Preparation method of ipratropium bromide

Abstract

The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a preparation method of sopropium bromide. The preparation method of sopropium bromide comprises the following steps: preparing (R)-α-cyclopentylmandelic acid; preparing a complex of (R)-α-cyclopentylmandelic acid-(R)-1-methyl-3-pyrrolidinol; preparing crude sopropium bromide; refining the crude product to obtain sopropium bromide; separating and purifying sopropium bromide by column chromatography to obtain high-purity A-1 and A-2. The present invention provides a preparation method of sopropium bromide, which has simple steps, avoids the use of toxic solvents, reduces environmental pollution and improves the yield at the same time. It is suitable for industrial production and has high economic benefits and practical significance.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a method for preparing solifenacin. Background Art

[0002] Solifenacin, chemically named: (2R,3'R)-3'-(2-cyclopentyl-2-hydroxy-2-phenylacetyl)-1'-(ethoxycarbonylmethyl)-1'-methylpyrrolidinium bromide. It is represented by the following formula A:

[0003]

[0004] The stereochemistry at each of the 2- and 3'-positions of solifenacin is identified as the R-configuration, but the stereochemistry of the quaternary nitrogen at the 1'-position is not identified.

[0005] More specifically, solifenacin is (2R,3'R,1'R)-3'-(2-cyclopentyl-2-hydroxy-2-phenylacetyl)-1'-(ethoxycarbonylmethyl)-1'-methylpyrrolidinium bromide represented by the following formula (A-1):

[0006]

[0007] And (2R,3'R,1'S)-3'-(2-cyclopentyl-2-hydroxy-2-phenylacetyl)-1'-(ethoxycarbonylmethyl)-1'-methylpyrrolidinium bromide represented by the following formula (A-2). The 1'R-diastereoisomer elsewhere in the specification of the present invention is also referred to as "Compound (A-1)":

[0008]

[0009] A mixture composed of, and the 1'S-diastereoisomer elsewhere in the specification of the present invention is referred to as "Compound (A-2)".

[0010] Solifenacin is a known anticholinergic agent that can be used for the therapeutic treatment of hyperhidrosis. It is classified as an anticholinergic drug that can inhibit the action of the neurotransmitter acetylcholine. Acetylcholine is considered to cause sweating by binding to the muscarinic receptors of sweat glands. Solifenacin inhibits the binding of acetylcholine by binding to the muscarinic receptors that cause hyperhidrosis in endocrine sweat glands, thereby reducing sweat gland secretion.

[0011] In the journal Pharmazie (2006), 61(2), 90 - 96 (Preparation and biological effects of pure stereoisomeric novel soft anticholinergics), Patent WO2007 / 05897 discloses the preparation methods of compounds (A), (A - 1) and (A - 2). Although the methods described therein can isolate and purify A - 1 and A - 2, the purity is relatively low and the yield is also low, and there is no in - depth study on the properties and crystal forms. Patent WO2018026869A1 discloses the preparation method and usage method of glycyrrhizin polymers. Although the above - mentioned prior arts all disclose the method of carrying out the N - alkylation reaction of ((2R,3'R)-3'-(2 - cyclopentyl - 2 - hydroxy - 2 - phenylacetoxy)-1'-methylpyrrolidine with methyl bromoacetate in acetonitrile, and then adding the dichloromethane solution of the obtained crude compound (A) to diethyl ether to obtain a precipitate, the purity is relatively low, there are many by - products, the crystal form is unstable, and the preparation method includes repeating the step of obtaining the precipitate three times. Such a synthesis method is difficult to be applied industrially, and dichloromethane and diethyl ether used therein are not solvents preferably used industrially.

[0012] According to the prior art, it is difficult to control the stereoselectivity at the N - 1'- position, so the obtained solifenacin is compound (A), that is, a pair of diastereoisomers (epimers). Moreover, the main method for separating compounds (A - 1) and (A - 2) is ordinary column chromatography, which is difficult to realize industrial production and has an extremely low yield. Patent CN114008023A discloses a crystal form of solifenacin and its preparation method. By optimizing the recrystallization process, the ratio of compounds (A - 1) and (A - 2) is controlled at 1:2 - 1:3 to obtain a physically and chemically stable crystal form, which has excellent properties as a medicinal substance of a drug, but it is difficult to realize industrial production, and the synthesis steps of this method are cumbersome. Especially when resolving DL - cyclopentylmandelic acid, the use of two resolving agents will result in a relatively low yield; at the same time, acetonitrile, a highly toxic solvent, is used as the refining solvent in the refining step, which is likely to cause the residue of toxic solvents and is not environmentally friendly, not meeting the requirements of green chemistry.

[0013] Therefore, it is very necessary to find a simple, efficient and environmentally friendly synthesis method to realize the industrial synthesis method of solifenacin. Summary of the Invention

[0014] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a preparation method of solifenacin, which has simple steps, avoids the use of toxic solvents, reduces environmental pollution while increasing the yield, is suitable for industrial production, and has high economic benefits and practical significance.

[0015] The preparation method of ipratropium bromide according to the present invention comprises the following steps:

[0016] (1) Add solvent A to (R / S)-α-cyclopentylmandelic acid and heat to dissolve. Continuously add L-tyrosine methyl ester and heat under reflux for 1 h to 3 h. Acidify the filtrate obtained after filtration and concentration to pH = 1 to 2, cool to room temperature, and perform post-treatment on the organic phase after extraction to obtain crude (R)-α-cyclopentylmandelic acid. Repeat the above steps until the optical purity (ee) is not less than 99.5% to obtain (R)-α-cyclopentylmandelic acid, which is Compound I. Preferably, the added L-tyrosine methyl ester is added in batches. Since the filtrate after filtration and concentration in this step is in the state of a yellow oil, it needs to be further dissolved and then heated, all of which are operations to achieve higher purity;

[0017] (2) Under the protection of an inert gas, dissolve Compound I in solvent B, add 1,1'-carbonyldiimidazole at 0°C to 5°C to react to obtain a mixed solution a; dissolve (R)-1-methyl-3-pyrrolidinol in solvent B, add sodium tert-butoxide at 40°C to 45°C to react to obtain a reaction solution b; drop the mixed solution a into the mixed solution b to react until the TLC detection shows that the reaction reactant spots disappear, cool to room temperature, and perform post-treatment to obtain (R)-α-cyclopentylmandelic acid-(R)-1-methyl-3-pyrrolidinol complex, denoted as Compound II;

[0018] (3) Dissolve Compound II in solvent C, add ethyl bromoacetate, and react at 50°C to 55°C for 1.5 h to 2 h. Cool to room temperature, wash and dry the obtained solid to obtain crude Compound III;

[0019] (4) Refine the crude Compound III to obtain ipratropium bromide;

[0020] (5) Separate and purify ipratropium bromide by column chromatography to obtain high-purity A-1 and A-2.

[0021] The post-treatment in step (1) is to dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure; Solvent A is one or more of acetonitrile, propionitrile, butyronitrile, and isobutyronitrile, preferably acetonitrile. Sulfuric acid, hydrochloric acid, or a mixed acid is used to adjust the pH, preferably hydrochloric acid.

[0022] The post-treatment in step (2) is to dilute with water, adjust the pH to 1 to 2, separate the layers, adjust the pH of the aqueous layer to 9 to 10, then extract with ethyl acetate, and concentrate under reduced pressure; Solvent B is a mixture of one or two of benzene and toluene, preferably toluene.

[0023] Solvent C in step (3) is ethyl acetate or methyl tert-butyl ether.

[0024] The molar amount of (R / S)-α-cyclopentylmandelic acid in step (1) is in a mass ratio of 1:1.07 to 1:1.08 with methyl L-tyrosinate.

[0025] The mass ratio of compound I, 1,1'-carbonyldiimidazole, (R)-1-methylpyrrolidin-3-ol, and sodium tert-butoxide in step (2) is (13 - 14):(11 - 12):(18 - 19):1.

[0026] In step (2), the inert protective gas is argon or nitrogen, preferably nitrogen.

[0027] The mass ratio of compound II and ethyl bromoacetate in step (3) is 1.7 - 1.8:1.

[0028] The purification step in step (4) is as follows: Dissolve the crude compound III in a purification solvent to obtain a suspension; heat to 50°C - 55°C and hold for 30 min - 31 min, and add methyl tert-butyl ether dropwise at a dropping rate of 0.18 ml / min - 1.9 ml / min for 50 min - 55 min; cool to 40°C - 41°C and add methyl tert-butyl ether dropwise at a dropping rate of 0.21 ml / min - 2.22 ml / min for 44 min - 45 min; cool to 20°C - 25°C and add methyl tert-butyl ether dropwise at a dropping rate of 0.13 ml / min - 1.6 ml / min for 35 min - 40 min; cool to 10°C - 11°C and add methyl tert-butyl ether dropwise at a dropping rate of 0.14 ml / min - 1.4 ml / min for 35 min - 36 min; cool to 0°C - 5°C and add methyl tert-butyl ether dropwise at a dropping rate of 0.08 ml / min - 0.9 ml / min for 30 min - 35 min; stir, wash, and dry to obtain solifenacin bromide.

[0029] There is no particular limitation on the volume of the purification solvent in the purification, as long as it can dissolve compound III. However, the volume of the purification solvent used (mL) can be 2 - 15 times the mass (g) of compound III, preferably 4 - 12 times, and more preferably 5 - 10 times.

[0030] The purification solvent is one or more of acetonitrile, methyl tert-butyl ether, ethyl acetate, diethyl ether, ethanol, chloroform, dichloromethane, and isopropanol. Preferably, the ratio of ethanol to methyl tert-butyl ether is 1:9, and more preferably, the ratio of ethyl acetate to methyl tert-butyl ether is 2:3.

[0031] In step (5), the silica gel used for column chromatography is 100 mesh - 200 mesh, 200 mesh - 300 mesh, or 300 mesh - 400 mesh; the eluent used is one or more of methanol, ethanol, dichloromethane, chloroform, and methyl tert-butyl ether, preferably a mixture of methanol and dichloromethane, with a ratio of 5:95 - 2:9, and more preferably 1:9 - 1:4.

[0032] Specifically, the preparation method of solifenacin succinate includes the following steps:

[0033] (1) Add (R / S)-α-cyclopentylmandelic acid to a 2.5 L reaction flask, then dissolve it by heating with acetonitrile. Continuously add L-tyrosine methyl ester (CDI), stir and heat under reflux for 1 h - 3 h, gradually cool to room temperature, filter off the precipitate, combine the washing liquid and the filtrate and concentrate under reduced pressure. The obtained filtrate is a yellow oil. Dissolve the oil in distilled water, heat to 60 °C and stir for 0.5 h, filter while it is hot. When the temperature of the filtrate drops to 40 °C, acidify it with hydrochloric acid to pH = 1 - 2, cool to room temperature, then extract with ethyl acetate. The extracted organic phase is dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a crude (R)-α-cyclopentylmandelic acid as a pale yellow solid, and its yield and ee value are detected.

[0034] Dissolve the obtained pale yellow solid in acetonitrile, react with L-tyrosine methyl ester again for 2 h, and after returning to room temperature, treat it in the same way as above to obtain a crude (R)-α-cyclopentylmandelic acid as a pale yellow solid. Repeat the resolution process many times until the ee value is not less than 99.5% to obtain (R)-α-cyclopentylmandelic acid, which is compound I.

[0035] The reaction formula is as follows:

[0036]

[0037] (2) Under the protection of nitrogen gas, add compound I to a 250 mL reaction flask, dissolve it with toluene, add 1,1'-carbonyldiimidazole at 0 °C - 5 °C to react, and obtain a mixed solution a; under nitrogen protection, add (R)-1-methyl-3-pyrrolidinol to another 250 mL reaction flask, dissolve it with 40 mL of toluene, and after complete dissolution, add sodium tert-butoxide, stir at 40 °C - 45 °C for 20 min to obtain a reaction solution b; drip the mixed solution a into the reaction solution b to react, stir the reaction until the reaction is completed by TLC detection, naturally cool to room temperature, add distilled water and stir, adjust the pH to 1 - 2, after liquid separation, adjust the pH of the aqueous layer to 9 - 10 with an aqueous potassium carbonate solution, then extract with ethyl acetate, and concentrate under reduced pressure to obtain a colorless oil, namely (R)-α-cyclopentylmandelic acid-(R)-1-methyl-3-pyrrolidinol complex, denoted as compound II.

[0038] The reaction formula is as follows:

[0039]

[0040] (3) At room temperature, dissolve Compound II in ethyl acetate. First, add a small portion of ethyl bromoacetate. After a white precipitate appears, add the remaining ethyl bromoacetate. React at 50 °C to 55 °C for 1.5 h to 2 h. Cool to room temperature. Collect the solid by filtration. Wash the obtained solid with ethyl acetate and dry it to obtain a white solid, which is the crude product of Compound III. The stepwise addition operation of ethyl bromoacetate is an existing technique and will not be described further.

[0041] The reaction formula is as follows:

[0042]

[0043] (4) Purify the crude product of Compound III. At room temperature, dissolve the crude product of Compound III in ethyl acetate to obtain a suspension; heat up to 50 - 55 °C and keep warm for 30 - 31 min. Dropwise add methyl tert-butyl ether at a dropping rate of 0.18 - 1.9 ml / min for 50 - 55 min; cool down to 40 - 41 °C and dropwise add methyl tert-butyl ether at a dropping rate of 0.21 - 2.22 ml / min for 44 - 45 min; cool down to 20 - 25 °C and dropwise add methyl tert-butyl ether at a dropping rate of 0.13 - 1.6 ml / min for 35 - 40 min; cool down to 10 - 11 °C and dropwise add methyl tert-butyl ether at a dropping rate of 0.14 - 1.4 ml / min for 35 - 36 min; cool down to 0 - 5 °C and dropwise add methyl tert-butyl ether at a dropping rate of 0.08 - 0.9 ml / min for 30 - 35 min; stir, wash, and dry to obtain a white solid, which is solpyrinium bromide, a mixture of Compounds A-1 and A-2.

[0044] (5) Use column chromatography to separate and purify solpyrinium bromide. Select silica gel of 300 - 400 mesh, and use a mixed solvent of methanol and dichloromethane as the eluent to obtain high-purity A-1 and A-2.

[0045] In the method for preparing solpyrinium bromide of the present invention, it includes the purification step of the crude product of Compound III. The solpyrinium bromide obtained through steps (1) and (2) is a mixture of A-1 and A-2 with an unfixed ratio, and this mixture does not have the characteristics of a medicinal substance suitable for drugs. After the purification step (3), a eutectic structure containing Compound (A-1 and A-2) in a ratio of 1:2 can be obtained. It has been reported in the existing literature that the eutectic structure with this ratio has extremely excellent properties as a medicinal substance for drugs.

[0046] Compared with the prior art, the beneficial effects of the present invention are:

[0047] (1) The preparation method of solifenacin of the present invention adopts the method of repeatedly resolving (R / S)-α-cyclopentylmandelic acid with L-tyrosine methyl ester to obtain (R)-α-cyclopentylmandelic acid, avoiding the disadvantages of cumbersome operation and reduced yield caused by replacing the resolving agent. Compared with using two resolving agents, the yield is significantly improved, and the purity is relatively high. It can simplify the steps and operations in industrial production while reducing costs and increasing benefits.

[0048] (2) The preparation method of solifenacin of the present invention adopts special refining conditions, not only avoiding the use of the solvent acetonitrile with relatively high toxicity, but also obtaining a crystal form with excellent properties for the medicinal substance of the drug, and at the same time improving the yield and purity.

[0049] (3) The preparation method of solifenacin of the present invention adopts a specific eluent and the selection of silica gel in column chromatography to separate high-purity A-1 and A-2, and their NMR characterizations are carried out, and the yield is increased to 30% - 40%. Description of the Drawings

[0050] Figure 1 is the 2θ angle of the X-ray powder diffraction of solifenacin with a ratio of A-1 to A-2 of 1:2 prepared in Example 1 of the present invention.

[0051] Figure 2 is the NMR spectrum of compound A-1 prepared in Example 2 of the present invention.

[0052] Figure 3 is the NMR spectrum of compound A-2 prepared in Example 3 of the present invention. Detailed Embodiments

[0053] The present invention will be further described below in conjunction with specific embodiments, but the present invention is not limited thereto.

[0054] The chemical shift values in the nuclear magnetic resonance spectrum and the characteristic diffraction angles observed in powder X-ray diffraction mentioned in the specification may vary with the measurement conditions. Therefore, the measured values of the crystal forms mentioned in the specification may contain errors. All raw materials used in the examples are commercially available unless otherwise specified. In the actual operation of the examples, some operations, such as stirring, drying, heating, etc., are all conventional operations of those skilled in the art, and their purposes are also to achieve the final purpose defined in this application.

[0055] Example 1

[0056] The preparation method of solifenacin described above includes the following steps:

[0057] (1) Add 60.0 g of (R / S)-α-cyclopentylmandelic acid (272.4 mmol) to a 2.5 L reaction flask, then dissolve it by heating with 600 mL of acetonitrile. Raise the temperature to 60 °C to obtain a clear solution. Continue to add 64.2 g (328.9 mmol) of L-tyrosine methyl ester (add about 1 / 4 first, and then slowly add the remaining part). Stir and reflux for 2 h, gradually cool to room temperature, filter off the precipitate, wash the filter residue with acetonitrile, combine the washing liquid and the filtrate, and concentrate under reduced pressure. The obtained filtrate is a yellow oil. Dissolve the oil in 300 mL of distilled water, heat to 60 °C and stir for 0.5 h, filter while it is hot. When the temperature of the filtrate drops to 40 °C, acidify it with hydrochloric acid to pH = 1, cool to room temperature, then extract with ethyl acetate. The extracted organic phase is dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain 29.1 g of crude (R)-α-cyclopentylmandelic acid as a pale yellow solid. The yield is detected to be 48.5%, and the ee value is 95.9%.

[0058] Dissolve the obtained pale yellow solid in 600 ml of acetonitrile, react with L-tyrosine methyl ester (64.2 g, 328.9 mmol) for another 2 h, and after returning to room temperature, treat it as above. 28.7 g of crude (R)-α-cyclopentylmandelic acid as a pale yellow solid is obtained, and its yield is 98.6%. After such five recrystallizations, 24.8 g of (R)-α-cyclopentylmandelic acid ((R)-CPMA), which is compound I, is obtained, with a yield of 85.2% and an ee value of 99.9%.

[0059] (2) Under the protection of nitrogen gas, add compound I (8.0 g, 36 mmol) to a 250 mL reaction flask, add 80 ml of toluene to dissolve it, add 7.0 g (43 mmol) of CDI at 5 °C, stir for 40 min to obtain a mixed solution a; under nitrogen protection, add 4.0 g of (R)-1-methyl-3-pyrrolidinol (40 mmol) to another 250 mL reaction flask, dissolve it completely with 40 mL of toluene, add 0.6 g of sodium tert-butoxide (6 mmol) after complete dissolution, and stir at 45 °C for 20 min to obtain a reaction solution b; drop the mixed solution a into the mixed solution b for reaction, stir until the reaction is completed by TLC detection, cool naturally to room temperature, add 70 ml of distilled water and stir for 0.5 h, adjust the pH to 1 with dilute hydrochloric acid, after liquid separation, adjust the pH of the aqueous layer to 9 with an aqueous potassium carbonate solution, then extract with ethyl acetate, and concentrate under reduced pressure to obtain 10.5 g of a colorless oil, namely (R)-α-cyclopentylmandelic acid-(R)-1-methyl-3-pyrrolidinol complex, denoted as compound II, with a yield of 95%.

[0060] (3) At room temperature, dissolve compound II (5.0 g, 16.5 mmol) in 60 mL of ethyl acetate. First, add 0.1 g of ethyl bromoacetate. After a white precipitate appears, add 2.8 g (16.8 mmol) of ethyl bromoacetate. React at 55 °C for 1.5 h. Cool to room temperature. Collect the solid by filtration. Wash the obtained solid with ethyl acetate and dry it to obtain a white solid, which is the crude compound III (6.9 g, yield 89.0%).

[0061] (4) Purify the crude compound III. At room temperature, dissolve 5.0 g of the crude compound III in 22 ml of ethyl acetate to obtain a suspension. Heat to 55 °C and keep warm for 30 min. Add methyl tert-butyl ether dropwise at a rate of 0.182 ml / min for 55 min. Cool to 40 °C and add methyl tert-butyl ether dropwise at a rate of 2.22 ml / min for 45 min. Cool to 20 °C and add methyl tert-butyl ether dropwise at a rate of 0.141 ml / min for 35 min. Cool to 10 °C and add methyl tert-butyl ether dropwise at a rate of 0.141 ml / min for 35 min. Cool to 5 °C and add methyl tert-butyl ether dropwise at a rate of 0.086 ml / min for 35 min. Stir for 1 h. Collect the obtained solid, wash it with ethyl acetate, and dry it to obtain 4.9 g of a white solid with a yield of 98.0%, obtaining solpyrinium bromide, which is a mixture of compound A-1 and A-2, a solpyrinium bromide crystal form with a ratio of 1:2, denoted as crystal form B. Conduct X-ray powder diffraction analysis on it, as Figure 1 shown, which is basically consistent with the reported literature.

[0062] (5) Separate and purify solpyrinium bromide by column chromatography. Select 300 - 400 mesh silica gel, and use a mixed solvent of methanol and dichloromethane as the eluent to obtain high-purity A-1 and A-2. Among them, the ratio of methanol and dichloromethane and the time are shown in Table 1.

[0063] Table 1 Separation conditions

[0064] Time (min) Methanol (vol%) Dichloromethane (vol%) 0～30 13 87 30～40 13→15 87→85 40～45 15 85 45～55 15→17 85→83 55～80 17 83

[0065] Among them, according to TLC detection, due to their different positions, the first eluted is compound A-1, and the later eluted is compound A-2. Concentrate the solution of compound A-1 under reduced pressure and add 5 - 7 times the volume of a mixed solution of ethyl acetate and methyl tert-butyl ether (2:3). Shake to obtain a suspension. Stir the suspension and gradually cool to room temperature. Filter and collect the precipitate, and wash it 2 times with 1 - 2 times the volume of a mixed solution of ethyl acetate and methyl tert-butyl ether (2:3). Dry the obtained solid to obtain a white powdery solid, which is the mixture A-1 with a yield of 32%.

[0066] The solution of compound A-2 was also used to prepare mixture A-2 by this method, with a yield of 45%.

[0067] The above compounds A-1 and A-2 were characterized by NMR, and their 1H NMR data are as follows: Compound A-1: 1 1H NMR(600MHz,Chloroform-d)δ1.26(3H,t,J=7.1Hz,CH3CH2O),1.32-1.69(8H,m,(CH2)4),2.18-2.23(1H,m,Hc-4’),2.83(1H,s,OH),2.88-2.92(1H,m,HC-C-2),2.95-3.03(1H,m,Ht-4’),3.16(3H,s,NCH3),3.98-4.01(1H,m,Hc-2’),4.19-4.25(4H,m,Hc-5’,CH3CH2OandHt-2’),4.45-4.48(1H,m,Ht-5’),5.11(1H,d,J=17.0Hz,NCH2),5.03(1H,d,J=17.0Hz,NCH2),5.56-5.57(1H,m,H-3’),7.25(1H,t,J=7.3Hz,H-Php),7.35(2H,t,J=7.7Hz,H-Phm),7.58(2H,d,J=7.7Hz,H-Pho).

[0068] Compound A-2: 1 1H NMR(600MHz,Chloroform-d,ppm)δ1.32(t,J=7.1Hz,3H,CH3CH2O),1.34-1.37,1.43-1.48,1.54-1.62and 1.64-1.72(8H,m,(CH2)4),2.21-2.25(m,1H,Hc-4'),2.84-2.91(1H,Ht-4'and 1H,m,HC-C-2),3.69(3H,s,NCH3),4.11(1H,s,OH),4.19-4.26(4H,m,H-5'and OCH2CH3),4.29-4.33(1H,m,Hc-2'),4.42(1H,dd,J=13.9,5.7Hz,Ht-2'),4.66(1H,d,J=17.0Hz,NCH2),4.74(1H,d,J=17.1Hz,NCH2),5.51-5.53(m,1H,H-3'),7.24-7.26(m,1H,H-Ph p ),7.34(t,J=7.7Hz,2H,H-Ph m), 7.59 (d, J = 7.5 Hz, 2H, H-Ph o )。

[0069] Example 2

[0070] The preparation method of the solifenacin bromide described above comprises the following steps:

[0071] (1) Add 60.0 g of (R / S)-α-cyclopentylmandelic acid (272.4 mmol) to a 2.5 L reaction flask, then heat and dissolve it with 600 mL of acetonitrile. Heat up to 60 °C to obtain a clear solution. Continue to add 64.2 g (328.7 mmol) of L-tyrosine methyl ester (add about 1 / 4 first, and then slowly add the remaining part). Stir and heat under reflux for 2 h, gradually cool to room temperature, filter off the precipitate, wash the filter residue with propionitrile, combine the washing liquid and the filtrate, and concentrate under reduced pressure. The obtained filtrate is a yellow oil. Dissolve the oil in 300 mL of distilled water, heat to 60 °C and stir for 0.5 h, filter while hot. When the temperature of the filtrate drops to 40 °C, acidify it with dilute sulfuric acid to pH = 1, cool to room temperature, then extract with ethyl acetate. The extracted organic phase is dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain 28.9 g of crude (R)-α-cyclopentylmandelic acid as a pale yellow solid. Detect its yield to be 48.2% and the ee value to be 96.0%;

[0072] Dissolve the obtained pale yellow solid in 600 ml of propionitrile, react with L-tyrosine methyl ester (64.2 g, 328.9 mmol) again for 2 h, and after returning to room temperature, treat it in the same manner as above to obtain 28.1 g of crude (R)-α-cyclopentylmandelic acid as a pale yellow solid, with a yield of 97.2%. After such 5 times of resolution, 24.2 g of (R)-CPMA is obtained, which is Compound I, with a yield of 83.7% and an ee value of 99.9%.

[0073] (2) Under the protection of argon gas, compound I (8.0 g, 36 mmol) was added to a 250 mL reaction flask, dissolved in 80 mL of toluene, and 7.0 g (43 mmol) of CDI was added at 0 °C. The mixture was stirred for 40 min to obtain mixture a. Under the protection of nitrogen gas, 4.1 g of (R)-1-methyl-3-pyrrolidinol (40 mmol) was added to another 250 mL reaction flask, dissolved in 40 mL of benzene. After complete dissolution, 0.6 g of sodium tert-butoxide (6 mmol) was added, and the mixture was stirred at 40 °C for 20 min to obtain reaction solution b. Mixture a was added dropwise to reaction solution b for reaction, and the reaction was stirred until the reaction was completed as detected by TLC. It was naturally cooled to room temperature, 70 mL of distilled water was added and stirred for 0.5 h, the pH was adjusted to 2 with dilute hydrochloric acid, and after liquid separation, the pH of the aqueous layer was adjusted to 9 with an aqueous potassium carbonate solution, and then extracted with ethyl acetate. After concentration under reduced pressure, 10.3 g of a colorless oil was obtained, namely (R)-α-cyclopentylmandelic acid-(R)-1-methyl-3-pyrrolidinol complex, denoted as compound II, with a yield of 91.2%.

[0074] (3) At room temperature, compound II (5.5 g, 18.1 mmol) was dissolved in 60 mL of ethyl acetate. First, 0.1 g of ethyl bromoacetate was added. After a white precipitate appeared, 3.1 g (18.6 mmol) of ethyl bromoacetate was added. The reaction was carried out at 50 °C for 2 h, cooled to room temperature, and the solid was collected by filtration. The obtained solid was washed with ethyl acetate and dried to obtain a white solid, namely crude compound III (7.0 g, yield 82.2%).

[0075] (4) The crude compound III was refined. At room temperature, 5.0 g of the crude compound III was dissolved in 5 mL of ethyl acetate to obtain a suspension. The temperature was raised to 50 °C and kept warm for 31 min. Methyl tert-butyl ether was added dropwise at a rate of 0.2 mL / min for 55 min. The temperature was lowered to 41 °C, and methyl tert-butyl ether was added dropwise at a rate of 0.25 mL / min for 44 min. The temperature was lowered to 20 °C, and methyl tert-butyl ether was added dropwise at a rate of 0.23 mL / min for 45 min. The temperature was lowered to 10 °C, and methyl tert-butyl ether was added dropwise at a rate of 0.29 mL / min for 35 min. The temperature was lowered to 0 °C, and methyl tert-butyl ether was added dropwise at a rate of 0.09 mL / min for 35 min. After stirring for 1 h, the obtained solid was collected, washed with ethyl acetate and dried to obtain 4.8 g of a white solid, with a yield of 96.0%, to obtain solpyrronium bromide, namely a mixture of compounds A-1 and A-2. According to liquid phase detection, the solpyrronium bromide crystal form with a ratio of 1:1.9 was denoted as crystal form B.

[0076] (5) Sopyrazone bromide was separated and purified by column chromatography, using 100-200 mesh silica gel and a mixed solvent of methanol and dichloromethane as the eluent to obtain high-purity A-1 and A-2. The ratio of methanol to dichloromethane and the time are shown in Table 2.

[0077] Table 2 Separation conditions

[0078] Time (min) Ethanol (vol%) Chloroform (vol%) 0～20 8 92 20～55 8→11 92→89 55～65 11 89 65～70 11→15 89→85 70～85 15 85

[0079] Among them, according to the TCL detection, the first outflow is compound A-1, and the later outflow is compound A-2. After the solution of compound A-1 is concentrated under reduced pressure, a mixture of about 5 to 7 volumes of ethyl acetate and methyl tert-butyl ether (2:3) is added and a suspension is obtained by shaking. The suspension is stirred and gradually cooled to room temperature. The precipitate is collected by filtration and washed twice with 1 to 2 volumes of ethyl acetate and methyl tert-butyl ether (2:3). The obtained solid is dried to obtain a white powdery solid, namely mixture A-1, with a yield of 20%. The solution of compound A-2 is also used to prepare mixture A-2 by this method, with a yield of 31%.

[0080] Example 3

[0081] The preparation method of sopyraclostrobin bromide comprises the following steps:

[0082] (1) Add 500.5 g (R / S)-α-cyclopentylmandelic acid (2.3 mol) to a 10 L reaction bottle, then heat and dissolve with 5 L acetonitrile, raise the temperature to 60°C, and obtain a clear solution. Continue to add 543.4 g (2.8 mol) of L-tyrosine methyl ester (add about 1 / 4 first, then slowly add the rest), stir and heat under reflux for 2 h, gradually cool to room temperature, filter out the precipitate, wash the filter residue with butyronitrile, combine the washing liquid and the filtrate, and concentrate under reduced pressure to obtain the filter residue. The liquid was a yellow oil, which was dissolved in 2.5L of distilled water, heated to 60°C and stirred for 0.5h, filtered while hot, and when the filtrate temperature dropped to 40°C, acidified to pH=1 with dilute sulfuric acid, cooled to room temperature, and then extracted with ethyl acetate. The organic phase after extraction was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 241.2g of crude (R)-α-cyclopentylmandelic acid as a light yellow solid, with a yield of 48.2% and an ee value of 96.2%;

[0083] The obtained pale yellow solid was dissolved in 5 L of propionitrile and reacted with L-tyrosine methyl ester (543.4 g, 2.8 mol) again for 2 h. After returning to room temperature, the post-treatment method was the same as above, and 237.1 g of crude (R)-α-cyclopentylmandelic acid as a pale yellow solid was obtained, with a yield of 98.3%. After such five recrystallizations, 200.7 g of (R)-CPMA, which is Compound I, was obtained, with a yield of 83.2% and an ee value of 99.7%.

[0084] (2) Under the protection of nitrogen gas, Compound I (50.2 g, 227.9 mmol) was added to a 2-L reaction flask, dissolved in 600 ml of toluene, and reacted with 48.8 g (298.6 mmol) of CDI at 5 °C, and stirred for 40 min to obtain a mixed solution a; under the protection of nitrogen, 25.2 g of (R)-1-methyl-3-pyrrolidinol (249.1 mmol) was added to another 2-L reaction flask, dissolved in 300 mL of toluene, and after complete dissolution, 4.2 g of sodium tert-butoxide (43.7 mmol) was added, and stirred at 45 °C for 20 min to obtain a reaction solution b; the mixed solution a was dropped into the mixed solution b for reaction, and stirred until the reaction was completed as detected by TLC, cooled naturally to room temperature, 450 ml of distilled water was added and stirred for 0.5 h, the pH was adjusted to 1 with dilute hydrochloric acid, after liquid separation, the pH of the aqueous layer was adjusted to 9 with an aqueous potassium carbonate solution, and then extracted with ethyl acetate, and concentrated under reduced pressure to obtain 64.3 g of a colorless oily substance, namely (R)-α-cyclopentylmandelic acid-(R)-1-methyl-3-pyrrolidinol complex, denoted as Compound II, with a yield of 93%.

[0085] (3) At room temperature, Compound II (50.6 g, 166.8 mmol) was dissolved in 600 mL of ethyl acetate. First, 0.9 g of ethyl bromoacetate was added. After a white precipitate appeared, 27.9 g (16.8 mmol) of ethyl bromoacetate was added, and the reaction was carried out at 55 °C for 1.5 h. After cooling to room temperature, the solid was collected by filtration, and the obtained solid was washed with ethyl acetate and dried to obtain a white solid, namely crude Compound III (69.8 g, yield 89.0%).

[0086] (4) The crude compound III was refined. At room temperature, 50.0 g of the crude compound III was dissolved in 220 ml of ethyl acetate to obtain a suspension; the temperature was raised to 55 °C and kept warm for 30 min, and methyl tert-butyl ether was added dropwise at a dropping rate of 1.8 ml / min for 55 min; the temperature was lowered to 40 °C, and methyl tert-butyl ether was added dropwise at a dropping rate of 2.22 ml / min for 45 min; the temperature was lowered to 20 °C, and methyl tert-butyl ether was added dropwise at a dropping rate of 1.43 ml / min for 35 min; the temperature was lowered to 10 °C, and methyl tert-butyl ether was added dropwise at a dropping rate of 1.43 ml / min for 35 min; the temperature was lowered to 5 °C, and methyl tert-butyl ether was added dropwise at a dropping rate of 0.86 ml / min for 35 min; it was stirred for 1 h, the obtained solid was collected, washed with ethyl acetate, and dried to obtain 48.7 g of a white solid, with a yield of 97.4%, obtaining tropicamide bromide, which is a mixture of compound A-1 and A-2, and the tropicamide bromide crystal form with a ratio of 1:2 is denoted as crystal form B.

[0087] (5) Tropicamide bromide was separated and purified by column chromatography. 200-300 mesh silica gel was selected, and the eluent was a mixed solvent of methanol and dichloromethane to obtain high-purity A-1 and A-2. Among them, the ratio and time of methanol and dichloromethane are shown in Table 3.

[0088] Table 3 Separation conditions

[0089] Time (min) Methanol (vol%) Dichloromethane (vol%) 0～20 13 87 20～25 13→15 87→85 25～45 15 85 45～50 15→17 85→83 50～70 17 83

[0090] Among them, according to TLC detection, due to the different positions, the first eluted is compound A-1, and the later eluted is compound A-2. The solution of compound A-1 was concentrated under reduced pressure and about 5-7 times the volume of a mixed solution of ethyl acetate and methyl tert-butyl ether (2:3) was added, and it was shaken to obtain a suspension. The suspension was stirred and gradually cooled to room temperature. The precipitate was filtered and collected, and washed 2 times with 1-2 times the volume of a mixed solution of ethyl acetate and methyl tert-butyl ether (2:3). The obtained solid was dried to obtain a white powdery solid, which is mixture A-1, with a yield of 23%. The solution of compound A-2 was also prepared into mixture A-2 by this method, with a yield of 35%.

[0091] Certainly, the above content is only a preferred embodiment of the present invention and cannot be considered as limiting the scope of the embodiments of the present invention. The present invention is not limited to the above examples either. Equivalent changes and improvements made by those of ordinary skill in the art within the scope of the essence of the present invention shall fall within the scope covered by the patent of the present invention.

Claims

1. A preparation method of ipratropium bromide, characterized in that: It includes the following steps: (1) Add solvent A to (R / S)-α-cyclopentylmandelic acid and heat to dissolve. Continuously add L-tyrosine methyl ester in batches, heat under reflux for 1 h to 3 h. Acidify the filtrate obtained after filtration and concentration to pH = 1 to 2, cool to room temperature, extract with ethyl acetate. The extracted organic phase is post-treated, and the post-treatment is to dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude (R)-α-cyclopentylmandelic acid. Repeat the above steps until the optical purity is not less than 99.5% to obtain (R)-α-cyclopentylmandelic acid, which is compound I; Solvent A is one or more of acetonitrile, propionitrile, and butyronitrile; (2) Under the protection of an inert gas, dissolve compound I in solvent B, add 1,1'-carbonyldiimidazole at 0 °C to 5 °C to react to obtain a mixed solution a; dissolve (R)-1-methyl-3-pyrrolidinol in solvent B, add sodium tert-butoxide at 40 °C to 45 °C to react to obtain a reaction solution b; drop the mixed solution a into the mixed solution b to react until the reactant spots detected by TLC disappear, cool to room temperature, and after post-treatment, obtain (R)-α-cyclopentylmandelic acid-(R)-1-methyl-3-pyrrolidinol complex, denoted as compound II; (3) Dissolve compound II in solvent C, add ethyl bromoacetate, react at 50 °C to 55 °C for 1.5 h to 2 h, cool to room temperature, wash and dry the obtained solid to obtain crude compound III; (4) Refine the crude compound III to obtain sobriplonium bromide; (5) Separate and purify sobriplonium bromide by column chromatography to obtain high-purity A-1 and A-2; The silica gel used in the column chromatography is 100 mesh to 200 mesh, 200 mesh to 300 mesh, 300 mesh to 400 mesh; the eluent used in the separation and purification is one or more of methanol, ethanol, dichloromethane, chloroform, and methyl tert-butyl ether.

2. The preparation method of solifenacin according to claim 1, wherein: The post-treatment of step (2) is to dilute with water, adjust the pH to 1 to 2, separate the layers, adjust the pH of the aqueous layer to 9 to 10, then extract with ethyl acetate, and concentrate under reduced pressure; solvent B is one or a mixture of two of benzene and toluene.

3. The preparation method of ipratropium bromide according to claim 1, characterized in that: Solvent C in step (3) is ethyl acetate or methyl tert-butyl ether.

4. The preparation method of ipratropium bromide according to claim 1, characterized in that: The mass ratio of (R / S)-α-cyclopentylmandelic acid to L-tyrosine methyl ester in step (1) is 1:1.

07.

5. The preparation method of ipratropium bromide according to claim 1, characterized in that: The mass ratio of compound I, 1,1'-carbonyldiimidazole, (R)-1-methyl-3-pyrrolidinol, and sodium tert-butoxide in step (2) is (13 to 14):(11 to 12):(18 to 19):

1.

6. The preparation method of ipratropium bromide according to claim 1, characterized in that: The mass ratio of compound II to ethyl bromoacetate in step (3) is (1.7 to 1.8):

1.

7. The preparation method of ipratropium bromide according to claim 1, characterized in that: The refining step of step (4) is: dissolve the crude compound III in ethyl acetate to obtain a suspension; Heat to 50°C - 55°C and hold for 30 min - 31 min. Add methyl tert-butyl ether dropwise at a rate of 0.18 ml / min - 1.9 ml / min for 50 min - 55 min; cool to 40°C - 41°C and add methyl tert-butyl ether dropwise at a rate of 0.21 ml / min - 2.22 ml / min for 44 min - 45 min; cool to 20°C - 25°C and add methyl tert-butyl ether dropwise at a rate of 0.13 ml / min - 1.6 ml / min for 35 min - 40 min; cool to 10°C - 11°C and add methyl tert-butyl ether dropwise at a rate of 0.14 ml / min - 1.4 ml / min for 35 min - 36 min; cool to 0°C - 5°C and add methyl tert-butyl ether dropwise at a rate of 0.08 ml / min - 0.9 ml / min for 30 min - 35 min; stir, wash, and dry to obtain solifenacin succinate.

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