WO2023178693A1 - Method for preparing lemborexant and method for preparing lemborexant intermediate - Google Patents

Abstract

Provided in the present invention is a method for preparing lemborexant, which method comprises the following steps: subjecting compound II and compound III as raw materials to a reaction in a second reaction solvent to obtain lemborexant. Further provided in the present invention is a method for preparing compound II. The prepared compound II of the present invention is an active ester intermediate of Oxyma, has a high reaction activity, and is a safe and non-explosive auxiliary nucleophile. According to the present invention, the use of traditional activators such as HOBt and HOAT is avoided, thereby eliminating potential safety hazards; and by using the method of the present invention to prepare lemborexant, the reaction is safe and efficient, and the racemization rate of the obtained product is low.

Description

A kind of preparation method of leborexine and its intermediates Technical field

The present invention relates to the field of medical technology, and in particular to a preparation method of leborexine and its intermediates.

Background technique

Insomnia refers to a subjective experience in which patients are dissatisfied with sleep time and/or quality and affect daytime social functioning. According to the international diagnostic standards for insomnia and epidemiological studies, at least 6% of people worldwide suffer from insomnia and sleep disorders. Leborexan is a dual receptor of orexin receptor 1 (OX1) and orexin receptor 2 (OX2). As an inhibitor, this compound inhibits orexin by competitively binding to two subtypes of orexin receptors (OX1 and OX2). Leborexan can interfere with orexinergic neurotransmission and promote the initiation and maintenance of sleep in a purposeful manner. Lemborexant, its chemical formula is as follows: Formula I:

Contents of the invention

A first aspect of the present invention provides a preparation method of leborexan, which includes the following steps:

B) Compound II and Compound III react in the second reaction solvent to obtain leboresen represented by formula I;

In some embodiments of the first aspect of the invention, the second reaction solvent is selected from organic solvents, including but not limited to acetonitrile, dioxane, ethylene glycol dimethyl ether, pyridine, toluene, acetic acid At least one of ethyl ester and tetrahydrofuran is preferably tetrahydrofuran or acetonitrile.

In some embodiments of the first aspect of the present invention, the reaction temperature of the reaction is -5°C to 40°C, preferably 10°C to 35°C.

In some embodiments of the first aspect of the present invention, the reaction time of the reaction is 1h-48h, preferably 12-24h.

A second aspect of the invention provides a compound represented by formula II:

The third aspect of the present invention provides a preparation method of compound II, which includes the following steps:

A) Compound IV, Compound V and Compound VI react in the first reaction solvent to obtain Compound II;

In some embodiments of the third aspect of the invention, the first reaction solvent is selected from organic solvents, including but not limited to acetonitrile, dioxane, ethylene glycol dimethyl ether, pyridine, toluene, acetic acid At least one of ethyl ester and tetrahydrofuran is preferably tetrahydrofuran or acetonitrile.

In some embodiments of the third aspect of the present invention, the reaction temperature of the reaction is -15°C to 10°C, preferably -10°C to 5°C.

In some embodiments of the third aspect of the present invention, the reaction time of the reaction is 1h-48h, preferably 4-24h.

The fourth aspect of the present invention provides a preparation method of compound IV, which includes the following steps:

A) Using compound VII as raw material, under the action of a catalyst and an oxidant, an oxidation reaction occurs in a mixed solvent of tert-butanol and water to generate compound IV;

In some embodiments of the fourth aspect of the invention, the catalyst is selected from 2,2,6,6-tetramethylpiperidine-nitrogen-oxide or 4-hydroxy-2,2,6,6- At least one of tetramethylpiperidine-1-oxyl radicals.

In some embodiments of the fourth aspect of the invention, the catalyst is used in an amount of 1% to 25% of the molar amount of Compound VII.

In some embodiments of the fourth aspect of the present invention, the volume ratio of tert-butyl alcohol and water in the mixed solvent is 4:1-3:2.

In some embodiments of the fourth aspect of the invention, the oxidizing agent is sodium hypochlorite.

In some embodiments of the fourth aspect of the invention, the oxidizing agent is used in an amount of 2.0 eq to 5.0 eq based on the molar amount of compound VII.

In some embodiments of the fourth aspect of the invention, the pH value of the oxidation reaction ranges from 6 to 12.

In some embodiments of the fourth aspect of the present invention, sodium bicarbonate and/or sodium carbonate is also added to the mixed solvent.

In some embodiments of the fourth aspect of the present invention, the reaction temperature of the oxidation reaction is -10°C to 45°C, preferably -3°C to 3°C.

In some embodiments of the fourth aspect of the present invention, the reaction time of the oxidation reaction is 1h-96h, preferably 1h-24h.

The fifth aspect of the present invention provides a preparation method of leborexine, which includes the following steps:

A) Compound IV, Compound V and Compound VI are used as raw materials to react in the first reaction solvent to obtain Compound II;

B) Compound II and compound III undergo a condensation reaction in the second reaction solvent to obtain leboresen represented by formula I.

In some embodiments of the fifth aspect of the present invention, compound IV is prepared by step A) described in the fourth aspect of the present invention, that is, using compound VII as a raw material, under the action of a catalyst and an oxidant, in a mixture of tert-butanol and water An oxidation reaction occurs in the solvent to form compound IV.

In some embodiments of the fifth aspect of the invention, compound II prepared in step A) is directly used in step B) without isolation.

Beneficial effects:

The method provided by the present invention can safely and efficiently prepare leborexine by preparing the Oxyma active ester intermediate, that is, compound II. Compared with the existing technology, the optical purity of leborexine prepared by the method of the present invention is higher. The racemization rate is lower and has better application prospects. At the same time, the intermediate compound II of the present invention is an Oxyma active ester intermediate, which is a safe and non-explosive auxiliary nucleophile, avoiding the explosion safety hazards of traditional activators such as HOBt and HOAt. Moreover, in the preparation method of intermediate compound IV provided by the present invention, tert-butyl alcohol and water are used as mixed solvents, and ((1R,2S)-2-(((2,4-dimethyl Pyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropyl)methanol is directly oxidized to ((1R,2S)-2-(((2,4-dimethylpyrimidine) -5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropyl)carboxylic acid, with high yield and almost no waste gas, no phosphorus-containing buffer is used, and no phosphorus-containing wastewater is produced. It is environmentally friendly, the process is safe and simple, and it is suitable for industrial production.

Description of the drawings

Figure 1 is a liquid chromatography-mass spectrometry (LC-MS) spectrum of the reaction solution that has reached the end point of the reaction in Example 1 of the present invention.

Figure 2 is a hydrogen nuclear magnetic spectrum ( ^1H NMR) spectrum of compound IV prepared in Example 1 of the present invention.

Figure 3 is a high performance liquid chromatography (HPLC) purity spectrum of compound IV prepared in Example 1 of the present invention.

Figure 4 shows the liquid chromatography and ion chromatogram of the LC-MS spectrum of compound IV prepared in Example 1 of the present invention; wherein 4a is the liquid chromatography spectrum and 4b is the ion chromatogram.

Figure 5 is the mass spectrum of compound IV prepared in Example 1 of the present invention in the LC-MS spectrum.

Figure 6 is the HPLC optical purity spectrum of compound IV prepared in Example 1 of the present invention.

Figure 7 is a chiral HPLC spectrum of the optical enantiomers of compound IV prepared in Example 1 of the present invention.

Figure 8 is a liquid chromatogram of the LC-MS spectrum of the reaction solution that reached the end point of the reaction in Example 2 of the present invention.

Figure 9 is a liquid chromatogram of the LC-MS spectrum of the reaction solution that reached the end point of the reaction in Comparative Example 1 of the present invention.

Figure 10 is a liquid chromatogram of the LC-MS spectrum of the reaction solution that reached the end point of the reaction in Comparative Example 2 of the present invention.

Figure 11 is a liquid chromatogram of the LC-MS spectrum of the reaction solution that reached the end point of the reaction in Comparative Example 3 of the present invention.

Figure 12 is the liquid chromatography mass spectrometry (LC-MS) spectrum of the reaction solution at the end of step A) in Example 3 of the present invention; wherein, 12a is the liquid chromatography spectrum, 12b is an ion current diagram.

Figure 13 is the mass spectrum of Compound II in the reaction solution in the LC-MS spectrum at the end of step A) in Example 3 of the present invention.

Figure 14 is the liquid chromatography and ion chromatogram of the LC-MS spectrum of the reaction solution at the end of step B) in Example 3 of the present invention; wherein 14a is the liquid chromatography spectrum and 14b is the ion chromatogram.

Figure 15 is the mass spectrum of the LC-MS spectrum of the reaction solution at the end of step B) in Example 3 of the present invention; wherein, 15a is the mass spectrum of compound IV in the reaction solution in the LC-MS spectrum, and 15b It is the mass spectrum of leborexine I in the LC-MS spectrum in the reaction solution.

Figure 16 is a proton nuclear magnetic spectrum ( ¹ H NMR) spectrum (500 MHz) of Leboreson I prepared in Example 3 of the present invention.

Figure 17 is an infrared spectrum of Lebraxane I prepared in Example 3 of the present invention.

Figure 18 is a high-performance liquid chromatography (HPLC) purity spectrum of leboresen I prepared in Example 3 of the present invention.

Figure 19 is a chiral HPLC spectrum of leborexine I prepared in Example 3 of the present invention.

Figure 20 is a chiral HPLC spectrum of the enantiomeric isomer of leborexan I in Example 3 of the present invention.

Detailed ways

Terms and definitions:

Oxyma: ethyl 2-oximecyanoacetate, also known as ethyl 2-cyano-2-(hydroxyimine)acetate.

Oxyma active ester intermediate refers to the O-acylisourea intermediate produced by the rapid reaction of acid and Oxyma. In some embodiments of the invention, the Oxyma active ester intermediate is Compound II.

A first aspect of the present invention provides a preparation method of leborexan, which includes the following steps:

B) react Compound II and Compound III in the second reaction solvent to obtain Leboresen represented by Formula I;

After in-depth research, the inventor found that by using the above method, compared with the existing technology, Lebraxen can be prepared more safely and efficiently.

In some embodiments of the first aspect of the invention, the second reaction solvent is selected from the group consisting of organic solvents, including but not limited to acetonitrile, dioxane, ethylene glycol dimethyl ether, pyridine, toluene, acetic acid At least one of ethyl ester and tetrahydrofuran is preferably tetrahydrofuran or acetonitrile.

The inventor has discovered through research that by using the above-mentioned second reaction solvent, the raw materials can be fully dissolved, thereby preparing leborexen more safely and efficiently.

In some embodiments of the first aspect of the present invention, the reaction temperature of the above reaction is called the second reaction temperature, and the second reaction temperature is -5°C-40°C, preferably 10°C-35°C. For example, the reaction temperature can be -5°C, 0°C, 12°C, 20°C, 25°C, 40°C or any range in between. The inventor found through research that by controlling the second reaction temperature of the above reaction to be within the above range , which can fully react between raw materials, thereby preparing Lebraxen more safely and efficiently.

In some embodiments of the first aspect of the present invention, the above reaction is called the second reaction time, and the second reaction time is 1h-48h, preferably 12-24h. For example, the second reaction time can be 1h, 4h, 8h, 10h, 12h, 18h, 24h, 48h or any range therebetween. The inventor found through research that by controlling the second reaction time of the above reaction to be within the above range, The raw materials can be fully reacted in the second reaction solvent, thereby preparing leborexin more safely and efficiently.

In the present invention, the molar ratio of compound II to compound III is not particularly limited. For example, the molar ratio of compound II can be 1:1, 1:5, 1:10, 10:1, 5:1, or any range in between. .

A second aspect of the invention provides a compound represented by formula II:

The third aspect of the present invention provides a preparation method of compound II, which includes the following steps:

Compound IV, compound V and compound VI react in the first reaction solvent to obtain compound II;

Through in-depth research, the inventor found that the compound of formula II prepared by the above method, which is an Oxyma active ester intermediate, can be used in the preparation process of leborexan to avoid the use of traditional activators with explosion hazards. HOBt and HOAt, thus making the preparation method of Leborexen safer and more efficient.

In some embodiments of the third aspect of the invention, the first reaction solvent is selected from organic solvents, including but not limited to acetonitrile, dioxane, ethylene glycol dimethyl ether, pyridine, toluene, ethyl acetate , at least one of tetrahydrofuran, preferably tetrahydrofuran or acetonitrile. The inventor found through research that by using the above-mentioned first reaction solvent to prepare Compound II, the raw materials can be fully dissolved and the reaction more efficient. The prepared Compound II is further applied to the preparation process of Leborexan, making Leborexan The preparation process is safer and more efficient.

In some embodiments of the present invention, the reaction temperature of the above reaction is called the first reaction temperature, and the first reaction temperature is -15°C to 10°C, preferably -10°C to 5°C, for example, the first reaction temperature It can be -15°C, -5°C, 0°C, 5°C, 10°C or any range in between. The inventor found through research that by controlling the first reaction temperature of the above reaction within the above range, the raw materials can be The reaction is sufficient, making the reaction more efficient, and the prepared compound II is further used in the preparation process of leborexan, making the preparation process of leborexan safer and more efficient.

In some embodiments of the third aspect of the present invention, the reaction time of the above reaction is called the first reaction time, and the first reaction time is 1h-48h, preferably 4-24h. For example, the first reaction time can be 1h, 14h, 28h, 42h, 48h or any range therebetween. The inventor found through research that by controlling the first reaction time of the above reaction to be within the above range, the reaction can be made more efficient, The prepared compound II is further applied to the preparation process of leborexan, making the preparation process of leborexan safer and more efficient.

In the present invention, the feeding molar ratio of compound IV, compound V and compound VI is not particularly limited. For example, the feeding molar ratio can be 1:1:1, 1:5:1, 1:10:1, 1:1: 5, 1:1:10, 5:1:1, 10:1:1 or any range in between.

In the prior art, the synthesis method of compound IV is: ((1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluoro Phenyl) cyclopropyl) methanol (VII) undergoes an oxidation reaction to generate the corresponding aldehyde (compound VIII), further oxidized under the action of sodium chlorite to form ((1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3- Fluorophenyl)cyclopropyl)carboxylic acid.

Since the above preparation method uses two chlorine-containing oxidants for oxidation and uses phosphorus-containing compounds to prepare buffer solutions, the production process will generate a large amount of waste gas containing chlorine dioxide and phosphorus-containing wastewater.

The fourth aspect of the present invention provides a preparation method of compound IV, which includes the following steps:

A) Using compound VII as raw material, under the action of a catalyst and an oxidant, an oxidation reaction occurs in a mixed solvent of tert-butanol and water to generate compound IV;

After in-depth research, the inventor found that using a mixed solvent of tert-butyl alcohol and water as the reaction solvent, the method of directly oxidizing alcohol to acid in the mixed solvent is simple, efficient and has simple post-processing steps. Without being limited to any theory, the inventor believes that because tert-butyl alcohol Alcohol is used as a solvent. During the reaction, part of the tert-butyl alcohol is oxidized to peroxide. The generated peroxide further catalyzes the above oxidation reaction, causing the alcohol to be directly oxidized into acid.

In some embodiments of the fourth aspect of the invention, the catalyst is selected from 2,2,6,6-tetramethylpiperidine-nitrogen-oxide or 4-hydroxy-2,2,6,6- At least one of tetramethylpiperidine-1-oxyl radicals. The inventor found through research that the oxidation reaction can be made more efficient by using the above-mentioned catalyst and the mixed solvent to act synergistically.

In some embodiments of the fourth aspect of the invention, the catalyst is used in an amount of 1% to 25% of the molar amount of Compound VII. In the present invention, the amount of catalyst used is not particularly limited and can be an amount known to those skilled in the art. Based on the molar amount of reaction raw material compound II, the amount of catalyst used can be selected from but not limited to 1%-25%, for example, the amount of catalyst The dosage can be 1%, 2%, 6%, 14%, 25% or any range in between.

In some embodiments of the fourth aspect of the present invention, the volume ratio of tert-butyl alcohol and water in the mixed solvent is 4:1-3:2, such as 4:1, 3:1, 2:1, 1.7:1, 1.6:1, 3:2; the inventor found through research that when the volume ratio of tert-butanol and water meets the above relationship, the oxidation reaction is more efficient.

In some embodiments of the fourth aspect of the invention, the oxidizing agent is sodium hypochlorite. The inventor found that only sodium hypochlorite was used as the oxidant. Compared with the prior art that used a combination of sodium hypochlorite and sodium chlorite, almost no chlorine-containing waste gas was produced during the oxidation reaction of the present invention, and sodium chlorite is a flammable chemical. Therefore, the preparation method of the present invention is more green, safe and efficient.

In some embodiments of the fourth aspect of the invention, the oxidizing agent is used in an amount of 2.0 eq to 5.0 eq based on the molar amount of compound VII. In the present invention, the amount of oxidizing agent is not particularly limited. Based on the molar amount of reaction raw material compound II, the amount of oxidizing agent can be selected from but not limited to 2.0eq-5.0eq. For example, the amount of oxidizing agent can be 2.0eq, 2.8eq, 3.4 eq, 4.6eq, 5.0eq, or any range in between.

In some embodiments of the fourth aspect of the present invention, the pH value of the oxidation reaction ranges from 6 to 12, such as: 6, 7, 8, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8 , 9.9, 10, 11, 12 or any range in between. The inventor found through research that by regulating the pH value of the oxidation reaction within the above range, the oxidation reaction can be made more efficient.

In some embodiments of the fourth aspect of the present invention, sodium bicarbonate and/or sodium carbonate is also added to the mixed solvent. The inventor has discovered through research that by using sodium bicarbonate and/or sodium carbonate as a buffer solution, compared with the prior art using sodium dihydrogen phosphate and disodium hydrogen phosphate as buffer solvents, the preparation method provided by the present invention does not produce any sodium bicarbonate. Phosphorus wastewater, environmentally friendly. Moreover, when sodium carbonate and sodium bicarbonate are added to the mixed solvent, the synergistic effect of sodium carbonate and sodium bicarbonate can achieve a better buffering effect.

In some embodiments of the fourth aspect of the present invention, the reaction temperature of the oxidation reaction is -10°C to 45°C, preferably -3°C to 3°C. For example, the reaction temperature can be -10°C, -5°C, 0℃, 15℃, 30℃, 45℃ or any range in between. The inventor found through research that by controlling the reaction temperature of the oxidation reaction within the above range, the raw materials can react fully and the oxidation reaction can be more efficient.

In some embodiments of the fourth aspect of the present invention, the reaction time of the oxidation reaction is 1h-96h, preferably 1h-24h. For example, the reaction time can be 1h, 5h, 16h, 29h, 42h, 55h, 68h, 81h, 96h or any range in between. The inventor found through research that by controlling the reaction time of the oxidation reaction within the above range, the oxidation reaction can be made more efficient.

The fifth aspect of the present invention provides a preparation method of leborexine, which includes the following steps:

A) Compound IV, Compound V and Compound VI react in the first reaction solvent to obtain Compound II,

B) Compound (II) and compound (III) undergo a condensation reaction in the second reaction solvent to generate leborexan represented by formula I.

In some embodiments of the fifth aspect of the present invention, compound IV is prepared by step A) described in the fourth aspect of the present invention, that is, using compound VII as a raw material, under the action of a catalyst and an oxidant, in a mixture of tert-butanol and water An oxidation reaction occurs in the solvent to form compound IV.

In some embodiments of the fifth aspect of the invention, compound II prepared in step A) is directly used in step B) without isolation.

In the present invention, the first reaction solvent and the second reaction solvent may be the same or different, and are preferably the same.

In the present invention, after the synthesis step of compound II is completed, compound II can be synthesized directly in one pot without isolating compound II. The inventor has found through research that the use of one-pot synthesis can simplify the process steps and reduce production. cost.

In the present invention, during the above-mentioned one-pot synthesis of leborexan, the reaction time and temperature for synthesizing intermediate compound II are the same as the selection ranges of reaction time and temperature in the preparation method of compound II in the third aspect of the present invention; The reaction time and temperature for synthesizing leborexan are the same as the selection ranges of the reaction time and temperature in the preparation method of leborexan in the first aspect of the present invention.

Example

Hereinafter, embodiments of the present application will be described in more detail with reference to examples. Various tests and evaluations were performed according to the following methods.

HPLC method:

In the embodiments, high performance liquid chromatography (HPLC) is used to monitor the reaction progress or analyze the purity of the product. High-performance liquid chromatography (HPLC) uses liquid as the mobile phase and uses a high-pressure infusion system to pump single solvents with different polarities or mixed solvents, buffers and other mobile phases in different proportions into a chromatographic column equipped with a stationary phase. After each component in the column is separated, it enters the detector for detection to realize the analysis of the sample components. The chromatographic detection conditions are as follows in Table 1:

Table 1

In the present invention, the test methods of hydrogen nuclear magnetic spectrum test ( ¹ H NMR), liquid chromatography-mass spectrometry (LC-MS) test, and infrared test are not particularly limited, and can be tested by methods known to those skilled in the art, wherein, The deuterated reagent used in the hydrogen nuclear magnetic spectrum test is commercially available deuterated dimethyl sulfoxide (DMSO).

ee value measurement:

Among the two enantiomers of the chiral molecule of the product in the embodiment, each enantiomer rotates plane polarized light to a certain angle, with the same numerical value but opposite directions. This property is called optical activity. The enantiomeric composition of a product is described by the term "enantiomeric excess" or "ee value", which represents the excess of one enantiomer over the other, usually expressed as a percentage.

In the examples, high performance liquid chromatography (HPLC) was used to measure the ee value of the product.

Unless otherwise specified, the raw materials and reagents of the present invention are commercially available. Compound III is commercially available 2-amino-5-fluoropyridine, purchased from Fuxin Jintelai Co., Ltd.; Compound V (2-oxime cyanoacetic acid Ethyl ester) and compound VI (diisopropylcarbodiimide) were purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.

Example 1

Dissolve 302g compound VII in a mixed solvent of 2000mL tert-butanol and 1200mL water in the reaction bottle, add 150g sodium bicarbonate, 15g sodium carbonate, 7.5 g 2,2,6,6,-tetramethylpiperidine-nitrogen-oxide material (TEMPO), stir thoroughly. The temperature outside the reaction bottle dropped to -10°C. Add sodium hypochlorite aqueous solution (2.2eq, 2200mL) dropwise, the aqueous phase pH=9, and keep the reaction system temperature at -3~3°C. After the dropwise addition is completed, react at 0°C for 12 hours. HPLC monitors that the reaction ends when the content of compound VII is less than 0.2%, and the pH of the aqueous phase is 9.2. Use LC-MS test to monitor the reaction end point, and obtain the LC-MS spectrum of the reaction solution that reaches the end point of the reaction (as shown in Figure 1, where peak ^{5 is} the peak corresponding to the target compound IV, and the peak of compound IV in the reaction solution is content is 98.7%).

Add quenching reagent dropwise (280g sodium sulfite and 150g sodium hydroxide dissolved in 1500mL water), ensuring that the temperature does not exceed 25°C during the dropwise addition. After the dropwise addition is completed, the temperature is raised to 60°C and stirred for 0.5h. The solution becomes clear and the aqueous phase pH=9.5. After standing, the water phase was separated and removed. Concentrate the organic phase to a volume of about 800 ml, add 1 L of sodium hydroxide aqueous solution (concentration is 10%), adjust the pH to >13.5, extract the aqueous phase with tert-butyl methyl ether, remove the organic phase by liquid separation, and control the temperature of the aqueous phase to not exceed 10°C. Add 3.1L concentrated hydrochloric acid (mass fraction >20%), adjust the pH to 1.5-2.5, filter to remove most of the water to obtain a viscous solid, dissolve this solid in 800mL of methylene chloride, and remove a small amount of water by liquid separation. The organic phase was concentrated and stripped with dichloromethane until the moisture content was less than 0.05% to obtain an off-white powdery solid. Add 400 mL of isopropyl ether, heat to reflux, vigorously stir and hot-beat, cool and then filter to obtain 295 g of white solid compound IV ( ¹ H NMR characterization is shown in Figure 2). The LC-MS spectra of compound IV are shown in Figures 4 and 5 (the theoretical value of compound IV C ₁₇ H ₁₇ FN ₂ O ₃ M+H is 317.13, and the measured value in Figure 5 is 317.1). The purity was 99.5% (as shown in Figure 3), the yield was 93%, and the ee value was 99.99% (as shown in Figures 6 and 7).

Example 2

Except that the mixed solvent includes 2000mL tert-butanol and 1000mL water, and the catalyst is 4-hydroxy-2,2,6,6,-tetramethylpiperidine-1-oxyl radical, and the catalyst dosage is 6.7g, the rest are the same as in the implementation Same as Example 1. Use LC-MS test to monitor the reaction end point, and obtain the LC-MS characterization of the reaction solution that reaches the reaction end point, as shown in Figure 8. Peak ^{11 is} the peak corresponding to the target compound IV. Compound IV, Compound VII and Compound VIII in the reaction solution The content is shown in Table 2.

Comparative example 1

Except that during the reaction process, the mixed solvent was a toluene-water mixed solvent, and the volume ratio of toluene and water was 2:1.2, the rest was the same as in Example 1. Use LC-MS test to monitor the reaction end point, and obtain the LC-MS characterization of the reaction solution that reaches the reaction end point, as shown in Figure 9, in which peak ^# 5 is the peak corresponding to the target compound IV, and compound IV, compound VII and compound VIII in the reaction solution The content is shown in Table 2.

Comparative example 2

Except that during the reaction process, the mixed solvent is a mixed solvent of acetonitrile-water, and the volume ratio of acetonitrile and water is 2:1.2, the rest is the same as in Example 1. The reaction end point is monitored by LC-MS test to obtain the reaction that reaches the reaction end point. The LC-MS characterization of the solution is shown in Figure 10, in which peak ^# 5 is the peak corresponding to the target compound IV. The contents of compound IV, compound VII and compound VIII in the reaction solution are as shown in Table 2.

Comparative example 3

The mixture was the same as Comparative Example 2 except that 0.3% tert-butyl hydroperoxide was added to the mixed solvent based on the total volume of the mixed solvent. Without being limited to any theory, the inventor believes that it may be because tert-butyl alcohol as a solvent is partially oxidized to peroxide, and the generated peroxide catalyzes the oxidation reaction, allowing it to be directly oxidized to the acid. Therefore, based on Comparative Example 2, tert-butyl hydroperoxide was further added to acetonitrile. Compared with Comparative Example 2, the reaction conversion rate was greatly improved. Use LC-MS test to monitor the reaction end point, and obtain the LC-MS characterization of the reaction solution that reaches the reaction end point, as shown in Figure 11. Peak ^{2 is} the peak corresponding to the target compound IV. Compound IV, Compound VII and Compound VIII in the reaction solution The content is shown in Table 2.

Table 2

It can be seen from Example 1, Comparative Example 1 and Comparative Example 2 (the solvent described in the original research patent CN104114524B) that different solvents have a greater impact on the reaction. The main product generated by toluene as a solvent is aldehyde, so the original research patent CN104114524B Sodium chlorite is used for further oxidation, and the acid can be directly prepared by using the mixed solvent of the present invention as the reaction solvent; at the same time, the method of the original patent CN104114524B will produce a large amount of waste gas containing chlorine dioxide and phosphorus-containing wastewater that pollutes the environment. , does not meet the requirements of green industry. The preparation method of the invention does not produce toxic and harmful waste gas and phosphorus-containing waste water, is environmentally friendly, and has a simple process. It can be seen from Comparative Examples 2 and 3 that adding a trace amount of tert-butyl hydroperoxide significantly improves the reaction. Without being limited to any theory, the inventor believes that it may be because tert-butyl alcohol is partially oxidized as a solvent. It is a peroxide, and the generated peroxide catalyzes the oxidation reaction, allowing it to be directly oxidized to acid. However, the reaction result of Comparative Example 3 is far less good than that of Example 1. It can be seen that the preparation method of the present invention to prepare the leborexine intermediate has a simple reaction process and is environmentally friendly.

Figure 1 shows the liquid chromatogram in the LC-MS spectrum of the reaction solution that reaches the reaction end point in Example 1 of the present invention. The data of the liquid chromatogram is reported in Table 3 below:

table 3

Figure 3 shows the HPLC purity spectrum of compound IV prepared in Example 1 of the present invention, wherein the data of the HPLC purity spectrum is reported in Table 4 below:

Table 4

Figure 5 shows the mass spectrum of compound IV prepared in the embodiment of the present invention in the LC-MS spectrum, wherein the data of the LC-MS spectrum is reported in Table 5 below:

table 5

Retention time(MS)	MS area	m/z of MS
15.045	57833156	318.10
​	​	317.10

Figure 6 shows the HPLC optical purity spectrum of compound IV prepared in Example 1 of the present invention, wherein the data of the HPLC optical purity spectrum is reported in Table 6 below:

Table 6

Figure 8 shows the liquid chromatogram in the LC-MS spectrum of the central control in Example 2 of the present invention. The data of the liquid chromatogram is reported in Table 7 as follows:

Table 7

Figure 9 shows the liquid chromatogram in the LC-MS spectrum of the control in Comparative Example 1 of the present invention, wherein the data of the liquid chromatogram is reported in Table 8 as follows:

Table 8

Figure 10 shows the liquid chromatogram in the LC-MS spectrum of the control in Comparative Example 2 of the present invention, wherein the data of the liquid chromatogram is reported in Table 9 as follows:

Table 9

Figure 11 shows the liquid chromatogram in the LC-MS spectrum of the control in Comparative Example 3 of the present invention, wherein the data of the liquid chromatogram is reported in Table 10 as follows:

Table 10

Example 3

A) (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropane-carboxylic acid (compound IV) (1.0eq, 316g) and ethyl 2-cyano-2-hydroxyiminoacetate (compound V) (1.05eq, 149g), dissolve in 10V tetrahydrofuran (first reaction solvent), stir, and cool to -10 ℃. Add diisopropylcarbodiimide (compound VI) (1.5eq, 189g) in three batches, each batch is 63g, with an interval of 20min each time. After the addition, react overnight at 0°C (first reaction temperature). The LC-MS spectra of the reaction solution are shown in Figures 12 and 13. The retention time of the ion current peak of compound II in 12b in Figure 12 is =22.113 min, the theoretical value of M+H ⁺ is 441.15[M+1] ⁺ , corresponding to the measured value in the mass spectrum in Figure 13 is 441.1[M+1] ⁺ , and the content of compound IV is less than 1%, which is considered the end of the reaction , at this time the first reaction time is 18 hours.

B) Further add the reactant 2-amino-5-fluoropyridine (compound III) (1.03eq, 115g) into the reaction system (at this time, the second reaction solvent of step B) is also the first reaction solvent of step A). ), the temperature was raised to 15°C (second reaction temperature) for a secondary reaction. After a period of reaction, the LC-MS spectra of the reaction solution were monitored as shown in Figures 14 and 15 (the ion current of compound I in 14b in Figure 14 The retention time of the peak = 18.261min, the theoretical value of M+H ⁺ is 411.16[M+1] ⁺ , corresponding to the measured value in the 15b mass spectrum in Figure 15 is 411.1[M+1] ⁺ ), the intermediate compound If the content of II is less than 3%, the reaction is deemed to be completed, and the reaction time is 4h (second reaction time). Pour the reaction solution into 3 liters of ice-water mixture, and extract once with 3 liters and 1.5 liters of isopropyl acetate respectively. The organic phase was washed once with 500 ml of 1 mol/L sodium carbonate aqueous solution. Wash once with 200 ml of 0.3 mol/L hydrochloric acid aqueous solution. The organic phase was concentrated, dissolved in isopropyl alcohol and spun to dryness. Add 1 liter of isopropyl alcohol and heat to reflux, then add 600 ml of n-heptane dropwise, put it into the low-temperature refrigeration system and set it to cool to 55°C within 2 hours, keep it at 55°C for 1 hour, and then set it to cool to 0°C within 5 hours. . Incubate at 0°C for 10 hours, filter to obtain 307g of Compound I, with a yield of 75%, a purity of 99.86% (as shown in Figure 16), an ee value of 100% (as shown in Figures 19 and 20), and the structure of Compound I Characterization is shown in Figures 17 and 18.

The method provided by the present invention can safely and efficiently prepare leborexine by preparing the Oxyma active ester intermediate, that is, compound II. Compared with the existing technology, the optical purity of leborexine prepared by the method of the present invention is higher. The racemization rate is lower and has better application prospects. At the same time, the intermediate compound II of the present invention is an Oxyma active ester intermediate, which is a safe and non-explosive auxiliary nucleophile, avoiding the explosion safety hazards of traditional activators such as HOBt and HOAt (see Fernando Albericio et al. in Chem The safety of Oxyma was evaluated in .Eur.J.2009,15,9394-9403).

Figure 16 shows the HPLC purity spectrum of compound I prepared in Example 3 of the present application, wherein the data report of the HPLC purity spectrum is as shown in Table 11:

Table 11

Figure 19 shows the chiral HPLC spectrum of compound I prepared in Example 3 of the present application, wherein the data report of the chiral HPLC spectrum is as shown in Table 12:

Table 12

Example 4 to Example 8

Examples 4 to 8 refer to step A) in Example 3. The differences lie in the differences in the first reaction solvent, the first reaction temperature and/or the first reaction time. See Table 13 for details.

In Examples 4 to 8, after step A) reacted for 18 hours (first reaction time), the content of related substances in the reaction solution was detected. The results are shown in Table 13.

Table 13

Example	first reaction solvent	first reaction temperature	Compound IV content	Compound II content
Example 4	Tetrahydrofuran	45℃	90%	2%
Example 5	Tetrahydrofuran	25℃	55%	38%
Example 6	Tetrahydrofuran	-5℃	0.2%	97%
Example 7	Toluene	-5℃	43%	51%
Example 8	Acetonitrile	-5℃	4%	93%

Example 9 to Example 13

Embodiments 9 to 13 refer to step B) of Embodiment 1, wherein Embodiment 9 is the subsequent reaction of Embodiment 4, Embodiment 10 is the subsequent reaction of Embodiment 5, and Embodiment 11 is the subsequent reaction of Embodiment 6. Example 12 is the follow-up reaction of Example 7, and Example 13 is the follow-up reaction of Example 8; the difference lies in the difference in the second reaction solvent, the second reaction temperature and/or the second reaction time in step B). For details, see Table 14.

In Examples 9 to 13, after step B) reacted for 24 hours (second reaction time), the content of related substances in the reaction solution was detected. The results are shown in Table 14.

Table 14

Example	Second reaction solvent	second reaction temperature	Compound IV content	Compound II content	Compound I content
Example 9	Tetrahydrofuran	-5℃	7%	twenty two%	66%
Example 10	Tetrahydrofuran	10℃	5%	2%	87%
Example 11	Tetrahydrofuran	35℃	14%	0.1%	75%
Example 12	Toluene	10℃	68%	5%	16%
Example 13	Acetonitrile	10℃	12%	1%	79%

The above-mentioned embodiments only express several implementation modes of the present invention, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the patent scope of the present invention. It should be noted that, for those of ordinary skill in the art, several modifications and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention.

Claims (22)

1. A preparation method of Leborexen, characterized by comprising the following steps:

   B) Compound II and Compound III react in the second reaction solvent to obtain leboresen represented by formula I;

   
2. The preparation method according to claim 1, characterized in that the second reaction solvent is selected from an organic solvent, and the organic solvent is selected from the group consisting of acetonitrile, dioxane, ethylene glycol dimethyl ether, pyridine, toluene, and ethyl acetate. At least one of ester and tetrahydrofuran is preferably tetrahydrofuran or acetonitrile.
3. The preparation method according to claim 1 or 2, characterized in that the reaction temperature of the reaction is -5°C-40°C, preferably 10°C-35°C.
4. The preparation method according to any one of claims 1-3, characterized in that the reaction time of the reaction is 1h-48h, preferably 12-24h.
5. A compound of formula II:

   
6. A preparation method of Compound II, characterized by comprising the following steps:

   A) Compound IV, Compound V and Compound VI react in the first reaction solvent to obtain Compound II;

   
7. The preparation method according to claim 6, characterized in that the first reaction solvent is selected from an organic solvent, and the organic solvent is selected from the group consisting of acetonitrile, dioxane, ethylene glycol dimethyl ether, pyridine, toluene, and ethyl acetate. At least one of ester and tetrahydrofuran is preferably tetrahydrofuran or acetonitrile.
8. The preparation method according to claim 6 or 7, characterized in that the reaction temperature of the reaction is -15°C-10°C, preferably -10°C-5°C.
9. The preparation method according to any one of claims 6-8, characterized in that the reaction time of the reaction is 1h-48h, preferably 4-24h.
10. A preparation method of compound IV, characterized by comprising the following steps:

    A) Using compound VII as raw material, under the action of a catalyst and an oxidant, an oxidation reaction occurs in a mixed solvent of tert-butanol and water to generate compound IV;

    
11. The preparation method according to claim 10, characterized in that the catalyst is selected from 2,2,6,6,-tetramethylpiperidine-nitrogen-oxide or 4-hydroxy-2,2,6,6, -At least one of tetramethylpiperidine-1-oxyl radicals.
12. The preparation method according to claim 10, characterized in that the amount of the catalyst is 1%-25% of the molar amount of compound VII.
13. The preparation method according to claim 10, characterized in that the volume ratio of tert-butyl alcohol and water in the mixed solvent is 4:1-3:2.
14. The preparation method according to claim 10, characterized in that the oxidizing agent is sodium hypochlorite.
15. The preparation method according to claim 10, characterized in that the amount of the oxidizing agent is 2.0eq-5.0eq of the molar amount of compound VII.
16. The preparation method according to claim 10, characterized in that the pH value of the oxidation reaction ranges from 6 to 12.
17. The preparation method according to claim 10, characterized in that sodium bicarbonate and/or sodium carbonate is also added to the mixed solvent.
18. The preparation method according to claim 10, characterized in that the reaction temperature of the oxidation reaction is -10°C to 45°C, preferably -3°C to 3°C.
19. The preparation method according to claim 10, characterized in that the reaction time of the oxidation reaction is 1h-96h, preferably 1h-24h.
20. A preparation method of Leborexen, characterized by comprising the following steps:

    Compound II is prepared by step A) as described in any one of claims 6 to 9;

    The leborexan represented by formula I is prepared by step B) according to any one of claims 1 to 4;

    
21. The preparation method according to claim 20, characterized in that compound IV is prepared by step A) according to any one of claims 10 to 19.
22. The preparation method according to claim 20 or 21, characterized in that it includes the following steps:

    Compound II prepared in step A) is directly used in step B) without isolation.

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