Method for preparing Lobrabosan without adding organic amine

Abstract

The invention provides a preparation method of lybologarithm as shown in a formula (I) and an intermediate compound of the lybologarithm. According to the preparation method of the liboxadone as shown in the formula (I), the reaction conditions are simple, the activity of the adopted intermediate compound is moderate, the intermediate compound can be condensed with 2-amino-5-fluoropyridine to generate the liboxadone as shown in the formula (I), and the yield is high; according to the preparation method of the intermediate compound, side reactions in the reaction process are few, post-treatment is easy, and the preparation method is suitable for industrial production of the libolifera.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a method for preparing lebrexan and an intermediate compound thereof. Background of the Invention

[0003] Insomnia refers to a subjective experience in which patients are dissatisfied with sleep duration and / or quality and their daytime social functions are affected. According to the international diagnostic criteria for insomnia and epidemiological studies, at least 6% of people worldwide suffer from insomnia and sleep disorders. Before Lebrexan was launched, all sleeping pills were sedatives, and Lebrexan was the first non-addictive sleeping pill.

[0004] Lemborexant is a dual inhibitor of orexin receptor OX1 and orexin receptor OX2, which may purposefully promote the initiation and maintenance of sleep by interfering with orexinergic neurotransmission. Its chemical formula is shown in Formula I:

[0005]

[0006] Patent CN10414524B discloses a method for preparing Lebrexan on page 52. Using T3P as an amide coupling agent and DIEA as an organic amine, (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-carboxylic acid is condensed with 2-amino-5-fluoropyridine in an ethyl acetate solvent to prepare Lebrexan, and the total yield of the reaction is 80%. The main claim of the patent claims claims protection: In an organic solvent, in the presence of an amide coupling agent and an organic amine, a method for preparing and synthesizing Lebrexan by (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-carboxylic acid and 2-amino-5-fluoropyridine. Summary of the invention

[0007] According to existing literature and patent reports, the commonly used method for preparing Lebrexan is: in an organic solvent, an organic amine and an amide coupling agent react to generate a product in the presence of the same time. If the reaction is carried out without adding an organic amine, the reaction result is often unsatisfactory. After many experiments by the inventor, since the nucleophilicity of 2-amino-5-fluoropyridine is very weak, if only an amide coupling agent is added without adding an organic amine to increase its nucleophilicity, the result is often no reaction or a very low conversion rate. However, the present invention can complete the reaction without adding an organic amine, and only needs to select an amide coupling agent with moderate activity to promote the occurrence of the reaction, which well avoids the limitations of patent CN10414524B and provides a new idea for the synthesis of Lebrexan.

[0008] In the present invention, the inventors found that the intermediate compound (VI) has moderate activity. After a lot of research, the inventors found that the activity ranking after the acid is activated is as follows: acyl bromide>acyl chloride>acyl fluoride>sulfonic acid anhydride>phosphoric acid anhydride>high steric hindrance carbonic acid anhydride>low steric hindrance carbonic acid anhydride>strong electron-pulling active ester>general active ester>methyl ester>ethyl ester.

[0009]

[0010] Since the nucleophilicity of 2-amino-5-fluoropyridine is very weak, direct condensation with it requires at least the activity of carbonic anhydride. When the activity is higher, such as acyl chloride and acyl bromide, it is easy to have two, forming high-risk impurities. The intermediate state selected in this patent has a moderate activity that is slightly lower, which can greatly improve the selectivity.

[0011] The first aspect of the present invention provides a method for preparing Lebrexan, comprising the following steps:

[0012] Compound (II) is activated by compound (III) [commercially available amide coupling agent EEDQ or IIDQ] and then reacted with compound (IV) in an organic solvent to generate Lebrexan shown in formula (I);

[0013] In compound (III), R is selected from ethyl or isobutyl;

[0014]

[0015] 2. R is selected from ethyl or isobutyl, and the organic solvent is selected from one or more of aromatic hydrocarbon solvents, halogenated hydrocarbon solvents and ether solvents. The inventors found in actual work that the amide coupling agent is IIDQ, and the yield and intermediate stability of its transition state product (VI) are higher than those of the transition state product (V) corresponding to EEDQ.

[0016] 3. The molar ratio of compound (III) to compound (II) is 2:1 to 1:1, preferably 1.5:1 to 1.1:1.

[0017] 4. The reaction temperature is 35-60°C. When the amide coupling agent is EEDQ, the reaction temperature is preferably 35-40°C. When the amide coupling agent is IIDQ, the reaction temperature is preferably 55-60°C.

[0018] 5. It is characterized in that the preparation method of compound (II) comprises the following steps:

[0019] Adding compound (II) and compound (III) together into an organic solvent, and first generating a highly active transition state compound (V) or compound (VI) or compound (VII) and directly reacting it with compound (IV) without separation to prepare compound (I);

[0020]

[0021] 6. The reaction solvent is selected from at least one of toluene, dichloromethane, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, isopropyl ether, tert-butyl methyl ether and acetonitrile.

[0022] The second aspect of the present invention provides three intermediate transition state compounds of Lebrexan, which are shown in any of the following structural formulas:

[0023]

[0024] When the amide coupling agent is EEDQ, the intermediate transition state compounds of the reaction are (V) and (VII), and when the amide coupling agent is IIDQ, the intermediate transition state compounds of the reaction are (VI) and (VII), among which the reaction activity (VII)>(VI)>(V).

[0025] In the present invention, the purification method of the above-mentioned Lebrexan is not particularly limited, as long as the purpose of the present application can be achieved.

[0026] The invention adopts an intermediate compound represented by formula (II) to condense with 2-amino-5-fluoropyridine to generate lebrexan; the preparation process has few side reactions and high yield. The preparation method of the intermediate compound represented by formula (II) of the invention has few side reactions during the reaction process, almost no other halogenated byproducts are generated, and the post-processing is easy, which is suitable for the industrial production of lebrexan. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for use in the embodiments are briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention, and a person skilled in the art can also obtain other drawings based on these drawings.

[0028] Figure 1-Figure 3 This is the LC-MS chart of the reaction solution after the reaction in Example 1 was completed.

[0029] Figure 4 This is the H NMR spectrum (DMSO-d6) of Lebroxan of Example 1.

[0030] Figure 5 This is the nuclear magnetic carbon spectrum (CDCl3) of Labreson in Example 1.

[0031] Figure 6 This is the infrared spectrum of Labrexant in Example 1.

[0032] Figure 7The HPLC purity spectrum of Lebrexan in Example 1 is shown in FIG.

[0033] Figure 8 This is the HPLC optical purity spectrum of Lebrexan in Example 1.

[0034] Fig. 9 The figure is a diagram showing the positioning of the enantiomers of Lebrexan of Example 1 in the optical purity diagram. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with implementation cases so that those skilled in the art can fully understand the technical content of the present invention. It should be understood that the following examples are used to further illustrate the present invention, but are not limited thereto. Some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention belong to the protection scope of the present invention. The specific process parameters of the following embodiments are also only a case in a suitable range, that is, those skilled in the art can make a suitable range selection according to the description herein, and are not limited to the specific values ​​of the following embodiments.

[0036] All ranges recited in the present invention include those endpoints of the range between two values. Regardless of whether it is indicated, all values ​​recited in the present invention include the expected experimental error, technical error and instrument error of the given technology used to measure the value, and when the error degree is not recorded, all values ​​recited in the present invention and the range of ± 10% of the recorded value are included.

[0037] In the present invention, unless otherwise specified, % is a percentage of weight / weight (w / w).

[0038] Example

[0039] Hereinafter, the 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.

[0040] HPLC method:

[0041] In the embodiments, high performance liquid chromatography (HPLC) is used to monitor the reaction process or analyze the purity of the product. High performance liquid chromatography (HPLC) uses liquid as the mobile phase and a high-pressure infusion system to pump a single solvent with different polarities or a mixed solvent with different proportions, a buffer and other mobile phases into a chromatographic column equipped with a stationary phase. After the components in the column are separated, they enter the detector for detection to achieve analysis of the sample components. The chromatographic conditions are shown in Table 1 below:

[0042] Table 1

[0043]

[0044] ee value measurement:

[0045] In the two enantiomers of the chiral molecule in the example, each enantiomer rotates plane polarized light to a certain angle, the value of which is the same but the direction is opposite. This property is called optical activity. The enantiomeric composition of the product is described by the term "enantiomeric excess" or "ee value", which indicates the excess of one enantiomer over the other enantiomer, usually expressed as a percentage.

[0046] In the examples, high performance liquid chromatography (HPLC) was used to measure the ee value of the product.

[0047] Unless otherwise specified, the raw materials and reagents of the present invention can be obtained commercially, such as compound EEDQ / IIDQ purchased from Suzhou Haofan Biotechnology Co., Ltd.; 2-amino-5-fluoropyridine purchased from Fuxin Jintelai Fluorine Chemical Co., Ltd.; tetrahydrofuran, toluene, and n-heptane purchased from Sinopharm Group Co., Ltd.

[0048] The preparation of compound II ((1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropyl)carboxylic acid was prepared by the company. The specific reaction steps are as follows:

[0049] In a reaction flask, 302g ((1R, 2S)-2-((2,4-dimethylpyrimidin-5-yloxy)methyl)-2-(3-fluorophenyl)cyclopropyl)methanol was dissolved in 2000mL tert-butyl alcohol and 1200mL water, and 150g sodium bicarbonate, 15g sodium carbonate, and 7.5g 2,2,6,6,-tetramethylpiperidine-nitrogen-oxide (TEMPO) were added and stirred thoroughly. The temperature outside the reaction flask dropped to -10°C. Sodium hypochlorite aqueous solution (2.2eq, 2200mL) was added dropwise, the pH of the aqueous phase was 9, and the temperature of the reaction system was maintained at -5-3°C. After the addition was completed, the reaction was carried out at 0°C for 12h. A quenching reagent (280g sodium sulfite and 150g sodium hydroxide dissolved in 1500mL water) was added dropwise, and the temperature did not exceed 25°C during the addition. After the addition was completed, the temperature was raised to 60°C and stirred for 0.5h. The solution was clear and the pH of the aqueous phase was 9.5. After standing, the aqueous phase was separated and removed. The organic phase was concentrated to a volume of about 800 ml, 1 L of sodium hydroxide aqueous solution (concentration of 10%) was added, the pH was adjusted to > 13.5, the aqueous phase was extracted with tert-butyl methyl ether, the organic phase was separated and removed, the temperature of the aqueous phase was controlled not to exceed 10 ° C, 3.1 L of concentrated hydrochloric acid (mass fraction > 20%) was added, the pH was adjusted to 1.5-2.5, most of the water was filtered out to obtain a viscous solid, which was dissolved in 800 mL of dichloromethane, and a small amount of water was removed by separation. The organic phase was concentrated and desorbed with dichloromethane until the moisture content was less than 0.05% to obtain an off-white powder solid, 400 mL of isopropyl ether was added, heated to reflux, vigorously stirred and hot slurried, and filtered after cooling to obtain 295 g of white solid compound (II) ((1R, 2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropyl)carboxylic acid.

[0050] Example 1

[0051] Preparation of Lebrexan represented by formula (I)

[0052]

[0053] 20 g of (1R, 2S)-2-((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropanecarboxylic acid (compound of formula (IV)) was added to a three-necked flask and dissolved in 200 mL of tetrahydrofuran. 7.3 g of 2-amino-5-fluoropyridine (1.02 eq) was added, and then 23 g of amide coupling agent IIDQ (1.2 eq) was added at once. After reacting at 25° C. for half an hour, the mixture was heated to 55° C. and continued to react for 12 hours. When the content of the compound of formula (II) was <1% under HPLC monitoring, the reaction was considered to have reached the end point.

[0054] The reaction solution reaching the end point of the reaction was slowly added dropwise to 280 mL of 0.5 mol / l dilute hydrochloric acid at 0°C and 300 mL of isopropyl acetate. After separation and removal of the aqueous phase, the obtained organic phase was washed once with 200 mL of saturated sodium bicarbonate solution at 0°C and once with 150 mL of saturated brine. After drying with anhydrous sodium sulfate, the organic phase was concentrated to an off-white solid and evaporated without solvent. 50 mL of toluene was added and heated to 95°C as the outer wall temperature of the container, 30 mL of n-heptane was added, and the program was set to cool to 5°C for 24 hours. Filter and dry to obtain 21 g of the product Lebroxan, with a yield of 81%, a purity of 99.88%, and ee 100%.

[0055] Figure 1-Figure 3 The LC-MS graph of the reaction solution when the reaction in Example 1 reaches the reaction endpoint is shown. Figure 1 is the liquid chromatography spectrum, Figure 2 is the ion current diagram, Figure 3 for Figure 2 Mass spectrum of the ion current peak at the retention time of 2.545min. Figure 2 The data of the ion current peaks and their corresponding mass spectra are reported in Table 2:

[0056] Table 2

[0057]

[0058] Figure 4 The nuclear magnetic hydrogen spectrum of Lebrexan of Example 1 is shown 1 H-NMR (DMSO-d6).

[0059] Figure 5 The NMR carbon spectrum (CDCl3) of Labreson of Example 1 is shown.

[0060] Figure 6 The infrared spectrum of Labrexant of Example 1 is shown.

[0061] Figure 7 The HPLC purity spectrum of Lebrexan of Example 1 is shown. The data of the HPLC purity spectrum is reported in Table 3 below:

[0062] Table 3

[0063]

[0064] As you can see, Figure 7 The retention time of lebrexan is 18.015 min, and the corresponding peak area ratio is 99.88%, indicating that the HPLC purity of the product lebrexan is 99.88%.

[0065] Figure 8This is the HPLC optical purity spectrum of Lebrexan in Example 1. The data of the HPLC optical purity spectrum is reported in Table 4 below:

[0066] Table 4

[0067]

[0068] Fig. 9 This is the enantiomer localization diagram of Lebrexan in Example 1. Figure 8 and Fig. 9 It can be seen that Figure 7 The retention time of Labrexant is 10.209min. Fig. 9 The retention time of the enantiomer of Lebrexan is 10.307min, while Figure 8 No peak appeared at the retention time of 10.307 min, indicating that the lebrexan prepared in Example 1 was a single-configuration compound represented by formula (I) and did not contain its enantiomers, that is, the ee value of the lebrexan prepared in Example 1 was 100%.

[0069] Example 2

[0070] Preparation of Lebrexan represented by formula (I)

[0071]

[0072] 20 g of (1R, 2S)-2-((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropanecarboxylic acid (compound of formula (IV)) was added to a three-necked flask and dissolved in 200 mL of acetonitrile. 7.3 g of 2-amino-5-fluoropyridine (1.02 eq) was added, and then 23 g of amide coupling agent IIDQ (1.2 eq) was added at once. After reacting at 25° C. for half an hour, the mixture was heated to 35° C. and continued to react for 12 hours. When the content of compound of formula (II) was <1% under HPLC monitoring, the reaction was considered to have reached the end point.

[0073] The reaction solution reaching the end point of the reaction was slowly added dropwise to 280 mL of 0.5 mol / l dilute hydrochloric acid at 0°C and 300 mL of isopropyl acetate. After separation and removal of the aqueous phase, the obtained organic phase was washed once with 200 mL of saturated sodium bicarbonate solution at 0°C and once with 150 mL of saturated brine. After drying with anhydrous sodium sulfate, the organic phase was concentrated to an off-white solid and evaporated without solvent. 50 mL of toluene was added and heated to 95°C as the outer wall temperature of the container, 30 mL of n-heptane was added, and the program was set to cool to 5°C for 24 hours. 17.1 g of the product Lebrezol was obtained by filtration and drying, with a yield of 66%, a purity of 99.6%, and an ee of 99.8%.

[0074] Example 3

[0075] Preparation of Lebrexan represented by formula (I)

[0076]

[0077] In a three-necked flask, 20 g of (1R, 2S)-2-((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropanecarboxylic acid (compound of formula (IV)) was added and dissolved in 200 mL of toluene. Then, 7.3 g of 2-amino-5-fluoropyridine (1.02 eq) was added, and then 18.78 g of amide coupling agent EEDQ (1.2 eq) was added at once. After reacting at 25° C. for half an hour, the mixture was heated to 35° C. and the reaction was continued for 12 hours.

[0078] The reaction solution reaching the end point of the reaction was slowly added dropwise to 280 mL of 0.5 mol / l dilute hydrochloric acid at 0°C and 300 mL of isopropyl acetate. After separation and removal of the aqueous phase, the obtained organic phase was washed once with 200 mL of saturated sodium bicarbonate solution at 0°C and once with 150 mL of saturated brine. After drying with anhydrous sodium sulfate, the organic phase was concentrated to an off-white solid and evaporated without solvent. 50 mL of toluene was added and heated to a temperature of 95°C on the outer wall of the container, 30 mL of n-heptane was added, and the program was set to cool to 5°C for 24 hours. 11.65 g of the product Lebroxan was obtained by filtration and drying, with a yield of 45% and a purity of 97.7%.

[0079] Comparative Example 1

[0080] 20g (1R, 2S)-2-((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropanecarboxylic acid (compound of formula (IV)) was added to a three-necked flask and dissolved in 200mL tetrahydrofuran, and then 7.3g 2-amino-5-fluoropyridine (1.02eq) was added, and then 60.37g amide coupling agent EEDQ (3eq) was added at once, and after reacting at 25°C for half an hour, the reaction was heated to 55°C and continued for 12 hours. According to HPLC detection, the in situ yield of the reaction was only about 15%, and the reaction was not processed.

[0081] Comparative Example 2

[0082] 20g (1R, 2S)-2-((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropanecarboxylic acid (compound of formula (IV)) was added to a three-necked flask, dissolved in 200mL dichloromethane, and then 7.3g 2-amino-5-fluoropyridine (1.02eq) was added, and then 28.87g amide coupling agent HATU (1.2eq) was added at once, reacted at 25°C for half an hour, and then heated to reflux and continued to react for 12 hours. According to HPLC detection, the in situ yield of the reaction was only about 5%, and the reaction was not processed.

[0083] Comparative Example 3

[0084] 20 g of (1R, 2S)-2-((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropanecarboxylic acid (compound of formula (IV)) was added to a three-necked flask and dissolved in 200 mL of tetrahydrofuran, and then 7.3 g of 2-amino-5-fluoropyridine (1.02 eq) was added, and then 8.73 g of amide coupling agent SUOH (1.2 eq) was added at once, and reacted at 25° C. for half an hour, and then heated to reflux and continued to react for 12 hours. According to HPLC detection, no product was generated in the reaction, and the reaction was not processed.

[0085] Comparative Example 4

[0086] 20g (1R, 2S)-2-((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropanecarboxylic acid (compound of formula (IV)) was added to a three-necked flask, dissolved in 200mL tetrahydrofuran, and then 7.3g 2-amino-5-fluoropyridine (1.02eq) was added, followed by 26.83g HOBT (2eq), 24.26g EDCI (2eq) and 17.49g potassium carbonate (2eq). After reacting at 25°C for half an hour, the mixture was heated to reflux and continued to react for 12 hours. According to HPLC detection, no product was generated in the reaction, and the reaction was not processed.

[0087] The difference between Examples 1 to 3 and Comparative Examples 1 to 4 is that the amide coupling agents, solvents and temperatures used are different, as shown in Table 5 below.

[0088] The yield, purity and ee value of Lebrexan obtained in Examples 1 to 3 and Comparative Examples 1 to 4 are shown in Table 5.

[0089] Table 5

[0090]

[0091]

[0092] The above description is only a partial embodiment repeated in this application and is not intended to limit this application. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of this application should be included in the scope of protection of this application.

Claims

1. A method for preparing Lebroxan, characterized in that The following steps are involved: Compound (II) is activated by compound (III) [commercially available amide coupling agent EEDQ or IIDQ] and then reacted with compound (IV) in an organic solvent to generate Lebrexan represented by formula (I); In compound (III), R is selected from ethyl or isobutyl; 2. The method for preparing Lebrexan according to claim 1, characterized in that In compound (III), R is selected from ethyl or isobutyl.

3. The method for preparing lebrexan according to claim 4, wherein the molar ratio of compound (III) to compound (II) is 2:1 to 1:1, preferably 1.5:1 to 1.1:

1.

4. The method for preparing Lebrexan according to claim 1, characterized in that The reaction temperature is 35-60°C, preferably in the range of 55-60°C.

5. The method for preparing Lebrexan according to claim 1, characterized in that The preparation method of the compound (II) comprises the following steps: Adding compound (II) and compound (III) together into an organic solvent, and first generating a highly active transition state compound (V) or compound (VI) or compound (VII) and directly reacting it with compound (IV) without separation to prepare compound (I); 6. According to the method for preparing Lebrexan as claimed in claim 1, the reaction solvent is selected from at least one of toluene, dichloromethane, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, isopropyl ether, tert-butyl methyl ether and acetonitrile.

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