A process for the preparation of SNRIs drugs

Abstract

This application provides a method for preparing compound I-b or a pharmaceutically acceptable salt thereof, wherein (S)-N-methylamino-1-(2-thiophene)-1-propanol reacts with 4-fluorobenzo[1,3]dioxolane in a system containing sodium hydride and potassium benzoate to obtain compound I-b. This method has short steps, mild reaction conditions, and is simple to operate, making it suitable for industrial scale-up; moreover, the obtained product has high purity and low isomer content.

Description

Technical Field

[0001] This patent belongs to the pharmaceutical field and specifically relates to a method for preparing a 5-hydroxytryptamine / norepinephrine (5-HT / NE) dual reuptake inhibitor (SNRI) drug. Background Technology

[0002] Depression, characterized by its high incidence, high suicide rate, high relapse rate, high disability rate, low recognition, low consultation rate, and low treatment rate, has become a serious global public health problem and a prominent social issue. Currently, clinical antidepressants mainly consist of dual serotonin / norepinephrine (5-HT / NE) reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs). SNRIs can simultaneously increase the levels of 5-HT and NE in the synaptic cleft of brain tissue, exhibiting superior antidepressant activity, onset rate, and analgesic activity compared to SSRIs. Therefore, novel antidepressants with dual reuptake inhibition have a clearly defined target, enormous market potential, and significant social implications.

[0003] Chinese patent CN200810127171.5 discloses a compound I (structure shown in Formula I) with SNRI activity. Compound I selectively binds to SERT and NET with high affinity and strongly inhibits the reuptake of 5-HT and NE. Its target affinity and reuptake inhibition are stronger than those of the antidepressant duloxetine. CN201110183400.7 further discloses the R and S isomers of compound I (structures shown in Formulas Ia and Ib, denoted as compounds Ia and Ib).

[0004]

[0005] Chinese patent CN200810127171.5 discloses a method for synthesizing compound I. This method is not only lengthy, but also uses toxic and harmful reagents in the reaction, requires anhydrous solvents, and requires column chromatography separation, making it unsuitable for industrial production.

[0006]

[0007] Chinese patent CN201110183400.7 discloses a method for synthesizing compounds Ia, Ib (referred to as compounds Ia and Ib in patent 400.7) and their salts. Each step requires column chromatography separation, which is not suitable for industrial scale-up.

[0008]

[0009] Example 3 of Chinese patent CN201710840871.8 discloses a method for synthesizing compound Ib (referred to as compound I in patent 871.8). This method involves high reaction temperature and long reaction time, and requires column chromatography for separation, making it unsuitable for industrial scale-up.

[0010] Summary of the Invention

[0011] To address the aforementioned deficiencies, this application provides a novel method for preparing compound Ib or its pharmaceutically acceptable salts. The compound Ib or its pharmaceutically acceptable salts prepared according to this method have high purity and low isomerism. Furthermore, the method has a short route, high yield, simple operation, and mild reaction conditions, making it suitable for industrial production.

[0012] This application provides a method for preparing compound Ib or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0013]

[0014] (S)-N-methylamino-1-(2-thiophene)-1-propanol (SM2) reacts with 4-fluorobenzo[1,3]dioxolane in a system containing sodium hydride and potassium benzoate to give compound Ib.

[0015] In some embodiments, the preparation method includes: dissolving SM2 in solvent 1, adding sodium hydride and potassium benzoate, adding a solution of 4-fluorobenzo[1,3]dioxane dissolved in solvent 1, and reacting to obtain compound Ib.

[0016] In some embodiments, the preparation method includes: dissolving SM2 in solvent 1, adding sodium hydride and potassium benzoate, heating to 50-70°C, adding a solution of 4-fluorobenzo[1,3]dioxolane dissolved in solvent 1, and reacting to obtain compound Ib.

[0017] In some embodiments, the preparation method includes: dissolving SM2 in solvent 1, adding sodium hydride and potassium benzoate, heating to 50-70°C, adding a solution of 4-fluorobenzo[1,3]dioxane dissolved in solvent 1, and reacting. After the reaction is complete, water is added, the mixture is extracted with an organic solvent, the organic phases are combined, and the mixture is concentrated under reduced pressure to obtain compound Ib.

[0018] In some embodiments, the preparation method includes: dissolving SM2 in solvent 1, adding sodium hydride and potassium benzoate, heating to 50-70°C, adding a solution of 4-fluorobenzo[1,3]dioxane dissolved in solvent 1, and reacting. After the reaction is complete, water is added, the mixture is extracted with an organic solvent, the organic phases are combined, washed with water, dried, and concentrated under reduced pressure to obtain compound Ib.

[0019] In some embodiments, the preparation method includes: dissolving SM2 in solvent 1, adding sodium hydride, adding potassium benzoate, heating to 50-70°C, adding a solution of 4-fluorobenzo[1,3]dioxane dissolved in solvent 1, and reacting for 3-10 hours. After the reaction is complete, water is added, and the mixture is extracted with n-hexane. The organic phases are combined and concentrated under reduced pressure to obtain compound Ib.

[0020] In some embodiments, the preparation method includes: dissolving SM2 in solvent 1, adding sodium hydride, adding potassium benzoate, heating to 50-70°C, adding a solution of 4-fluorobenzo[1,3]dioxane dissolved in solvent 1, and reacting for 3-10 hours. After the reaction is complete, water is added, and the mixture is extracted with n-hexane. The organic phases are combined, washed with water, dried, and concentrated under reduced pressure to obtain compound Ib.

[0021] In some embodiments, the solvent 1 is selected from one or more of N,N-dimethylformamide and dimethyl sulfoxide.

[0022] In some embodiments, the molar ratio of 4-fluorobenzo[1,3]dioxolane to SM2 is about 1:(1-5), preferably 1:(1-3) or 1:(1-2).

[0023] In some embodiments, the SM2 is dissolved in solvent 1, and the volume ratio of SM2 to solvent 1 is approximately 1:(3-15), 1:(3-12), or 1:(5-10).

[0024] In some embodiments, the SM2 is dissolved in solvent 1, and the weight-to-volume ratio of SM2 to solvent 1 is approximately 1:(3-15), 1:(3-12), or 1:(5-10).

[0025] In some embodiments, the 4-fluorobenzo[1,3]dioxolane is dissolved in a solution of solvent 1, and the volume ratio of 4-fluorobenzo[1,3]dioxolane to solvent 1 is approximately 1:(0.5-10) or 1:(0.8-8) or 1:(1-5).

[0026] In some embodiments, the 4-fluorobenzo[1,3]dioxolane is dissolved in a solution of solvent 1, and the weight-to-volume ratio of 4-fluorobenzo[1,3]dioxolane to solvent 1 is approximately 1:(0.5-10) or 1:(0.8-8) or 1:(1-5).

[0027] In some embodiments, the molar ratio of 4-fluorobenzo[1,3]dioxolane to sodium hydride is 1:(1-3) or 1:(1-2) or 1:(1-1.5).

[0028] In some embodiments, the molar ratio of 4-fluorobenzo[1,3]dioxolane to potassium benzoate is 1:(0.3-1.5) or 1:(0.5-1) or 1:(0.5-0.8).

[0029] In some embodiments, the preferred molar ratio of 4-fluorobenzo[1,3]dioxolane to sodium hydride and potassium benzoate is 1:(1-2):(0.5-1) or 1:(1-1.5):(0.5-0.8).

[0030] In some implementations, the reaction temperature is 50-70°C, preferably 50-65°C or 50-60°C.

[0031] In some implementations, the reaction time is 3-10 hours, preferably 3-8 hours.

[0032] In some embodiments, water is added at the end of the reaction, the volume of which is 10-20 times the volume of 4-fluorobenzo[1,3]dioxolane, preferably 10-15 times the volume of 4-fluorobenzo[1,3]dioxolane.

[0033] In some embodiments, water is added at the end of the reaction, wherein the weight-to-volume ratio of the 4-fluorobenzo[1,3]dioxolane to water is 1:(10-20), preferably 1:(10-15).

[0034] In some embodiments, the organic solvent extraction is performed using an organic solvent selected from petroleum ether, n-hexane, n-pentane, isopentane, cyclohexane, isooctane, and trimethylpentane, preferably n-hexane. The volume of the organic solvent is 1-10 times the volume of 4-fluorobenzo[1,3]dioxolane, preferably 3-8 times the volume of 4-fluorobenzo[1,3]dioxolane. In some embodiments, the organic solvent extraction is performed 3-5 times. In some embodiments, the weight-to-volume ratio of 4-fluorobenzo[1,3]dioxolane to the organic solvent is 1:(1-10), preferably 1:(3-8).

[0035] In some embodiments, hexane extraction is performed, wherein the volume of hexane is 1-10 times the volume of 4-fluorobenzo[1,3]dioxolane, preferably 3-8 times the volume of 4-fluorobenzo[1,3]dioxolane. In some embodiments, hexane extraction is performed 3-5 times. In some embodiments, the weight-to-volume ratio of 4-fluorobenzo[1,3]dioxolane to hexane is 1:(1-10), preferably 1:(3-8).

[0036] In some embodiments, washing is performed with water, the volume of which is 10-20 times the volume of 4-fluorobenzo[1,3]dioxolane, preferably 10-15 times the volume of 4-fluorobenzo[1,3]dioxolane. In some embodiments, the weight-to-volume ratio of 4-fluorobenzo[1,3]dioxolane to water is 1:(10-20), preferably 1:(10-15).

[0037] In some implementations, the drying process uses anhydrous sodium sulfate.

[0038] In some embodiments, the preparation method further includes:

[0039]

[0040] 3-Fluoro-catechol (SM1) was dissolved in solvent 2, and potassium carbonate and dibromomethane were added to react and give 4-fluorobenzo[1,3]dioxolane.

[0041] In some embodiments, the preparation method includes: dissolving 3-fluorocatechol (SM1) in solvent 2, adding potassium carbonate and dibromomethane, heating to 70-120°C to react, and reacting to obtain 4-fluorobenzo[1,3]dioxolane.

[0042] In some embodiments, the preparation method includes: dissolving 3-fluorocatechol (SM1) in solvent 2, adding potassium carbonate and dibromomethane, and heating to 70-120°C for reaction; after the reaction is completed, adding water, extracting with an organic solvent, combining the organic phases, washing with water, drying, and concentrating under reduced pressure to obtain 4-fluorobenzo[1,3]dioxolane.

[0043] In some embodiments, the preparation method includes: dissolving 3-fluorocatechol (SM1) in solvent 2, adding potassium carbonate and dibromomethane, heating to 70-120°C and reacting for 1-6 hours; after the reaction is completed, adding water, extracting with n-hexane, combining the organic phases, concentrating under reduced pressure to obtain 4-fluorobenzo[1,3]dioxolane.

[0044] In some embodiments, the preparation method includes: dissolving 3-fluorocatechol (SM1) in solvent 2, adding potassium carbonate and dibromomethane, heating to 70-120°C and reacting for 1-6 hours; after the reaction is completed, adding water, extracting with n-hexane, combining the organic phases, washing with water, drying, and concentrating under reduced pressure to obtain 4-fluorobenzo[1,3]dioxolane.

[0045] In some embodiments, the solvent 2 is selected from one or both of N,N-dimethylformamide and N,N-dimethylacetamide.

[0046] In some embodiments, the volume ratio of SM1 to solvent 2 is approximately 1:(5-30) or 1:(10-20). In some embodiments, the weight-volume ratio of SM1 to solvent 2 is approximately 1:(5-30) or 1:(10-20).

[0047] In some embodiments, the molar ratio of SM1 to dibromomethane is 1:(1-5) or 1:(1.5-3).

[0048] In some embodiments, the molar ratio of SM1 to potassium carbonate is 1:(0.5-5), 1:(1-3), or 1:(1-2.5).

[0049] In some embodiments, the molar ratio of SM1 to dibromomethane and potassium carbonate is preferably 1:(1-5):(0.5-5), 1:(1.5-3):(1-3), or 1:(1.5-3):(1-2.5).

[0050] In some implementations, the reaction temperature is 70-120°C, preferably 80-110°C.

[0051] In some implementations, the reaction time is 1-6 hours, preferably 1-3 hours.

[0052] In some embodiments, water is added after the reaction is complete, the volume of which is 10-20 times the volume of SM1, preferably 10-15 times the volume of SM1. In some embodiments, the weight-to-volume ratio of SM1 to water is 1:(10-20), preferably 1:(10-15).

[0053] In some embodiments, extraction is performed using an organic solvent selected from petroleum ether, n-hexane, n-pentane, isopentane, cyclohexane, isooctane, and trimethylpentane, with n-hexane being preferred. The volume of the organic solvent is 1-10 times the volume of SM1, preferably 3-8 times or 3-5 times the volume of SM1. In some embodiments, the organic solvent is used for 3-5 extractions. In some embodiments, the weight-to-volume ratio of SM1 to the organic solvent is 1:(1-10), preferably 1:(3-8) or 1:(3-5).

[0054] In some embodiments, hexane extraction is performed, wherein the volume of hexane is 1-10 times the volume of SM1, preferably 3-8 times or 3-5 times the volume of SM1. In some embodiments, hexane extraction is performed 3-5 times. In some embodiments, the weight-to-volume ratio of SM1 to hexane is 1:(1-10), preferably 1:(3-8) or 1:(3-5).

[0055] In some embodiments, water washing is performed, wherein the volume of water is 5-20 times the volume of SM1, preferably 8-15 times the volume of SM1. In some embodiments, the weight-to-volume ratio of SM1 to water is 1:(5-20), preferably 1:(8-15).

[0056] In some implementations, the drying process uses anhydrous sodium sulfate.

[0057] In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt with the structure shown in Formula II (denoted as Compound II):

[0058]

[0059] The preparation method of compound II includes:

[0060]

[0061] Compound Ib was dissolved in solvent 3, hydrochloric acid was added, the mixture was stirred to crystallize, centrifuged, washed, and dried under vacuum to obtain compound II.

[0062] In some embodiments, the preparation method includes: dissolving compound Ib in solvent 3, cooling to 0-20°C, adding hydrochloric acid, stirring to crystallize, centrifuging, washing, and vacuum drying to obtain compound II.

[0063] In some embodiments, the solvent 3 is selected from acetonitrile, ethyl acetate, and acetone.

[0064] In some embodiments, the volume ratio of compound Ib to solvent 3 is approximately 1:(5-15), preferably 1:(5-10). In some embodiments, the weight-volume ratio of compound Ib to solvent 3 is approximately 1:(5-15), preferably 1:(5-10).

[0065] In some embodiments, the molar ratio of compound Ib to hydrochloric acid is 1:(1-3) or 1:(1-2), preferably 1:(1-1.5).

[0066] In some implementations, the temperature is lowered to 0-20°C, preferably to 0-10°C.

[0067] In some implementations, the reaction time is 2-8 hours, preferably 2-5 hours.

[0068] In some embodiments, the preparation method of compound II includes:

[0069]

[0070] or

[0071]

[0072] or

[0073]

[0074] The specific methods and parameters for each step are as described above.

[0075] Secondly, this application also provides a compound II active pharmaceutical ingredient, which is prepared by the above method.

[0076] In some embodiments, the purity of the active pharmaceutical ingredient of Compound II described in this application is above 99%, preferably above 99.5%.

[0077] In some embodiments, the content of the R-isomer of the compound II active pharmaceutical ingredient described in this application is less than 0.5%, preferably less than 0.3%.

[0078] For the sake of brevity, the term "about" is not used for some quantitative data herein. It should be understood that, whether the term "about" is explicitly used or not, every numerical value given herein includes not only the actual given value (the given value), but also an approximation of such a given value based on reasonable deduction by one of ordinary skill in the art, including equivalents and approximations of such a given value due to experimental and / or measurement conditions. These approximations are preferably ±20%, ±15%, ±10%, ±8%, ±6%, ±5%, ±4%, ±3%, 2%, or ±1% of the given value. In some embodiments, the approximations are obtained by rounding.

[0079] The weight-to-volume ratio mentioned in this application refers to the weight of the solid material (g) / the volume of the liquid material (ml).

[0080] This application provides a method for preparing compound Ib or its pharmaceutically acceptable salt, resulting in a product with high purity and low isomer content; moreover, the method has short steps, mild reaction conditions, and is easy to operate, making it suitable for industrial scale-up. Specific Implementation

[0081] The present application is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the application. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer.

[0082] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this application. The preferred embodiments and materials described herein are for illustrative purposes only.

[0083] Unless otherwise specified, all compounds, solvents and other materials used in this application are commercially available products.

[0084] The "purity" mentioned in this article refers to high performance liquid chromatography purity, determined according to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0085] The content of the R-isomer was determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0086] Synthesis of 4-fluorobenzo[1,3]dioxolane:

[0087] Example 1

[0088] 100 g of 3-fluorocatechol (SM1) was dissolved in 1200 ml of N,N-dimethylformamide, and 136 g of potassium carbonate and 204 g of dibromomethane were added. The mixture was heated to 80 °C and reacted for 4 h. After the reaction was completed, 1000 ml of purified water was added, and the mixture was extracted three times with 450 ml of n-hexane. The organic phases were combined, washed with 800 ml of purified water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 95.1 g of 4-fluorobenzo[1,3]dioxolane, with a yield of 87.0% and a purity of 93.2%. MS (ESI) m / z: 142.14 (M+1). 1 H-NMR (600MHz, MeOD): 5.99 (s, 2H); 6.66-6.69 (m, 2H); 6.78-6.81 (m, 1H).

[0089] Example 2

[0090] 150g of SM1 was dissolved in 2200ml of N,N-dimethylformamide, and 324g of potassium carbonate and 407g of dibromomethane were added. The mixture was heated to 90℃ and reacted for 4 hours. After the reaction was completed, 1800ml of purified water was added, and the mixture was extracted three times with 500ml of n-hexane. The organic phases were combined, washed with 1600ml of purified water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 143.6g of 4-fluorobenzo[1,3]dioxolane, with a yield of 87.5% and a purity of 94.1%.

[0091] Example 3

[0092] 120g of SM1 was dissolved in 2160ml of N,N-dimethylformamide, and 325g of potassium carbonate and 408g of dibromomethane were added. The mixture was heated to 100℃ and reacted for 3 hours. After the reaction was completed, 1700ml of purified water was added, and the mixture was extracted three times with 450ml of n-hexane. The organic phases were combined, washed with 1500ml of purified water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 113.9g of 4-fluorobenzo[1,3]dioxolane, with a yield of 86.8% and a purity of 94.9%.

[0093] Example 4

[0094] 180g of SM1 was dissolved in 3600ml of N,N-dimethylformamide, and 485g of potassium carbonate and 733g of dibromomethane were added. The mixture was heated to 110℃ and reacted for 2 hours. After the reaction was completed, 2700ml of purified water was added, and the mixture was extracted three times with 900ml of n-hexane. The organic phases were combined, washed with 1800ml of purified water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 170.3g of 4-fluorobenzo[1,3]dioxolane, with a yield of 86.5% and a purity of 94.2%.

[0095] Preparation of compound Ib:

[0096] In Examples 5-8 below, the purity of (S)-N-methylamino-1-(2-thiophene)-1-propanol (SM2) was 99.5%, and the content of the R-isomer was 0.4%.

[0097] Example 5

[0098] 121 g of SM2 was dissolved in 610 ml of N,N-dimethylformamide, 29 g of sodium hydride was added, 52 g of potassium benzoate was added, the mixture was heated to 60 °C, and 90 g of 4-fluorobenzo[1,3]dioxolane (prepared from Example 1) dissolved in 90 ml of N,N-dimethylformamide solution was added. The reaction was allowed to proceed for 5 h, 900 ml of purified water was added, and the mixture was extracted three times with 320 ml of n-hexane. The organic phases were combined, washed with 650 ml of purified water, dried over 30 g of anhydrous sodium sulfate, and concentrated under reduced pressure to give 84.0 g of compound Ib. Yield 44.9%, purity 94.8%, isomers 1.8%. MS (ESI) m / z: 292.07 (M+1); 1 H-NMR (600MHz, MeOD): δ2.09-2.11(m,1H),2.28-2.30(m,1H); 2.35(s,3H); 2.66-2.69(m,1H); 2.7-2.73(m,1H); 5.67- 5.69(m,1H); 5.89(d,2H); 6.45-6.47(t,2H); 6.61-6.64(t,1H); 6.90-6.92(dd,1H); 7.02(dd,1H); 7.31-7.32(d,1H).

[0099] Example 6

[0100] 239 g of SM2 was dissolved in 1430 ml of dimethyl sulfoxide, 56 g of sodium hydride was added, followed by 89 g of potassium benzoate. The mixture was heated to 50 °C, and 130 g of 4-fluorobenzo[1,3]dioxolane (prepared in Example 2) dissolved in 260 ml of dimethyl sulfoxide was added. The reaction was allowed to proceed for 6 h. 1300 ml of purified water was added, and the mixture was extracted three times with 400 ml of n-hexane. The combined organic phases were washed with 800 ml of purified water, dried over 50 g of anhydrous sodium sulfate, and concentrated under reduced pressure to give 122.2 g of compound Ib. The yield was 45.2%, the purity was 93.4%, and the isomers were 1.5%.

[0101] Example 7

[0102] 175 g of SM2 was dissolved in 1500 ml of N,N-dimethylformamide, 38 g of sodium hydride was added, followed by 100 g of potassium benzoate. The mixture was heated to 60 °C, and 110 g of 4-fluorobenzo[1,3]dioxolane (prepared in Example 3) was added to a solution of 330 ml of N,N-dimethylformamide. The reaction was allowed to proceed for 5 h. The mixture was then extracted three times with 1650 ml of purified water and 600 ml of n-hexane. The combined organic phases were washed with 1000 ml of purified water, dried over 60 g of anhydrous sodium sulfate, and concentrated under reduced pressure to give 107.1 g of compound Ib. The yield was 45.0%, the purity was 95.6%, and the isomers were 1.7%.

[0103] Example 8

[0104] 391 g of SM2 was dissolved in 3900 ml of dimethyl sulfoxide, 68 g of sodium hydride was added, 146 g of potassium benzoate was added, the mixture was heated to 60 °C, and 160 g of 4-fluorobenzo[1,3]dioxolane (prepared in Example 4) dissolved in 800 ml of dimethyl sulfoxide was added. The reaction was allowed to proceed for 3 h, then 2000 ml of purified water was added, and the mixture was extracted three times with 1200 ml of n-hexane. The organic phases were combined, washed with 1500 ml of purified water, dried over 100 g of anhydrous sodium sulfate, and concentrated under reduced pressure to give 150.7 g of compound Ib. Yield: 45.3%, purity: 94.1%, isomers: 1.6%. Preparation of compound II:

[0105] In the following Examples 9-12, the hydrochloric acid concentration was 33%, and the amount of hydrochloric acid used was calculated as HCl.

[0106] Example 9

[0107] 80 g of compound Ib (prepared in Example 5) was dissolved in 800 ml of acetonitrile, cooled to 10 °C, and 33 g of hydrochloric acid was added. The mixture was stirred to induce crystallization for 2 h, centrifuged, washed, and dried under vacuum to give 78.3 g of compound II. Yield: 87.0%, purity: 99.8%, isomers: 0.15%. Melting point: 151–152 °C; specific rotation: -132°; MS (ESI) m / z: 292.06 (M+1). 1 H-NMR (600MHz, MeOD): δ2.32-2.34(m,1H),2.49-2.50(m,1H); 2.73(s,3H); 3.20-3.22(m,1H); 3.28-3.31(m,1H); 5.76 -5.78(m,1H); 5.93(d,2H); 6.47-6.51(t,2H); 6.63-6.66(t,1H); 6.94-6.96(dd,1H); 7.09(dd,1H); 7.37-7.38(d,1H).

[0108] Example 10

[0109] 120 g of compound Ib (prepared in Example 6) was dissolved in 1200 ml of ethyl acetate, cooled to 8 °C, and 61 g of hydrochloric acid was added. The mixture was stirred and crystallized for 5 h. After centrifugation, washing, and vacuum drying, 120.3 g of compound II was obtained. The yield was 89.1%, the purity was 99.8%, and the isomers were 0.16%.

[0110] Example 11

[0111] 100g of compound Ib (prepared in Example 7) was dissolved in 800ml of acetone, cooled to 5°C, and 61g of hydrochloric acid was added. The mixture was stirred and crystallized for 3 hours. After centrifugation, washing, and vacuum drying, 102.1g of compound II was obtained. The yield was 90.7%, the purity was 99.7%, and the isomers were 0.14%.

[0112] Example 12

[0113] 140 g of compound Ib (prepared in Example 8) was dissolved in 1400 ml of ethyl acetate, cooled to 7°C, and 66 g of hydrochloric acid was added. The mixture was stirred to induce crystallization for 4 h, centrifuged, washed, and dried under vacuum to give 139.6 g of compound II. The yield was 88.6%, the purity was 99.8%, and the isomers were 0.15%.

[0114] Comparative Example 1

[0115] Compound Ib was prepared according to the method described in Examples 3-5 of Chinese Patent CN201110183400.7, with the specific steps as follows:

[0116] 35.3 g of compound 4b (purity 99.5%, R-isomer content 0.4%) was added to 200 mL of anhydrous DMSO and stirred thoroughly to dissolve. Then, 6.9 g of NaH was added in portions, the temperature was raised to 60 °C, and the mixture was stirred vigorously for about 0.5 h until the reaction solution was clear. 6.1 g of potassium benzoate was added and stirred for 20 min. 40 g of 4-fluorobenzo[1,3]dioxolane (compound 3, purity 94.2%) dissolved in 50 mL of DMSO solution was added dropwise. After the addition was complete, the reaction was maintained at 60 °C for about 8 h. The reaction solution was poured into 200 mL of ice water, the pH was adjusted to 4.5 with dilute hydrochloric acid (0.5 mol / L), and extracted three times with petroleum ether. The aqueous phase was adjusted to pH 10 with 25% ammonia water, extracted with ethyl acetate, washed with saturated sodium chloride solution until neutral, and then dried with anhydrous sodium sulfate. The desiccant was filtered off, the solvent was removed by vacuum distillation, and the residue was separated by silica gel column chromatography. The residue was eluted with dichloromethane: ethyl acetate: anhydrous ethanol: ammonium hydroxide (8:1:1:0.05), and the desired fraction was collected and evaporated to dryness under vacuum to give a yellow oily substance (S)-N,N-dimethyl-3-[(benzo[1,3]dioxolane-4-yl)-oxy]-3-(thiophene-2-yl)-propylamine (intermediate 5b).

[0117] Intermediate 5b and 33 mL of diisopropylethylamine were added to 900 mL of toluene and stirred thoroughly. The mixture was then heated to 50 °C. 24 mL of phenyl chloroformate solution dissolved in 100 mL of toluene was added dropwise. After the addition was complete, the temperature was controlled at 55-60 °C and the reaction was carried out for about 2.5 h. After the reaction was complete as monitored by TLC, 600 mL of 5% sodium bicarbonate aqueous solution was added and the mixture was stirred at room temperature for 30 min. The organic layer was separated, washed twice with 5% sodium bicarbonate aqueous solution, and washed with distilled water until neutral. Toluene was removed by vacuum distillation, and a yellow oily substance was obtained, which was intermediate 6b.

[0118] Intermediate 6b was added to 1000 mL of DMSO and stirred thoroughly. A solution of 24.3 g NaOH dissolved in 150 mL of water was added dropwise. After the addition was complete, the temperature was raised to 55-60 °C and the reaction was controlled for 14 h. The reaction solution was poured into 3000 mL of ice water and placed in an ice-salt bath. The pH was adjusted to 4-5 with 1 mol / L hydrochloric acid. Extraction was performed with 900 mL × 2 of petroleum ether. The aqueous phase was adjusted to pH 10 with 25% ammonia, extracted with ethyl acetate, washed with saturated sodium chloride solution until neutral, and dried with anhydrous sodium sulfate. The drying agent was filtered off, and the solvent was removed under reduced pressure. The residue was separated by silica gel column chromatography, eluted with dichloromethane:ethyl acetate:anhydrous ethanol:ammonium hydroxide (8:2:2:0.1), and the desired fraction was collected. The fraction was evaporated under reduced pressure to obtain a yellow oily substance, which was the target compound Ib (i.e., compound Ib described in this application).

[0119] The overall yield of the above reaction was 40.6%, the purity of the product was 92.9%, and the R-isomer content was 2.8%.

[0120] Comparative Example 2

[0121] Compound Ib was prepared according to the method described in Example 3 of Chinese Patent 201710840871.8:

[0122] 20 g of 4-fluorobenzo[1,3]dioxolane (purity 94.2%), 12.2 g of SM2 (purity 99.5%, R-isomer content 0.4%), and 8 g of potassium tert-butoxide were dissolved in 714 mL of dimethyl sulfoxide and reacted at 140 °C for 12 hours. After the reaction was completed, water was added to the reaction system, and the mixture was extracted three times with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by column chromatography (methanol / dichloromethane = 1:10) to give 13.6 g of compound Ib, yield 32.6%, purity 93.1%, R-isomer content 3.5%.

[0123] The reaction time, yield, product purity, and isomer content of Examples 5-8, Comparative Example 1, and Comparative Example 2 are summarized in the table below:

[0124]

[0125]

[0126] As can be seen, the method described in this application shortens the reaction steps and reaction time, provides milder reaction conditions, eliminates the need for column chromatography, and is more suitable for industrial production. Furthermore, the method of this application achieves higher overall yield, higher purity of the obtained product, and significantly reduced isomer content, resulting in unexpected technical benefits.

[0127] The main parameters for the synthesis of compound Ib were screened as follows:

[0128] Screening Example 1: Screening of Alkali Types

[0129] For the synthesis of compound Ib, the method described in Example 5 was followed, but the type of base was adjusted to investigate its effect on product yield, purity, and isomer content. The amount of 4-fluorobenzo[1,3]dioxolane remained unchanged, the molar ratio of 4-fluorobenzo[1,3]dioxolane to the base was 1:1, and the remaining parameters were the same as in Example 5. Specific parameters and results are shown in Table 1.

[0130] Table 1. Effects of base type on product yield, purity, and isomer content.

[0131] Reaction number Types of alkalis yield purity Isomer content 1 NaH 45.1％ 94.8％ 1.8％ 2 Sodium tert-butoxide 28.1％ 86.1％ 3.3％ 3 Potassium tert-butoxide 29.2％ 87.2％ 3.2％

[0132] Screening Example 2: Screening of 4-fluorobenzo[1,3]dioxolane / NaH ratio

[0133] For the synthesis of compound Ib, the method described in Example 5 was followed, with the amount of 4-fluorobenzo[1,3]dioxolane remaining unchanged. The ratio of 4-fluorobenzo[1,3]dioxolane to NaH was adjusted, and the effects on product yield, purity, and isomer content were investigated. The remaining parameters were the same as in Example 5. Specific parameters and results are shown in Table 2.

[0134] Table 24. Effects of the ratio of fluorobenzo[1,3]dioxolane to NaH on product yield, purity, and isomer content.

[0135]

[0136] Screening Example 3: Post-treatment Extractant Screening

[0137] For the synthesis of compound Ib, the method described in Example 5 was followed, but the type of extractant was adjusted to investigate its effect on product yield, purity, and isomer content. All other parameters remained the same as in Example 5. The results are shown in Table 3.

[0138] Table 3. Effects of post-treatment extractant on product yield, purity, and isomer content.

[0139] Reaction number Extractant yield purity Isomer content 1 n-Hexane 45.5％ 95.1％ 1.8％ 2 Ethyl acetate 47.8％ 88.6％ 1.9％

[0140] It is evident that, compared to ethyl acetate, using n-hexane as the extractant, although the yield and isomer content are comparable, results in a higher purity of the product.

Claims

1. A method for preparing a compound Ib or a pharmaceutically acceptable salt thereof, comprising the following steps: (S)-N-methylamino-1-(2-thiophene)-1-propanol (SM2) reacts with 4-fluorobenzo[1,3]dioxolane in a system containing sodium hydride and potassium benzoate to give compound Ib.

2. The preparation method according to claim 1, comprising: SM2 was dissolved in solvent 1, sodium hydride and potassium benzoate were added, and a solution of 4-fluorobenzo[1,3]dioxolane dissolved in solvent 1 was added to react and give compound Ib.

3. The preparation method according to claim 1, comprising: SM2 is dissolved in solvent 1, sodium hydride and potassium benzoate are added, the mixture is heated to 50-70℃, and a solution of 4-fluorobenzo[1,3]dioxolane dissolved in solvent 1 is added. The reaction proceeds. After the reaction is complete, water is added, and the mixture is extracted with an organic solvent. The organic phases are combined and concentrated under reduced pressure to obtain compound Ib. Or SM2 was dissolved in solvent 1, sodium hydride and potassium benzoate were added, and the mixture was heated to 50-70℃. A solution of 4-fluorobenzo[1,3]dioxane dissolved in solvent 1 was added, and the reaction was carried out. After the reaction was completed, water was added, and the mixture was extracted with an organic solvent. The organic phases were combined, washed with water, dried, and concentrated under reduced pressure to obtain compound Ib.

4. The preparation method according to claim 3, characterized in that: Solvent 1 is selected from one or more of N,N-dimethylformamide and dimethyl sulfoxide; and / or The molar ratio of 4-fluorobenzo[1,3]dioxolane to SM2 is approximately 1:(1-5), preferably 1:(1-3) or 1:(1-2); and / or The SM2 is dissolved in solvent 1, and the weight-to-volume ratio of SM2 to solvent 1 is approximately 1:(3-15) or 1:(3-12) or 1:(5-10); and / or The 4-fluorobenzo[1,3]dioxolane is dissolved in solvent 1, and the weight-to-volume ratio of 4-fluorobenzo[1,3]dioxolane to solvent 1 is approximately 1:(0.5-10) or 1:(0.8-8) or 1:(1-5); and / or The molar ratio of 4-fluorobenzo[1,3]dioxolane to sodium hydride is 1:(1-3) or 1:(1-2) or 1:(1-1.5); and / or The molar ratio of 4-fluorobenzo[1,3]dioxolane to potassium benzoate is 1:(0.3-1.5) or 1:(0.5-1) or 1:(0.5-0.8); and / or The preferred molar ratio of 4-fluorobenzo[1,3]dioxolane to sodium hydride and potassium benzoate is 1:(1-2):(0.5-1) or 1:(1-1.5):(0.5-0.8); and / or The reaction temperature is 50-70℃, preferably 50-65℃ or 50-60℃; and / or Reaction time 3-10 h, preferably 3-8 h; and / or Water is added at the end of the reaction, wherein the weight-to-volume ratio of the 4-fluorobenzo[1,3]dioxolane to water is 1:(10-20), preferably 1:(10-15; and / or Organic solvent extraction, wherein the organic solvent is selected from petroleum ether, n-hexane, preferably n-hexane; and / or The weight-to-volume ratio of 4-fluorobenzo[1,3]dioxolane to the organic solvent is 1:(1-10), preferably 1:(3-8); and / or Organic solvent extraction 3-5 times; and / or Washed with water, the weight-to-volume ratio of 4-fluorobenzo[1,3]dioxolane to water being 1:(10-20), preferably 1:(10-15); and / or The drying process uses anhydrous sodium sulfate.

5. The preparation method according to claim 1, comprising: 3-Fluoro-catechol was dissolved in solvent 2, and potassium carbonate and dibromomethane were added to react and give 4-fluorobenzo[1,3]dioxolane.

6. The preparation method according to any one of claims 1-5, wherein the pharmaceutically acceptable salt is a hydrochloride salt with the structure shown in formula II (denoted as compound II): The preparation method of compound II includes: Compound Ib was dissolved in solvent 3, hydrochloric acid was added, the mixture was stirred to crystallize, centrifuged, washed, and dried under vacuum to obtain compound II.

7. The preparation method according to claim 6, characterized in that: The preparation method of compound II includes:

8. A compound II active pharmaceutical ingredient, prepared by the method according to any one of claims 1-7.

9. The active pharmaceutical ingredient of compound II as described in claim 8, wherein the purity of compound II is above 99%, preferably above 99.5%.

10. The active pharmaceutical ingredient of compound II as described in claim 8, wherein the content of the R-isomer is less than 0.5%, preferably less than 0.3%.

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