A method for preparing a monoamine oxidase b inhibitor and salts thereof

Abstract

The application discloses a preparation method of a monoamine oxidase B inhibitor, and comprises the following steps: 6-fluoroindole and 1-(dimethylamino)-2-nitroethylene are subjected to trifluoroacetic acid catalysis to generate 6-fluoro-3-[(E)-2-nitrovinyl]-1H-indole, and then subjected to sodium borohydride and iron powder / hydrochloric acid reduction to generate 6-fluoro-tryptamine; under an acidic condition, Pictet-Spengler reaction is carried out between 6-fluoro-tryptamine and ethyl glyoxylate to generate ethyl 7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate and 7-fluoro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-carboxylate, and then subjected to oxidative dehydrogenation aromatization reaction to generate ethyl 7-fluoro-9H-pyrido[3,4-b]indole-1-carboxylate; under the catalysis of aluminum trichloride, amine ester exchange reaction is carried out between ethyl 7-fluoro-9H-pyrido[3,4-b]indole-1-carboxylate and 3-fluorobenzylamine to generate a target compound. The method has high overall yield.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a monoamine oxidase B inhibitor (7-fluoro-N-(3-fluorobenzyl)-9H-pyrido[3,4-b]indole-1-carboxamide) and a method for preparing its pharmaceutically acceptable salt. Background Technology

[0002] Monoamine oxidase B (MAO-B) is a flavin adenine dinucleotide (FAD)-dependent mitochondrial membrane-bound enzyme, mainly distributed in glial cells and peripheral tissues of the substantia nigra and striatum in the brain. Its core physiological function is to catalyze the oxidative deamination and degradation of monoamine neurotransmitters such as dopamine and norepinephrine, maintaining the homeostasis of monoamine substances in the nervous system (Neural Regen Res. 2024; 19, 16-21). Abnormal MAO-B activity is closely related to the occurrence and development of various diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), depression, neuropathic pain, and cerebral ischemia-reperfusion injury (Expert Opin Ther Pat. 2018; 28, 211-226).

[0003] Given the crucial role of MAO-B in neurotransmitter metabolism and disease pathology, it has become an important therapeutic target for neurodegenerative diseases. Studies have confirmed that MAO-B inhibitors can reduce dopamine degradation and improve neurotransmitter imbalance by inhibiting enzyme activity, while simultaneously reducing the generation of reactive oxygen species (ROS) in enzyme-catalyzed reactions, alleviating neuronal oxidative stress damage, thus exerting a dual effect of neuroprotection and symptom relief (Curr Neuropharmacol. 2024; 22, 1606-1620). Clinical studies have shown that MAO-B inhibitors can not only improve motor symptoms in patients with Parkinson's disease (PD) but also delay cognitive decline in patients with Alzheimer's disease (AD), and can produce a synergistic therapeutic effect when used in combination with drugs such as levodopa. Therefore, the development of highly effective MAO-B inhibitors has significant clinical value and market potential.

[0004] The inventors disclosed 7-fluoro-N-(3-fluorobenzyl)-9H-pyrido[3,4-b]indole-1-carboxamide (Formula I) in CN117003752A. This is a highly selective, reversible MAO-B inhibitor with good pharmacokinetic properties and safety. It not only improves motor symptoms of Parkinson's disease (PD) but also shows therapeutic potential in neuroprotection, improvement of non-motor symptoms, and delaying disease progression. However, the original synthetic route uses expensive starting materials 6-fluorotryptamine and palladium on carbon, and the product purification is cumbersome with a low overall yield (<30%), which is not conducive to large-scale industrial production. Therefore, it is necessary to develop an efficient method for preparing Compound I and its pharmaceutically acceptable salt to facilitate the development of novel MAO-B inhibitors.

[0005] Summary of the Invention

[0006] The purpose of this invention is to address the shortcomings of existing methods for preparing 7-fluoro-N-(3-fluorobenzyl)-9H-pyrido[3,4-b]indole-1-carboxamide, and to provide a new method for preparing 7-fluoro-N-(3-fluorobenzyl)-9H-pyrido[3,4-b]indole-1-carboxamide. This preparation process has the advantages of low reaction cost, simple operation, and high yield, and can meet the needs of large-scale production of pharmaceutical products.

[0007] The objective of this invention is achieved through the following technical solution:

[0008] A method for preparing a monoamine oxidase B inhibitor with the structure shown in Formula I, the synthetic route is as follows:

[0009] The process includes: using 6-fluoroindole and 1-(dimethylamino)-2-nitroethylene as raw materials, catalyzing with trifluoroacetic acid to generate 6-fluoro-3-[(E)-2-nitrovinyl]-1H-indole (compound III), which is then successively reduced by sodium borohydride and iron powder / hydrochloric acid to generate 6-fluorotryptamine (compound V); under acidic conditions, 6-fluorotryptamine reacts with ethyl glyoxylate in a Pictet-Spengler reaction to generate ethyl 7-fluoro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. Ethyl 7-fluoro-1-carboxylic acid ester (compound VIa) and ethyl 7-fluoro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-carboxylate (compound VIb) are then subjected to oxidative dehydrogenation aromatization with iodophenyl diacetate to generate ethyl 7-fluoro-9H-pyrido[3,4-b]indole-1-carboxylate (compound VII). Finally, under the catalysis of aluminum trichloride, ethyl 7-fluoro-9H-pyrido[3,4-b]indole-1-carboxylate undergoes an amino-ester exchange reaction with 3-fluorobenzylamine to generate the target compound.

[0010] Specifically, it includes the following steps:

[0011] Step (1): Using 6-fluoroindole (compound II) and 1-(dimethylamino)-2-nitroethylene as raw materials and trifluoroacetic acid as catalyst, 6-fluoroindole and 1-(dimethylamino)-2-nitroethylene undergo an electrophilic substitution reaction to generate compound III;

[0012] Step (2): Using a mixed solvent of tetrahydrofuran and methanol as the reaction solvent and sodium borohydride as the reducing agent, compound III undergoes a reduction reaction to generate compound IV;

[0013] Step (3): Using 60%–80% ethanol aqueous solution as the reaction solvent, in the presence of iron powder and hydrochloric acid, compound IV undergoes a reduction reaction to generate compound V;

[0014] Step (4): Using dichloromethane as the reaction solvent, under acidic conditions, compound V reacts with ethyl glyoxylate in a Pictet-Spengler cyclization reaction to generate a mixture of compounds VIa and VIb.

[0015] Step (5): Using N,N-dimethylformamide as the reaction solvent and iodophenyl diacetate as the oxidant, compounds VIa and VIb undergo an oxidative dehydrogenation aromatization reaction to generate compound VII;

[0016] Step (6): Using tetrahydrofuran as the reaction solvent, under the catalysis of aluminum trichloride, compound VII undergoes an amine transesterification reaction with 3-fluorobenzylamine to generate the monoamine oxidase B inhibitor shown in Formula I.

[0017] In step (1), the molar ratio of 6-fluoroindole to 1-(dimethylamino)-2-nitroethylene is 1:1 to 1:1.5, preferably 1:1.

[0018] The molar ratio of 6-fluoroindole to trifluoroacetic acid is 1:8 to 1:15, preferably 1:10.

[0019] The electrophilic substitution reaction is carried out at a temperature of 20–40°C, preferably 25°C; the electrophilic substitution reaction is carried out for a time of 1–3 h, preferably 2 h.

[0020] Specifically, at 0°C, 1-(dimethylamino)-2-nitroethylene was dissolved in trifluoroacetic acid, stirred, and 6-fluoroindole was added. The mixture was then heated to carry out an electrophilic substitution reaction.

[0021] After the reaction was completed, the reaction solution was added to a saturated NaHCO3 aqueous solution cooled by ice water, filtered, the filter cake was collected, and the filter cake was washed with water until the pH of the washing solution was neutral. After drying, compound III was obtained.

[0022] In step (2), the molar ratio of compound III to sodium borohydride is 1:1 to 1:1.5, preferably 1:1.1.

[0023] The volume ratio of tetrahydrofuran to methanol is 1:1 to 5:1, preferably 1:3 to 3.5:1, and more preferably 3.25:1.

[0024] The reduction reaction is carried out at a temperature of 20–40°C, preferably 25°C, and the reduction reaction is carried out for a time of 2–4 h, preferably 3 h.

[0025] Specifically, compound III is dissolved in a mixed solvent of tetrahydrofuran and methanol to obtain a solution of compound III; sodium borohydride is dissolved in tetrahydrofuran at 0°C to obtain a sodium borohydride solution; the solution of compound III is added dropwise to the sodium borohydride solution, and compound III undergoes a reduction reaction to generate compound IV.

[0026] After the reaction was complete, a saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous Na2SO4, and the solvent was removed by vacuum distillation to obtain compound IV.

[0027] In step (3), the molar ratio of compound IV to iron powder is 1:3 to 1:7, preferably 1:5 to 1:5.1, and more preferably 1:5; the molar ratio of compound IV to hydrochloric acid (calculated as HCl) is 1:2 to 1:4, preferably 1:3.

[0028] The temperature of the reduction reaction is 20-40℃, preferably 25℃; the time of the reduction reaction is 2-4 h, preferably 3 h.

[0029] Specifically, compound IV is dissolved in a reaction solvent, concentrated hydrochloric acid is added dropwise at 0°C, and the mixture is stirred until homogeneous. Iron powder is then added, and in the presence of iron powder and hydrochloric acid, compound IV undergoes a reduction reaction to generate compound V.

[0030] The concentration of the concentrated hydrochloric acid is 12.0 mol / L.

[0031] After the reaction was completed, the reaction solution was filtered, and the pH of the filtrate was adjusted to 9 with NaOH solution. The solid was removed by filtration, and the filtrate was extracted with dichloromethane. The organic layer was washed with saturated brine, dried with anhydrous Na2SO4, and the solvent was removed by vacuum distillation to obtain compound V.

[0032] In step (4), the molar ratio of compound V to ethyl glyoxylate is 1:1 to 1:1.5, preferably 1:1.2.

[0033] The acidic conditions are provided by an acidic substance. The acidic substance is any one of trifluoroacetic acid, hydrochloric acid, or sulfuric acid, preferably trifluoroacetic acid.

[0034] The molar ratio of compound V to the acidic substance is 1:1 to 1:3, preferably 1:2.

[0035] The Pictet-Spengler cyclization reaction is carried out at a temperature of 20–40°C, preferably 25°C; the Pictet-Spengler cyclization reaction is carried out for a time of 10–14 h, preferably 12 h.

[0036] Specifically, at 0°C, ethyl glyoxylate and an acidic substance are added to a dichloromethane solution of compound V. Under acidic conditions, compound V and ethyl glyoxylate undergo a Pictet-Spengler cyclization reaction to generate a mixture of compounds VIa and VIb.

[0037] After the reaction was completed, the pH of the reaction solution was adjusted to 8 with saturated NaHCO3 solution, extracted with dichloromethane, the organic layer was washed with saturated brine, dried with anhydrous Na2SO4, and the solvent was removed by vacuum distillation to obtain a mixture of compounds VIa and VIb.

[0038] In step (5), the total amount of compounds VIa and VIb is in a mass ratio of iodophenyl diacetate to 1:1 to 1:3, preferably 1:2.45 to 1:2.5.

[0039] The temperature of the oxidative dehydrogenation aromatization reaction is 80–120°C, preferably 100°C; the time of the oxidative dehydrogenation aromatization reaction is 2–4 h, preferably 3 h.

[0040] After the reaction was completed, the reaction was quenched with saturated NaHCO3 solution, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried with anhydrous Na2SO4, and the solvent was removed by vacuum distillation to obtain compound VII.

[0041] In step (6), the molar ratio of compound VII to aluminum trichloride is 1:0.5 to 1:1.5, preferably 1:1; the molar ratio of compound VII to 3-fluorobenzylamine is 1:1 to 1:5, preferably 1:3.

[0042] The temperature of the amine-ester exchange reaction is 20–40°C, preferably 25°C; the time of the amine-ester exchange reaction is 2–6 h, preferably 4 h.

[0043] After the reaction was completed, the pH of the reaction solution was adjusted to weakly acidic with dilute hydrochloric acid, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried with anhydrous Na2SO4, and the solvent was removed by vacuum distillation to obtain the crude monoamine oxidase B inhibitor shown in Formula I; at a temperature of 25°C, the crude monoamine oxidase B inhibitor shown in Formula I was recrystallized with a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:5 to obtain the monoamine oxidase B inhibitor shown in Formula I.

[0044] The concentration of the dilute hydrochloric acid is 2 mol / L.

[0045] The present invention also provides a method for preparing a salt of a monoamine oxidase B inhibitor represented by structural formula I, comprising: preparing a monoamine oxidase B inhibitor represented by formula I according to the method of the present invention, wherein the monoamine oxidase B inhibitor represented by formula I undergoes a salt-forming reaction with an acidic substance to obtain a salt of the monoamine oxidase B inhibitor.

[0046] The molar ratio of the monoamine oxidase B inhibitor shown in Formula I to the acidic substance is 1:1 to 1:3, preferably 1:2.

[0047] The acidic substance is any one of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, and p-toluenesulfonic acid.

[0048] The temperature of the salt-forming reaction is 20–40°C, preferably 25°C; the time of the salt-forming reaction is 2–6 h, preferably 4 h.

[0049] The reaction solvent is ethyl acetate, isopropyl acetate, tert-butyl acetate, ethanol, or isopropanol, preferably ethyl acetate.

[0050] The method described in this invention prepares a salt of the monoamine oxidase B inhibitor of structural formula I.

[0051] When the acidic substances are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, and p-toluenesulfonic acid, the salts of the monoamine oxidase B inhibitors are as follows:

[0052]

[0053] The beneficial effects of this invention are:

[0054] The preparation method of this invention is mild and simple to operate, does not require inert gas protection, uses inexpensive and readily available raw materials, and does not require column chromatography purification of intermediate and target products. It can be obtained by continuous feeding, recrystallization or pulping. Moreover, the yield of 7-fluoro-N-(3-fluorobenzyl)-9H-pyrido[3,4-b]indole-1-carboxamide is as high as about 56.9%, which is very suitable for large-scale industrial production. Attached Figure Description

[0055] Figure 1The image shows the XRD pattern of the target compound Ia.

[0056] Figure 2 The image shows the XRD pattern of the target compound Ib.

[0057] Figure 3 The image shows the XRD pattern of the target compound Ic.

[0058] Figure 4 The image shows the XRD pattern of the target compound Id.

[0059] Figure 5 The image shows the XRD pattern of the target compound Ie. Detailed Implementation

[0060] The technical solution of the present invention will be described through the following specific embodiments, but the scope of protection of the present invention is not limited to the embodiments.

[0061] Example 1

[0062] Preparation of 6-fluoro-3-(2-nitrovinyl)-1H-indole (compound III)

[0063]

[0064] At 0 °C, 1-(dimethylamino)-2-nitroethylene (8.6 g, 74.0 mmol) was dissolved in trifluoroacetic acid (56.7 mL, 740.5 mmol) and stirred for 0.5 h. 6-fluoroindole (10.0 g, 74.0 mmol) was added, and the mixture was heated to room temperature (25 °C) and stirred for 2 h. The reaction was monitored by TLC until it was complete. While stirring, the reaction solution was slowly added to a saturated NaHCO3 aqueous solution cooled with ice water. A solid precipitated, which was filtered, and the filter cake was collected. The filter cake was washed with water until the pH of the washing solution was neutral and dried to give compound III (yellow solid, 14.2 g, yield 93%). 1 H NMR (400 MHz, DMSO-d6) δ 12.21 (s,1H), 8.34 (d, J = 13.4 Hz, 1H), 8.20 (d, J = 2.9 Hz, 1H), 8.03 – 7.89 (m,2H), 7.28 (d, J = 9.5 Hz, 1H), 7.03 (t, J = 9.3 Hz, 1H).

[0065] Preparation of 6-fluoro-3-(2-nitroethyl)-1H-indole (compound IV)

[0066]

[0067] Compound III (10.3 g, 50 mmol) was dissolved in 80 mL of a mixed solvent of tetrahydrofuran and methanol in a volume ratio of 3:1 to obtain a solution of compound III. Sodium borohydride (2.1 g, 55 mmol) was dissolved in 5 mL of tetrahydrofuran at 0 °C and stirred for 10 min to obtain a sodium borohydride solution. Then, the solution of compound III (10.3 g, 50 mmol) was added dropwise to the sodium borohydride solution. After the addition was complete, the mixture was stirred at room temperature (25 °C) for 3 h. The reaction was monitored by TLC until it was complete. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (50 mL × 3), and the organic layer was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and the solvent was removed by vacuum distillation to obtain 10 g of crude compound IV.

[0068] Preparation of 6-fluorotryptamine (compound V)

[0069]

[0070] The crude compound IV (10.0 g, 48 mmol) was dissolved in 50 mL of 80% ethanol aqueous solution. Then, concentrated hydrochloric acid (12.0 mL, 144 mmol) with a concentration of 12 mol / L was added dropwise at 0 °C and stirred for 10 minutes. Iron powder (13.4 g, 240.2 mmol) was added and stirred at room temperature (25 °C) for 3 h. The reaction was monitored by TLC until it was complete. The mixture was filtered through diatomaceous earth, and 0.5 mol / L NaOH solution (100 mL) was added to the filtrate until the pH of the filtrate was 9. The solid was removed by filtration, and the filtrate was extracted with dichloromethane (50 mL × 3). The organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the solvent was removed by vacuum distillation to obtain compound V (yellow oil, 7.0 g, total yield of 79% in 2 steps). 1 H NMR (400 MHz, DMSO-d6) δ 7.69 (dd, J= 8.2, 5.0 Hz, 1H), 7.17 (d, J = 7.0 Hz, 1H), 7.11 – 7.01 (m, 2H), 3.07 –2.97 (m, 1H), 2.85 (d, J = 10.0 Hz, 1H), 1.73 (q, J = 6.6 Hz, 1H), 1.53 (q, J= 6.6 Hz, 1H).

[0071] Preparation of ethyl 7-fluoro-2,3,4-9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate (compound VIa) and ethyl 7-fluoro-4,9-dihydro-3H-pyrido[3,4-b]indole-1-carboxylate (compound VIb)

[0072]

[0073] At 0°C, ethyl glyoxylate (13.5 g, 132 mmol) and trifluoroacetic acid (16.8 mL, 220 mmol) were added to a dichloromethane (150 mL) solution of compound V (19.6 g, 110 mmol). The mixture was stirred at room temperature (25°C) for 12 h, and the reaction was monitored by TLC until complete. The pH of the reaction solution was adjusted to 8 with saturated NaHCO3 solution. The mixture was extracted with dichloromethane (50 mL × 3), the organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the solvent was removed by vacuum distillation to obtain 26 g of a crude mixture (pale yellow) of compounds VIa and VIb. Compound VIa: 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 9.55 (s, 1H), 7.54 – 7.46 (m, 1H), 7.09 (td, J = 8.1, 2.1 Hz, 1H), 7.01 – 6.94 (m, 1H), 4.89 (d, J = 6.0 Hz, 1H), 4.73 (m, J = 6.1, 4.1 Hz, 1H), 4.04 (q, J = 6.3 Hz, 2H), 3.18 – 3.04 (m, 2H), 2.97 – 2.83 (m, 2H), 1.23 (t, J = 6.3 Hz, 3H). Compound VIb: 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.80 – 7.72 (m,1H), 7.22 – 7.01 (m, 2H), 4.35 – 4.20 (m, 3H), 4.16 – 4.06 (m, 1H), 2.82 (m,J = 8.3, 7.3, 4.7 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H).

[0074] Preparation of ethyl 7-fluoro-9H-pyrido[3,4-b]indole-1-carboxylate (compound VII)

[0075]

[0076] Iodophenyl diacetate (63.8 g, 198 mmol) was added to a solution of 26 g crude mixture of compounds VIa and VIb in N,N-dimethylformamide (80 mL). The mixture was heated at 100 °C for 3 hours. The reaction was monitored by TLC until it was complete. The reaction was quenched with saturated NaHCO3 solution and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the solvent was removed by vacuum distillation to give compound VII (pale yellow solid, 25.0 g, 88% overall yield in two steps). 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 4.8 Hz, 1H), 8.54 – 8.49 (m,1H), 8.14 (m, J = 8.2, 5.0, 0.7 Hz, 1H), 7.25 – 7.18 (m, 1H), 7.14 (td, J =8.1, 2.0 Hz, 1H), 4.36 (q, J = 6.4 Hz, 2H), 1.35 (t, J = 6.4 Hz, 3H).

[0077] Preparation of 7-fluoro-N-(3-fluorobenzyl)-9H-pyrido[3,4-b]indole-1-carboxamide (Compound I)

[0078]

[0079] Anhydrous aluminum trichloride (13.3 g, 100 mmol) was added to a tetrahydrofuran (150 mL) solution of compound VII (25.8 g, 100 mmol) at 0 °C, and the mixture was stirred for 10 min. Then, 3-fluorobenzylamine (37.5 g, 300 mmol) was added dropwise, and the mixture was stirred at room temperature (25 °C) for 4 h. The reaction was monitored by TLC until it was complete. After the reaction was complete, the pH of the reaction solution was adjusted to 6 with 2 mol / L dilute HCl, and then extracted with ethyl acetate (50 mL × 3). The organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and the solvent was removed by vacuum distillation to obtain crude compound I. At room temperature (25 °C), crude compound I was recrystallized from the crude compound I with 240 mL of a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:5 to obtain compound I (pale yellow solid, 29.7 g, yield 88%). 1HNMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.57 (t, J = 6.4 Hz, 1H), 8.39 (d, J= 5.1 Hz, 1H), 8.35 – 8.24 (m, 2H), 7.46 (dd, J = 10.1, 2.3 Hz, 1H), 7.33 (q,J = 7.5 Hz, 1H), 7.19 (t, J = 9.7 Hz, 2H), 7.12 – 6.96 (m, 2H), 4.55 (d, J =6.4 Hz, 2H); 13 C NMR (100 MHz, DMSO-d6) δ 166.11, 164.24, 161.82, 143.29,143.04, 137.81, 135.60, 132.81, 130.91, 130.75, 124.23, 124.05, 118.43,117.26, 114.07, 113.97, 108.84, 99.58, 42.40; HRMS calcd for C 19 H 13 F2N3ONa [M +Na] + m / z 360.09189, found 360.09185.

[0080] Example 2

[0081] Preparation of 7-fluoro-N-(3-fluorobenzyl)-9H-pyrido[3,4-b]indole-1-carboxamide hydrochloride (Ia)

[0082]

[0083] Add 2 mol / L ethyl hydrochloride solution (29.7 mL) to an ethyl acetate (25 mL) solution of compound I (10 g, 29.6 mmol), stir at room temperature (25 °C) for 4 h, filter and dry to give compound Ia (white solid target, 9.8 g, yield 88%). 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 9.69 (t, J = 6.4 Hz,1H), 8.45 – 8.35 (m, 2H), 8.32 (dd, J = 8.7, 5.5 Hz, 1H), 7.47 (dd, J = 10.0,2.3 Hz, 1H), 7.33 (m, J = 8.1, 6.1 Hz, 1H), 7.24 – 7.16 (m, 2H), 7.11 (m, J =9.2, 2.4 Hz, 1H), 7.03 (m, J = 10.5, 8.1, 2.7 Hz, 1H), 4.56 (d, J = 6.2 Hz, 2H).

[0084] Example 3

[0085] Preparation of 7-fluoro-N-(3-fluorobenzyl)-9H-pyrido[3,4-b]indole-1-carboxamide hydrobromide (Ib)

[0086]

[0087] Following the preparation method of compound Ia, hydrogen chloride was replaced with an equal amount of hydrobromic acid to obtain compound Ib (yield 85%). 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 9.60 (t, J = 6.4 Hz, 1H), 8.43 (d, J = 5.1 Hz, 1H), 8.39 (d, J = 5.3 Hz, 1H), 8.32 (dd, J = 8.7, 5.5Hz, 1H), 7.47 (dd, J = 9.8, 2.4 Hz, 1H), 7.33 (m, J = 8.0, 6.1 Hz, 1H), 7.19 (dd, J = 8.9, 2.0 Hz, 2H), 7.10 (m, J = 9.2, 2.3 Hz, 1H), 7.02 (m, J = 10.5,8.1, 2.7 Hz, 1H), 4.56 (d, J = 6.3 Hz, 2H).

[0088] Example 4

[0089] Preparation of 7-fluoro-N-(3-fluorobenzyl)-9H-pyrido[3,4-b]indole-1-carboxamide sulfate (Ic)

[0090]

[0091] Following the preparation method of compound Ia, hydrogen chloride was replaced with half the amount of sulfuric acid to obtain compound Ic (yield 87%). 1 H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 9.58 (t, J = 6.5 Hz, 1H), 8.50 – 8.35 (m, 2H), 8.31 (t, J = 7.2 Hz, 1H), 7.47 (d, J = 10.0 Hz, 1H), 7.33 (q, J = 7.4 Hz, 1H), 7.19 (t, J = 8.8 Hz, 2H), 7.10 (t, J = 9.3 Hz, 1H), 7.02 (t, J = 8.9 Hz, 1H), 4.56 (d, J = 6.1 Hz, 2H).

[0092] Example 5

[0093] Preparation of 7-fluoro-N-(3-fluorobenzyl)-9H-pyrido[3,4-b]indole-1-carboxamide methanesulfonate (Id)

[0094]

[0095] Following the preparation method of compound Ia, hydrogen chloride was replaced with an equal amount of methanesulfonic acid to obtain compound Id (yield 83%). 1 H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 9.59 (t, J = 6.3 Hz, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.38 (d, J = 5.1 Hz, 1H), 8.31 (dd, J = 8.7, 5.5Hz, 1H), 7.47 (dd, J = 10.0, 2.5 Hz, 1H), 7.32 (td, J = 7.9, 5.9 Hz, 1H), 7.19 (dd, J = 12.2, 4.7 Hz, 2H), 7.10 (m, J = 9.1, 2.4 Hz, 1H), 7.02 (m, J =8.4, 7.8, 2.6 Hz, 1H), 4.56 (d, J = 6.3 Hz, 2H), 2.44 (s, 3H).

[0096] Example 6

[0097] Preparation of 7-fluoro-N-(3-fluorobenzyl)-9H-pyrido[3,4-b]indole-1-carboxamide p-toluenesulfonate (Ie)

[0098]

[0099] Following the preparation method of compound Ia, hydrogen chloride was replaced with an equal amount of p-toluenesulfonic acid to obtain compound Ie (yield 80%). 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.58 (t, J = 6.5 Hz,1H), 8.42 (d, J = 5.3 Hz, 1H), 8.37 (d, J = 5.3 Hz, 1H), 8.31 (dd, J = 8.7,5.6 Hz, 1H), 7.49 – 7.42 (m, 3H), 7.33 (q, J = 7.4 Hz, 1H), 7.20 (t, J = 9.0Hz, 2H), 7.08 (d, J = 8.0 Hz, 3H), 7.03 (t, J = 8.8 Hz, 1H), 4.56 (d, J = 6.3Hz, 2H), 2.24 (s, 3H).

[0100] Example 7

[0101] Powder X-ray diffraction analysis of compounds Ia-Ie

[0102] Test method: Powder X-ray diffraction (XRD) analysis was performed using a D8 ADVANCE, BRUKER diffractometer at 40 kV and 40 mA with Cu Kα radiation (λ = 1.54184 Å), and each data was collected at room temperature in the 2θ range of 5–60°.

[0103] Test results: The X-ray diffraction patterns of compounds Ia-Ie are as follows: Figures 1-5As shown, the XRD patterns of compounds Ia, Ib, Ic, Id, and Ie are different, indicating the formation of different new solid phases. Compound Ia has obvious diffraction peaks at 7.17°, 12.88°, 14.93°, 19.28°, 23.47°, 25.63°, 28.66°, and 31.24°; compound Ib has obvious diffraction peaks at 7.17°, 12.85°, 15.39°, 19.39°, 21.54°, 23.10°, 25.77°, and 32.45°; and compound Ic has obvious diffraction peaks at 6.65°, 13.19°, 17.40°, and 22.76°. The diffraction patterns show distinct diffraction peaks at 25.96°, 26.86°, and 29.82°; compound Id shows distinct diffraction peaks at 7.04°, 13.19°, 15.31°, 18.50°, 19.79°, 20.43°, 21.10°, 24.39°, 27.60°, and 28.25°; and compound Ie shows distinct diffraction peaks at 5.84°, 11.53°, 14.99°, 17.63°, 19.00°, 21.35°, 24.11°, 26.49°, and 27.49°. Furthermore, the diffraction patterns agree well with the simulation results, further confirming the formation of a single phase of compounds Ia-Ie.

[0104] Example 8

[0105] Comparative analysis of the drug metabolism properties of compound I and compound Id

[0106] Male C57BL / 6J mice were administered compounds I and Id (20 mg / kg, solvent: DMSO, Solutol (polyethylene glycol-15-hydroxystearate), and Saline in a volume ratio of 5:10:85) via intravenous (IV) and oral (PO) administration, with three mice per administration route. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h after IV administration or at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after oral administration. Blood samples were placed in K2-EDTA-containing centrifuge tubes, stored on ice, and centrifuged at 6800 rpm for 6 min at 2–8 °C. The resulting supernatant plasma was temporarily stored at approximately -80 °C until LC-MS analysis. Relevant pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0.

[0107] Bioavailability (F) (%) = (AUC po / AUC iv) × (dosei.v. / dose po) × 100.

[0108] Table 1. Analysis of the drug metabolism properties of compound I and compound Id

[0109]

[0110] The experimental results are shown in Table 1: Compared with compound I, compound Id has better pharmacokinetic parameters, including an oral half-life Td. 1 / 2 The AUC was 3.92 h. 0−∞ The concentration was 4383.82 h*ng / mL, and the oral bioavailability F (%) was 46.38%.

Claims

1. A method for preparing a monoamine oxidase B inhibitor with a structure as shown in Formula I, characterized in that: The synthesis route is as follows: ； Includes the following steps: Step (1): Using 6-fluoroindole and 1-(dimethylamino)-2-nitroethylene as raw materials and trifluoroacetic acid as catalyst, 6-fluoroindole and 1-(dimethylamino)-2-nitroethylene undergo an electrophilic substitution reaction to generate compound III; Step (2): Using a mixed solvent of tetrahydrofuran and methanol as the reaction solvent and sodium borohydride as the reducing agent, compound III undergoes a reduction reaction to generate compound IV; Step (3): Using 60%–80% ethanol aqueous solution as the reaction solvent, in the presence of iron powder and hydrochloric acid, compound IV undergoes a reduction reaction to generate compound V; Step (4): Using dichloromethane as the reaction solvent, under acidic conditions, compound V reacts with ethyl glyoxylate in a Pictet-Spengler cyclization reaction to generate a mixture of compounds VIa and VIb. Step (5): Using N,N-dimethylformamide as the reaction solvent and iodophenyl diacetate as the oxidant, compounds VIa and VIb undergo an oxidative dehydrogenation aromatization reaction to generate compound VII; Step (6): Using tetrahydrofuran as the reaction solvent, under the catalysis of aluminum trichloride, compound VII undergoes an amine transesterification reaction with 3-fluorobenzylamine to generate the monoamine oxidase B inhibitor shown in Formula I.

2. The method for preparing the monoamine oxidase B inhibitor according to claim 1, characterized in that: In step (1), the molar ratio of 6-fluoroindole to 1-(dimethylamino)-2-nitroethylene is 1:1 to 1:1.5, preferably 1:1; the molar ratio of 6-fluoroindole to trifluoroacetic acid is 1:8 to 1:15, preferably 1:10; and the temperature of the electrophilic substitution reaction is 20 to 40°C, preferably 25°C.

3. The method for preparing the monoamine oxidase B inhibitor according to claim 1, characterized in that: In step (2), the molar ratio of compound III to sodium borohydride is 1:1 to 1:1.5, preferably 1:1.1; the volume ratio of tetrahydrofuran to methanol is 1:1 to 5:1, preferably 1:3 to 3.5:1, more preferably 3.25:1; and the temperature of the reduction reaction is 20 to 40°C, preferably 25°C.

4. The method for preparing the monoamine oxidase B inhibitor according to claim 1, characterized in that: In step (3), the molar ratio of compound IV to iron powder is 1:3 to 1:7, preferably 1:5 to 1:5.1, preferably 1:5; the molar ratio of compound IV to hydrochloric acid is 1:2 to 1:4, preferably 1:

3. The temperature of the reduction reaction is 20-40℃, preferably 25℃; the time of the reduction reaction is 2-4 h, preferably 3 h.

5. The method for preparing the monoamine oxidase B inhibitor according to claim 1, characterized in that: In step (4), the molar ratio of compound V to ethyl glyoxylate is 1:1 to 1:1.5, preferably 1:1.2; the acidic conditions are provided by an acidic substance; the acidic substance is any one of trifluoroacetic acid, hydrochloric acid, or sulfuric acid, preferably trifluoroacetic acid; the molar ratio of compound V to the acidic substance is 1:1 to 1:3, preferably 1:2; the temperature of the Pictet-Spengler cyclization reaction is 20 to 40°C, preferably 25°C; the time of the Pictet-Spengler cyclization reaction is 10 to 14 h, preferably 12 h.

6. The method for preparing the monoamine oxidase B inhibitor according to claim 1, characterized in that: In step (5), the total amount of compounds VIa and VIb is in a mass ratio of iodophenyl diacetate to 1:1 to 1:3, preferably 1:2.45 to 1:2.5; the temperature of the oxidative dehydrogenation aromatization reaction is 80 to 120°C, preferably 100°C; and the time of the oxidative dehydrogenation aromatization reaction is 2 to 4 h, preferably 3 h.

7. The method for preparing the monoamine oxidase B inhibitor according to claim 1, characterized in that: In step (6), the molar ratio of compound VII to aluminum trichloride is 1:0.5 to 1:1.5, preferably 1:1; the molar ratio of compound VII to 3-fluorobenzylamine is 1:1 to 1:5, preferably 1:3; the temperature of the amine-ester exchange reaction is 20 to 40°C, preferably 25°C; and the time of the amine-ester exchange reaction is 2 to 6 h, preferably 4 h.

8. The method for preparing the monoamine oxidase B inhibitor according to claim 1, characterized in that: In step (1), after the reaction is complete, the reaction solution is added to a saturated NaHCO3 aqueous solution cooled by ice water, filtered, the filter cake is collected, the filter cake is washed with water until the pH of the washing solution is neutral, and dried to obtain compound III. In step (2), after the reaction is complete, a saturated ammonium chloride solution is added, the mixture is extracted with ethyl acetate, the organic layer is washed with saturated brine, dried with anhydrous Na2SO4, and the solvent is removed by vacuum distillation to obtain compound IV. In step (3), after the reaction is completed, the reaction solution is filtered, the pH of the filtrate is adjusted to 9 with NaOH solution, the solid is removed by filtration, the filtrate is extracted with dichloromethane, the organic layer is washed with saturated brine, dried with anhydrous Na2SO4, and the solvent is removed by vacuum distillation to obtain compound V; In step (4), after the reaction is complete, the pH of the reaction solution is adjusted to 8 with saturated NaHCO3 solution, extracted with dichloromethane, the organic layer is washed with saturated brine, dried with anhydrous Na2SO4, and the solvent is removed by vacuum distillation to obtain a mixture of compounds VIa and VIb. In step (5), after the reaction is completed, the reaction is quenched with saturated NaHCO3 solution, extracted with ethyl acetate, the organic layer is washed with saturated brine, dried with anhydrous Na2SO4, and the solvent is removed by vacuum distillation to obtain compound VII. In step (6), after the reaction is completed, the pH of the reaction solution is adjusted to weakly acidic with dilute hydrochloric acid, extracted with ethyl acetate, the organic layer is washed with saturated brine, dried with anhydrous Na2SO4, and the solvent is removed by vacuum distillation to obtain the crude monoamine oxidase B inhibitor shown in Formula I; at a temperature of 25°C, the crude monoamine oxidase B inhibitor shown in Formula I is recrystallized with a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:5 to obtain the monoamine oxidase B inhibitor shown in Formula I.

9. A method for preparing a salt of a monoamine oxidase B inhibitor represented by structural formula I, characterized in that: include: The monoamine oxidase B inhibitor of Formula I is prepared according to the method of claim 1. The monoamine oxidase B inhibitor of Formula I undergoes a salt-forming reaction with an acidic substance to obtain a salt of the monoamine oxidase B inhibitor. The acidic substance is any one of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, and p-toluenesulfonic acid. The reaction solvent is ethyl acetate, isopropyl acetate, tert-butyl acetate, ethanol, or isopropanol, preferably ethyl acetate. The molar ratio of the monoamine oxidase B inhibitor of Formula I to the acidic substance is 1:1 to 1:3, preferably 1:

2. The temperature of the salt-forming reaction is 20 to 40°C, preferably 25°C. The time of the salt-forming reaction is 2 to 6 h, preferably 4 h.

10. A salt of the monoamine oxidase B inhibitor prepared by the method of claim 9.

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