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WO2023178702A1 - Method for preparing lemborexant and method for preparing lemborexant intermediate compound - Google Patents

Method for preparing lemborexant and method for preparing lemborexant intermediate compound Download PDF

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Publication number
WO2023178702A1
WO2023178702A1 PCT/CN2022/083200 CN2022083200W WO2023178702A1 WO 2023178702 A1 WO2023178702 A1 WO 2023178702A1 CN 2022083200 W CN2022083200 W CN 2022083200W WO 2023178702 A1 WO2023178702 A1 WO 2023178702A1
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Prior art keywords
compound
reaction
leborexan
preparation
solvent
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PCT/CN2022/083200
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French (fr)
Chinese (zh)
Inventor
沈冀钧
简正军
程虎
何先亮
黄鲁宁
陶安平
顾虹
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浙江华海药业股份有限公司
上海奥博生物医药股份有限公司
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Priority to PCT/CN2022/083200 priority Critical patent/WO2023178702A1/en
Priority to CN202280090355.7A priority patent/CN118843622A/en
Publication of WO2023178702A1 publication Critical patent/WO2023178702A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of medical technology, and in particular to a preparation method of leborexan and its intermediate compounds.
  • Insomnia refers to a subjective experience in which patients are dissatisfied with sleep time and/or quality and affect daytime social functions. According to the international diagnostic criteria for insomnia and epidemiological studies, at least 6% of people worldwide suffer from insomnia and sleep disorders.
  • Lemborexant is a dual inhibitor of the orexin receptor OX1 and the orexin receptor OX2. It may promote the initiation and maintenance of sleep by interfering with orexinergic neurotransmission. Its chemical formula is as shown in formula I. Show:
  • Example 100 of patent US20120095031A1 discloses a preparation method of Lebraxen.
  • oxalyl chloride ((COCl) 2 ) as the acid chlorination reagent
  • 200 mg of (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2- (3-Fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-carboxylic acid reacts with oxalyl chloride in dichloromethane solvent to generate an acid chloride intermediate; the acid chloride intermediate is then reacted with 2-amino- 5-Fluoropyridine was condensed to prepare 102 mg of leborexan, and the total reaction yield was only 40%.
  • a first aspect of the present invention provides a preparation method of leborexine, which includes the following steps:
  • X is selected from fluorine or chlorine
  • X in compound (II) is selected from fluorine
  • the second reaction solvent is selected from organic solvents or mixed solvents of organic solvents and alkaline aqueous solutions
  • the organic solvent is selected from aromatic hydrocarbon solvents , one or more of halogenated hydrocarbon solvents and ether solvents.
  • X in compound (II) is selected from fluorine, the organic solvent is toluene, dichloromethane or tetrahydrofuran; the alkaline aqueous solution is sodium carbonate aqueous solution or sodium bicarbonate aqueous solution.
  • X in compound (II) is selected from fluorine, and the second reaction solvent is toluene or a mixed solvent of toluene and saturated sodium bicarbonate aqueous solution.
  • the volume ratio of toluene to saturated sodium bicarbonate aqueous solution in the mixed solvent is 2:1 to 1:2, preferably 1:0.8 to 1:1.
  • X in compound (II) is selected from fluorine, and the organic amine is selected from triethylamine, pyridine, N,N-diisopropylethylamine, 4-dimethylaminopyridine and triethylamine.
  • At least one of the ethanolamines is preferably pyridine; the volume of the organic amine is 5% to 15% of the volume of the second reaction solvent, preferably 8% to 12%.
  • X in compound (II) is selected from chlorine, and the second reaction solvent is selected from tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, acetonitrile, 2-methyl It is preferably at least one of ethylene glycol dimethyl ether, tetrahydrofuran and 1,4-dioxane.
  • X in compound (II) is selected from chlorine, and the organic base is selected from diisopropylethylamine, triethylamine, pyridine, N-methylimidazole, picoline, 1, In 8-diazabicyclo[5.4.0]undec-7-ene, quinoline, tetramethylethylenediamine, triethylenediamine, hexamethylenetetramine and N-methylmorpholine At least one, preferably at least one of diisopropylethylamine and triethylamine.
  • X in compound (II) is selected from chlorine, and the order of addition of the condensation reaction in step B) is:
  • the mixed solvent c is slowly added dropwise to the mixed solvent d to carry out the reaction to generate leborexan.
  • X in compound (II) is selected from chlorine, and the reaction temperature in step B) is 20-100°C, preferably 25-75°C, and most preferably 45-75°C.
  • a second aspect of the present invention provides a leborexine intermediate compound (II), which is represented by any of the following structural formulas:
  • the preparation method of compound (II) includes the following steps:
  • X is selected from fluorine or chlorine
  • the acid halide reagent is selected from one of trifluoro-s-triazine or phosphorus oxychloride.
  • the acid halide reagent is selected from trifluoro-s-triazine, and X in compound (II) is selected from fluorine;
  • the first reaction solvent is selected from toluene, dichloromethane, ethyl acetate, At least one of pyridine, tetrahydrofuran, dioxane, acetonitrile and acetone, preferably toluene, dichloromethane or tetrahydrofuran, more preferably toluene;
  • the organic amine is selected from triethylamine, pyridine, N,N-bis At least one of isopropylethylamine, 4-dimethylaminopyridine and triethanolamine is preferably pyridine;
  • the volume of the organic amine is 1 to 10% of the first reaction solvent, preferably 4 to 5%.
  • the acid halide reagent is selected from trifluoro-s-triazine, and X in compound (II) is selected from fluorine.
  • step A) generates compound (II), it also includes adding dilute The step of removing water-soluble impurities with acid aqueous solution.
  • the acid halide reagent is selected from phosphorus oxychloride
  • X in compound (II) is selected from chlorine
  • the first reaction solvent is selected from toluene, fluorobenzene, chlorobenzene, xylene
  • the acid halide reagent is selected from phosphorus oxychloride
  • X in compound (II) is selected from chlorine
  • the order of addition of the reaction in step A) is:
  • the acid halide reagent is selected from phosphorus oxychloride
  • X in compound (II) is selected from chlorine
  • the reaction temperature in step A) is 20-100°C, preferably 60- 90°C, most preferably 60-65°C.
  • the third aspect of the present invention provides a preparation method of leborexine, which includes the following steps:
  • Compound (IV) reacts with an acid halide reagent in the first reaction solvent to generate compound (II), where X in compound (II) is selected from fluorine or chlorine;
  • the present invention adopts the intermediate compound represented by the formula (II) and condenses it with 2-amino-5-fluoropyridine to generate leboresen; there are few side reactions during the preparation process and the yield is high.
  • the present invention is represented by the formula (II).
  • the preparation method of the intermediate compound has few side reactions during the reaction process, almost no other halogenated by-products are generated, and the post-processing is easy, which is suitable for the industrial production of Lebraxen.
  • Figure 1 is an LC-MS diagram of the reaction solution after step A) of Example 1.
  • Figure 2 is the proton nuclear magnetic spectrum (DMSO-d 6 ) of Lebraxen in Example 1.
  • Figure 3 is the infrared spectrum of Lebraxen in Example 1.
  • Figure 4 is the HPLC purity spectrum of leborexan in Example 1.
  • Figure 5 is the HPLC optical purity spectrum of Lebraxen in Example 1.
  • Figure 6 is an enantiomeric positioning diagram of leborexan in Example 1.
  • Figure 7 is an LC-MS diagram of the reaction solution in step A) of methanol quenching in Example 9.
  • Figure 8 is an LC-MS diagram of the reaction solution in step B) after the reaction in Example 9 is completed.
  • Figure 9 is the hydrogen nuclear magnetic spectrum (DMSO-d 6 ) of leborexan in Example 9.
  • Figure 10 is the infrared spectrum of Lebraxen in Example 9.
  • Figure 11 is the HPLC purity spectrum of leborexan in Example 9.
  • Figure 12 is the HPLC optical purity spectrum of Lebraxen in Example 9.
  • Figure 13 is an enantiomeric positioning diagram of Lebraxen in Example 9.
  • Figure 14 is the mass spectrum of the by-product (VIII) in Comparative Example 2.
  • Figure 15 is the hydrogen nuclear magnetic spectrum (DMSO-d 6 ) of the by-product (VIII) in Comparative Example 2.
  • % is a weight/weight (w/w) percentage unless otherwise stated.
  • a first aspect of the present invention provides a preparation method of leborexine, which includes the following steps:
  • X is selected from fluorine or chlorine
  • the inventor found that the intermediate compound (II) has moderate activity and can be directly condensed with 2-amino-5-fluoropyridine to generate leborexine with high yield; the reaction conditions are simple and the synthesis process is undesirable. It has less reaction and easy post-processing, so it is suitable for industrial production of Lebraxen.
  • X in compound (II) is selected from fluorine
  • the second reaction solvent is selected from organic solvents or mixed solvents of organic solvents and alkaline aqueous solutions
  • the organic solvent is selected from aromatic hydrocarbon solvents , one or more of halogenated hydrocarbon solvents and ether solvents.
  • aromatic hydrocarbon solvents include but are not limited to toluene, chlorobenzene, xylene, and ethylbenzene, preferably toluene; halogenated hydrocarbon solvents include but are not limited to methylene chloride and dichloroethane, preferably methylene chloride. ; Ether solvents include but are not limited to tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diglyme, 2-methyltetrahydrofuran, cyclopentyl methyl ether, isopropyl ether, Tert-butyl methyl ether, preferably tetrahydrofuran.
  • the pH value of the alkaline aqueous solution is 8-12, for example, the pH value is 8, 9, 10, 11, 12 or any range therebetween.
  • the alkaline aqueous solution is a sodium carbonate aqueous solution, such as: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, saturated of sodium carbonate aqueous solution or any range of sodium carbonate aqueous solution therebetween.
  • the alkaline aqueous solution is sodium bicarbonate aqueous solution, such as: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10 %, saturated sodium bicarbonate aqueous solution or sodium bicarbonate aqueous solution in any range therebetween.
  • X in compound (II) is selected from fluorine, and the second reaction solvent is toluene, dichloromethane or tetrahydrofuran.
  • X in compound (II) is selected from fluorine
  • the second reaction solvent is a mixed solvent of toluene and saturated sodium bicarbonate aqueous solution, wherein the volume ratio of toluene to saturated sodium bicarbonate aqueous solution is 2:1 ⁇ 1:2, such as 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.5, 1:2 or any range in between, such as 1:0.8 ⁇ 1:1 .
  • X in compound (II) is selected from fluorine
  • the organic amine is selected from triethylamine, pyridine, N,N-diisopropylethylamine, 4-diisopropylethylamine, At least one of methylaminopyridine and triethanolamine, preferably pyridine; the volume of the organic amine is 5% to 15% of the volume of the second reaction solvent, preferably 8% to 12%, such as 8%, 8.5%, 9% , 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 13%, 14%, 15%.
  • reaction time and reaction temperature of step B) may be as long as they can achieve the purpose of the present invention.
  • reaction time and reaction temperature of step B) may be as long as they can achieve the purpose of the present invention.
  • reaction time and reaction temperature of step B) may be as long as they can achieve the purpose of the present invention.
  • X in compound (II) is selected from chlorine, and the second reaction solvent is selected from tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, acetonitrile, 2-methyl It is preferably at least one of ethylene glycol dimethyl ether, tetrahydrofuran and 1,4-dioxane.
  • X in compound (II) is selected from chlorine, and the organic base is selected from diisopropylethylamine, triethylamine, pyridine, N-methylimidazole, picoline, 1, In 8-diazabicyclo[5.4.0]undec-7-ene, quinoline, tetramethylethylenediamine, triethylenediamine, hexamethylenetetramine and N-methylmorpholine At least one, preferably at least one of diisopropylethylamine and triethylamine.
  • X in compound (II) is selected from chlorine, and the order of addition of the condensation reaction in step B) is:
  • the mixed solvent c is slowly added dropwise to the mixed solvent d to carry out the reaction to generate leborexan.
  • X in compound (II) is selected from chlorine, and the reaction temperature in step B) is called the second reaction temperature, and the second reaction temperature is 20-100°C, preferably 25-75°C, most preferably 45-75°C.
  • the molar ratio of compound (II) and compound (III) in step B) is 1:1 to 1:1.5; for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 ,1:1.5.
  • the purification method for obtaining leborexine represented by formula (I) through the above reaction is not particularly limited, as long as the purpose of the present application can be achieved.
  • a second aspect of the present invention provides a leborexine intermediate compound (II), which is represented by any of the following structural formulas:
  • the preparation method of compound (II) includes the following steps:
  • X is selected from fluorine or chlorine
  • the acid halide reagent is selected from one of trifluoro-s-triazine or phosphorus oxychloride.
  • intermediate compound (II-2) When preparing intermediate compound (II-2), the inventor repeated the method disclosed in patent US20120095031A1 and found that: the repeated experimental results were similar to the results of patent US20120095031A1, and the yield of leborexan was only 40%; when amplified When reaching the level of tens of grams, the yield drops sharply from 40-50% to 10-20%. It is speculated that the reason may be that the intermediate compound (II-2) generated under the condition of oxalyl chloride is easily carbonized. The amplified reaction requires longer reaction time and concentration time. As time goes by, carbonization will become more severe. The inventor has tried most common solvents and found that the best condition is acetonitrile.
  • Product (VI) was analyzed as a dimerization by-product; that is, it was found that after using oxalyl chloride as the acid chlorination reagent to prepare the intermediate compound (II-2), the generated intermediate compound (II-2) was then subjected to a condensation reaction , due to the easy generation of by-product (VI), the yield of the prepared leborexan is low. Therefore, the method of preparing intermediate compound (II-2) using oxalyl chloride as the acid chlorination reagent is not feasible.
  • oxalyl chloride (COCl 2 ) is used as the acyl chlorination reagent to prepare the intermediate compound (II-2), and then the generated intermediate compound (II-2) is subjected to a condensation reaction to generate the target products leboreson and byproducts.
  • the reaction process of product (VI) is as follows:
  • the inventor also found that when another commonly used acid chloride reagent, thionyl chloride, is used to prepare intermediate compound (II-2), intermediate (VII) is easily generated; thereby the generated intermediate can be directly entered into the condensation reaction to prepare Lebo When thunder occurs, by-product (VIII) is easily generated.
  • the reaction rate to generate the target intermediate compound (II-2) is not as fast as the rate to generate the intermediate (VII), which results in the generation of the target product leborexine not as fast as the rate of generation of by-products.
  • This by-product is simulated as a genotoxic impurity (by-product (VIII) in the picture) by FDA official certification software.
  • Sulfoxide chloride (SOCl 2 ) is used as the acyl chlorination reagent to prepare the intermediate compound, and then the generated intermediate compound is directly subjected to a condensation reaction to generate the target product leborexan and the by-product (VIII), that is, the genotoxic impurity (
  • the reaction process of VIII) is as follows:
  • genotoxic impurity (VIII) may further react with compound (III) to generate by-product (IX).
  • the inventor found that: 1) Using trifluoro-s-triazine as the carboxyl activating reagent to prepare the acyl fluoride intermediate compound (II-1) can avoid the above-mentioned problems in the reaction of preparing the acyl bromide intermediate and the acyl chloride intermediate. Moreover, compared to active lipids and acid anhydrides such as HOBT and HOAT, the intermediate compound (II-1) has better reactivity and has a good effect in synthesizing Leborexan.
  • the intermediate compound (II-2) is prepared to effectively reduce the occurrence of side reactions and avoid by-products during the acid chlorination process.
  • the by-products are only phosphoric acid and hydrochloric acid, and no other pollutants are produced, making the reaction more environmentally friendly.
  • the acid halide reagent is selected from trifluoro-s-triazine
  • X in compound (II) is selected from fluorine
  • the first reaction solvent is selected from toluene, dichloromethane, ethyl acetate, At least one of pyridine, tetrahydrofuran, dioxane, acetonitrile and acetone is preferably toluene, dichloromethane or tetrahydrofuran, more preferably toluene
  • the organic amine is selected from triethylamine, pyridine, N,N-bis At least one of isopropylethylamine, 4-dimethylaminopyridine and triethanolamine is preferably pyridine; the volume of the organic amine is 1 to 10% of the first reaction solvent, preferably 4 to 5%.
  • the acid halide reagent is selected from trifluoro-s-triazine
  • X in compound (II) is selected from fluorine
  • the molar ratio of compound (IV) to trifluoro-s-triazine is 1:1 or 1:1.5, for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5.
  • the reaction time and reaction temperature may be sufficient to achieve the purpose of the present invention.
  • the reaction temperature can be -20-75°C, and the reaction time can be 1-96h.
  • the reaction temperature is 0-15°C, and the reaction time is 2-5h.
  • the acid halide reagent is selected from trifluoro-s-triazine, and X in compound (II) is selected from fluorine.
  • step A) generates compound (II), it also includes adding dilute The step of removing water-soluble impurities with acid aqueous solution.
  • the acid halide reagent is selected from phosphorus oxychloride
  • X in compound (II) is selected from chlorine
  • the first reaction solvent is selected from toluene, fluorobenzene, chlorobenzene, xylene
  • the acid halide reagent is selected from phosphorus oxychloride
  • X in compound (II) is selected from chlorine
  • the order of addition of the reaction in step A) is:
  • the acid halide reagent is phosphorus oxychloride
  • X in compound (II) is chlorine
  • the reaction temperature in step A) is 20-100°C, preferably 60-90°C , most preferably 60-65°C
  • the reaction time can be as long as it can achieve the purpose of the present invention, for example, the reaction time can be 1-96h.
  • the third aspect of the present invention provides a preparation method of leborexine, which includes the following steps:
  • Compound (IV) reacts with an acid halide reagent in the first reaction solvent to generate compound (II).
  • X is selected from fluorine or chlorine;
  • the first reaction solvent and the second reaction solvent may be the same or different.
  • high performance liquid chromatography is used to monitor the reaction progress or analyze the purity of the product.
  • High-performance liquid chromatography 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 conditions are as follows in Table 1:
  • 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.
  • HPLC high performance liquid chromatography
  • the raw materials and reagents of the present invention are commercially available.
  • the compound trifluoro-s-triazine was purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.; 2-amino-5-fluoropyridine was purchased from Fuxin Jinteleflon Chemical Co., Ltd.; pyridine reagent, sodium bicarbonate, sodium carbonate, ethylene glycol dimethyl ether, and toluene were purchased from Sinopharm Holdings Co., Ltd.; phosphorus oxychloride was purchased from Shanghai Titan Technology Co., Ltd.
  • the reaction is considered complete and the reaction time is about 1 hour (second reaction time).
  • the liquids were separated, and the organic phase was washed once with 500 mL of 0.5 mol/l dilute hydrochloric acid and once with 350 mL of saturated brine. After drying over anhydrous sodium sulfate, the organic phase was concentrated to an off-white solid and evaporated without solvent. Then add 150 mL of toluene and heat it until the outer wall temperature of the container is 95°C. Add 100 mL of n-heptane and set the program to cool down to 5°C for 24 hours. After filtration and drying, 60g of the product Leboreson was obtained, with a yield of 85%, a purity of 99.88%, and an ee of 100%.
  • Figure 1 (a-f) shows the LC-MS diagram of the reaction solution quenched by methanol when the reaction of step A) in Example 1 reaches the end point of the reaction.
  • Figure 1-a is the liquid chromatography spectrum
  • Figure 1-b is the ion chromatogram
  • Figure 1-c to Figure 1-f show that the retention times in Figure 1-b are 2.289min, 2.541min, 2.713min and Mass spectrum of the ion current peak at 2.943 min.
  • the ion current peak in Figure 1-b and its corresponding mass spectrum data are reported in Table 2 below:
  • Figure 2 shows the hydrogen nuclear magnetic spectrum 1 H-NMR (DMSO-d 6 ) of Lebraxen in Example 1.
  • Figure 3 shows the infrared spectrum of leborexan in Example 1.
  • FIG. 4 shows the HPLC purity spectrum of leborexan in Example 1, where the data of the HPLC purity spectrum is reported in Table 3 below:
  • FIG. 5 shows the HPLC optical purity spectrum of leborexan in Example 1; wherein, the data of the HPLC optical purity spectrum is reported in Table 4 below:
  • Figure 6 shows the location map of the enantiomers of the product leborexan. Combining Figure 5 and Figure 6, it can be seen that the retention time of leborexan in Figure 4 is 10.209min, the retention time of the enantiomer of leborexan in Figure 6 is 10.307min, and the retention time in Figure 5 is 10.307min. There is no peak appearing at , indicating that the leborexine prepared in Example 1 is a single configuration compound represented by formula (I) and does not contain its enantiomer, that is, the ee value of leborexine prepared in Example 1 is 100%.
  • Examples 2 to 8 refer to the preparation method of Example 1, except that the first reaction solvent and the second reaction solvent are used, as shown in Table 5 below.
  • the reaction solution is concentrated to dryness to remove the solvent and diisopropylethylamine.
  • 2L isopropyl acetate After adding 2L isopropyl acetate, add 1mol/L concentrated hydrochloric acid to adjust the pH to 2-3, and extract the water with 1L isopropyl acetate. Phases were separated to obtain the organic phase.
  • the obtained organic phase was washed with 200 mL saturated sodium bicarbonate and 300 mL water in sequence, the solvent was removed, then 1 L of isopropyl alcohol was added, and the solvent was removed again; then, 300 mL of isopropyl alcohol was added, and the temperature was raised to 100°C on the outer wall of the container.
  • the solution is clear, add 500mL n-heptane dropwise.
  • Figure 7 (a-f) shows the LC-MS diagram of the reaction solution in step A) of methanol quenching in Example 9.
  • Figure 1-a is the liquid chromatography spectrum
  • Figure 7-b is the ion chromatogram
  • the ion current peaks in Figure 7 and their corresponding mass spectrum data are reported in Table 6 below:
  • Figure 8 shows the LC-MS diagram of the reaction solution of step B) after the reaction in Example 9 is completed.
  • Figure 8-a is the liquid chromatography spectrum
  • Figure 8-b is the ion current chart
  • Figure 8-c to Figure 8-d are the ion currents at the retention times of 15.086min and 18.261min in Figure 8-b respectively.
  • the ion current peak in Figure 8 and its corresponding mass spectrum data are reported in Table 7 below:
  • Figure 9 shows the hydrogen nuclear magnetic spectrum (DMSO-d 6 ) of the product leborexan in Example 9.
  • Figure 10 shows the infrared spectrum of leborexan, the product of Example 9.
  • FIG 11 shows the HPLC purity spectrum of the product leborexan of Example 9, where the data report of the HPLC purity spectrum is as shown in Table 8:
  • Figure 12 shows the HPLC optical purity spectrum of the product Leboresen in Example 9;
  • Figure 13 shows the positioning map of the enantiomers of the title product Leboresen.
  • the data report of HPLC optical purity spectrum is as shown in Table 9:
  • Example 9 Referring to step A) in Example 9, the difference lies in the differences in the first reaction solvent and the first reaction temperature. After the reaction for 5 hours, the content of related substances in the reaction solution was detected. The results are shown in Table 10.
  • step B) After 1 hour of reaction, detect the content of related substances in the reaction solution and the maximum single impurity content in the purified compound (I). The results are shown in Table 11.
  • reaction solution that reached the end of the reaction was slowly added dropwise to a 40°C mixed solution containing 100 mL of methylene chloride, 3.8 g of 2-amino-5-fluoropyridine (compound (III)), and 20 mL of DIEA. After the dropwise addition, Continue stirring for 1 hour. When HPLC detects that the content of compound (IV) in the reaction solution is ⁇ 3%, the reaction is deemed to be complete.
  • Add 50g silica gel and concentrate to solid. Use 500g silica gel as the stationary phase, PE:EA 10:1 ⁇ 1:1 as the mobility, gradient elution, and chromatography to prepare 6.0g of the product leborexan, with a yield of 45%, purity 93%.
  • Example 9 Refer to step A) in Example 9. The difference is that the reactant phosphorus oxychloride is replaced with thionyl chloride for the reaction.
  • the first reaction solvent and the first reaction temperature are shown in Table 12. After the reaction is completed, the reaction solution is detected. The purity of related substances in the product is shown in Table 12.

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Abstract

Provided in the present invention are a method for preparing lemborexant as represented by formula (I) and a method for preparing a lemborexant intermediate compound. According to the method for preparing lemborexant as represented by formula (I) of the present invention, the reaction conditions are simple, the used intermediate compound has a moderate activity and can be condensed with 2-amino-5-fluoropyridine to generate lemborexant as represented by formula (I), and the yield is high. The method for preparing the intermediate compound in the present invention has the characteristics of less side reactions in the reaction process and easy post-treatment, and is suitable for the industrial production of lemborexant.

Description

莱博雷生及其中间体化合物的制备方法Preparation methods of leborexan and its intermediate compounds 技术领域Technical field
本发明涉及医药技术领域,特别是涉及莱博雷生及其中间体化合物的制备方法。The present invention relates to the field of medical technology, and in particular to a preparation method of leborexan and its intermediate compounds.
背景技术Background technique
失眠是指患者对睡眠时间和(或)质量不满足并影响日间社会功能的一种主观体验。根据失眠症国际诊断标准以及流行病学研究,全世界至少有6%的人遭受失眠和睡眠紊乱。Insomnia refers to a subjective experience in which patients are dissatisfied with sleep time and/or quality and affect daytime social functions. According to the international diagnostic criteria for insomnia and epidemiological studies, at least 6% of people worldwide suffer from insomnia and sleep disorders.
莱博雷生(lemborexant)为食欲素受体OX1和食欲素受体OX2的双重抑制剂,其可能通过干扰食欲素能神经传递,有目的地促进睡眠的启动和维持,其化学式如式I所示:Lemborexant is a dual inhibitor of the orexin receptor OX1 and the orexin receptor OX2. It may promote the initiation and maintenance of sleep by interfering with orexinergic neurotransmission. Its chemical formula is as shown in formula I. Show:
Figure PCTCN2022083200-appb-000001
Figure PCTCN2022083200-appb-000001
专利US20120095031A1的example100中公开了一种莱博雷生的制备方法。采用草酰氯((COCl) 2)为酰氯化试剂,将200mg的(1R,2S)-2-(((2,4-二甲基嘧啶-5-基)氧基)甲基)-2-(3-氟代苯基)-N-(5-氟代吡啶-2-基)环丙烷-甲酸在二氯甲烷溶剂中与草酰氯反应生成酰氯中间体;酰氯中间体再与2-氨基-5-氟代吡啶缩合,制备得到102mg的莱博雷生,反应总收率仅为40%。 Example 100 of patent US20120095031A1 discloses a preparation method of Lebraxen. Using oxalyl chloride ((COCl) 2 ) as the acid chlorination reagent, 200 mg of (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2- (3-Fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-carboxylic acid reacts with oxalyl chloride in dichloromethane solvent to generate an acid chloride intermediate; the acid chloride intermediate is then reacted with 2-amino- 5-Fluoropyridine was condensed to prepare 102 mg of leborexan, and the total reaction yield was only 40%.
发明内容Contents of the invention
本发明第一方面提供一种莱博雷生的制备方法,包括以下步骤:A first aspect of the present invention provides a preparation method of leborexine, which includes the following steps:
B)化合物(II)与化合物(III)在第二反应溶剂中,有机胺作用下发生反应,生成式(I)所示的莱博雷生;B) Compound (II) and compound (III) react in the second reaction solvent under the action of organic amine to generate leborexan represented by formula (I);
化合物(II)中,X选自氟或氯;In compound (II), X is selected from fluorine or chlorine;
Figure PCTCN2022083200-appb-000002
Figure PCTCN2022083200-appb-000002
在本发明的一些实施方案中,化合物(II)中X选自氟,所述第二反应溶剂选自有机溶剂或有机溶剂与碱性水溶液的混合溶剂;所述有机溶剂选自芳族烃溶剂、卤代烃溶剂和醚类溶剂中的一种或多种。In some embodiments of the present invention, X in compound (II) is selected from fluorine, the second reaction solvent is selected from organic solvents or mixed solvents of organic solvents and alkaline aqueous solutions; the organic solvent is selected from aromatic hydrocarbon solvents , one or more of halogenated hydrocarbon solvents and ether solvents.
在本发明的一些实施方案中,化合物(II)中X选自氟,所述有机溶剂为甲苯、二氯甲烷或四氢呋喃;所述碱性水溶液为碳酸钠水溶液或碳酸氢钠水溶液。In some embodiments of the present invention, X in compound (II) is selected from fluorine, the organic solvent is toluene, dichloromethane or tetrahydrofuran; the alkaline aqueous solution is sodium carbonate aqueous solution or sodium bicarbonate aqueous solution.
在本发明的一些实施方案中,化合物(II)中X选自氟,所述第二反应溶剂为甲苯或甲苯与饱和碳酸氢钠水溶液的混合溶剂。In some embodiments of the present invention, X in compound (II) is selected from fluorine, and the second reaction solvent is toluene or a mixed solvent of toluene and saturated sodium bicarbonate aqueous solution.
在本发明的一些实施方案中,所述混合溶剂中,甲苯与饱和碳酸氢钠水溶液的体积比为2:1~1:2,优选1:0.8~1:1。In some embodiments of the present invention, the volume ratio of toluene to saturated sodium bicarbonate aqueous solution in the mixed solvent is 2:1 to 1:2, preferably 1:0.8 to 1:1.
在本发明的一些实施方案中,化合物(II)中X选自氟,所述有机胺选自三乙胺、吡啶、N,N-二异丙基乙胺、4-二甲氨基吡啶和三乙醇胺中的至少一种,优选为吡啶;所述有机胺的体积为第二反应溶剂体积的5~15%,优选为8~12%。In some embodiments of the present invention, X in compound (II) is selected from fluorine, and the organic amine is selected from triethylamine, pyridine, N,N-diisopropylethylamine, 4-dimethylaminopyridine and triethylamine. At least one of the ethanolamines is preferably pyridine; the volume of the organic amine is 5% to 15% of the volume of the second reaction solvent, preferably 8% to 12%.
在本发明的一些实施方案中,化合物(II)中X选自氯,所述第二反应溶剂选自四氢呋喃、1,4-二氧六环、乙二醇二甲醚、乙腈、2-甲基四氢呋喃、环戊基甲醚、异丙醚和叔丁基甲醚中的至少一种,优选为乙二醇二甲醚,四氢呋喃和1,4-二氧六环中的至少一种。In some embodiments of the present invention, X in compound (II) is selected from chlorine, and the second reaction solvent is selected from tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, acetonitrile, 2-methyl It is preferably at least one of ethylene glycol dimethyl ether, tetrahydrofuran and 1,4-dioxane.
在本发明的一些实施方案中,化合物(II)中X选自氯,所述有机碱选自二异丙基乙胺、三乙胺、吡啶、N-甲基咪唑、甲基吡啶、1,8-二氮杂双环[5.4.0]十一碳-7-烯、喹啉、四甲基乙二胺、三亚乙基二胺、六亚甲基四胺和N-甲基吗啉中的至少一种,优选为二异丙基乙胺、三乙胺中的至少一种。In some embodiments of the present invention, X in compound (II) is selected from chlorine, and the organic base is selected from diisopropylethylamine, triethylamine, pyridine, N-methylimidazole, picoline, 1, In 8-diazabicyclo[5.4.0]undec-7-ene, quinoline, tetramethylethylenediamine, triethylenediamine, hexamethylenetetramine and N-methylmorpholine At least one, preferably at least one of diisopropylethylamine and triethylamine.
在本发明的一些实施方案中,化合物(II)中X选自氯,所述步骤B)缩合反应的加料顺序为:In some embodiments of the present invention, X in compound (II) is selected from chlorine, and the order of addition of the condensation reaction in step B) is:
将化合物(II)溶解在第二反应溶剂,形成混合溶液c;Dissolve compound (II) in the second reaction solvent to form mixed solution c;
将化合物(III)和有机碱溶解在第二反应溶剂中,形成混合溶液d;Dissolve compound (III) and organic base in the second reaction solvent to form mixed solution d;
将混合溶剂c缓慢滴加到混合溶剂d中进行反应,生成莱博雷生。The mixed solvent c is slowly added dropwise to the mixed solvent d to carry out the reaction to generate leborexan.
在本发明的一些实施方案中,化合物(II)中X选自氯,所述步骤B)中的反应温度为20-100℃,优选为25-75℃,最优选为45-75℃。In some embodiments of the present invention, X in compound (II) is selected from chlorine, and the reaction temperature in step B) is 20-100°C, preferably 25-75°C, and most preferably 45-75°C.
本发明第二方面提供一种莱博雷生中间体化合物(II),其如以下任一结构式所示:A second aspect of the present invention provides a leborexine intermediate compound (II), which is represented by any of the following structural formulas:
Figure PCTCN2022083200-appb-000003
Figure PCTCN2022083200-appb-000003
在本发明的一些实施方案中,所述化合物(II)的制备方法包括以下步骤:In some embodiments of the present invention, the preparation method of compound (II) includes the following steps:
A)化合物(IV)与酰卤化试剂在第一反应溶剂中,有机胺作用下发生反应,生成化合物(II);A) Compound (IV) and acid halide reagent react in the first reaction solvent under the action of organic amine to generate compound (II);
Figure PCTCN2022083200-appb-000004
Figure PCTCN2022083200-appb-000004
化合物(II)中,X选自氟或氯;In compound (II), X is selected from fluorine or chlorine;
所述酰卤化试剂选自三氟均三嗪或三氯氧磷中的一种。The acid halide reagent is selected from one of trifluoro-s-triazine or phosphorus oxychloride.
在本发明的一些实施方案中,所述酰卤化试剂选自三氟均三嗪,化合物(II)中X选自氟;所述第一反应溶剂选自甲苯、二氯甲烷、乙酸乙酯、吡啶、四氢呋喃、二氧六环、 乙腈和丙酮中的至少一种,优选为甲苯、二氯甲烷或四氢呋喃,更优选为甲苯;所述有机胺选自三乙胺、吡啶、N,N-二异丙基乙胺、4-二甲氨基吡啶和三乙醇胺中的至少一种,优选为吡啶;所述有机胺的体积为述第一反应溶剂的1~10%,优选为4~5%。In some embodiments of the present invention, the acid halide reagent is selected from trifluoro-s-triazine, and X in compound (II) is selected from fluorine; the first reaction solvent is selected from toluene, dichloromethane, ethyl acetate, At least one of pyridine, tetrahydrofuran, dioxane, acetonitrile and acetone, preferably toluene, dichloromethane or tetrahydrofuran, more preferably toluene; the organic amine is selected from triethylamine, pyridine, N,N-bis At least one of isopropylethylamine, 4-dimethylaminopyridine and triethanolamine is preferably pyridine; the volume of the organic amine is 1 to 10% of the first reaction solvent, preferably 4 to 5%.
在本发明的一些实施方案中,所述酰卤化试剂选自三氟均三嗪,化合物(II)中X选自氟,步骤A)生成化合物(II)后,还包括向反应液中加入稀酸水溶液去除水溶性杂质的步骤。In some embodiments of the present invention, the acid halide reagent is selected from trifluoro-s-triazine, and X in compound (II) is selected from fluorine. After step A) generates compound (II), it also includes adding dilute The step of removing water-soluble impurities with acid aqueous solution.
在本发明的一些实施方案中,所述酰卤化试剂选自三氯氧磷,化合物(II)中X选自氯,所述第一反应溶剂选自甲苯、氟苯、氯苯、二甲苯、二氯甲烷、四氢呋喃、1,4-二氧六环、乙二醇二甲醚、2-甲基四氢呋喃、环戊基甲醚、异丙醚、叔丁基甲醚和乙腈中的至少一种,优选为甲苯、二甲苯、乙腈和四氢呋喃中的至少一种。In some embodiments of the present invention, the acid halide reagent is selected from phosphorus oxychloride, X in compound (II) is selected from chlorine, and the first reaction solvent is selected from toluene, fluorobenzene, chlorobenzene, xylene, At least one of methylene chloride, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, isopropyl ether, tert-butyl methyl ether and acetonitrile, preferably It is at least one of toluene, xylene, acetonitrile and tetrahydrofuran.
在本发明的一些实施方案中,所述酰卤化试剂选自三氯氧磷,化合物(II)中X选自氯,所述步骤A)中反应的加料顺序为:In some embodiments of the present invention, the acid halide reagent is selected from phosphorus oxychloride, X in compound (II) is selected from chlorine, and the order of addition of the reaction in step A) is:
将化合物(IV)溶解在第一反应溶剂,形成混合溶液a;Dissolve compound (IV) in the first reaction solvent to form mixed solution a;
将三氯氧磷溶解在第一反应溶剂中,形成混合溶液b;Dissolve phosphorus oxychloride in the first reaction solvent to form mixed solution b;
将混合溶剂a缓慢滴加到混合溶剂b中进行反应,生成中间体化合物(II-2)。Mixed solvent a is slowly added dropwise to mixed solvent b to carry out reaction to generate intermediate compound (II-2).
在本发明的一些实施方案中,所述酰卤化试剂选自三氯氧磷,化合物(II)中X选自氯,所述步骤A)中的反应温度为20-100℃,优选为60-90℃,最优选为60-65℃。In some embodiments of the present invention, the acid halide reagent is selected from phosphorus oxychloride, X in compound (II) is selected from chlorine, and the reaction temperature in step A) is 20-100°C, preferably 60- 90°C, most preferably 60-65°C.
本发明第三方面提供了一种莱博雷生的制备方法,包括以下步骤:The third aspect of the present invention provides a preparation method of leborexine, which includes the following steps:
A)化合物(IV)与酰卤化试剂在第一反应溶剂中反应,生成化合物(II),化合物(II)中X选自氟或氯;A) Compound (IV) reacts with an acid halide reagent in the first reaction solvent to generate compound (II), where X in compound (II) is selected from fluorine or chlorine;
B)化合物(II)与化合物(III)在第二反应溶剂中发生缩合反应,生成式(I)所示的莱博雷生。B) Compound (II) and compound (III) undergo a condensation reaction in the second reaction solvent to generate leboresen represented by formula (I).
Figure PCTCN2022083200-appb-000005
Figure PCTCN2022083200-appb-000005
在本发明的一些实施方案中,包括以下步骤:In some embodiments of the invention, the following steps are included:
步骤A)制备得到化合物(II)不经分离直接用于步骤B)。Compound (II) prepared in step A) is directly used in step B) without isolation.
本发明采用式(II)所示的中间体化合物,与2-氨基-5-氟代吡啶缩合生成莱博雷生;制备过程中副反应少,收率高本发明的式(II)所示的中间体化合物的制备方法,反应过程中副反应少,几乎无其他卤化副产物生成,后处理容易,适合莱博雷生的工业化生产。The present invention adopts the intermediate compound represented by the formula (II) and condenses it with 2-amino-5-fluoropyridine to generate leboresen; there are few side reactions during the preparation process and the yield is high. The present invention is represented by the formula (II). The preparation method of the intermediate compound has few side reactions during the reaction process, almost no other halogenated by-products are generated, and the post-processing is easy, which is suitable for the industrial production of Lebraxen.
附图说明Description of the drawings
为了更清楚地说明本申请实施例的技术方案,下面对实施例所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,本领域普通技术人员来讲还可以根据这些附图获得其他的附图。In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings required for the embodiments are briefly introduced below. Obviously, the drawings in the following description are only some embodiments of the present invention, and ordinary people in the art Technical personnel can also obtain other drawings based on these drawings.
图1为实施例1的步骤A)反应完成的反应液的LC-MS图。Figure 1 is an LC-MS diagram of the reaction solution after step A) of Example 1.
图2为实施例1的莱博雷生的核磁氢谱图(DMSO-d 6)。 Figure 2 is the proton nuclear magnetic spectrum (DMSO-d 6 ) of Lebraxen in Example 1.
图3为实施例1的莱博雷生的红外谱图。Figure 3 is the infrared spectrum of Lebraxen in Example 1.
图4为实施例1的莱博雷生的HPLC纯度谱图。Figure 4 is the HPLC purity spectrum of leborexan in Example 1.
图5为实施例1的莱博雷生的HPLC光学纯度谱图。Figure 5 is the HPLC optical purity spectrum of Lebraxen in Example 1.
图6为实施例1的莱博雷生的对映异构体定位图。Figure 6 is an enantiomeric positioning diagram of leborexan in Example 1.
图7为实施例9的甲醇淬灭的步骤A)的反应液的LC-MS图。Figure 7 is an LC-MS diagram of the reaction solution in step A) of methanol quenching in Example 9.
图8为实施例9的反应完成的步骤B)的反应液的LC-MS图。Figure 8 is an LC-MS diagram of the reaction solution in step B) after the reaction in Example 9 is completed.
图9为实施例9的莱博雷生的核磁氢谱图(DMSO-d 6)。 Figure 9 is the hydrogen nuclear magnetic spectrum (DMSO-d 6 ) of leborexan in Example 9.
图10为实施例9的莱博雷生的红外谱图。Figure 10 is the infrared spectrum of Lebraxen in Example 9.
图11为实施例9的莱博雷生的HPLC纯度谱图。Figure 11 is the HPLC purity spectrum of leborexan in Example 9.
图12为实施例9的莱博雷生的HPLC光学纯度谱图。Figure 12 is the HPLC optical purity spectrum of Lebraxen in Example 9.
图13为实施例9莱博雷生的对映异构体定位图。Figure 13 is an enantiomeric positioning diagram of Lebraxen in Example 9.
图14为对比例2副产物(VIII)的质谱图。Figure 14 is the mass spectrum of the by-product (VIII) in Comparative Example 2.
图15为对比例2副产物(VIII)的核磁氢谱谱图(DMSO-d 6)。 Figure 15 is the hydrogen nuclear magnetic spectrum (DMSO-d 6 ) of the by-product (VIII) in Comparative Example 2.
具体实施方式Detailed ways
为了使本发明的目的,技术方案及优点更加清楚明白,以下结合实施案例,对本发明进一步的详细说明,以使本领域技术人员能够充分理解对本发明的技术内容。应理解,以下实施例用于对本发明的进一步说明,但是并不仅限于此。本领域的技术人员根据本发明的上述内容作出的一些非本质的改进和调整均属于本发明的保护范围。下述实施例具体的工艺参数等也仅是合适范围中的一个案例,即本领域技术人员可以通过本文的说明做出合适的范围内选择,而并非要限定于以下实施例的具体数值。In order to make the purpose, technical solutions and advantages of the present invention more clear, the present invention is further described in detail below with reference to implementation examples, 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 contents of the present invention all fall within the protection scope of the present invention. The specific process parameters in the following examples are only an example of the appropriate range, that is, those skilled in the art can make selections within the appropriate range through the description herein, and are not limited to the specific numerical values in the following examples.
本发明叙述的所有范围包括列举两个值之间的范围的那些端点。不管是否指出,本发明所列举的所有值包括用于测量该值的给定技术的预期实验误差、技术误差和仪器误差的程度,当没有记载所述误差程度是,本发明所列举的所有值及包含所记载值的±10%的范围。All ranges recited herein include those endpoints reciting the range between the two values. All values recited herein include the degree of experimental, technical and instrumental error expected for the given technique used to measure the value, whether or not stated otherwise, and when no stated degree of error is stated, all values recited herein include and includes a range of ±10% of the stated value.
在本发明中,如无另外说明,%是重量/重量(w/w)的百分数。In the present invention, % is a weight/weight (w/w) percentage unless otherwise stated.
本发明第一方面提供一种莱博雷生的制备方法,包括以下步骤:A first aspect of the present invention provides a preparation method of leborexine, which includes the following steps:
B)化合物(II)与化合物(III)在第二反应溶剂中,有机胺作用下发生反应,生成式(I)所示的莱博雷生;B) Compound (II) and compound (III) react in the second reaction solvent under the action of organic amine to generate leborexan represented by formula (I);
化合物(II)中,X选自氟或氯;In compound (II), X is selected from fluorine or chlorine;
Figure PCTCN2022083200-appb-000006
Figure PCTCN2022083200-appb-000006
在本发明中,发明人发现,采用中间体化合物(II),活性适中,可与2-氨基-5-氟代吡啶直接缩合生成莱博雷生,收率高;反应条件简单,合成过程副反应少,后处理容易,适合用于莱博雷生的工业化生产。In the present invention, the inventor found that the intermediate compound (II) has moderate activity and can be directly condensed with 2-amino-5-fluoropyridine to generate leborexine with high yield; the reaction conditions are simple and the synthesis process is undesirable. It has less reaction and easy post-processing, so it is suitable for industrial production of Lebraxen.
在本发明的一些实施方案中,化合物(II)中X选自氟,所述第二反应溶剂选自有机溶剂或有机溶剂与碱性水溶液的混合溶剂;所述有机溶剂选自芳族烃溶剂、卤代烃溶剂和醚类溶剂中的一种或多种。In some embodiments of the present invention, X in compound (II) is selected from fluorine, the second reaction solvent is selected from organic solvents or mixed solvents of organic solvents and alkaline aqueous solutions; the organic solvent is selected from aromatic hydrocarbon solvents , one or more of halogenated hydrocarbon solvents and ether solvents.
本发明中,芳族烃溶剂包括但不限于甲苯、氯苯、二甲苯、乙苯,优选地为甲苯;卤代烃溶剂包括不限于二氯甲烷、二氯乙烷,优选地为二氯甲烷;醚类溶剂包括但不限于四氢呋喃、1,4-二氧六环、乙二醇二甲醚、二乙二醇二甲醚、2-甲基四氢呋喃、环戊基甲醚、异丙醚、叔丁基甲醚,优选地为四氢呋喃。In the present invention, aromatic hydrocarbon solvents include but are not limited to toluene, chlorobenzene, xylene, and ethylbenzene, preferably toluene; halogenated hydrocarbon solvents include but are not limited to methylene chloride and dichloroethane, preferably methylene chloride. ; Ether solvents include but are not limited to tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, diglyme, 2-methyltetrahydrofuran, cyclopentyl methyl ether, isopropyl ether, Tert-butyl methyl ether, preferably tetrahydrofuran.
在本发明的一些实施方案中,碱性水溶液的pH值为8~12,例如pH值为8、9、10、11、12或其间的任意范围。In some embodiments of the present invention, the pH value of the alkaline aqueous solution is 8-12, for example, the pH value is 8, 9, 10, 11, 12 or any range therebetween.
在本发明的一些实施方案中,碱性水溶液为碳酸钠水溶液,例如:1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、饱和的碳酸钠水溶液或其间任意范围的碳酸钠水溶液。In some embodiments of the invention, the alkaline aqueous solution is a sodium carbonate aqueous solution, such as: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, saturated of sodium carbonate aqueous solution or any range of sodium carbonate aqueous solution therebetween.
在本发明的一些实施方案中,所述碱性水溶液为碳酸氢钠水溶液,例如:1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、饱和碳酸氢钠水溶液或其间任意范围的碳酸氢钠水溶液。In some embodiments of the present invention, the alkaline aqueous solution is sodium bicarbonate aqueous solution, such as: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10 %, saturated sodium bicarbonate aqueous solution or sodium bicarbonate aqueous solution in any range therebetween.
在本发明的一些实施方案中,化合物(II)中X选自氟,第二反应溶剂为甲苯、二氯甲烷或四氢呋喃。In some embodiments of the present invention, X in compound (II) is selected from fluorine, and the second reaction solvent is toluene, dichloromethane or tetrahydrofuran.
在本发明的一些实施方案中,化合物(II)中X选自氟,第二反应溶剂为甲苯与饱和碳酸氢钠水溶液的混合溶剂,其中甲苯与饱和碳酸氢钠水溶液的体积比为2:1~1:2,例如1:0.5、1:0.6、1:0.7、1:0.8、1:0.9、1:1、1:1.5、1:2或其间任意范围,例如1:0.8~1:1。In some embodiments of the present invention, X in compound (II) is selected from fluorine, and the second reaction solvent is a mixed solvent of toluene and saturated sodium bicarbonate aqueous solution, wherein the volume ratio of toluene to saturated sodium bicarbonate aqueous solution is 2:1 ~1:2, such as 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.5, 1:2 or any range in between, such as 1:0.8~1:1 .
在本发明的一些实施方案中,化合物(II)中X选自氟,步骤B)中,所述有机胺选自三乙胺、吡啶、N,N-二异丙基乙胺、4-二甲氨基吡啶和三乙醇胺中的至少一种,优选为吡啶;所述有机胺的体积为第二反应溶剂体积的5~15%,优选为8~12%,例如8%、8.5%、9%、9.5%、10%、10.5%、11%、11.5%、12%、13%、14%、15%。In some embodiments of the present invention, X in compound (II) is selected from fluorine, and in step B), the organic amine is selected from triethylamine, pyridine, N,N-diisopropylethylamine, 4-diisopropylethylamine, At least one of methylaminopyridine and triethanolamine, preferably pyridine; the volume of the organic amine is 5% to 15% of the volume of the second reaction solvent, preferably 8% to 12%, such as 8%, 8.5%, 9% , 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 13%, 14%, 15%.
在本发明中,化合物(II)中X选自氟时,步骤B)的反应时间和反应温度只要能实现本发明的目的即可。例如,X选自氟时步骤B)的反应温度可以为-20~75℃,反应时间可以为1-96h;优选反应温度为0~5℃,反应时间1-5h,例如1h、2h、3h、4h、5h或其间的任意范围。In the present invention, when X in compound (II) is selected from fluorine, the reaction time and reaction temperature of step B) may be as long as they can achieve the purpose of the present invention. For example, when , 4h, 5h or any range in between.
在本发明的一些实施方案中,化合物(II)中X选自氯,所述第二反应溶剂选自四氢呋喃、1,4-二氧六环、乙二醇二甲醚、乙腈、2-甲基四氢呋喃、环戊基甲醚、异丙醚和叔丁基甲醚中的至少一种,优选为乙二醇二甲醚,四氢呋喃和1,4-二氧六环中的至少一种。In some embodiments of the present invention, X in compound (II) is selected from chlorine, and the second reaction solvent is selected from tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, acetonitrile, 2-methyl It is preferably at least one of ethylene glycol dimethyl ether, tetrahydrofuran and 1,4-dioxane.
在本发明的一些实施方案中,化合物(II)中X选自氯,所述有机碱选自二异丙基乙胺、三乙胺、吡啶、N-甲基咪唑、甲基吡啶、1,8-二氮杂双环[5.4.0]十一碳-7-烯、喹啉、四甲基乙二胺、三亚乙基二胺、六亚甲基四胺和N-甲基吗啉中的至少一种,优选为二异丙基乙胺、三乙胺中的至少一种。In some embodiments of the present invention, X in compound (II) is selected from chlorine, and the organic base is selected from diisopropylethylamine, triethylamine, pyridine, N-methylimidazole, picoline, 1, In 8-diazabicyclo[5.4.0]undec-7-ene, quinoline, tetramethylethylenediamine, triethylenediamine, hexamethylenetetramine and N-methylmorpholine At least one, preferably at least one of diisopropylethylamine and triethylamine.
在本发明的一些实施方案中,化合物(II)中X选自氯,所述步骤B)缩合反应的加料顺序为:In some embodiments of the present invention, X in compound (II) is selected from chlorine, and the order of addition of the condensation reaction in step B) is:
将化合物(II)溶解在第二反应溶剂,形成混合溶液c;Dissolve compound (II) in the second reaction solvent to form mixed solution c;
将化合物(III)和有机碱溶解在第二反应溶剂中,形成混合溶液d;Dissolve compound (III) and organic base in the second reaction solvent to form mixed solution d;
将混合溶剂c缓慢滴加到混合溶剂d中进行反应,生成莱博雷生。The mixed solvent c is slowly added dropwise to the mixed solvent d to carry out the reaction to generate leborexan.
在本发明的一些实施方案中,化合物(II)中X选自氯,所述步骤B)中的反应温度称为第二反应温度,所述第二反应温度为为20-100℃,优选为25-75℃,最优选为45-75℃。In some embodiments of the present invention, X in compound (II) is selected from chlorine, and the reaction temperature in step B) is called the second reaction temperature, and the second reaction temperature is 20-100°C, preferably 25-75°C, most preferably 45-75°C.
在本发明中,步骤B)中化合物(II)与化合物(III)的摩尔为1:1~1:1.5;例如,1:1、1:1.1、1:1.2、1:1.3、1:1.4、1:1.5。In the present invention, the molar ratio of compound (II) and compound (III) in step B) is 1:1 to 1:1.5; for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 ,1:1.5.
在本发明中,上述反应得到式(I)所示的莱博雷生的提纯方法没有特别限制,只要可以实现本申请的目的即可。In the present invention, the purification method for obtaining leborexine represented by formula (I) through the above reaction is not particularly limited, as long as the purpose of the present application can be achieved.
本发明第二方面提供一种莱博雷生中间体化合物(II),其如以下任一结构式所示:A second aspect of the present invention provides a leborexine intermediate compound (II), which is represented by any of the following structural formulas:
Figure PCTCN2022083200-appb-000007
Figure PCTCN2022083200-appb-000007
在本发明的一些实施方案中,所述化合物(II)的制备方法包括以下步骤:In some embodiments of the present invention, the preparation method of compound (II) includes the following steps:
A)化合物(IV)与酰卤化试剂在第一反应溶剂中,有机胺作用下发生反应,生成化合物(II);A) Compound (IV) and acid halide reagent react in the first reaction solvent under the action of organic amine to generate compound (II);
Figure PCTCN2022083200-appb-000008
Figure PCTCN2022083200-appb-000008
其中,化合物(II)中,X选自氟或氯;Wherein, in compound (II), X is selected from fluorine or chlorine;
所述酰卤化试剂选自三氟均三嗪或三氯氧磷中的一种。The acid halide reagent is selected from one of trifluoro-s-triazine or phosphorus oxychloride.
发明人发现,以CBr 4/PPh 3为溴化试剂,副产物为难以除去的三苯氧磷,其反应机理如下: The inventor found that using CBr 4 /PPh 3 as the brominating reagent, the by-product is triphenoxyphosphonate which is difficult to remove. The reaction mechanism is as follows:
Figure PCTCN2022083200-appb-000009
Figure PCTCN2022083200-appb-000009
在制备中间化合物(II-2)时,发明人在重复专利US20120095031A1中公开的方法后,发现:重复的实验结果和专利US20120095031A1结果相仿,莱博雷生的收率仅有40%;但当放大到几十克级别时,其收率从40-50%急剧下降至10-20%。推测原因可能是草酰氯条件下生成的中间体化合物(II-2)很容易碳化。而反应放大后需要更长的反应时间和浓缩时间。随着时间的增加,碳化会愈演愈烈。发明人尝试过绝大部分常用溶剂,发现:最好的条件是乙腈,即使在乙腈中几十克合成级别,收率也仅仅维持在40%上下。发明人推断这种碳化可能是某种程度的聚合,尝试过一些常用的阻聚剂,有一定的效果,但是很不明显。此外,发明人采用草酰氯为酰氯化试剂制备中间体化合物(II-2)时,还尝试了不拖带溶剂减少反应时间的方法来降低碳化程度,发现:其结果是生成了约30%的副产物(VI),分析为二聚副产物;即发现:采用草酰氯为酰氯化试剂,制备中间体化合物(II-2)后,再将生成的中间体化合物(II-2)进行缩合反应时,由于容易生成副产物(VI),制备得到的莱博雷生的收率低。因此,采用草酰氯为酰氯化试剂制备中间体化合物(II-2)的方法不可行。When preparing intermediate compound (II-2), the inventor repeated the method disclosed in patent US20120095031A1 and found that: the repeated experimental results were similar to the results of patent US20120095031A1, and the yield of leborexan was only 40%; when amplified When reaching the level of tens of grams, the yield drops sharply from 40-50% to 10-20%. It is speculated that the reason may be that the intermediate compound (II-2) generated under the condition of oxalyl chloride is easily carbonized. The amplified reaction requires longer reaction time and concentration time. As time goes by, carbonization will become more severe. The inventor has tried most common solvents and found that the best condition is acetonitrile. Even if dozens of grams of acetonitrile are synthesized, the yield is only maintained at around 40%. The inventor deduced that this carbonization may be due to polymerization to some extent. He tried some commonly used polymerization inhibitors and had a certain effect, but it was not obvious. In addition, when the inventor used oxalyl chloride as the acid chlorination reagent to prepare the intermediate compound (II-2), he also tried a method of reducing the reaction time without dragging the solvent to reduce the degree of carbonization, and found that: as a result, about 30% of by-products were generated. Product (VI) was analyzed as a dimerization by-product; that is, it was found that after using oxalyl chloride as the acid chlorination reagent to prepare the intermediate compound (II-2), the generated intermediate compound (II-2) was then subjected to a condensation reaction , due to the easy generation of by-product (VI), the yield of the prepared leborexan is low. Therefore, the method of preparing intermediate compound (II-2) using oxalyl chloride as the acid chlorination reagent is not feasible.
其中,采用草酰氯(COCl 2)为酰氯化试剂,制备中间体化合物(II-2)后,再将生成的中间体化合物(II-2)进行缩合反应,生成目标产物莱博雷生和副产物(VI)的反应过程如下: Among them, oxalyl chloride (COCl 2 ) is used as the acyl chlorination reagent to prepare the intermediate compound (II-2), and then the generated intermediate compound (II-2) is subjected to a condensation reaction to generate the target products leboreson and byproducts. The reaction process of product (VI) is as follows:
Figure PCTCN2022083200-appb-000010
Figure PCTCN2022083200-appb-000010
发明人还发现,采用另一个常用的酰氯化试剂氯化亚砜制备中间体化合物(II-2)时, 容易生成中间体(VII);从而使将生成的中间体直接进入缩合反应制备莱博雷生时,容易生成副产物(VIII)。尤其在降速实验中,生成目标中间体化合物(II-2)的反应速率不如生成中间体(VII)的速率快,从而导致生成目标产物莱博雷生不如生成副产物的速率快。而该副产物经FDA官方认证软件模拟为基因毒杂质(图中副产物(VIII))。由于氯代与否理化性质差异很小,莱博雷生无法与基因毒杂质,也即副产物(VIII)完全分离。因此,采用氯化亚砜为酰氯化试剂制备中间体化合物(II-2)的方法也不可行。The inventor also found that when another commonly used acid chloride reagent, thionyl chloride, is used to prepare intermediate compound (II-2), intermediate (VII) is easily generated; thereby the generated intermediate can be directly entered into the condensation reaction to prepare Lebo When thunder occurs, by-product (VIII) is easily generated. Especially in the speed-down experiment, the reaction rate to generate the target intermediate compound (II-2) is not as fast as the rate to generate the intermediate (VII), which results in the generation of the target product leborexine not as fast as the rate of generation of by-products. This by-product is simulated as a genotoxic impurity (by-product (VIII) in the picture) by FDA official certification software. Due to the very small difference in the physical and chemical properties of chlorinated or not, leborexan cannot be completely separated from the genotoxic impurity, that is, the by-product (VIII). Therefore, the method of preparing intermediate compound (II-2) using thionyl chloride as the acid chlorination reagent is also not feasible.
采用氯化亚砜(SOCl 2)为酰氯化试剂,制备中间体化合物,再将生成中间体化合物直接进行缩合反应,生成目标产物莱博雷生和副产物(VIII),也即基因毒杂质(VIII)的反应过程如下: Sulfoxide chloride (SOCl 2 ) is used as the acyl chlorination reagent to prepare the intermediate compound, and then the generated intermediate compound is directly subjected to a condensation reaction to generate the target product leborexan and the by-product (VIII), that is, the genotoxic impurity ( The reaction process of VIII) is as follows:
Figure PCTCN2022083200-appb-000011
Figure PCTCN2022083200-appb-000011
其中,基因毒杂质(VIII)还可能进一步与化合物(III)反应,生成副产物(IX)。Among them, genotoxic impurity (VIII) may further react with compound (III) to generate by-product (IX).
鉴于上述采用草酰氯或氯化亚砜为酰氯化试剂,将化合物(IV)转化为相应中间体化合物(II-2)时,前者可能由于反应碳化,收率急剧降低,后者则容易生成二氯代中间体(VII),从而导致将制备的中间体直接进入缩合反应制备莱博雷生时,容易生成副产物(VIII)。而副产物(VIII)经FDA官方认证软件模拟为基因毒杂质。此外,副产物(VI)溶解度差,较难去除。In view of the above-mentioned use of oxalyl chloride or thionyl chloride as the acid chlorination reagent, when compound (IV) is converted into the corresponding intermediate compound (II-2), the former may be carbonized in the reaction and the yield will decrease sharply, while the latter will easily generate dihydrogen. Chlorinated intermediate (VII), thus leading to the easy formation of by-product (VIII) when the prepared intermediate is directly entered into the condensation reaction to prepare leborexan. The by-product (VIII) is simulated as a genotoxic impurity by FDA official certification software. In addition, the by-product (VI) has poor solubility and is difficult to remove.
发明人经深入研究发现:1)采用三氟均三嗪作为羧基活化试剂,制备得到酰氟中间体化合物(II-1),能够避免上述制备酰溴中间体和酰氯中间体反应出现的问题。并且,相对于HOBT、HOAT等活性脂以及酸酐,中间体化合物(II-1)具有更好的反应活性,用于合成莱博雷生的效果良好。After in-depth research, the inventor found that: 1) Using trifluoro-s-triazine as the carboxyl activating reagent to prepare the acyl fluoride intermediate compound (II-1) can avoid the above-mentioned problems in the reaction of preparing the acyl bromide intermediate and the acyl chloride intermediate. Moreover, compared to active lipids and acid anhydrides such as HOBT and HOAT, the intermediate compound (II-1) has better reactivity and has a good effect in synthesizing Leborexan.
2)采用三氯氧磷作为酰氯化试剂,代替草酰氯、氯化亚砜或其他酰氯化试剂,制备得到中间体化合物(II-2)有效减少副反应的发生,避免酰氯化过程中副产另一酰氯中间体(VII)的生成,以及避免下一步制备莱博雷生的缩合反应的过程中生成副产物(VI)或基因毒杂质(VIII),从而将莱博雷生的收率提高到95%,降低了后续分离提纯的难度,从而适合莱博雷生的工业化生产。此外,采用三氯氧磷作为酰氯化试剂,制备中间体化合物(II-2)后,副产物仅为磷酸和盐酸,无其他污染物产生,反应较为环保。2) Using phosphorus oxychloride as the acid chlorination reagent instead of oxalyl chloride, thionyl chloride or other acid chlorination reagents, the intermediate compound (II-2) is prepared to effectively reduce the occurrence of side reactions and avoid by-products during the acid chlorination process. The generation of another acid chloride intermediate (VII), and the avoidance of the generation of by-products (VI) or genotoxic impurities (VIII) in the next step of the condensation reaction to prepare leborexan, thereby increasing the yield of leborexan to 95%, which reduces the difficulty of subsequent separation and purification, making it suitable for the industrial production of Lebraxen. In addition, after using phosphorus oxychloride as the acid chlorination reagent to prepare the intermediate compound (II-2), the by-products are only phosphoric acid and hydrochloric acid, and no other pollutants are produced, making the reaction more environmentally friendly.
在本发明的一些实施方案中,所述酰卤化试剂选自三氟均三嗪,化合物(II)中X选自氟,所述第一反应溶剂选自甲苯、二氯甲烷、乙酸乙酯、吡啶、四氢呋喃、二氧六环、乙腈和丙酮中的至少一种,优选为甲苯、二氯甲烷或四氢呋喃,更优选为甲苯;所述有机胺选自三乙胺、吡啶、N,N-二异丙基乙胺、4-二甲氨基吡啶和三乙醇胺中的至少一种,优选为吡啶;所述有机胺的体积为述第一反应溶剂的1~10%,优选为4~5%。In some embodiments of the present invention, the acid halide reagent is selected from trifluoro-s-triazine, X in compound (II) is selected from fluorine, and the first reaction solvent is selected from toluene, dichloromethane, ethyl acetate, At least one of pyridine, tetrahydrofuran, dioxane, acetonitrile and acetone is preferably toluene, dichloromethane or tetrahydrofuran, more preferably toluene; the organic amine is selected from triethylamine, pyridine, N,N-bis At least one of isopropylethylamine, 4-dimethylaminopyridine and triethanolamine is preferably pyridine; the volume of the organic amine is 1 to 10% of the first reaction solvent, preferably 4 to 5%.
在本发明的一些实施方案中,所述酰卤化试剂选自三氟均三嗪,化合物(II)中X选自氟,化合物(IV)与三氟均三嗪的摩尔比为1:1或者1:1.5,例如,1:1、1:1.1、1:1.2、1:1.3、1:1.4、1:1.5。反应时间和反应温度只要能实现本发明的目的即可。例如,反应温度可以为-20-75℃,反应时间可以为1-96h,优选反应温度0-15℃,反应时间2-5h。In some embodiments of the present invention, the acid halide reagent is selected from trifluoro-s-triazine, X in compound (II) is selected from fluorine, and the molar ratio of compound (IV) to trifluoro-s-triazine is 1:1 or 1:1.5, for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5. The reaction time and reaction temperature may be sufficient to achieve the purpose of the present invention. For example, the reaction temperature can be -20-75°C, and the reaction time can be 1-96h. Preferably, the reaction temperature is 0-15°C, and the reaction time is 2-5h.
在本发明的一些实施方案中,所述酰卤化试剂选自三氟均三嗪,化合物(II)中X选自氟,步骤A)生成化合物(II)后,还包括向反应液中加入稀酸水溶液去除水溶性杂质的步骤。In some embodiments of the present invention, the acid halide reagent is selected from trifluoro-s-triazine, and X in compound (II) is selected from fluorine. After step A) generates compound (II), it also includes adding dilute The step of removing water-soluble impurities with acid aqueous solution.
在本发明的一些实施方案中,所述酰卤化试剂选自三氯氧磷,化合物(II)中X选自氯,所述第一反应溶剂选自甲苯、氟苯、氯苯、二甲苯、二氯甲烷、四氢呋喃、1,4-二氧六环、乙二醇二甲醚、2-甲基四氢呋喃、环戊基甲醚、异丙醚、叔丁基甲醚和乙腈中的至少一种,优选为甲苯、二甲苯、乙腈和四氢呋喃中的至少一种。In some embodiments of the present invention, the acid halide reagent is selected from phosphorus oxychloride, X in compound (II) is selected from chlorine, and the first reaction solvent is selected from toluene, fluorobenzene, chlorobenzene, xylene, At least one of methylene chloride, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, isopropyl ether, tert-butyl methyl ether and acetonitrile, preferably It is at least one of toluene, xylene, acetonitrile and tetrahydrofuran.
在本发明的一些实施方案中,所述酰卤化试剂选自三氯氧磷,化合物(II)中X选自氯,所述步骤A)中反应的加料顺序为:In some embodiments of the present invention, the acid halide reagent is selected from phosphorus oxychloride, X in compound (II) is selected from chlorine, and the order of addition of the reaction in step A) is:
将化合物(IV)溶解在第一反应溶剂,形成混合溶液a;Dissolve compound (IV) in the first reaction solvent to form mixed solution a;
将三氯氧磷溶解在第一反应溶剂中,形成混合溶液b;Dissolve phosphorus oxychloride in the first reaction solvent to form mixed solution b;
将混合溶剂a缓慢滴加到混合溶剂b中进行反应,生成中间体化合物(II)。Mixed solvent a is slowly added dropwise to mixed solvent b to carry out reaction to generate intermediate compound (II).
在本发明的一些实施方案中,所述酰卤化试剂为三氯氧磷,化合物(II)中X为氯,所述步骤A)中的反应温度为20-100℃,优选为60-90℃,最优选为60-65℃,反应时间只要能实现本发明的目的即可,例如,反应时间可以为1-96h。In some embodiments of the present invention, the acid halide reagent is phosphorus oxychloride, X in compound (II) is chlorine, and the reaction temperature in step A) is 20-100°C, preferably 60-90°C , most preferably 60-65°C, the reaction time can be as long as it can achieve the purpose of the present invention, for example, the reaction time can be 1-96h.
本发明第三方面提供了一种莱博雷生的制备方法,包括以下步骤:The third aspect of the present invention provides a preparation method of leborexine, which includes the following steps:
A)化合物(IV)与酰卤化试剂在第一反应溶剂中反应,生成化合物(II),化合物(II)中,X选自氟或氯;A) Compound (IV) reacts with an acid halide reagent in the first reaction solvent to generate compound (II). In compound (II), X is selected from fluorine or chlorine;
B)化合物(II)与化合物(III)在第二反应溶剂中发生缩合反应,生成式(I)所示的莱博雷生。B) Compound (II) and compound (III) undergo a condensation reaction in the second reaction solvent to generate leboresen represented by formula (I).
Figure PCTCN2022083200-appb-000012
Figure PCTCN2022083200-appb-000012
在本发明的一些实施方案中,包括以下步骤:In some embodiments of the invention, the following steps are included:
步骤A)制备得到化合物(II)不经分离直接用于步骤B)。Compound (II) prepared in step A) is directly used in step B) without isolation.
在本发明中,第一反应溶剂和第二反应溶剂可以相同或不相同。In the present invention, the first reaction solvent and the second reaction solvent may be the same or different.
实施例Example
以下,举出实施例来对本申请的实施方式进行更具体地说明。各种的试验及评价按照下述的方法进行。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法:HPLC method:
实施例中采用高效液相色谱法(HPLC)对反应进程进行监控,或者对产物的纯度进行分析。高效液相色谱法(HPLC)以液体为流动相,采用高压输液系统,将具有不同极性的单一溶剂或不同比例的混合溶剂、缓冲液等流动相泵入装有固定相的色谱柱,在柱内各成分被分离后,进入检测器进行检测,实现对试样成分的分析,色谱条件如下表1: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 conditions are as follows in Table 1:
表1Table 1
Figure PCTCN2022083200-appb-000013
Figure PCTCN2022083200-appb-000013
ee值测量:ee value measurement:
实施例中产物手性分子的两个对映体中,各对映体都把平面偏振光旋转到一定的角度,其数值相同但方向相反,这种性质称为光学活性。产物的对映体组成以术语“对映体过量(enantiomeric excess)”或“ee值”来描述,表示一个对映体对另一个对映体的过量,通常用百分数表示。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.
实施例中采用高效液相色谱法(HPLC)测量产物的ee值。In the examples, high performance liquid chromatography (HPLC) was used to measure the ee value of the product.
如无特别说明,本发明的原料及试剂可获得经市售,如化合物三氟均三嗪购自上海毕得医药科技股份有限公司;2-氨基-5-氟吡啶购自阜新金特莱氟化学有限公司;吡啶试剂、碳酸氢钠、碳酸钠、乙二醇二甲醚、甲苯购自国药控股有限公司;三氯氧磷采购自上海泰 坦科技股份有限公司。Unless otherwise specified, the raw materials and reagents of the present invention are commercially available. For example, the compound trifluoro-s-triazine was purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.; 2-amino-5-fluoropyridine was purchased from Fuxin Jinteleflon Chemical Co., Ltd.; pyridine reagent, sodium bicarbonate, sodium carbonate, ethylene glycol dimethyl ether, and toluene were purchased from Sinopharm Holdings Co., Ltd.; phosphorus oxychloride was purchased from Shanghai Titan Technology Co., Ltd.
化合物(IV)((1R,2S)-2-(((2,4-二甲基嘧啶-5-基)氧基)甲基)-2-(3-氟苯基)环丙基)甲酸的制备为公司自制,具体反应步骤如下:Compound (IV) ((1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropyl)carboxylic acid The preparation is self-made by the company, and the specific reaction steps are as follows:
在反应瓶中将302g((1R,2S)-2-((2,4-二甲基嘧啶-5-基氧基)甲基)-2-(3-氟苯基)环丙基)甲醇溶于2000mL叔丁醇和1200mL水,加入150g碳酸氢钠、15g碳酸钠、7.5g 2,2,6,6,-四甲基哌啶-氮-氧化物(TEMPO),充分搅拌。反应瓶外温度降至-10℃。滴加次氯酸钠水溶液(2.2eq,2200mL),水相pH=9,保持反应体系温度为-5-3℃。滴加完毕后,于0℃反应12h。滴加淬灭试剂(280g亚硫酸钠和150g氢氧化钠溶于1500mL水),保证滴加时温度不超过25℃,滴加结束后升温至60℃搅拌0.5h,溶液澄清,水相pH=9.5。静置后分液去除水相。浓缩有机相至约800ml体积,加入1L的氢氧化钠水溶液(浓度为10%),调节pH>13.5,用叔丁基甲醚萃取水相,分液除去有机相,控制水相温度不超过10℃,加入3.1L浓盐酸(质量分数>20%),调节pH至1.5-2.5,过滤除去大部分水得到粘稠状固体,此固体溶于800mL二氯甲烷,分液去除少量的水。浓缩有机相,用二氯甲烷脱带至水分含量低于0.05%,得到类白色粉末状固体,加入400mL异丙醚,加热至回流剧烈搅拌热打浆,冷却后过滤得到295g白色固体化合物(IV)((1R,2S)-2-(((2,4-二甲基嘧啶-5-基)氧基)甲基)-2-(3-氟苯基)环丙基)甲酸。In the reaction bottle, 302g ((1R,2S)-2-((2,4-dimethylpyrimidin-5-yloxy)methyl)-2-(3-fluorophenyl)cyclopropyl)methanol Dissolve in 2000mL tert-butyl alcohol and 1200mL water, add 150g sodium bicarbonate, 15g sodium carbonate, 7.5 g 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.
实施例1Example 1
式(I)所示莱博雷生的制备Preparation of leborexine shown in formula (I)
Figure PCTCN2022083200-appb-000014
Figure PCTCN2022083200-appb-000014
A)在三口烧瓶中加入55g(1R,2S)-2-((2,4-二甲基嘧啶-5-基)氧基)甲基)-2-(3-氟苯基)环丙烷甲酸(式(IV)化合物),溶于1L甲苯(第一反应溶剂)和40mL吡啶(有机胺)的混合溶液,然后冷却至0℃。分三次加入23g新鲜活化的三氟均三嗪后,在15℃下反应(第一反应温度)。取几滴反应液滴加入无水甲醇淬灭后,HPLC监测甲醇淬灭液中式(IV)化合物含量<1%,视为到达反应终点。反应时间约2小时(第一反应时 间)。A) Add 55g (1R, 2S)-2-((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropanecarboxylic acid into the three-necked flask (Compound of formula (IV)), dissolved in a mixed solution of 1 L of toluene (first reaction solvent) and 40 mL of pyridine (organic amine), and then cooled to 0°C. After adding 23g of freshly activated trifluoro-s-triazine in three times, the reaction was carried out at 15°C (first reaction temperature). After adding a few drops of the reaction liquid to anhydrous methanol for quenching, HPLC monitors the content of the compound of formula (IV) in the methanol quenching liquid to be <1%, which is deemed to have reached the end of the reaction. The reaction time is about 2 hours (first reaction time).
B)将上述到达反应终点的反应液缓慢滴加入680mL的0℃的0.5mol/l的稀盐酸中,分液去除水相后,将得到的有机相加入0℃的含有500mL甲苯和400mL饱和碳酸氢钠溶液的混合溶剂(第二反应溶剂)中、混合均匀后再滴加入20g的2-氨基-5-氟吡啶(化合物(III))和100mL吡啶(有机胺和催化剂)的混合溶液中。滴加完毕后,反应液在0-5℃下搅拌HPLC监测到反应液中化合物(IV)含量<0.3%,视为反应完成,反应时间约为1小时(第二反应时间)。分液,有机相用500mL的0.5mol/l的稀盐酸洗涤一次,350mL的饱和食盐水洗涤一次,无水硫酸钠干燥后,有机相浓缩至类白色固体无溶剂蒸出。再加入150mL甲苯加热至容器外壁温度为95℃,加入100mL正庚烷,设定程序24小时降温至5℃。过滤、烘干得到产物莱博雷生60g,收率为85%,纯度99.88%,ee 100%。B) Slowly add the above reaction solution that has reached the end of the reaction dropwise into 680 mL of 0.5 mol/l dilute hydrochloric acid at 0°C. After separating and removing the water phase, add the obtained organic phase to 0°C containing 500 mL of toluene and 400 mL of saturated carbonic acid. into the mixed solvent of sodium hydrogen solution (second reaction solvent), mix evenly, and then add dropwise to a mixed solution of 20 g of 2-amino-5-fluoropyridine (compound (III)) and 100 mL of pyridine (organic amine and catalyst). After the dropwise addition is completed, the reaction solution is stirred at 0-5°C. HPLC detects that the content of compound (IV) in the reaction solution is <0.3%. The reaction is considered complete and the reaction time is about 1 hour (second reaction time). The liquids were separated, and the organic phase was washed once with 500 mL of 0.5 mol/l dilute hydrochloric acid and once with 350 mL of saturated brine. After drying over anhydrous sodium sulfate, the organic phase was concentrated to an off-white solid and evaporated without solvent. Then add 150 mL of toluene and heat it until the outer wall temperature of the container is 95°C. Add 100 mL of n-heptane and set the program to cool down to 5°C for 24 hours. After filtration and drying, 60g of the product Leboreson was obtained, with a yield of 85%, a purity of 99.88%, and an ee of 100%.
图1(a-f)示出了实施例1中步骤A)的反应到达反应终点时,甲醇淬灭的反应液的LC-MS图。其中,图1-a为液相色谱谱图,图1-b为离子流图,图1-c至图1-f分别为图1-b中保留时间为2.289min、2.541min、2.713min和2.943min处离子流峰的质谱谱图。图1-b的离子流峰及其相应质谱的数据报告如下表2:Figure 1 (a-f) shows the LC-MS diagram of the reaction solution quenched by methanol when the reaction of step A) in Example 1 reaches the end point of the reaction. Among them, Figure 1-a is the liquid chromatography spectrum, Figure 1-b is the ion chromatogram, Figure 1-c to Figure 1-f show that the retention times in Figure 1-b are 2.289min, 2.541min, 2.713min and Mass spectrum of the ion current peak at 2.943 min. The ion current peak in Figure 1-b and its corresponding mass spectrum data are reported in Table 2 below:
表2Table 2
Figure PCTCN2022083200-appb-000015
Figure PCTCN2022083200-appb-000015
结合图1-a至图1-f可以看到,实施例1中步骤A)反应完成的反应液经甲醇淬灭后,主要成分为中间体化合物(II-1)的甲酯衍生物,其在图1-b中保留时间为2.541min,对应离子流峰面积比例为94%,对应离子流峰的质谱图图1-d中MS为331.1[M+1] +,332.1[M+2] +。说明采用三氟均三嗪作为酰氟化试剂,生成中间体化合物(II-1),反应过程转化率高,副反应少,几乎无其他副产物或基因毒杂质生成。 It can be seen from Figure 1-a to Figure 1-f that after the reaction solution in step A) in Example 1 is quenched with methanol, the main component is the methyl ester derivative of the intermediate compound (II-1), which In Figure 1-b, the retention time is 2.541min, and the corresponding ion current peak area ratio is 94%. The MS corresponding to the ion current peak in Figure 1-d is 331.1[M+1] + , 332.1[M+2] + . It shows that trifluoro-s-triazine is used as the acyl fluorination reagent to generate the intermediate compound (II-1). The reaction process has a high conversion rate, few side reactions, and almost no other by-products or genotoxic impurities are generated.
图2示出了实施例1的莱博雷生的核磁氢谱谱图 1H-NMR(DMSO-d 6)。 Figure 2 shows the hydrogen nuclear magnetic spectrum 1 H-NMR (DMSO-d 6 ) of Lebraxen in Example 1.
图3示出了实施例1的莱博雷生的红外谱图。Figure 3 shows the infrared spectrum of leborexan in Example 1.
图4示出了实施例1的莱博雷生的HPLC纯度谱图,其中HPLC纯度谱图的数据报告如下表3:Figure 4 shows the HPLC purity spectrum of leborexan in Example 1, where the data of the HPLC purity spectrum is reported in Table 3 below:
表3table 3
Figure PCTCN2022083200-appb-000016
Figure PCTCN2022083200-appb-000016
可以看到,图4中莱博雷生的保留时间为18.015min,对应的峰面积比例为99.88%,说明产物莱博雷生的HPLC纯度为99.88%。It can be seen that the retention time of leborexan in Figure 4 is 18.015 min, and the corresponding peak area ratio is 99.88%, indicating that the HPLC purity of the product leiborexan is 99.88%.
图5示出了实施例1的莱博雷生的HPLC光学纯度谱图;其中,HPLC光学纯度谱图的数据报告如下表4:Figure 5 shows the HPLC optical purity spectrum of leborexan in Example 1; wherein, the data of the HPLC optical purity spectrum is reported in Table 4 below:
表4Table 4
Figure PCTCN2022083200-appb-000017
Figure PCTCN2022083200-appb-000017
Figure PCTCN2022083200-appb-000018
Figure PCTCN2022083200-appb-000018
图6示出了产物莱博雷生的对映异构体的定位图。结合图5和图6可知,图4中莱博雷生的保留时间为10.209min,图6中莱博雷生的对映异构体的保留时间为10.307min,而图5在保留时间10.307min处没有峰出现,说明实施例1制备的莱博雷生为式(I)所示的单一构型化合物,不含有其对映异构体,即实施例1制备的莱博雷生的ee值为100%。Figure 6 shows the location map of the enantiomers of the product leborexan. Combining Figure 5 and Figure 6, it can be seen that the retention time of leborexan in Figure 4 is 10.209min, the retention time of the enantiomer of leborexan in Figure 6 is 10.307min, and the retention time in Figure 5 is 10.307min. There is no peak appearing at , indicating that the leborexine prepared in Example 1 is a single configuration compound represented by formula (I) and does not contain its enantiomer, that is, the ee value of leborexine prepared in Example 1 is 100%.
实施例2至实施例8Example 2 to Example 8
实施例2~8参照实施例1的制备方法,不同之处在于所采用的第一反应溶剂和第二反应溶剂,具体见下表5。Examples 2 to 8 refer to the preparation method of Example 1, except that the first reaction solvent and the second reaction solvent are used, as shown in Table 5 below.
实施例2~8所得莱博雷生的收率、纯度及ee值见表5。The yield, purity and ee value of leborexine obtained in Examples 2 to 8 are shown in Table 5.
表5table 5
Figure PCTCN2022083200-appb-000019
Figure PCTCN2022083200-appb-000019
Figure PCTCN2022083200-appb-000020
Figure PCTCN2022083200-appb-000020
实施例9Example 9
式(I)所示莱博雷生的制备Preparation of leborexine shown in formula (I)
Figure PCTCN2022083200-appb-000021
Figure PCTCN2022083200-appb-000021
A)将200g含水率低于0.12%的(1R,2S)-2-(((2,4-二甲基嘧啶-5-基)氧基)甲基)-2-(3-氟代苯基)环丙烷-甲酸(式(IV)化合物)溶于1.6L甲苯(第一反应溶剂),混合均匀,形成混合溶液a。在三口烧瓶中加入47mL三氯氧磷和200mL甲苯(第一反应溶剂),形成混合溶液b。将混合溶液b加热至65℃,再将混合溶液a缓慢滴加入混合溶液b中,3小时滴加完毕,然后65℃(第一反应温度)下继续反应,取少量用甲醇淬灭,HPLC检测淬灭液反应液中式(IV)化合物含量<0.15%,视为反应完成,反应时间约5小时;A) 200g of (1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorobenzene) with a moisture content lower than 0.12% base) cyclopropane-formic acid (compound of formula (IV)) was dissolved in 1.6L toluene (first reaction solvent), and mixed evenly to form mixed solution a. Add 47 mL of phosphorus oxychloride and 200 mL of toluene (first reaction solvent) into the three-necked flask to form mixed solution b. Heat mixed solution b to 65°C, then slowly add mixed solution a dropwise into mixed solution b, and complete the dropwise addition in 3 hours. Then continue the reaction at 65°C (first reaction temperature), take a small amount to quench with methanol, and detect by HPLC. If the content of the compound of formula (IV) in the quenching solution reaction solution is <0.15%, the reaction is deemed to be completed, and the reaction time is about 5 hours;
B)将上述反应完成的反应液脱除溶剂后,用1L无水甲苯脱带一次后降温至10℃以下,加入2L无水乙二醇二甲醚(第二反应溶剂)搅拌均匀,形成混合溶液c。将80g的2-氨基-5-氟吡啶(化合物(III)),300mL二异丙基乙胺(有机胺)和1.5L无水乙二醇二甲醚(第二反应溶剂)搅拌均匀,升温至45℃,形成混合溶液d。将混合溶液c缓慢滴加入混合溶液d中,3小时滴完;然后45℃(第二反应温度)下继续反应,HPLC监测到反应液 中化合物(IV)含量<0.3%,视为反应完成,反应时间约1小时。B) After removing the solvent from the reaction solution that has completed the above reaction, use 1L anhydrous toluene to remove the strip once and then cool the temperature to below 10°C. Add 2L anhydrous ethylene glycol dimethyl ether (second reaction solvent) and stir evenly to form a mixture. Solution c. Stir 80g of 2-amino-5-fluoropyridine (compound (III)), 300mL of diisopropylethylamine (organic amine) and 1.5L of anhydrous ethylene glycol dimethyl ether (second reaction solvent) evenly and raise the temperature. to 45°C to form mixed solution d. Slowly add mixed solution c into mixed solution d dropwise, and finish dropping in 3 hours; then continue the reaction at 45°C (second reaction temperature). HPLC monitors that the content of compound (IV) in the reaction solution is <0.3%, and the reaction is deemed to be completed. The reaction time is about 1 hour.
反应完成的反应液浓缩至干脱除溶剂和二异丙基乙胺,加入2L乙酸异丙酯后,再加入1mol/L的浓盐酸调节pH至2-3,用1L乙酸异丙酯萃取水相,分液,得到有机相。所得有机相依次经过200mL饱和碳酸氢钠洗涤和300mL水洗涤后,脱除溶剂,再加入1L异丙醇,再次脱除溶剂;然后,加入300mL异丙醇,升温至容器外壁温度为100℃,溶解清澈,再滴加500mL正庚烷。设置程序6小时降温至55℃,18小时降温至0℃,然后保温8小时。过滤,用200mL正庚烷润洗,烘干滤饼至恒重,得到标题产物莱博雷生245g;收率为95%。After the reaction is completed, the reaction solution is concentrated to dryness to remove the solvent and diisopropylethylamine. After adding 2L isopropyl acetate, add 1mol/L concentrated hydrochloric acid to adjust the pH to 2-3, and extract the water with 1L isopropyl acetate. Phases were separated to obtain the organic phase. The obtained organic phase was washed with 200 mL saturated sodium bicarbonate and 300 mL water in sequence, the solvent was removed, then 1 L of isopropyl alcohol was added, and the solvent was removed again; then, 300 mL of isopropyl alcohol was added, and the temperature was raised to 100°C on the outer wall of the container. When the solution is clear, add 500mL n-heptane dropwise. Set the program to cool down to 55°C in 6 hours, cool down to 0°C in 18 hours, and then keep warm for 8 hours. Filter, rinse with 200 mL of n-heptane, and dry the filter cake to a constant weight to obtain 245 g of the title product Lebrasin; the yield is 95%.
图7(a-f)示出了实施例9的甲醇淬灭的步骤A)的反应液的LC-MS图。其中,图1-a为液相色谱谱图,图7-b为离子流图,图7-c至图7-f分别为图7-b中保留时间(Retention Time)=2.284min、2.540min、2.949min和3.117min处的离子流峰的质谱谱图。图7的离子流峰及其相应质谱的数据报告如下表6:Figure 7 (a-f) shows the LC-MS diagram of the reaction solution in step A) of methanol quenching in Example 9. Among them, Figure 1-a is the liquid chromatography spectrum, Figure 7-b is the ion chromatogram, Figure 7-c to Figure 7-f are the retention time (Retention Time) = 2.284min, 2.540min in Figure 7-b respectively. , the mass spectra of the ion current peaks at 2.949min and 3.117min. The ion current peaks in Figure 7 and their corresponding mass spectrum data are reported in Table 6 below:
表6Table 6
Figure PCTCN2022083200-appb-000022
Figure PCTCN2022083200-appb-000022
结合图7-a至图7-f可知,实施例9中甲醇淬灭的步骤A)的反应液的主要成分为中间体化合物(II-2)的甲酯衍生物,其在图7-b中的离子流峰的保留时间为2.540min,MS峰面积比例为93.8%,对应的质谱图图7-d中的MS为331.1[M+1] +,332.1[M+2] +。说明采用三氯氧磷作为酰氯化试剂,生成中间体化合物(II-2)的过程反应转化率高,副反应少,几乎无其他氯化副产物或基因毒杂质生成。 Combining Figures 7-a to 7-f, it can be seen that the main component of the reaction solution in step A) of methanol quenching in Example 9 is the methyl ester derivative of the intermediate compound (II-2), which is shown in Figure 7-b The retention time of the ion current peak in is 2.540min, and the MS peak area ratio is 93.8%. The corresponding MS in the mass spectrum Figure 7-d is 331.1[M+1] + and 332.1[M+2] + . It shows that the process of using phosphorus oxychloride as the acid chlorination reagent to generate the intermediate compound (II-2) has a high reaction conversion rate, few side reactions, and almost no other chlorination by-products or genotoxic impurities are generated.
图8示出了实施例9反应完成的步骤B)的反应液的LC-MS图。其中,图8-a为液相色谱谱图,图8-b为离子流图,图8-c至图8-d分别为图8-b中保留时间为15.086min和18.261min处的离子流峰的质谱谱图。图8的离子流峰及其相应质谱的数据报告如下表7:Figure 8 shows the LC-MS diagram of the reaction solution of step B) after the reaction in Example 9 is completed. Among them, Figure 8-a is the liquid chromatography spectrum, Figure 8-b is the ion current chart, Figure 8-c to Figure 8-d are the ion currents at the retention times of 15.086min and 18.261min in Figure 8-b respectively. The mass spectrum of the peak. The ion current peak in Figure 8 and its corresponding mass spectrum data are reported in Table 7 below:
表7Table 7
Figure PCTCN2022083200-appb-000023
Figure PCTCN2022083200-appb-000023
结合图8-a至图8-d可知,实施例9中反应完成的步骤B)的反应液的主要成分为产物莱博雷生,其在图8-b中的保留时间为18.261min,对应离子流峰的质谱图图8-d中的MS为411.2[M+1] +,412.2[M+2] +,对应MS峰面积的比例为99.7%。说明采用中间体化合物(II-2)与化合物(III),即2-氨基-5-氟代吡啶缩合生成莱博雷生,制备过程中几乎无副反应,从而使标题产物莱博雷生的收率高达95%。 Combining Figure 8-a to Figure 8-d, it can be seen that the main component of the reaction liquid in step B) of the reaction in Example 9 is the product Leborexen, and its retention time in Figure 8-b is 18.261 min, corresponding to The MS in the mass spectrum of the ion current peak in Figure 8-d are 411.2[M+1] + and 412.2[M+2] + , and the corresponding MS peak area ratio is 99.7%. It shows that the intermediate compound (II-2) is condensed with the compound (III), that is, 2-amino-5-fluoropyridine, to generate leborexan. There are almost no side reactions during the preparation process, so that the title product leborexan is The yield is as high as 95%.
图9示出了实施例9的产物莱博雷生的核磁氢谱谱图(DMSO-d 6)。 Figure 9 shows the hydrogen nuclear magnetic spectrum (DMSO-d 6 ) of the product leborexan in Example 9.
图10示出了实施例9的产物莱博雷生的红外谱图。Figure 10 shows the infrared spectrum of leborexan, the product of Example 9.
图11示出了实施例9的产物莱博雷生的HPLC纯度谱图,其中HPLC纯度谱图的数据报告如表8:Figure 11 shows the HPLC purity spectrum of the product leborexan of Example 9, where the data report of the HPLC purity spectrum is as shown in Table 8:
表8Table 8
Figure PCTCN2022083200-appb-000024
Figure PCTCN2022083200-appb-000024
Figure PCTCN2022083200-appb-000025
Figure PCTCN2022083200-appb-000025
可以看到,标题产物莱博雷生在图11中的保留时间为17.977min,对应的峰面积比例为99.92%,说明标题产物莱博雷生的HPLC纯度为99.92%。It can be seen that the retention time of the title product leborexan in Figure 11 is 17.977 min, and the corresponding peak area ratio is 99.92%, indicating that the HPLC purity of the title product leborexan is 99.92%.
图12示出了实施例9的产物莱博雷生的HPLC光学纯度谱图;图13示出了标题产物莱博雷生的对映异构体的定位图。其中,HPLC光学纯度谱图的数据报告如表9:Figure 12 shows the HPLC optical purity spectrum of the product Leboresen in Example 9; Figure 13 shows the positioning map of the enantiomers of the title product Leboresen. Among them, the data report of HPLC optical purity spectrum is as shown in Table 9:
表9Table 9
Figure PCTCN2022083200-appb-000026
Figure PCTCN2022083200-appb-000026
结合图12和图13可知,图12中产物莱博雷生的保留时间(Ret Time)为10.201min,图13中莱博雷生的对映异构体的保留时间为10.307min,而图12在保留时间10.307min处没有峰出现,说明实施例9制备的莱博雷生为式(I)所示的单一构型化合物,不含有其对映异构体,即制备的产物莱博雷生的ee值为100%。Combining Figure 12 and Figure 13, it can be seen that the retention time (Ret Time) of the product Leboreson in Figure 12 is 10.201min, the retention time of the enantiomer of Leboreson in Figure 13 is 10.307min, and Figure 12 There is no peak appearing at the retention time of 10.307 min, indicating that leborexan prepared in Example 9 is a single configuration compound represented by formula (I) and does not contain its enantiomers, that is, the prepared product leborexan The ee value is 100%.
实施例10至实施例15Example 10 to Example 15
参考实施例9中的步骤A),其不同点在于第一反应溶剂、第一反应温度的差异,反应5小时后,检测反应液中相关物质的含量,结果见表10。Referring to step A) in Example 9, the difference lies in the differences in the first reaction solvent and the first reaction temperature. After the reaction for 5 hours, the content of related substances in the reaction solution was detected. The results are shown in Table 10.
表10Table 10
Figure PCTCN2022083200-appb-000027
Figure PCTCN2022083200-appb-000027
Figure PCTCN2022083200-appb-000028
Figure PCTCN2022083200-appb-000028
实施例16至实施例26Example 16 to Example 26
参考实施例9中的步骤A)和步骤B),其不同点在于步骤B)中的第二反应溶剂,第二反应温度和有机碱的差异。步骤B)反应1小时后的检测反应液中相关物质的含量,以及纯化后化合物(I)中最大单杂含量,结果见表11。Referring to step A) and step B) in Example 9, the difference lies in the difference in the second reaction solvent, the second reaction temperature and the organic base in step B). Step B) After 1 hour of reaction, detect the content of related substances in the reaction solution and the maximum single impurity content in the purified compound (I). The results are shown in Table 11.
表11Table 11
Figure PCTCN2022083200-appb-000029
Figure PCTCN2022083200-appb-000029
Figure PCTCN2022083200-appb-000030
Figure PCTCN2022083200-appb-000030
从实施例16~实施例26可知,由于中间体化合物(II-2)不稳定,存在部分化合物(II-2)重新转化为化合物(IV)。From Examples 16 to 26, it can be seen that since the intermediate compound (II-2) is unstable, part of the compound (II-2) is re-converted into the compound (IV).
对比例1Comparative example 1
在三口烧瓶中加入10g(1R,2S)-2-((2,4-二甲基嘧啶-5-基)氧基)甲基)-2-(3-氟苯基)环丙烷甲酸(式(IV)化合物)和8.9g三苯基膦,加入150mL二氯甲烷溶液,然后冷却至-20℃。滴加溶于50mL的5.5g溴素后,在25℃下反应,反应1小时,取几滴反应液滴加入无水甲醇淬灭后,HPLC监测甲醇淬灭液中式(IV)化合物含量<5%,视为到达反应终点。Add 10g (1R, 2S)-2-((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropanecarboxylic acid (formula (IV) Compound) and 8.9 g of triphenylphosphine, add 150 mL of methylene chloride solution, and then cool to -20°C. After dropwise adding 5.5g bromine dissolved in 50mL, react at 25°C for 1 hour. Add a few drops of the reaction liquid dropwise to anhydrous methanol to quench it. HPLC monitors the content of the compound of formula (IV) in the methanol quenching solution <5 %, is regarded as reaching the reaction end point.
将上述到达反应终点的反应液缓慢滴加入含有100mL二氯甲烷、3.8g的2-氨基-5-氟吡啶(化合物(III))、20mL DIEA的40℃的混合溶液中,滴加完毕后,继续搅拌1小时,HPLC监测到反应液中化合物(IV)含量<3%,视为反应完成。加入50g硅胶,浓缩至固体,以500g硅胶为固定相,以PE:EA=10:1~1:1为流动性,梯度洗脱,层析制备得到产物莱博雷生6.0g,收率为45%,纯度93%。The reaction solution that reached the end of the reaction was slowly added dropwise to a 40°C mixed solution containing 100 mL of methylene chloride, 3.8 g of 2-amino-5-fluoropyridine (compound (III)), and 20 mL of DIEA. After the dropwise addition, Continue stirring for 1 hour. When HPLC detects that the content of compound (IV) in the reaction solution is <3%, the reaction is deemed to be complete. Add 50g silica gel and concentrate to solid. Use 500g silica gel as the stationary phase, PE:EA=10:1~1:1 as the mobility, gradient elution, and chromatography to prepare 6.0g of the product leborexan, with a yield of 45%, purity 93%.
对比例2Comparative example 2
将10g化合物(IV)溶于100mL的二氯甲烷中,于-25℃下缓慢滴加20mL氯化亚砜,反应24小时候,浓缩去除溶剂二氯甲烷和反应物氯化亚砜,将该浓缩液溶于80mL四氢呋喃中,缓慢滴入45℃的化合物(III)与30mL二异丙基乙胺的四氢呋喃溶液中,滴完反应1小时,直接加入200mL冰水混合物中,再用100mL乙酸异丙酯提取,浓缩得粗品,粗品经柱层析纯化得到化合物(VIII),收率22%。其质谱图如图14所示,核磁氢谱谱图如图15所示。Dissolve 10g of compound (IV) in 100mL of dichloromethane, slowly add 20mL of thionyl chloride dropwise at -25°C, react for 24 hours, concentrate to remove the solvent dichloromethane and the reactant thionyl chloride, and concentrate Dissolve the solution in 80 mL of tetrahydrofuran, slowly drop into the tetrahydrofuran solution of compound (III) at 45°C and 30 mL of diisopropylethylamine, complete the reaction for 1 hour, add directly to 200 mL of ice-water mixture, and then add 100 mL of isopropyl acetate. The crude product was obtained by ester extraction and concentration. The crude product was purified by column chromatography to obtain compound (VIII) with a yield of 22%. The mass spectrum is shown in Figure 14, and the hydrogen nuclear magnetic spectrum is shown in Figure 15.
对比例3Comparative example 3
参考实施例9中的步骤A),其不同点在于将反应物三氯氧磷替换为氯化亚砜进行反 应,第一反应溶剂和第一反应温度见表12,反应结束后,检测反应液中相关物质的纯度,结果见表12。Refer to step A) in Example 9. The difference is that the reactant phosphorus oxychloride is replaced with thionyl chloride for the reaction. The first reaction solvent and the first reaction temperature are shown in Table 12. After the reaction is completed, the reaction solution is detected. The purity of related substances in the product is shown in Table 12.
表12Table 12
Figure PCTCN2022083200-appb-000031
Figure PCTCN2022083200-appb-000031
以上所述仅为本申请的较佳实施例,并不用以限制本申请,凡在本申请的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本申请保护的范围之内。The above are only preferred embodiments of the present application and are not intended to limit the present application. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present application shall be included in the protection of the present application. within the range.

Claims (19)

  1. 一种莱博雷生的制备方法,其特征在于包括以下步骤:A preparation method of Leborexen, characterized by comprising the following steps:
    B)化合物(II)与化合物(III)在第二反应溶剂中,有机胺作用下发生反应,生成式(I)所示的莱博雷生;B) Compound (II) and compound (III) react in the second reaction solvent under the action of organic amine to generate leborexan represented by formula (I);
    化合物(II)中,X选自氟或氯;In compound (II), X is selected from fluorine or chlorine;
    Figure PCTCN2022083200-appb-100001
    Figure PCTCN2022083200-appb-100001
  2. 根据权利要求1所述莱博雷生的制备方法,其特征在于化合物(II)中X选自氟,所述第二反应溶剂选自有机溶剂或有机溶剂与碱性水溶液的混合溶剂;所述有机溶剂选自芳族烃溶剂、卤代烃溶剂和醚类溶剂中的一种或多种。The preparation method of leborexan according to claim 1, wherein X in compound (II) is selected from fluorine, and the second reaction solvent is selected from organic solvents or mixed solvents of organic solvents and alkaline aqueous solutions; The organic solvent is selected from one or more of aromatic hydrocarbon solvents, halogenated hydrocarbon solvents and ether solvents.
  3. 根据权利要求2所述莱博雷生的制备方法,其特征在于化合物(II)中X选自氟,所述有机溶剂为甲苯、二氯甲烷或四氢呋喃;所述碱性水溶液为碳酸钠水溶液或碳酸氢钠水溶液。The preparation method of leborexan according to claim 2, wherein X in compound (II) is selected from fluorine, the organic solvent is toluene, dichloromethane or tetrahydrofuran; the alkaline aqueous solution is sodium carbonate aqueous solution or Sodium bicarbonate aqueous solution.
  4. 根据权利要求2所述莱博雷生的制备方法,其特征在于化合物(II)中X选自氟,所述第二反应溶剂为甲苯或甲苯与饱和碳酸氢钠水溶液的混合溶剂。The preparation method of leborexan according to claim 2, characterized in that X in compound (II) is selected from fluorine, and the second reaction solvent is toluene or a mixed solvent of toluene and saturated sodium bicarbonate aqueous solution.
  5. 根据权利要求4所述莱博雷生的制备方法,其特征在于所述混合溶剂中,甲苯与饱和碳酸氢钠水溶液的体积比为2:1~1:2,优选1:0.8~1:1。The preparation method of leborexan according to claim 4, characterized in that in the mixed solvent, the volume ratio of toluene and saturated sodium bicarbonate aqueous solution is 2:1~1:2, preferably 1:0.8~1:1 .
  6. 根据权利要求2所述的莱博雷生的制备方法,其特征在于化合物(II)中X选自氟,所述有机胺选自三乙胺、吡啶、N,N-二异丙基乙胺、4-二甲氨基吡啶和三乙醇胺中的至少一种,优选为吡啶;所述有机胺的体积为第二反应溶剂体积的5~15%,优选为8~12%。The preparation method of leborexan according to claim 2, characterized in that X in compound (II) is selected from fluorine, and the organic amine is selected from triethylamine, pyridine, N,N-diisopropylethylamine , at least one of 4-dimethylaminopyridine and triethanolamine, preferably pyridine; the volume of the organic amine is 5 to 15% of the volume of the second reaction solvent, preferably 8 to 12%.
  7. 根据权利要求1所述莱博雷生的制备方法,其特征在于化合物(II)中X选自氯,所述第二反应溶剂选自四氢呋喃、1,4-二氧六环、乙二醇二甲醚、乙腈、2-甲基四氢呋喃、环戊基甲醚、异丙醚和叔丁基甲醚中的至少一种,优选为乙二醇二甲醚,四氢呋喃和1,4- 二氧六环中的至少一种。The preparation method of leborexane according to claim 1, characterized in that X in compound (II) is selected from chlorine, and the second reaction solvent is selected from tetrahydrofuran, 1,4-dioxane, ethylene glycol di At least one of methyl ether, acetonitrile, 2-methyltetrahydrofuran, cyclopentyl methyl ether, isopropyl ether and tert-butyl methyl ether, preferably ethylene glycol dimethyl ether, tetrahydrofuran and 1,4-dioxane of at least one.
  8. 根据权利要求7所述莱博雷生的制备方法,其特征在于化合物(II)中X选自氯,所述有机碱选自二异丙基乙胺、三乙胺、吡啶、N-甲基咪唑、甲基吡啶、1,8-二氮杂双环[5.4.0]十一碳-7-烯、喹啉、四甲基乙二胺、三亚乙基二胺、六亚甲基四胺和N-甲基吗啉中的至少一种,优选为二异丙基乙胺、三乙胺中的至少一种。The preparation method of leborexan according to claim 7, characterized in that X in compound (II) is selected from chlorine, and the organic base is selected from diisopropylethylamine, triethylamine, pyridine, N-methyl Imidazole, methylpyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, quinoline, tetramethylethylenediamine, triethylenediamine, hexamethylenetetramine and At least one of N-methylmorpholine is preferably at least one of diisopropylethylamine and triethylamine.
  9. 根据权利要求7-8任一项所述莱博雷生的制备方法,其特征在于化合物(II)中X选自氯,所述步骤B)缩合反应的加料顺序为:The preparation method of leborexan according to any one of claims 7-8, characterized in that X in compound (II) is selected from chlorine, and the order of addition of step B) condensation reaction is:
    将化合物(II)溶解在第二反应溶剂,形成混合溶液c;Dissolve compound (II) in the second reaction solvent to form mixed solution c;
    将化合物(III)和有机碱溶解在第二反应溶剂中,形成混合溶液d;Dissolve compound (III) and organic base in the second reaction solvent to form mixed solution d;
    将混合溶剂c缓慢滴加到混合溶剂d中进行反应,生成莱博雷生。The mixed solvent c is slowly added dropwise to the mixed solvent d to carry out the reaction to generate leborexan.
  10. 根据权利要求8-9任一项所述莱博雷生的制备方法,其特征在于化合物(II)中X选自氯,所述步骤B)中的反应温度为20-100℃,优选为25-75℃,最优选为45-75℃。The preparation method of leborexan according to any one of claims 8-9, characterized in that X in compound (II) is selected from chlorine, and the reaction temperature in step B) is 20-100°C, preferably 25 -75°C, most preferably 45-75°C.
  11. 一种莱博雷生中间体化合物(II),其如以下任一结构式所示:A leborexine intermediate compound (II), which is represented by any of the following structural formulas:
    Figure PCTCN2022083200-appb-100002
    Figure PCTCN2022083200-appb-100002
  12. 根据权利要求1所述莱博雷生的制备方法,其特征在于所述化合物(II)的制备方法包括以下步骤:The preparation method of leborexan according to claim 1, characterized in that the preparation method of compound (II) includes the following steps:
    A)化合物(IV)与酰卤化试剂在第一反应溶剂中,有机胺作用下发生反应,生成化合物(II);A) Compound (IV) and acid halide reagent react in the first reaction solvent under the action of organic amine to generate compound (II);
    Figure PCTCN2022083200-appb-100003
    Figure PCTCN2022083200-appb-100003
    化合物(II)中,X选自氟或氯;In compound (II), X is selected from fluorine or chlorine;
    所述酰卤化试剂选自三氟均三嗪或三氯氧磷中的一种。The acid halide reagent is selected from one of trifluoro-s-triazine or phosphorus oxychloride.
  13. 根据权利要求12所述莱博雷生的制备方法,其特征在于所述酰卤化试剂为三氟均三嗪,化合物(II)中X为氟;所述第一反应溶剂选自甲苯、二氯甲烷、乙酸乙酯、吡啶、四氢呋喃、二氧六环、乙腈和丙酮中的至少一种,优选为甲苯、二氯甲烷或四氢呋喃,更优选为甲苯;所述有机胺选自三乙胺、吡啶、N,N-二异丙基乙胺、4-二甲氨基吡啶和三乙醇胺中的至少一种,优选为吡啶;所述有机胺的体积为述第一反应溶剂的1~10%,优选为4~5%。The preparation method of leborexan according to claim 12, characterized in that the acid halide reagent is trifluoro-s-triazine, X in compound (II) is fluorine; the first reaction solvent is selected from toluene, dichloro At least one of methane, ethyl acetate, pyridine, tetrahydrofuran, dioxane, acetonitrile and acetone, preferably toluene, dichloromethane or tetrahydrofuran, more preferably toluene; the organic amine is selected from triethylamine, pyridine , at least one of N,N-diisopropylethylamine, 4-dimethylaminopyridine and triethanolamine, preferably pyridine; the volume of the organic amine is 1 to 10% of the first reaction solvent, preferably It is 4~5%.
  14. 根据权利要求12所述莱博雷生的制备方法,其特征在于所述酰卤化试剂为三氟均三嗪,化合物(II)中X为氟;生成化合物(II)后,还包括向反应液中加入稀酸水溶液去除水溶性杂质的步骤。The preparation method of leborexan according to claim 12, characterized in that the acid halide reagent is trifluoro-s-triazine, and X in compound (II) is fluorine; after generating compound (II), it also includes adding to the reaction solution The step of adding dilute acid aqueous solution to remove water-soluble impurities.
  15. 根据权利要求12所述莱博雷生的制备方法,其特征在于所述酰卤化试剂为三氯氧磷,化合物(II)中X为氯;所述第一反应溶剂选自甲苯、氟苯、氯苯、二甲苯、二氯甲烷、四氢呋喃、1,4-二氧六环、乙二醇二甲醚、2-甲基四氢呋喃、环戊基甲醚、异丙醚、叔丁基甲醚和乙腈中的至少一种,优选为甲苯、二甲苯、乙腈和四氢呋喃中的至少一种。The preparation method of leborexan according to claim 12, characterized in that the acid halide reagent is phosphorus oxychloride, X in compound (II) is chlorine; the first reaction solvent is selected from toluene, fluorobenzene, In chlorobenzene, xylene, dichloromethane, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, isopropyl ether, tert-butyl methyl ether and acetonitrile At least one of, preferably at least one of toluene, xylene, acetonitrile and tetrahydrofuran.
  16. 根据权利要求12或15任一项所述莱博雷生的制备方法,其特征在于所述酰卤化试剂为三氯氧磷,化合物(II)中X为氯;所述步骤A)中反应的加料顺序为:The preparation method of leborexan according to any one of claims 12 or 15, characterized in that the acid halide reagent is phosphorus oxychloride, X in compound (II) is chlorine; the reaction in step A) The order of adding ingredients is:
    将化合物(IV)溶解在第一反应溶剂,形成混合溶液a;Dissolve compound (IV) in the first reaction solvent to form mixed solution a;
    将三氯氧磷溶解在第一反应溶剂中,形成混合溶液b;Dissolve phosphorus oxychloride in the first reaction solvent to form mixed solution b;
    将混合溶剂a缓慢滴加到混合溶剂b中进行反应,生成中间体化合物(II-2)。Mixed solvent a is slowly added dropwise to mixed solvent b to carry out reaction to generate intermediate compound (II-2).
  17. 根据权利要求12或15-16任一项所述莱博雷生的制备方法,其特征在于所述酰卤 化试剂为三氯氧磷,化合物(II)中X为氯;所述步骤A)中的反应温度为20-100℃,优选为60-90℃,最优选为60-65℃。The preparation method of leborexan according to any one of claims 12 or 15-16, characterized in that the acid halide reagent is phosphorus oxychloride, X in compound (II) is chlorine; in step A) The reaction temperature is 20-100°C, preferably 60-90°C, and most preferably 60-65°C.
  18. 一种莱博雷生的制备方法,其特征在于,包括以下步骤:A preparation method of Leborexen, characterized by comprising the following steps:
    通过如权利要求12~17任一项所述的步骤A)制备得到化合物(II);Compound (II) is prepared by step A) as described in any one of claims 12 to 17;
    通过如权利要求1~10任一项所述的步骤B)制备得到式(I)所示的莱博雷生;Leboresen represented by formula (I) is prepared by step B) according to any one of claims 1 to 10;
    化合物(II)中X选自氟或氯;In compound (II), X is selected from fluorine or chlorine;
    Figure PCTCN2022083200-appb-100004
    Figure PCTCN2022083200-appb-100004
  19. 根据权利要求18中所述莱博雷生的制备方法,其特征在于包括以下步骤:The preparation method of leborexane according to claim 18, characterized in that it includes the following steps:
    步骤A)制备得到化合物(II)不经分离直接用于步骤B)。Compound (II) prepared in step A) is directly used in step B) without isolation.
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