CN116836151A - Preparation methods of leborexan and its intermediates - Google Patents

Abstract

The application provides a method for preparing a microblog Lei Sheng, which comprises the following steps: and (3) reacting the compound II with the compound III in a second reaction solvent to obtain the lebone Lei Sheng. The application also provides a preparation method of the compound II, the compound II prepared by the method is an Oxyma active ester intermediate, has high reaction activity, is a safe and non-explosive auxiliary nucleophile, avoids using traditional HOBt, HOAt and other activators, and eliminates potential safety hazards; the preparation method of the application for preparing the lebo Lei Sheng has safer and more efficient reaction and lower racemization rate of the obtained product.

Description

Preparation method of leborexan and its intermediates

Technical field

The present invention relates to the field of medical technology, and in particular to a preparation method of leborexan 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:

The existing methods for preparing leborexine have high racemization rates and low coupling efficiency. And in traditional amide coupling reactions, the commonly used activators are 1-hydroxybenzotriazole (HOBt) and 1-hydroxy-7-azabentriazole (HOAt). Both HOBt and HOAt are used. There are certain explosion safety hazards. In view of this, it is urgent to propose a new preparation method for Lebraxen.

Contents of the invention

The object of the present invention is to provide a preparation method of leborexan and its intermediates. The specific technical solutions are as follows:

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 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 present 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.

Description of the drawings

Figure 1 is the liquid chromatography mass spectrometry (LC-MS) spectrum of the reaction solution at the end of the reaction in step A) in Example 1 of the present invention. The liquid chromatography and ion flow diagrams are shown in the figure. 1a is the liquid chromatography spectrum, and 1b is the liquid chromatography spectrum. is an ion current diagram.

Figure 2 is the mass spectrum of Compound II in the LC-MS spectrum of the reaction solution at the end of step A) in Example 1 of the present invention.

Figure 3 is the liquid chromatography and ion chromatogram of the LC-MS spectrum of the reaction solution at the end of step B) in Example 1 of the present invention, wherein 3a is the liquid chromatography spectrum and 3b is the ion chromatogram.

Figure 4 is a mass spectrum of the LC-MS spectrum of the reaction solution at the end of step B) in Example 1 of the present invention. Among them, 4a is the mass spectrum of Compound IV in the reaction solution in the LC-MS spectrum, and 4b is the mass spectrum of Leboresen I in the reaction solution in the LC-MS spectrum.

Figure 5 is a hydrogen nuclear magnetic spectrum ( ¹ H NMR) spectrum (500 MHz) of Leboreson I prepared in Example 1 of the present invention;

Figure 6 is an infrared spectrum of Lebraxane I prepared in Example 1 of the present invention.

Figure 7 is a high-performance liquid chromatography (HPLC) purity spectrum of leboresen I prepared in Example 1 of the present invention.

Figure 8 is a chiral HPLC spectrum of leborexine I prepared in Example 1 of the present invention.

Figure 9 is a chiral HPLC spectrum of the enantiomeric isomer of leborexan I in Example 1 of the present invention.

Detailed ways

Terms and Definitions: Oxyma: ethyl 2-oximecyanoacetate.

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.

The fourth 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 present 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 testing methods of ¹ H NMR, LC-MS testing, and infrared testing are not particularly limited. Methods known to those skilled in the art can be used for testing. Among them, the deuterated reagent used in the hydrogen nuclear magnetic spectrum test is commercially available. of 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 both purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.;

Preparation of compound IV ((1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropyl)carboxylic acid Made for the company, the specific reaction steps are as follows:

In the reaction bottle, 302g ((1R,2S)-2-((2,4-dimethylpyrimidin-5-yloxy)methyl)-2-(3-fluorophenyl)cyclopropyl)methanol Dissolve in 2000mL tert-butanol and 1200mL water, add 150g sodium bicarbonate, 15g sodium carbonate, 7.5g 2,2,6,6,-tetramethylpiperidine-nitrogen-oxide (TEMPO), and 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 -5-3°C. After the dropwise addition is completed, react at 0°C for 12 hours. 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. Concentrate the organic phase, use dichloromethane to remove the moisture content to less than 0.05%, and obtain an off-white powdery solid. Add 400 mL of isopropyl ether, heat to reflux, vigorously stir and heat to beat, cool and filter to obtain 295g of white solid compound (IV). ((1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropyl)carboxylic acid.

Example 1

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 1 and 2. The retention time of the ion current peak of compound II in 1b in Figure 1 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 2 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 3 and 4 (the ion current of compound I in 3b in Figure 3 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 4b in Figure 4 is 411.1[M+1] ⁺ ), the intermediate compound II When the content 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 5), and an ee value of 100% (as shown in Figures 8 and 9). The structure of Compound I Characterization is shown in Figures 6 and 7.

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 5 shows the HPLC purity spectrum of Compound I prepared in the Examples of the present application, wherein the data report of the HPLC purity spectrum is as shown in Table 2:

Table 2

Figure 8 shows the chiral HPLC spectrum of Compound I prepared in the Examples of the present application, wherein the data of the chiral HPLC spectrum is reported in Table 3:

table 3

Example 2 to Example 6

Examples 2 to 6 refer to step A) in Example 1. The differences lie in the difference in the first reaction solvent, the first reaction temperature and/or the first reaction time. See Table 4 for details.

In Examples 2 to 6, 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 4.

Table 4

Example first reaction solvent first reaction temperature Compound IV content Compound II content Example 2 Tetrahydrofuran 45℃ 90% 2% Example 3 Tetrahydrofuran 25℃ 55% 38% Example 4 Tetrahydrofuran -5℃ 0.2% 97% Example 5 Toluene -5℃ 43% 51% Example 6 Acetonitrile -5℃ 4% 93%

Example 7 to Example 11

Embodiments 7 to 11 refer to step B) of Embodiment 1, wherein Embodiment 7 is the subsequent reaction of Embodiment 2, Embodiment 8 is the subsequent reaction of Embodiment 3, and Embodiment 9 is the subsequent reaction of Embodiment 4. Example 10 is the follow-up reaction of Example 5, and Example 11 is the follow-up reaction of Example 6; 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 5.

In Examples 7 to 11, 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 5.

table 5

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 (11)

1. A preparation method of leborexan, which is 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, At least one of ethyl acetate 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, At least one of ethyl acetate 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 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 leborexan, which is 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; 11. The preparation method of Leborexen as claimed in claim 10, characterized in that it includes the following steps: Compound II prepared in step A) is directly used in step B) without isolation.