A method for synthesizing a solifenacin succinate impurity

Abstract

The application provides a preparation method of (R)-quinine cyclohexane-3-yl (2-benzoylphenethyl) urethane, which uses o-phenyl halogen ethylamine as raw material, and the product is obtained through only three steps, the process route is short, the operation is simple, the product has high purity, and high-quality control samples are provided for succinic acid solifenacin quality research.

Description

Technical Field

[0001] This patent belongs to the field of drug synthesis, specifically relating to a method for synthesizing a solifenaxin impurity (R)-quinincycline-3-yl(2-benzoylphenylethyl)carbamate. Background Technology

[0002] Solifenacin succinate, marketed as Vesicare, is a highly selective M-receptor blocker developed by Astellas Pharma Inc. of Japan. Clinically, it is primarily used to treat overactive bladder (OAB) accompanied by urinary urgency, frequency, and urge incontinence. It was first launched in Europe in August 2004 and approved for marketing in China in 2009. Solifenacin succinate has potential selectivity for M3 receptors in the urethra and bladder, can contract bladder smooth muscle, and can stimulate salivation. Compared with traditional anticholinergic drugs, it has fewer adverse reactions (such as dry mouth, constipation, blurred vision, etc.) and is better tolerable. Its structural formula is as follows:

[0003]

[0004] Certain impurities in drugs may possess biological activity; if their levels exceed certain standards, they can cause side effects, threatening patients' lives and directly impacting the safety of clinical drug use. Impurities can interact with drugs and affect their efficacy. The toxicity of the active ingredient in chemically synthesized drugs and impurities in the formulation, particularly genotoxicity, affect drug safety. Impurities significantly influence analytical methods and storage studies in drug dosage form selection, formulation, and process decisions, making them a key focus of innovative drug quality and safety research.

[0005] Astellas Pharma Inc. of Japan reported a degradation product of solifenacin succinate, including compound I, (R)-quinincycline-3-yl(2-benzoylphenylethyl)carbamate. In Japanese pharmaceutical data, it is designated YM-217880, and in the quality standard for solifenacin succinate tablets, this compound is controlled as an impurity with a limit of 0.5%. Its structural formula is as follows:

[0006]

[0007] Patent CN105348278 A provides a method for preparing racemic quininecycline-3-yl(2-benzoylphenylethyl)carbamate through oxidative degradation. Analysis of the literature revealed that the oxidation process uses potassium permanganate, a flammable and explosive material, posing a significant safety hazard. Repeating the literature's procedures showed that due to the numerous oxidation sites in the solifena novel structure, the resulting product was highly complex, difficult to purify, and had a low yield.

[0008] Tilch (TLC) patent CN107011338 A reports a directional synthesis method for (R)-quininylcycline-3-yl(2-benzoylphenylethyl)carbamate, involving 9 reaction steps. The synthetic route is lengthy and uses the highly toxic reagent triphosgene. The route is as follows:

[0009] Summary of the Invention

[0010] The purpose of this invention is to provide a method for preparing (R)-quinin-3-yl(2-benzoylphenylethyl)carbamate.

[0011] The objective of this invention is achieved through the following technical solution.

[0012] A method for preparing a compound of formula I includes the following steps:

[0013]

[0014] Where X is Cl, Br, or I;

[0015] a) The compound of formula II was reacted with N,N'-carbonyldiimidazole (CDI) in the presence of a base to give the compound of formula III;

[0016] b) Reacting compound III with compound IV in the presence of a base yields compound V;

[0017] c) React compound V with an organolithium reagent, and then react it with compound VI to obtain compound I.

[0018] According to the embodiments of the present invention, in step a), the base is an inorganic base or an organic base, such as triethylamine, N,N-diisopropylethylamine, potassium carbonate, etc., preferably N,N-diisopropylethylamine.

[0019] According to the embodiments of the present invention, in step a), the reaction is carried out in a solvent, such as acetonitrile, N,N-dimethylformamide, tetrahydrofuran, or dichloromethane, preferably tetrahydrofuran.

[0020] According to the embodiment of the present invention, in step a), the temperature of the reaction is, for example, 20°C to 80°C, such as 30°C.

[0021] According to the embodiments of the present invention, in step a), the molar ratio of compound II, CDI, and base is 1:(0.8-1.2):(1.0-3.0), preferably 1:1.1:2.0; the mass-volume ratio of compound II and solvent is 1:20.

[0022] According to the embodiments of the present invention, in step b), the base is an inorganic base or an organic base, for example selected from triethylamine, N,N-diisopropylethylamine, potassium tert-butoxide, sodium tert-butoxide, sodium hydride, preferably sodium hydride.

[0023] According to the embodiments of the present invention, in step b), the reaction is carried out in a solvent, such as acetonitrile, N,N-dimethylformamide, tetrahydrofuran, or dichloromethane, preferably N,N-dimethylformamide.

[0024] According to the embodiment of the present invention, in step b), the temperature of the reaction is 20°C to 60°C, for example, 20°C.

[0025] According to the embodiment of the present invention, in step b), the molar ratio of compound III, compound IV and base is 1:(0.8-1.5):(0.8-1.5), preferably 1:1.25:1.25; the mass-volume ratio of compound III and solvent is 1:20.

[0026] According to the embodiments of the present invention, in step c), the organolithium reagent is, for example, n-butyllithium, tert-butyllithium, or diisopropylaminolithium, preferably n-butyllithium.

[0027] According to the embodiments of the present invention, in step c), the reaction is carried out in a solvent, such as diethyl ether or tetrahydrofuran, preferably tetrahydrofuran.

[0028] According to the embodiment of the present invention, in step c), the temperature of the reaction is 20°C to 40°C, for example 30°C.

[0029] According to the embodiments of the present invention, in step c), the molar ratio of compound V, VI, and organolithium reagent is 1:(1.0-3.0):(1.0-3.0), preferably 1:2.5:2.5; the mass-volume ratio of compound V and tetrahydrofuran is 1:20.

[0030] Beneficial effects

[0031] This invention provides a method for preparing (R)-quinin-3-yl(2-benzoylphenylethyl)carbamate, which uses o-phenylhaloethylamine as a raw material, which is simple and readily available. This invention yields the product in only three reaction steps, with a short process route, simple operation, and high product purity, providing a high-quality reference standard for the quality study of solifenacin succinate. Detailed Implementation

[0032] The method of the present invention will be further described below with reference to embodiments. The following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0033] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0034] Example 1

[0035]

[0036] Synthesis of Compounds of Formula III

[0037] Compound II (14.3 g, 71.5 mmol) and THF (286 ml) were added to a 500 ml round-bottom flask and stirred until completely dissolved. N,N-diisopropylethylamine (18.5 g, 143.0 mmol) and N,N'-carbonyldiimidazole (CDI) (12.7 g, 78.6 mmol) were added, and the mixture was reacted at 30 °C for 3 h. The reaction mixture was added to water (300 ml), extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until no fraction remained. Dichloromethane (30 ml) was added to the concentrate, and the mixture was stirred at 30 °C for 30 min, filtered, and the filter cake was dried at 50 °C for 8 h to give 20.0 g of white solid compound III, with a yield of 95%.

[0038] Synthesis of compound V

[0039] Compound IV (7.0 g, 55.1 mmol) and N,N-dimethylformamide (180 ml) were added to a 500 ml round-bottom flask, protected with argon gas, and cooled with stirring. 内 At 0°C, add NaH (2.2 g, 55.1 mmol), stir for 20 min, and add dropwise a solution of N,N-dimethylformamide (80 ml) containing compound III (13 g, 44.2 mmol). After the addition is complete, react at 20°C for 3 h. Add the reaction solution to water (800 ml), extract with ethyl acetate, wash the organic phase with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure until no fraction remains, purify the concentrate by column chromatography, elute with dichloromethane:methanol = 10:1, collect the eluent and concentrate under reduced pressure until no fraction remains, to give 12.5 g of pale yellow oily compound V, yield 80.0%.

[0040] Synthesis of Compound I

[0041] Compound V (12.5 g, 35.4 mmol) and THF (200 ml) were added to a 500 ml round-bottom flask, protected with argon gas, and cooled with stirring. 内 At -70℃, n-butyllithium (35.4 ml, 88.5 mmol) was added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 20 min. Then, a tetrahydrofuran (50 ml) solution of compound VI (14.4 g, 88.5 mmol) was added dropwise. After the addition was complete, the mixture was reacted at 30℃ for 1 h. The reaction was quenched by adding saturated ammonium chloride aqueous solution (80 ml). The mixture was extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until no fraction remained. The concentrate was purified by column chromatography using dichloromethane:methanol = 7:1. The eluent was collected and concentrated under reduced pressure until no fraction remained, yielding 10.5 g of a colorless oily compound I, with a yield of 78.3% and an HPLC area-normalized purity of 99.60%.

[0042] 1 H-NMR (400MH) Z ,d 6 -DMSO): (ppm)=1.57~1.83(m, 4H); 1.97~2.03(m, 1H); 2.73(t, 2H); 2.80~2.84(m, 1H); 2.94~3.17(m, 6H); 3.37 ~3.42 (m, 1H); 4.63 ~ 4.65 (m, 1H); 7.23 (d, 1H); 7.33 (t, 1H); 7.39 (d, 1H); 7.47 ~ 7.55 (m, 3H); 7.65 ~ 7.71 (m, 3H).

[0043] MS-ESI: 379.1 [M+1] + 757.2 [2M+1] + 779.2[2M+Na] + .

Claims

1. A method for preparing a compound of formula I, comprising the following steps: in, X is Cl, Br, or I. a) The compound of formula II was reacted with N,N'-carbonyldiimidazole (CDI) in the presence of a base to give the compound of formula III; b) Reacting compound III with compound IV in the presence of a base yields compound V; c) React compound V with an organolithium reagent, and then react it with compound VI to obtain compound I; The organolithium reagent mentioned in step c) is n-butyllithium, tert-butyllithium, or diisopropylaminolithium.

2. The preparation method according to claim 1, wherein, The molar ratio of compound II, CDI, and base in step a) is 1:(0.8-1.2):(1.0-3.0).

3. The preparation method according to claim 2, wherein, The molar ratio of compound II, CDI, and base in step a) is 1:1.1:2.

0.

4. The preparation method according to claim 1, wherein, The base mentioned in step a) is an inorganic base or an organic base.

5. The preparation method according to claim 4, wherein, The base mentioned in step a) is selected from triethylamine, N,N-diisopropylethylamine or potassium carbonate.

6. The preparation method according to claim 1, wherein, The reaction described in step a) is carried out in a solvent, wherein the solvent is acetonitrile, N,N-dimethylformamide, tetrahydrofuran, or dichloromethane; and / or the reaction temperature is 20°C to 80°C.

7. The preparation method according to any one of claims 1-6, wherein, In step b), the molar ratio of compound III, compound IV, and the base is 1:(0.8-1.5):(0.8-1.5).

8. The preparation method according to claim 7, wherein, In step b), the molar ratio of compound III, compound IV, and the base is 1:1.25:1.

25.

9. The preparation method according to any one of claims 1-6, wherein, The base mentioned in step b) is an inorganic base or an organic base.

10. The preparation method according to claim 9, wherein, The base mentioned in step b) is selected from triethylamine, N,N-diisopropylethylamine, potassium tert-butoxide, sodium tert-butoxide, or sodium hydride.

11. The preparation method according to any one of claims 1-6, wherein, The reaction described in step b) is carried out in a solvent, wherein the solvent is acetonitrile, N,N-dimethylformamide, tetrahydrofuran, or dichloromethane; and / or the reaction temperature is 20°C to 60°C.

12. The preparation method according to any one of claims 1-6, wherein, In step c), the molar ratio of compounds V, VI, and organolithium reagent is 1:(1.0-3.0):(1.0-3.0).

13. The preparation method according to claim 12, wherein, In step c), the molar ratio of compounds V, VI, and the organolithium reagent is 1:2.5:2.

5.

14. The preparation method according to any one of claims 1-6, wherein the reaction in step c) is carried out in a solvent, wherein the solvent is diethyl ether or tetrahydrofuran; and / or, the temperature of the reaction is 20°C to 40°C.

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