo-2-butanol 7.5mL and sodium ethoxide 0.4g were added to 150mL n-hexane, stirred and heated to 70°C, and TLC was monitored until compound 1 was absent. After the reaction was completed, the temperature was lowered to room temperature, cooled to below 10°C, 3mol / L hydrochloric acid 10mL was added dropwise, n-heptane was added to separate the aqueous phase, the aqueous phase was adjusted to pH 8-9 with 10% sodium hydroxide aqueous solution, extracted twice with n-heptane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to constant weight to obtain 220.6g of an oily liquid compound with a yield of 74.4% and a HPLC purity of 97.6%.

[0064] Examples 1-3

[0065] Under nitrogen protection, compound 115g, 1,4-dibromo-2-butanol 9.0mL and sodium hydroxide 0.3g were added to 150mL butanone, stirred and heated to 80°C, and TLC was monitored until compound 1 was absent. After the reaction was completed, the temperature was lowered to room temperature, cooled to below 10°C, 3mol / L hydrochloric acid 10mL was added dropwise, and n-heptane was added to separate the aqueous phase. The aqueous phase was adjusted to pH 8-9 with 10% potassium carbonate aqueous solution, extracted twice with n-heptane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to constant weight to obtain 221.7g of an oily liquid compound with a yield of 78.3% and a HPLC purity of 97.5%.

[0066] Examples 1-4

[0067] Under nitrogen protection, compound 115 g, 1,4-dibromo-2-butanol 15 mL and potassium hydroxide 0.7 g were added to 150 mL isopropanol, stirred and heated to 85 ° C, and TLC was monitored until compound 1 was absent. After the reaction was completed, the temperature was lowered to room temperature, cooled to below 10 ° C, 3 mol / L hydrochloric acid 10 mL was added dropwise, and n-heptane was added to separate the aqueous phase. The aqueous phase was adjusted to pH 8-9 with 10% potassium hydroxide aqueous solution, and extracted twice with n-heptane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to constant weight to obtain 222.1 g of oily liquid compound with a yield of 79.8% and HPLC purity of 97.9%.

[0068] Examples 1-5

[0069] Under nitrogen protection, compound 115g, 12mL of 1,4-dibromo-2-butanol and 1g of sodium tert-butoxide were added to 150mL of isopropanol, stirred and heated to 85°C, and TLC was monitored until compound 1 was absent. After the reaction was completed, the temperature was lowered to room temperature, cooled to below 10°C, 10mL of 3mol / L hydrochloric acid was added dropwise, and n-heptane was added to separate the aqueous phase. The aqueous phase was adjusted to pH 8-9 with 10% potassium hydroxide aqueous solution, extracted twice with n-heptane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to constant weight to obtain 222.0g of an oily liquid compound with a yield of 79.6% and a HPLC purity of 97.5%.

[0070] Examples 1-6

[0071] Under nitrogen protection, compound 115g, 13.5mL of 1,4-dibromo-2-butanol and 1.3g of potassium tert-butoxide were added to 150mL of isopropanol, stirred and heated to 85°C, and TLC was monitored until there was no compound 1. After the reaction was completed, the temperature was lowered to room temperature, cooled to below 10°C, 10mL of 3mol / L hydrochloric acid was added dropwise, and n-heptane was added to separate the aqueous phase. The aqueous phase was adjusted to pH 8-9 with 10% potassium hydroxide aqueous solution, extracted twice with n-heptane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to constant weight to obtain 221.3g of oily liquid compound with a yield of 77.0% and a HPLC purity of 97.8%.

[0072] Examples 1-7

[0073] The difference between this embodiment and embodiment 1-1 is that the reaction temperature in this embodiment is 80° C., and the other conditions are the same, and 223.2 g of an oily liquid compound is obtained with a yield of 84.0% and a HPLC purity of 98.1%.

[0074] Examples 1-8

[0075] The difference between this embodiment and embodiment 1-1 is that the reaction temperature in this embodiment is 90° C., and the other conditions are the same, and 223.4 g of an oily liquid compound is obtained with a yield of 84.5% and a HPLC purity of 98.2%.

[0076] Examples 1-9

[0077] The difference between this embodiment and embodiment 1-1 is that the reaction temperature in this embodiment is 70° C., and the other conditions are the same, and 220.8 g of an oily liquid compound is obtained with a yield of 75.1% and a HPLC purity of 97.3%.

[0078] Example 2 Preparation of Glycopyrrolate

[0079] Example 2-1

[0080]

[0081] Example 2-1

[0082] Compound 210 g and K2CO34.3 g were added to 50 mL of methanol, stirred and heated to 65°C, and then 10 mL of a methanol solution containing 1.0 g of dimethylamine was slowly added dropwise, and TLC was monitored until no compound 2 was present. After the reaction was completed, the reaction solution was filtered to remove the residual inorganic salts, and the supernatant was poured into excess ether to precipitate 6.9 g of white solid glycopyrrolate, with a yield of 75.0% and a HPLC purity of 98.1%.

[0083] Example 2-2

[0084] Compound 210 g and Na2CO33.7 g were added to 50 mL of ethanol, stirred and heated to 80°C, and then 13 mL of ethanol solution containing 1.3 g of dimethylamine was slowly added dropwise, and TLC was monitored until no compound 2 was present. After the reaction was completed, the reaction solution was filtered to remove the residual inorganic salts, and the supernatant was poured into excess ether to precipitate 7.0 g of white solid glycopyrrolate, with a yield of 76.1% and a HPLC purity of 98.1%.

[0085] Example 2-3

[0086] Compound 210 g and 4.6 ml of diisopropylethylamine were added to 50 mL of N-methylpyrrolidone, stirred and heated to 100°C, and then 14 mL of N-methylpyrrolidone solution containing 1.4 g of dimethylamine was slowly added dropwise, and TLC was monitored until there was no compound 2. After the reaction was completed, the reaction solution was filtered to remove the residual inorganic salts, and the supernatant was poured into excess ether to precipitate 6.2 g of white solid glycopyrrolate, with a yield of 67.4% and a HPLC purity of 97.8%.

[0087] Embodiment 2-4

[0088] Compound 210 g and 2.8 g of 4-dimethylaminopyridine were added to 50 mL of isopropanol, stirred and heated to 85°C, and then 17 mL of ethanol solution containing 1.7 g of dimethylamine was slowly added dropwise, and TLC was monitored until no compound 2 was present. After the reaction was completed, the reaction solution was filtered to remove residual inorganic salts, and the supernatant was poured into excess ether to precipitate 6.5 g of white solid glycopyrrolate, with a yield of 70.7% and a HPLC purity of 97.9%.

[0089] Embodiment 2-5

[0090] Compound 210 g and 3.9 g of sodium bicarbonate were added to 50 mL of isopropanol, stirred and heated to 85°C, and then 19 mL of isopropanol solution containing 1.9 g of dimethylamine was slowly added dropwise, and TLC was monitored until no compound 2 was present. After the reaction was completed, the reaction solution was filtered to remove residual inorganic salts, and the supernatant was poured into excess ether to precipitate 6.3 g of white solid glycopyrrolate, with a yield of 68.5% and a HPLC purity of 98.1%.

[0091] Embodiment 2-6

[0092] Compound 210 g and 1.7 g of sodium hydroxide were added to 50 mL of methanol, stirred and heated to 65°C, and then 21 mL of a methanol solution containing 2.1 g of dimethylamine was slowly added dropwise, and TLC was monitored until no compound 2 was present. After the reaction was completed, the reaction solution was filtered to remove the residual inorganic salts, and the supernatant was poured into excess ether to precipitate 6.8 g of white solid glycopyrrolate, with a yield of 73.9% and a HPLC purity of 98.2%.

[0093] Embodiment 2-7

[0094] Compound 210 g and 2.8 g of triethylamine were added to 50 mL of methanol, stirred and heated to 65°C, and then 21 mL of a methanol solution containing 2.1 g of dimethylamine was slowly added dropwise, and TLC was monitored until no compound 2 was present. After the reaction was completed, the reaction solution was filtered to remove the residual inorganic salts, and the supernatant was poured into excess ether to precipitate 6.6 g of white solid glycopyrrolate, with a yield of 71.7% and a HPLC purity of 97.5%.

[0095] Embodiment 2-8

[0096] The difference between this embodiment and embodiment 2-3 is that the reaction temperature in this embodiment is 65° C., and the other conditions are the same, and 6.8 g of white solid glycopyrrolate is precipitated with a yield of 73.9% and a HPLC purity of 98.2%.

[0097] Embodiment 2-9

[0098] The difference between this embodiment and embodiment 2-3 is that the reaction temperature in this embodiment is 80° C., and the other conditions are the same, and 6.9 g of white solid glycopyrrolate is precipitated with a yield of 75.0% and a HPLC purity of 98.3%.

[0099] Embodiment 2-10

[0100] The difference between this embodiment and embodiment 2-3 is that the reaction temperature in this embodiment is 90° C., and the other conditions are the same, and 6.3 g of white solid glycopyrrolate is precipitated with a yield of 68.5% and a HPLC purity of 98.1%.

[0101] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A glycopyrrolate intermediate, characterized in that That is, compound 2 has the following structure:

2. A method for preparing the glycopyrrolate intermediate according to claim 1, characterized in that: The steps include: (a) Compound 1 reacts with 1,4-dibromo-2-butanol in the presence of a first base catalyst to obtain compound 2, as shown in the following reaction formula: Wherein, the first base catalyst is selected from an organic base or an inorganic base; Wherein, 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.

3. The method for preparing a glycopyrrolate intermediate according to claim 2, wherein The steps include: (a) Compound 1, 1,4-dibromo-2-butanol and a first base catalyst are added to a first solvent and reacted at 70-100° C. to obtain Compound 2.

4. The method for preparing a glycopyrrolate intermediate according to claim 3, wherein In the step (a), the first solvent is selected from one or a combination of n-heptane, n-hexane, isopropanol or butanone.

5. The method for preparing the glycopyrrolate intermediate according to any one of claims 2 to 4, characterized in that: In the step (a), the molar ratio of the first base catalyst, 1,4-dibromo-2-butanol and compound 1 is (0.1-0.2):(1.0-2.0):

1.

6. Use of the glycopyrrolate intermediate according to claim 1 or the glycopyrrolate intermediate prepared by the preparation method according to any one of claims 2 to 5 in the preparation of glycopyrrolate.

7. The use according to claim 6, characterized in that: The preparation method of glycopyrrolate comprises the following steps: (b) Compound 2 reacts with dimethylamine in the presence of a second base catalyst to obtain glycopyrrolate; the reaction formula is as follows: Wherein, the second base catalyst is selected from an organic base or an inorganic base; Wherein, the inorganic base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide; the organic base is selected from diisopropylethylamine, 4-dimethylaminopyridine or triethylamine.

8. The use according to claim 7, characterized in that: The preparation method of glycopyrrolate comprises the following steps: (b) adding compound 2, dimethylamine and a second base catalyst into a second solvent and reacting at 65-100° C. to obtain glycopyrrolate.

9. The use according to claim 8, characterized in that: In the step (b), the second solvent is selected from a C1-C3 alcohol solvent or N-methylpyrrolidone.

10. The use of glycopyrrolate according to any one of claims 7 to 8, characterized in that 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.

11. The use of glycopyrrolate according to claim 8, characterized in that In the step (b), the reaction temperature is 65-80°C.

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