WO2023178693A1 - 一种莱博雷生及其中间体的制备方法 - Google Patents

一种莱博雷生及其中间体的制备方法 Download PDF

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WO2023178693A1
WO2023178693A1 PCT/CN2022/083178 CN2022083178W WO2023178693A1 WO 2023178693 A1 WO2023178693 A1 WO 2023178693A1 CN 2022083178 W CN2022083178 W CN 2022083178W WO 2023178693 A1 WO2023178693 A1 WO 2023178693A1
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compound
reaction
preparation
present
solvent
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French (fr)
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沈冀钧
穆永乐
简正军
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
上海科胜药物研发有限公司
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Priority to PCT/CN2022/083178 priority Critical patent/WO2023178693A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/16—Acetic acid esters of dihydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/02—Heterocyclic 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
    • C07D401/12—Heterocyclic 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 leborexine and its intermediates.
  • Insomnia refers to a subjective experience in which patients are dissatisfied with sleep time and/or quality and affect daytime social functioning. According to the international diagnostic standards for insomnia and epidemiological studies, at least 6% of people worldwide suffer from insomnia and sleep disorders.
  • Leborexan is a dual receptor of orexin receptor 1 (OX1) and orexin receptor 2 (OX2). As an inhibitor, this compound inhibits orexin by competitively binding to two subtypes of orexin receptors (OX1 and OX2). Leborexan can interfere with orexinergic neurotransmission and promote the initiation and maintenance of sleep in a purposeful manner.
  • Lemborexant its chemical formula is as follows: Formula I:
  • a first aspect of the present invention provides a preparation method of leborexan, which includes the following steps:
  • the second reaction solvent is selected from organic solvents, including but not limited to acetonitrile, dioxane, ethylene glycol dimethyl ether, pyridine, toluene, acetic acid At least one of ethyl ester and tetrahydrofuran is preferably tetrahydrofuran or acetonitrile.
  • the reaction temperature of the reaction is -5°C to 40°C, preferably 10°C to 35°C.
  • the reaction time of the reaction is 1h-48h, preferably 12-24h.
  • a second aspect of the invention provides a compound represented by formula II:
  • the third aspect of the present invention provides a preparation method of compound II, which includes the following steps:
  • the first reaction solvent is selected from organic solvents, including but not limited to acetonitrile, dioxane, ethylene glycol dimethyl ether, pyridine, toluene, acetic acid At least one of ethyl ester and tetrahydrofuran is preferably tetrahydrofuran or acetonitrile.
  • the reaction temperature of the reaction is -15°C to 10°C, preferably -10°C to 5°C.
  • the reaction time of the reaction is 1h-48h, preferably 4-24h.
  • the fourth aspect of the present invention provides a preparation method of compound IV, which includes the following steps:
  • the catalyst is selected from 2,2,6,6-tetramethylpiperidine-nitrogen-oxide or 4-hydroxy-2,2,6,6- At least one of tetramethylpiperidine-1-oxyl radicals.
  • the catalyst is used in an amount of 1% to 25% of the molar amount of Compound VII.
  • the volume ratio of tert-butyl alcohol and water in the mixed solvent is 4:1-3:2.
  • the oxidizing agent is sodium hypochlorite.
  • the oxidizing agent is used in an amount of 2.0 eq to 5.0 eq based on the molar amount of compound VII.
  • the pH value of the oxidation reaction ranges from 6 to 12.
  • sodium bicarbonate and/or sodium carbonate is also added to the mixed solvent.
  • the reaction temperature of the oxidation reaction is -10°C to 45°C, preferably -3°C to 3°C.
  • the reaction time of the oxidation reaction is 1h-96h, preferably 1h-24h.
  • the fifth aspect of the present invention provides a preparation method of leborexine, which includes the following steps:
  • Compound IV, Compound V and Compound VI are used as raw materials to react in the first reaction solvent to obtain Compound II;
  • compound IV is prepared by step A) described in the fourth aspect of the present invention, that is, using compound VII as a raw material, under the action of a catalyst and an oxidant, in a mixture of tert-butanol and water An oxidation reaction occurs in the solvent to form compound IV.
  • compound II prepared in step A) is directly used in step B) without isolation.
  • the method provided by the present invention can safely and efficiently prepare leborexine by preparing the Oxyma active ester intermediate, that is, compound II.
  • the optical purity of leborexine prepared by the method of the present invention is higher.
  • the racemization rate is lower and has better application prospects.
  • the intermediate compound II of the present invention is an Oxyma active ester intermediate, which is a safe and non-explosive auxiliary nucleophile, avoiding the explosion safety hazards of traditional activators such as HOBt and HOAt.
  • tert-butyl alcohol and water are used as mixed solvents, and ((1R,2S)-2-(((2,4-dimethyl Pyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropyl)methanol is directly oxidized to ((1R,2S)-2-(((2,4-dimethylpyrimidine) -5-yl)oxy)methyl)-2-(3-fluorophenyl)cyclopropyl)carboxylic acid, with high yield and almost no waste gas, no phosphorus-containing buffer is used, and no phosphorus-containing wastewater is produced. It is environmentally friendly, the process is safe and simple, and it is suitable for industrial production.
  • Figure 1 is a liquid chromatography-mass spectrometry (LC-MS) spectrum of the reaction solution that has reached the end point of the reaction in Example 1 of the present invention.
  • LC-MS liquid chromatography-mass spectrometry
  • Figure 2 is a hydrogen nuclear magnetic spectrum ( 1H NMR) spectrum of compound IV prepared in Example 1 of the present invention.
  • Figure 3 is a high performance liquid chromatography (HPLC) purity spectrum of compound IV prepared in Example 1 of the present invention.
  • Figure 4 shows the liquid chromatography and ion chromatogram of the LC-MS spectrum of compound IV prepared in Example 1 of the present invention; wherein 4a is the liquid chromatography spectrum and 4b is the ion chromatogram.
  • Figure 5 is the mass spectrum of compound IV prepared in Example 1 of the present invention in the LC-MS spectrum.
  • Figure 6 is the HPLC optical purity spectrum of compound IV prepared in Example 1 of the present invention.
  • Figure 7 is a chiral HPLC spectrum of the optical enantiomers of compound IV prepared in Example 1 of the present invention.
  • Figure 8 is a liquid chromatogram of the LC-MS spectrum of the reaction solution that reached the end point of the reaction in Example 2 of the present invention.
  • Figure 9 is a liquid chromatogram of the LC-MS spectrum of the reaction solution that reached the end point of the reaction in Comparative Example 1 of the present invention.
  • Figure 10 is a liquid chromatogram of the LC-MS spectrum of the reaction solution that reached the end point of the reaction in Comparative Example 2 of the present invention.
  • Figure 11 is a liquid chromatogram of the LC-MS spectrum of the reaction solution that reached the end point of the reaction in Comparative Example 3 of the present invention.
  • Figure 12 is the liquid chromatography mass spectrometry (LC-MS) spectrum of the reaction solution at the end of step A) in Example 3 of the present invention; wherein, 12a is the liquid chromatography spectrum, 12b is an ion current diagram.
  • LC-MS liquid chromatography mass spectrometry
  • Figure 13 is the mass spectrum of Compound II in the reaction solution in the LC-MS spectrum at the end of step A) in Example 3 of the present invention.
  • Figure 14 is the liquid chromatography and ion chromatogram of the LC-MS spectrum of the reaction solution at the end of step B) in Example 3 of the present invention; wherein 14a is the liquid chromatography spectrum and 14b is the ion chromatogram.
  • Figure 15 is the mass spectrum of the LC-MS spectrum of the reaction solution at the end of step B) in Example 3 of the present invention; wherein, 15a is the mass spectrum of compound IV in the reaction solution in the LC-MS spectrum, and 15b It is the mass spectrum of leborexine I in the LC-MS spectrum in the reaction solution.
  • Figure 16 is a proton nuclear magnetic spectrum ( 1 H NMR) spectrum (500 MHz) of Leboreson I prepared in Example 3 of the present invention.
  • Figure 17 is an infrared spectrum of Lebraxane I prepared in Example 3 of the present invention.
  • Figure 18 is a high-performance liquid chromatography (HPLC) purity spectrum of leboresen I prepared in Example 3 of the present invention.
  • Figure 19 is a chiral HPLC spectrum of leborexine I prepared in Example 3 of the present invention.
  • Figure 20 is a chiral HPLC spectrum of the enantiomeric isomer of leborexan I in Example 3 of the present invention.
  • Oxyma ethyl 2-oximecyanoacetate, also known as ethyl 2-cyano-2-(hydroxyimine)acetate.
  • Oxyma active ester intermediate refers to the O-acylisourea intermediate produced by the rapid reaction of acid and Oxyma.
  • the Oxyma active ester intermediate is Compound II.
  • a first aspect of the present invention provides a preparation method of leborexan, which includes the following steps:
  • Lebraxen can be prepared more safely and efficiently.
  • the second reaction solvent is selected from the group consisting of organic solvents, including but not limited to acetonitrile, dioxane, ethylene glycol dimethyl ether, pyridine, toluene, acetic acid At least one of ethyl ester and tetrahydrofuran is preferably tetrahydrofuran or acetonitrile.
  • the inventor has discovered through research that by using the above-mentioned second reaction solvent, the raw materials can be fully dissolved, thereby preparing leborexen more safely and efficiently.
  • the reaction temperature of the above reaction is called the second reaction temperature
  • the second reaction temperature is -5°C-40°C, preferably 10°C-35°C.
  • the reaction temperature can be -5°C, 0°C, 12°C, 20°C, 25°C, 40°C or any range in between.
  • the inventor found through research that by controlling the second reaction temperature of the above reaction to be within the above range , which can fully react between raw materials, thereby preparing Lebraxen more safely and efficiently.
  • the above reaction is called the second reaction time, and the second reaction time is 1h-48h, preferably 12-24h.
  • the second reaction time can be 1h, 4h, 8h, 10h, 12h, 18h, 24h, 48h or any range therebetween.
  • the inventor found through research that by controlling the second reaction time of the above reaction to be within the above range, The raw materials can be fully reacted in the second reaction solvent, thereby preparing leborexin more safely and efficiently.
  • the molar ratio of compound II to compound III is not particularly limited.
  • the molar ratio of compound II can be 1:1, 1:5, 1:10, 10:1, 5:1, or any range in between. .
  • a second aspect of the invention provides a compound represented by formula II:
  • the third aspect of the present invention provides a preparation method of compound II, which includes the following steps:
  • the inventor found that the compound of formula II prepared by the above method, which is an Oxyma active ester intermediate, can be used in the preparation process of leborexan to avoid the use of traditional activators with explosion hazards. HOBt and HOAt, thus making the preparation method of Leborexen safer and more efficient.
  • the first reaction solvent is selected from organic solvents, including but not limited to acetonitrile, dioxane, ethylene glycol dimethyl ether, pyridine, toluene, ethyl acetate , at least one of tetrahydrofuran, preferably tetrahydrofuran or acetonitrile.
  • organic solvents including but not limited to acetonitrile, dioxane, ethylene glycol dimethyl ether, pyridine, toluene, ethyl acetate , at least one of tetrahydrofuran, preferably tetrahydrofuran or acetonitrile.
  • the reaction temperature of the above reaction is called the first reaction temperature
  • the first reaction temperature is -15°C to 10°C, preferably -10°C to 5°C, for example, the first reaction temperature It can be -15°C, -5°C, 0°C, 5°C, 10°C or any range in between.
  • the inventor found through research that by controlling the first reaction temperature of the above reaction within the above range, the raw materials can be The reaction is sufficient, making the reaction more efficient, and the prepared compound II is further used in the preparation process of leborexan, making the preparation process of leborexan safer and more efficient.
  • the reaction time of the above reaction is called the first reaction time, and the first reaction time is 1h-48h, preferably 4-24h.
  • the first reaction time can be 1h, 14h, 28h, 42h, 48h or any range therebetween.
  • the inventor found through research that by controlling the first reaction time of the above reaction to be within the above range, the reaction can be made more efficient,
  • the prepared compound II is further applied to the preparation process of leborexan, making the preparation process of leborexan safer and more efficient.
  • the feeding molar ratio of compound IV, compound V and compound VI is not particularly limited.
  • the feeding molar ratio can be 1:1:1, 1:5:1, 1:10:1, 1:1: 5, 1:1:10, 5:1:1, 10:1:1 or any range in between.
  • the synthesis method of compound IV is: ((1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluoro Phenyl) cyclopropyl) methanol (VII) undergoes an oxidation reaction to generate the corresponding aldehyde (compound VIII), further oxidized under the action of sodium chlorite to form ((1R,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3- Fluorophenyl)cyclopropyl)carboxylic acid.
  • the fourth aspect of the present invention provides a preparation method of compound IV, which includes the following steps:
  • the inventor found that using a mixed solvent of tert-butyl alcohol and water as the reaction solvent, the method of directly oxidizing alcohol to acid in the mixed solvent is simple, efficient and has simple post-processing steps. Without being limited to any theory, the inventor believes that because tert-butyl alcohol Alcohol is used as a solvent. During the reaction, part of the tert-butyl alcohol is oxidized to peroxide. The generated peroxide further catalyzes the above oxidation reaction, causing the alcohol to be directly oxidized into acid.
  • the catalyst is selected from 2,2,6,6-tetramethylpiperidine-nitrogen-oxide or 4-hydroxy-2,2,6,6- At least one of tetramethylpiperidine-1-oxyl radicals.
  • the inventor found through research that the oxidation reaction can be made more efficient by using the above-mentioned catalyst and the mixed solvent to act synergistically.
  • the catalyst is used in an amount of 1% to 25% of the molar amount of Compound VII.
  • the amount of catalyst used is not particularly limited and can be an amount known to those skilled in the art. Based on the molar amount of reaction raw material compound II, the amount of catalyst used can be selected from but not limited to 1%-25%, for example, the amount of catalyst The dosage can be 1%, 2%, 6%, 14%, 25% or any range in between.
  • the volume ratio of tert-butyl alcohol and water in the mixed solvent is 4:1-3:2, such as 4:1, 3:1, 2:1, 1.7:1, 1.6:1, 3:2; the inventor found through research that when the volume ratio of tert-butanol and water meets the above relationship, the oxidation reaction is more efficient.
  • the oxidizing agent is sodium hypochlorite.
  • the inventor found that only sodium hypochlorite was used as the oxidant. Compared with the prior art that used a combination of sodium hypochlorite and sodium chlorite, almost no chlorine-containing waste gas was produced during the oxidation reaction of the present invention, and sodium chlorite is a flammable chemical. Therefore, the preparation method of the present invention is more green, safe and efficient.
  • the oxidizing agent is used in an amount of 2.0 eq to 5.0 eq based on the molar amount of compound VII.
  • the amount of oxidizing agent is not particularly limited. Based on the molar amount of reaction raw material compound II, the amount of oxidizing agent can be selected from but not limited to 2.0eq-5.0eq.
  • the amount of oxidizing agent can be 2.0eq, 2.8eq, 3.4 eq, 4.6eq, 5.0eq, or any range in between.
  • the pH value of the oxidation reaction ranges from 6 to 12, such as: 6, 7, 8, 9, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8 , 9.9, 10, 11, 12 or any range in between.
  • the inventor found through research that by regulating the pH value of the oxidation reaction within the above range, the oxidation reaction can be made more efficient.
  • sodium bicarbonate and/or sodium carbonate is also added to the mixed solvent.
  • the inventor has discovered through research that by using sodium bicarbonate and/or sodium carbonate as a buffer solution, compared with the prior art using sodium dihydrogen phosphate and disodium hydrogen phosphate as buffer solvents, the preparation method provided by the present invention does not produce any sodium bicarbonate. Phosphorus wastewater, environmentally friendly.
  • sodium carbonate and sodium bicarbonate are added to the mixed solvent, the synergistic effect of sodium carbonate and sodium bicarbonate can achieve a better buffering effect.
  • the reaction temperature of the oxidation reaction is -10°C to 45°C, preferably -3°C to 3°C.
  • the reaction temperature can be -10°C, -5°C, 0°C, 15°C, 30°C, 45°C or any range in between. The inventor found through research that by controlling the reaction temperature of the oxidation reaction within the above range, the raw materials can react fully and the oxidation reaction can be more efficient.
  • the reaction time of the oxidation reaction is 1h-96h, preferably 1h-24h.
  • the reaction time can be 1h, 5h, 16h, 29h, 42h, 55h, 68h, 81h, 96h or any range in between.
  • the inventor found through research that by controlling the reaction time of the oxidation reaction within the above range, the oxidation reaction can be made more efficient.
  • the fifth aspect of the present invention provides a preparation method of leborexine, which includes the following steps:
  • compound IV is prepared by step A) described in the fourth aspect of the present invention, that is, using compound VII as a raw material, under the action of a catalyst and an oxidant, in a mixture of tert-butanol and water An oxidation reaction occurs in the solvent to form compound IV.
  • compound II prepared in step A) is directly used in step B) without isolation.
  • the first reaction solvent and the second reaction solvent may be the same or different, and are preferably the same.
  • compound II can be synthesized directly in one pot without isolating compound II.
  • the inventor has found through research that the use of one-pot synthesis can simplify the process steps and reduce production. cost.
  • reaction time and temperature for synthesizing intermediate compound II are the same as the selection ranges of reaction time and temperature in the preparation method of compound II in the third aspect of the present invention;
  • the reaction time and temperature for synthesizing leborexan are the same as the selection ranges of the reaction time and temperature in the preparation method of leborexan in the first aspect of the present invention.
  • 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 detection conditions are as follows in Table 1:
  • the test methods of hydrogen nuclear magnetic spectrum test ( 1 H NMR), liquid chromatography-mass spectrometry (LC-MS) test, and infrared test are not particularly limited, and can be tested by methods known to those skilled in the art, wherein,
  • the deuterated reagent used in the hydrogen nuclear magnetic spectrum test is commercially available deuterated dimethyl sulfoxide (DMSO).
  • 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.
  • Compound III is commercially available 2-amino-5-fluoropyridine, purchased from Fuxin Jintelai Co., Ltd.;
  • Compound V (2-oxime cyanoacetic acid Ethyl ester) and compound VI (diisopropylcarbodiimide) were purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd.
  • TEMPO 2,2,6,6,-tetramethylpiperidine-nitrogen-oxide material
  • the mixed solvent includes 2000mL tert-butanol and 1000mL water
  • the catalyst is 4-hydroxy-2,2,6,6,-tetramethylpiperidine-1-oxyl radical
  • the catalyst dosage is 6.7g
  • the rest are the same as in the implementation Same as Example 1.
  • Use LC-MS test to monitor the reaction end point, and obtain the LC-MS characterization of the reaction solution that reaches the reaction end point, as shown in Figure 8. Peak 11 is the peak corresponding to the target compound IV.
  • Compound IV, Compound VII and Compound VIII in the reaction solution The content is shown in Table 2.
  • Example 2 Except that during the reaction process, the mixed solvent was a toluene-water mixed solvent, and the volume ratio of toluene and water was 2:1.2, the rest was the same as in Example 1.
  • Use LC-MS test to monitor the reaction end point, and obtain the LC-MS characterization of the reaction solution that reaches the reaction end point, as shown in Figure 9, in which peak # 5 is the peak corresponding to the target compound IV, and compound IV, compound VII and compound VIII in the reaction solution The content is shown in Table 2.
  • the mixed solvent is a mixed solvent of acetonitrile-water, and the volume ratio of acetonitrile and water is 2:1.2, the rest is the same as in Example 1.
  • the reaction end point is monitored by LC-MS test to obtain the reaction that reaches the reaction end point.
  • the LC-MS characterization of the solution is shown in Figure 10, in which peak # 5 is the peak corresponding to the target compound IV.
  • the contents of compound IV, compound VII and compound VIII in the reaction solution are as shown in Table 2.
  • the mixture was the same as Comparative Example 2 except that 0.3% tert-butyl hydroperoxide was added to the mixed solvent based on the total volume of the mixed solvent.
  • 0.3% tert-butyl hydroperoxide was added to the mixed solvent based on the total volume of the mixed solvent.
  • the inventor believes that it may be because tert-butyl alcohol as a solvent is partially oxidized to peroxide, and the generated peroxide catalyzes the oxidation reaction, allowing it to be directly oxidized to the acid. Therefore, based on Comparative Example 2, tert-butyl hydroperoxide was further added to acetonitrile. Compared with Comparative Example 2, the reaction conversion rate was greatly improved.
  • Peak 2 is the peak corresponding to the target compound IV.
  • Compound IV, Compound VII and Compound VIII in the reaction solution The content is shown in Table 2.
  • Example 1 Comparative Example 1 and Comparative Example 2 (the solvent described in the original research patent CN104114524B) that different solvents have a greater impact on the reaction.
  • the main product generated by toluene as a solvent is aldehyde, so the original research patent CN104114524B Sodium chlorite is used for further oxidation, and the acid can be directly prepared by using the mixed solvent of the present invention as the reaction solvent; at the same time, the method of the original patent CN104114524B will produce a large amount of waste gas containing chlorine dioxide and phosphorus-containing wastewater that pollutes the environment. , does not meet the requirements of green industry.
  • the preparation method of the invention does not produce toxic and harmful waste gas and phosphorus-containing waste water, is environmentally friendly, and has a simple process. It can be seen from Comparative Examples 2 and 3 that adding a trace amount of tert-butyl hydroperoxide significantly improves the reaction. Without being limited to any theory, the inventor believes that it may be because tert-butyl alcohol is partially oxidized as a solvent. It is a peroxide, and the generated peroxide catalyzes the oxidation reaction, allowing it to be directly oxidized to acid. However, the reaction result of Comparative Example 3 is far less good than that of Example 1. It can be seen that the preparation method of the present invention to prepare the leborexine intermediate has a simple reaction process and is environmentally friendly.
  • Figure 1 shows the liquid chromatogram in the LC-MS spectrum of the reaction solution that reaches the reaction end point in Example 1 of the present invention.
  • the data of the liquid chromatogram is reported in Table 3 below:
  • FIG. 3 shows the HPLC purity spectrum of compound IV prepared in Example 1 of the present invention, wherein the data of the HPLC purity spectrum is reported in Table 4 below:
  • Figure 5 shows the mass spectrum of compound IV prepared in the embodiment of the present invention in the LC-MS spectrum, wherein the data of the LC-MS spectrum is reported in Table 5 below:
  • FIG. 6 shows the HPLC optical purity spectrum of compound IV prepared in Example 1 of the present invention, wherein the data of the HPLC optical purity spectrum is reported in Table 6 below:
  • Figure 8 shows the liquid chromatogram in the LC-MS spectrum of the central control in Example 2 of the present invention.
  • the data of the liquid chromatogram is reported in Table 7 as follows:
  • Figure 9 shows the liquid chromatogram in the LC-MS spectrum of the control in Comparative Example 1 of the present invention, wherein the data of the liquid chromatogram is reported in Table 8 as follows:
  • Figure 10 shows the liquid chromatogram in the LC-MS spectrum of the control in Comparative Example 2 of the present invention, wherein the data of the liquid chromatogram is reported in Table 9 as follows:
  • Figure 11 shows the liquid chromatogram in the LC-MS spectrum of the control in Comparative Example 3 of the present invention, wherein the data of the liquid chromatogram is reported in Table 10 as follows:
  • the LC-MS spectra of the reaction solution are shown in Figures 12 and 13.
  • the theoretical value of M+H + is 441.15[M+1] +
  • corresponding to the measured value in the mass spectrum in Figure 13 is 441.1[M+1] +
  • the content of compound IV is less than 1%, which is considered the end of the reaction , at this time the first reaction time is 18 hours.
  • step B) Further add the reactant 2-amino-5-fluoropyridine (compound III) (1.03eq, 115g) into the reaction system (at this time, the second reaction solvent of step B) is also the first reaction solvent of step A). ), the temperature was raised to 15°C (second reaction temperature) for a secondary reaction.
  • the organic phase was washed once with 500 ml of 1 mol/L sodium carbonate aqueous solution. Wash once with 200 ml of 0.3 mol/L hydrochloric acid aqueous solution.
  • the organic phase was concentrated, dissolved in isopropyl alcohol and spun to dryness. Add 1 liter of isopropyl alcohol and heat to reflux, then add 600 ml of n-heptane dropwise, put it into the low-temperature refrigeration system and set it to cool to 55°C within 2 hours, keep it at 55°C for 1 hour, and then set it to cool to 0°C within 5 hours. .
  • the method provided by the present invention can safely and efficiently prepare leborexine by preparing the Oxyma active ester intermediate, that is, compound II.
  • the optical purity of leborexine prepared by the method of the present invention is higher.
  • the racemization rate is lower and has better application prospects.
  • the intermediate compound II of the present invention is an Oxyma active ester intermediate, which is a safe and non-explosive auxiliary nucleophile, avoiding the explosion safety hazards of traditional activators such as HOBt and HOAt (see Fernando Albericio et al. in Chem
  • HOBt and HOAt see Fernando Albericio et al. in Chem
  • the safety of Oxyma was evaluated in .Eur.J.2009,15,9394-9403).
  • FIG 16 shows the HPLC purity spectrum of compound I prepared in Example 3 of the present application, wherein the data report of the HPLC purity spectrum is as shown in Table 11:
  • Figure 19 shows the chiral HPLC spectrum of compound I prepared in Example 3 of the present application, wherein the data report of the chiral HPLC spectrum is as shown in Table 12:
  • Examples 4 to 8 refer to step A) in Example 3.
  • the differences lie in the differences in the first reaction solvent, the first reaction temperature and/or the first reaction time. See Table 13 for details.
  • Example first reaction solvent first reaction temperature Compound IV content Compound II content
  • Example 4 Tetrahydrofuran 45°C 90% 2%
  • Example 5 Tetrahydrofuran 25°C 55% 38%
  • Example 6 Tetrahydrofuran -5°C 0.2% 97%
  • Example 7 Toluene -5°C 43% 51%
  • Example 8 Acetonitrile -5°C 4% 93%
  • Embodiments 9 to 13 refer to step B) of Embodiment 1, wherein Embodiment 9 is the subsequent reaction of Embodiment 4, Embodiment 10 is the subsequent reaction of Embodiment 5, and Embodiment 11 is the subsequent reaction of Embodiment 6.
  • Example 12 is the follow-up reaction of Example 7, and Example 13 is the follow-up reaction of Example 8; the difference lies in the difference in the second reaction solvent, the second reaction temperature and/or the second reaction time in step B). For details, see Table 14.
  • Example Second reaction solvent second reaction temperature Compound IV content Compound II content Compound I content
  • Example 9 Tetrahydrofuran -5°C 7% twenty two% 66%
  • Example 10 Tetrahydrofuran 10°C 5% 2% 87%
  • Example 11 Tetrahydrofuran 35°C 14% 0.1% 75%
  • Example 12 Toluene 10°C 68% 5% 16%
  • Example 13 Acetonitrile 10°C 12% 1% 79%

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Abstract

本发明提供了一种制备莱博雷生的方法，其包括以下步骤：以化合物II和化合物III为原料在第二反应溶剂中发生反应，得到莱博雷生的步骤。本发明还提供了化合物II的制备方法，本发明制备得到的化合物II为Oxyma活性酯中间体，其反应活性高，是一种安全且非***性辅助亲核体，本发明避免使用传统的HOBt、HOAt等活化剂，消除了安全隐患；采用本发明方法制备莱博雷生，反应更安全高效，所得产物的消旋率更低。

Description

一种莱博雷生及其中间体的制备方法 技术领域
本发明涉及医药技术领域，特别是涉及一种莱博雷生及其中间体的制备方法。
背景技术
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，莱博雷生是食欲素受体1(OX1)和食欲素受体2(OX2)的双重抑制剂，该化合物通过竞争性结合2种亚型的食欲素受体(OX1和OX2)抑制食欲素，莱博雷生可以干扰食欲素能神经传递，有目的的促进睡眠的启动和维持。莱博雷生(Lemborexant)，其化学式如下式I所示：
Figure PCTCN2022083178-appb-000001
发明内容
本发明第一方面提供了一种莱博雷生的制备方法，其包括以下步骤：
B)化合物II和化合物III在第二反应溶剂中发生反应，得到式I所示的莱博雷生；
Figure PCTCN2022083178-appb-000002
在本发明第一方面的一些实施方案中，所述第二反应溶剂选自有机溶剂，所述有机溶剂包括但不限于乙腈、二氧六环、乙二醇二甲醚、吡啶、甲苯、乙酸乙酯、四氢呋喃中的 至少一种，优选为四氢呋喃或乙腈。
在本发明第一方面的一些实施方案中，所述反应的反应温度为-5℃-40℃，优选为10℃-35℃。
在本发明第一方面的一些实施方案中，所述反应的反应时间为1h-48h，优选12-24h。
本发明第二方面提供了一种如式II所示的化合物：
Figure PCTCN2022083178-appb-000003
本发明第三方面提供了一种化合物II的制备方法，其包括以下步骤：
A)化合物IV、化合物V和化合物VI在第一反应溶剂中发生反应，得到化合物II；
Figure PCTCN2022083178-appb-000004
在本发明第三方面的一些实施方案中，所述第一反应溶剂选自有机溶剂，所述有机溶剂包括但不限于乙腈、二氧六环、乙二醇二甲醚、吡啶、甲苯、乙酸乙酯、四氢呋喃中的至少一种，优选为四氢呋喃或乙腈。
在本发明第三方面的一些实施方案中，所述反应的反应温度为-15℃至10℃，优选为-10℃-5℃。
在本发明第三方面的一些实施方案中，所述反应的反应时间为1h-48h，优选为4-24h。
本发明第四方面提供了一种化合物IV的制备方法，其包括以下步骤：
A)以化合物VII为原料，在催化剂和氧化剂作用下，在叔丁醇和水的混合溶剂中发生氧化反应，生成化合物IV；
Figure PCTCN2022083178-appb-000005
在本发明第四方面的一些实施方案中，所述催化剂选自2,2,6,6,-四甲基哌啶-氮-氧化物或4-羟基-2,2,6,6,-四甲基哌啶-1-氧自由基中的至少一种。
在本发明第四方面的一些实施方案中，所述催化剂的用量为化合物VII的摩尔量的1％-25％。
在本发明第四方面的一些实施方案中，所述混合溶剂中叔丁醇和水的体积比为4∶1-3∶2。
在本发明第四方面的一些实施方案中，所述氧化剂为次氯酸钠。
在本发明第四方面的一些实施方案中，所述氧化剂的用量为化合物VII的摩尔量的2.0eq-5.0eq。
在本发明第四方面的一些实施方案中，所述氧化反应的pH值范围为6-12。
在本发明第四方面的一些实施方案中，所述混合溶剂中还加入碳酸氢钠和/或碳酸钠。
在本发明第四方面的一些实施方案中，所述氧化反应的反应温度为-10℃～45℃，优选为-3℃～3℃。
在本发明第四方面的一些实施方案中，所述氧化反应的反应时间为1h-96h，优选为1h-24h。
本发明第五方面提供了一种莱博雷生的制备方法，其包括以下步骤：
A)化合物IV、化合物V和化合物VI为原料在第一反应溶剂中发生反应，得到化合物II；
B)化合物II与化合物III在第二反应溶剂中发生缩合反应，得到式I所示的莱博雷生。
Figure PCTCN2022083178-appb-000006
在本发明第五方面的一些实施方案中，通过本发明第四方面所述的步骤A)制备得到化合物IV，即以化合物VII为原料，在催化剂和氧化剂作用下，在叔丁醇和水的混合溶剂中发生氧化反应，生成化合物IV。
在本发明第五方面的一些实施方案中，步骤A)制备得到化合物II不经分离直接用于步骤B)。
有益效果：
本发明提供的方法，通过制备Oxyma活性酯中间体即化合物II，可以安全高效的制备莱博雷生，与现有技术相比，本发明的方法制备得到的莱博雷生光学纯度更高，消旋率更低，具有更好的应用前景。同时，本发明的中间体化合物II为Oxyma活性酯中间体，其是一种安全且非***性辅助亲核体，避免了HOBt，HOAt等传统活化剂的***安全隐患。并且，本发明提供的中间体化合物IV的制备方法中，以叔丁醇和水为混合溶剂，在氧化剂和催化剂作用下将((1R,2S)-2-(((2,4-二甲基嘧啶-5-基)氧基)甲基)-2-(3-氟苯基)环丙基)甲醇直接氧化生成((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，收率高，同时几乎无废气产生，不使用含磷缓冲液，无含磷废水产生，环境友好，工艺安全、简单，适合工业化生产。
附图说明
图1为本发明实施例1中中控到达反应终点的反应液的液相色谱-质谱(LC-MS)谱图中的液相色谱图。
图2为本发明实施例1制备得到的化合物IV的核磁氢谱( 1H NMR)谱图。
图3为本发明实施例1制备得到的化合物IV的高效液相色谱(HPLC)纯度谱图。
图4为本发明实施例1制备得到的化合物IV的LC-MS谱图中的液相色谱和离子流图；其中，4a为液相色谱谱图，4b为离子流图。
图5为本发明实施例1制备得到的化合物IV在LC-MS谱图中的质谱图。
图6为本发明实施例1制备得到的化合物IV的HPLC光学纯度谱图。
图7为本发明实施例1制备得到的化合物IV的光学对映异构体手性HPLC谱图。
图8为本发明实施例2中中控到达反应终点的反应液的LC-MS谱图中的液相色谱图。
图9为本发明对比例1中中控到达反应终点的反应液的LC-MS谱图中的液相色谱图。
图10为本发明对比例2中中控到达反应终点的反应液的LC-MS谱图中的液相色谱图。
图11为本发明对比例3中中控到达反应终点的反应液的LC-MS谱图中的液相色谱图。
图12为本发明实施例3中步骤A)反应结束时反应液的液相色谱质谱(LC-MS)谱图中的液相色谱和离子流图；其中，12a为液相色谱谱图，12b为离子流图。
图13为本发明实施例3中步骤A)反应结束时反应液中的化合物II在LC-MS谱图中的质谱图。
图14为本发明实施例3中步骤B)反应结束时反应液的LC-MS谱图中的液相色谱和离子流图；其中，14a为液相色谱谱图，14b为离子流图。
图15为本发明实施例3中步骤B)反应结束时反应液的LC-MS谱图中的质谱图；其中，15a为反应液中的化合物IV在LC-MS谱图中的质谱图，15b为反应液中的莱博雷生I在LC-MS谱图中的质谱图。
图16为本发明实施例3中制备得到的莱博雷生I的核磁氢谱( 1H NMR)谱图(500MHz)。
图17为本发明实施例3中制备得到的莱博雷生I的红外谱图。
图18为本发明实施例3中制备得到的莱博雷生I的高效液相色谱(HPLC)纯度谱图。
图19为本发明实施例3中制备得到的莱博雷生I的手性HPLC谱图。
图20为本发明实施例3莱博雷生I的对应异构体的手性HPLC谱图。
具体实施方式
术语和定义：
Oxyma：2-肟氰乙酸乙酯，又名2-氰基-2-(羟基亚胺)乙酸乙酯。
Oxyma活性酯中间体指酸和Oxyma快速反应生成的O-酰基异脲(O-acylisourea)中间体。在本发明的一些实施例中，Oxyma活性酯中间体为化合物II。
本发明第一方面提供了一种莱博雷生的制备方法，其包括以下步骤：
B)以化合物II和化合物III在第二反应溶剂中发生反应，得到式I所示的莱博雷生；
Figure PCTCN2022083178-appb-000007
发明人经深入研究发现，通过使用上述方法，与现有技术相比，可以更加安全高效地制备得到莱博雷生。
在本发明第一方面的一些实施方案中，第二反应溶剂选自选自有机溶剂，所述有机溶剂包括但不限于乙腈、二氧六环、乙二醇二甲醚、吡啶、甲苯、乙酸乙酯、四氢呋喃中的至少一种，优选为四氢呋喃或乙腈。
发明人经研究发现，通过使用上述第二反应溶剂，可以使原料充分溶解，从而更加安全高效地制备莱博雷生。
在本发明第一方面的一些实施方案中，上述反应的反应温度称为第二反应温度，所述第二反应温度为-5℃-40℃，优选为10℃-35℃。例如，反应温度可以为-5℃、0℃、12℃、20℃、25℃、40℃或为其间的任意范围，发明人经研究发现，通过控制上述反应的第二反应温度在上述范围内，可以使原料之间充分反应，从而更加安全高效地制备莱博雷生。
在本发明第一方面的一些实施方案中，上述反应称为第二反应时间，所述第二反应时间为1h-48h，优选12-24h。例如，第二反应时间可以为1h、4h、8h、10h、12h、18h、24h、48h或为其间的任意范围，发明人经研究发现，通过控制上述反应的第二反应时间在上述范围内，可以使原料在第二反应溶剂中充分反应，从而更加安全高效地制备莱博雷生。
在本发明中，化合物II与化合物III的投料摩尔比没有特别限定，例如，投料摩尔比可以为1:1、1:5、1:10、10:1、5:1或为其间的任意范围。
本发明第二方面提供了一种式II所示的化合物：
Figure PCTCN2022083178-appb-000008
本发明第三方面提供了一种化合物II的制备方法，其包括以下步骤：
化合物IV、化合物V和化合物VI在第一反应溶剂中发生反应，得到化合物II；
Figure PCTCN2022083178-appb-000009
发明人通过深入研究发现，通过上述方法制备的式II所示化合物，所述化合物II为Oxyma活性酯中间体，应用于莱博雷生的制备过程中，可以避免使用具有***危险的传统活化剂HOBt和HOAt，从而使莱博雷生的制备方法更加安全高效。
在本发明第三方面的一些实施方案中，第一反应溶剂选自有机溶剂，所述有机溶剂包括但不限于乙腈、二氧六环、乙二醇二甲醚、吡啶、甲苯、乙酸乙酯、四氢呋喃中的至少一种，优选为四氢呋喃或乙腈。发明人经研究发现，通过使用上述第一反应溶剂制备化合物II，可以使原料溶解充分，使反应更加高效，进一步将制备得到的化合物II应用于莱博雷生的制备过程，使莱博雷生的制备过程更加安全高效。
在本发明的一些实施方案中，上述反应的反应温度称为第一反应温度，所述第一反应温度为-15℃至10℃，优选为-10℃-5℃，例如，第一反应温度可以为-15℃、-5℃、0℃、5℃、10℃或为其间的任意范围，发明人经研究发现，通过控制上述反应的第一反应温度在上述范围内，可以使原料之间反应充分，使反应更加高效，进一步将制备得到的化合物II应用于莱博雷生的制备过程，使莱博雷生的制备过程更加安全高效。
在本发明第三方面的一些实施方案中，上述反应的反应时间称为第一反应时间，所述第一反应时间为1h-48h，优选为4-24h。例如，第一反应时间可以为1h、14h、28h、42h、48h或为其间的任意范围，发明人经研究发现，通过控制上述反应的第一反应时间在上述范围内，可以使反应更加高效，进一步将制备得到的化合物II应用于莱博雷生的制备过程，使莱博雷生的制备过程更加安全高效。
在本发明中，化合物IV、化合物V和化合物VI的投料摩尔比没有特别限定，例如，投料摩尔比可以为1:1:1、1:5:1、1:10:1、1:1:5、1:1:10、5:1:1、10:1:1或为其间的任意范围。
现有技术中，化合物IV的合成方法为：((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(VII)在次氯酸钠氧化和2,2,6,6,-四甲基哌啶-氮-氧化物(TEMPO)催化作用下，发生氧化反应生成对应的醛(化合物VIII)，在亚氯酸钠作用下进一步氧化生成((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。
Figure PCTCN2022083178-appb-000010
上述制备方法由于采用两次含氯氧化剂进行氧化并且使用含磷化合物配制缓冲液，生产过程会产生大量含有二氧化氯的废气及含磷废水。
本发明第四方面提供了一种化合物IV的制备方法，其包括以下步骤：
A)以化合物VII为原料，在催化剂和氧化剂作用下，在叔丁醇和水的混合溶剂中发生氧化反应，生成化合物IV；
Figure PCTCN2022083178-appb-000011
发明人经过深入研究发现，使用叔丁醇和水的混合溶剂作为反应溶剂，在混合溶剂中将醇直接氧化为酸的方法简洁高效且后处理步骤简单，不限于任何理论，发明人认为由于叔丁醇作为溶剂，在反应过程中部分叔丁醇被氧化为过氧化物，所生成的过氧化物进一步催化上述氧化反应，使醇直接氧化成酸。
在本发明第四方面的一些实施方案中，所述催化剂选自2,2,6,6,-四甲基哌啶-氮-氧化物或4-羟基-2,2,6,6,-四甲基哌啶-1-氧自由基中的至少一种。发明人经研究发现，通过使用上述催化剂与混合溶剂协同作用，可以使氧化反应更加高效。
在本发明第四方面的一些实施方案中，所述催化剂的用量为化合物VII的摩尔量的1％-25％。在本发明中，催化剂的用量没有特别限定，可以为本领域技术人员公知的用量，基于反应原料化合物II的摩尔量，催化剂的用量可以选自但不限于1％-25％，例如，催化剂的用量可以为1％、2％、6％、14％、25％或为其间的任意范围。
在本发明第四方面的一些实施方案中，所述混合溶剂中叔丁醇和水的体积比为4∶1-3∶2，诸如4:1，3:1，2:1，1.7:1，1.6:1，3:2；发明人经研究发现，当叔丁醇和水的体积比符合上述关系时，氧化反应更加高效。
在本发明第四方面的一些实施方案中，所述氧化剂为次氯酸钠。发明人发现仅使用次氯酸钠作氧化剂，与现有技术使用次氯酸钠和亚氯酸钠的组合相比，本发明的氧化反应过程中几乎无含氯废气产生，且亚氯酸钠为易燃化学品，因此本发明的制备方法更加绿色安全高效。
在本发明第四方面的一些实施方案中，所述氧化剂的用量为化合物VII的摩尔量的2.0eq-5.0eq。在本发明中，氧化剂的用量没有特别限定，基于反应原料化合物II的摩尔量，氧化剂的用量可以选自但不限于2.0eq-5.0eq，例如，氧化剂的用量可以为2.0eq、2.8eq、3.4eq、4.6eq、5.0eq或为其间的任意范围。
在本发明第四方面的一些实施方案中，所述氧化反应的pH值范围为6-12，诸如：6、7、8、9、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10、11、12或为其间的任意范围。发明人经研究发现，通过调控氧化反应的pH值在上述范围内，能够使氧化反应更加高效。
在本发明第四方面的一些实施方案中，所述混合溶剂中还加入碳酸氢钠和/或碳酸钠。发明人经研究发现，通过使用碳酸氢钠和/或碳酸钠作为缓冲溶液，与现有技术使用磷酸二氢钠和磷酸氢二钠作为缓冲溶剂相比，本发明提供的制备方法不会产生含磷废水，环境友好。并且，混合溶剂中加入碳酸钠和碳酸氢钠时，碳酸钠和碳酸氢钠的协同作用可以实现 更好的缓冲效果。
在本发明第四方面的一些实施方案中，所述氧化反应的反应温度为-10℃～45℃，优选为-3℃～3℃，例如，反应温度可以为-10℃、-5℃、0℃、15℃、30℃、45℃或为其间的任意范围。发明人经研究发现，通过控制氧化反应的反应温度在上述范围内，可以使原料之间反应充分，使氧化反应更加高效。
在本发明第四方面的一些实施方案中，所述氧化反应的反应时间为1h-96h，优选为1h-24h，例如，反应时间可以为1h、5h、16h、29h、42h、55h、68h、81h、96h或为其间的任意范围。发明人经研究发现，通过控制氧化反应的反应时间在上述范围内，可以使氧化反应更加高效。
本发明第五方面提供了一种莱博雷生的制备方法，其包括以下步骤：
A)化合物IV、化合物V和化合物VI在第一反应溶剂中发生反应，得到化合物II，
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。
Figure PCTCN2022083178-appb-000012
在本发明第五方面的一些实施方案中，通过本发明第四方面所述的步骤A)制备得到化合物IV，即以化合物VII为原料，在催化剂和氧化剂作用下，在叔丁醇和水的混合溶剂中发生氧化反应，生成化合物IV。
在本发明第五方面的一些实施方案中，步骤A)制备得到化合物II不经分离直接用于步骤B)。
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，优选为相同。
在本发明中，可以在化合物II的合成步骤完成后，不分离化合物II，直接一锅法进行莱博雷生的合成，发明人经研究发现，使用一锅法合成可以简化工艺步骤，降低生产成本。
在本发明中，上述一锅法合成莱博雷生的过程中，合成中间体化合物II的反应时间和 温度，与本发明第三方面化合物II的制备方法中反应时间和温度的选择范围相同；合成莱博雷生的反应时间和温度，与本发明第一方面莱博雷生的制备方法中反应时间和温度的选择范围相同。
实施例
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。
HPLC法：
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***，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，色谱检测条件如下表1：
表1
Figure PCTCN2022083178-appb-000013
Figure PCTCN2022083178-appb-000014
在本发明中，核磁氢谱测试( 1H NMR)、液相色谱-质谱(LC-MS)测试、红外测试的测试方法没有特别限定，可以采用本领域技术人员公知的方法进行测试，其中，核磁氢谱测试所使用的氘代试剂为市售的氘代二甲基亚砜(DMSO)。
ee值测量：
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。
实施例中采用高效液相色谱法(HPLC)测量产物的ee值。
如无特别说明，本发明的原料及试剂可获得经市售，化合物III为市售的2-氨基-5-氟代吡啶，购自阜新金特莱有限公司；化合物V(2-肟氰乙酸乙酯)和化合物VI(二异丙基碳二亚胺)均购自上海毕得医药科技公司。
实施例1
Figure PCTCN2022083178-appb-000015
在反应瓶中将302g化合物VII溶于2000mL叔丁醇和1200mL水的混合溶剂，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-3～3℃。滴加完毕后，于0℃反应12h。HPLC监测化合物VII的含量小于0.2％时反应结束，此时水相pH＝9.2。利用LC-MS测试监控反应终点，得到中控到达反应终点的反应液的LC-MS谱图(如图1所示，其中，5 #峰为目标化合物IV对应的峰，反应液中化合物IV的含量为98.7％)。
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( 1H NMR表征如图2所示)。化合物IV的LC-MS谱图如图4和图5所示(化合物IV C 17H 17FN 2O 3 M+H的理论值为317.13，图5中实测值为317.1)。纯度为99.5％(如图3所示)，产率为93％，ee值为99.99％(如图6和图7所示)。
实施例2
除了混合溶剂中包括2000mL叔丁醇和1000mL水，以及催化剂为4-羟基-2,2,6,6,-四甲基哌啶-1-氧自由基，催化剂用量为6.7g以外，其余与实施例1相同。利用LC-MS测试监控反应终点，得到到达反应终点的反应液的LC-MS表征如图8所示，其中11 #峰为目标化合物IV对应的峰，反应液中化合物IV、化合物VII和化合物VIII的含量如表2所示。
对比例1
除了在反应过程中，混合溶剂使用甲苯-水的混合溶剂，甲苯和水的体积比为2∶1.2以外，其余与实施例1相同。利用LC-MS测试监控反应终点，得到到达反应终点的反应液的LC-MS表征如图9所示，其中5 #峰为目标化合物IV对应的峰，反应液中化合物IV、化合物VII和化合物VIII的含量如表2所示。
对比例2
除了在反应过程中，混合溶剂使用乙腈-水的混合溶剂，乙腈和水的体积比为2∶1.2以外，其余与实施例1相同，利用LC-MS测试监控反应终点，得到到达反应终点的反应液的LC-MS表征如图10所示，其中5 #峰为目标化合物IV对应的峰，反应液中化合物IV、化合物VII和化合物VIII的含量如表2所示。
对比例3
除了基于混合溶剂的总体积，在混合溶剂中加入0.3％的叔丁基过氧化氢以外，其余与对比例2相同。不限于任何理论，发明人认为可能是因为叔丁醇作为溶剂有部分被氧化为过氧化物，而生成的过氧化物催化了该氧化反应，使之可以直接氧化至酸。所以在对比例 2的基础上进一步在乙腈中添加了叔丁基过氧化氢，与对比例2相比，反应转化率大大提高。利用LC-MS测试监控反应终点，得到到达反应终点的反应液的LC-MS表征如图11所示，其中2 #峰为目标化合物IV对应的峰，反应液中化合物IV、化合物VII和化合物VIII的含量如表2所示。
表2
Figure PCTCN2022083178-appb-000016
从实施例1、和对比例1和对比例2(原研专利CN104114524B所述溶剂)中可以看出，不同的溶剂对于反应的影响较大，甲苯作为溶剂主要生成的产物是醛，所以原研专利CN104114524B又用了亚氯酸钠来进一步氧化，使用本发明的混合溶剂作为反应溶剂可以直接制备得到酸；同时，原研专利CN104114524B的方法会产生大量含有二氧化氯的废气以及对环境污染的含磷废水，不符合绿色工业的要求。本发明的制备方法不会产生有毒有害的废气以及含磷废水，对环境友好，工艺简单。从对比例2和对比例3能看出，加了微量的叔丁基过氧化氢对反应有了明显的提高，不限于任何理论，发明人认为可能是因为叔丁醇作为溶剂有部分被氧化为过氧化物，而生成的过氧化物催化了该氧化反应，使之可以直接氧化至酸。但是对比例3的反应结果又远不如实施例1好，可以看出通过本发明的制备方法制备莱博雷生中间体，反应工艺简单，对环境友好。
图1示出了本发明实施例1中到达反应终点的反应液的LC-MS谱图中的液相色谱图，其中，液相色谱图的数据报告如下表3：
表3
Figure PCTCN2022083178-appb-000017
Figure PCTCN2022083178-appb-000018
图3示出了本发明实施例1中制备得到的化合物IV的HPLC纯度谱图，其中，HPLC纯度谱图的数据报告如下表4：
表4
Figure PCTCN2022083178-appb-000019
图5示出了本发明实施例制备得到的化合物IV在LC-MS谱图中的质谱图，其中，LC-MS谱图的数据报告如下表5：
表5
保留时间(MS) MS面积 MS的m/z
15.045 57833156 318.10
    317.10
图6示出了本发明实施例1制备得到的化合物IV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6：
表6
Figure PCTCN2022083178-appb-000020
Figure PCTCN2022083178-appb-000021
图8示出了本发明实施例2中中控的LC-MS谱图中的液相色谱图，其中，液相色谱图的数据报告如下表7：
表7
Figure PCTCN2022083178-appb-000022
图9示出了本发明对比例1中中控的LC-MS谱图中的液相色谱图，其中，液相色谱图的数据报告如下表8：
表8
Figure PCTCN2022083178-appb-000023
Figure PCTCN2022083178-appb-000024
图10示出了本发明对比例2中中控的LC-MS谱图中的液相色谱图，其中，液相色谱图的数据报告如下表9：
表9
Figure PCTCN2022083178-appb-000025
图11示出了本发明对比例3中中控的LC-MS谱图中的液相色谱图，其中，液相色谱图的数据报告如下表10：
表10
Figure PCTCN2022083178-appb-000026
Figure PCTCN2022083178-appb-000027
实施例3
Figure PCTCN2022083178-appb-000028
A)将(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(化合物IV)(1.0eq，316g)和2-氰基-2-羟基亚氨基乙酸乙酯(化合物V)(1.05eq，149g)，溶解于10V四氢呋喃(第一反应溶剂)中搅拌，降温至-10℃。分三批加入二异丙基碳二亚胺(化合物VI)(1.5eq，189g)，每批63g，每次间隔20min。加完后于0℃(第一反应温度)一次反应过夜，反应液的LC-MS谱图如图12和图13所示，化合物II在图12中的12b中离子流峰的保留时间＝22.113min，M+H +的理论值为441.15[M+1] +，对应在图13质谱图中的实测值为441.1[M+1] +，而化合物IV的含量小于1％，视为反应结束，此时第一反应时间为18小时。
B)进一步向反应体系内加入反应物2-氨基-5-氟代吡啶(化合物III)(1.03eq，115g)(此时步骤B)的第二反应溶剂也即步骤A)的第一反应溶剂)，升温至15℃(第二反应温度)二次反应，反应一段时间后监测到反应液的LC-MS谱图如图14和图15所示(化合物I在图14中的14b的离子流峰的保留时间＝18.261min，M+H +的理论值为411.16[M+1] +，对应在图15中的15b质谱图中的实测值为411.1[M+1] +)，中间体化合物II的含量小于3％，视为反应结束，此时反应时间为4h(第二反应时间)。将反应液倾倒入3升冰水混合物中，分别用3升和1.5升乙酸异丙酯各提取1次。有机相用1mol/L碳酸钠水溶液500毫升洗涤一次。0.3mol/L盐酸水溶液200毫升洗涤一次。浓缩有机相，用异丙醇溶解旋干。加入1升异丙醇加热至回流，再滴加600毫升正庚烷，放入低温冷循***设置在2h内冷却至55℃，于55℃保温1小时，再设置在5h内冷却至0℃。于0℃保温10h，过滤得到化合物I 307g，收率为75％，纯度为99.86％(如图16所示)，ee值为100％(如图19和图20所示)，化合物I的结构表征如图17和图18所 示。
本发明提供的方法，通过制备Oxyma活性酯中间体即化合物II，可以安全高效的制备莱博雷生，与现有技术相比，本发明的方法制备得到的莱博雷生光学纯度更高，消旋率更低，具有更好的应用前景。同时，本发明的中间体化合物II为Oxyma活性酯中间体，其是一种安全且非***性辅助亲核体，避免了HOBt，HOAt等传统活化剂的***安全隐患(参见Fernando Albericio等人在Chem.Eur.J.2009,15,9394-9403中对于Oxyma的安全性予以评估)。
图16示出了本申请实施例3中制备得到的化合物I的HPLC纯度谱图，其中，HPLC纯度谱图的数据报告如表11：
表11
Figure PCTCN2022083178-appb-000029
图19示出了本申请实施例3中制备得到的化合物I的手性HPLC谱图，其中，手性HPLC谱图的数据报告如表12：
表12
Figure PCTCN2022083178-appb-000030
实施例4至实施例8
实施例4～8参照实施例3中的步骤A)，其不同点在于第一反应溶剂，第一反应温度和/或第一反应时间的差异，详见表13。
实施例4～8中，步骤A)反应18小时(第一反应时间)后，检测反应液中相关物质的含量，结果见表13。
表13
实施例 第一反应溶剂 第一反应温度 化合物IV含量 化合物II含量
实施例4 四氢呋喃 45℃ 90％ 2％
实施例5 四氢呋喃 25℃ 55％ 38％
实施例6 四氢呋喃 -5℃ 0.2％ 97％
实施例7 甲苯 -5℃ 43％ 51％
实施例8 乙腈 -5℃ 4％ 93％
实施例9至实施例13
实施例9～13参考实施例1的步骤B)，其中，实施例9为实施例4的后续反应，实施例10为实施例5的后续反应，实施例11为实施例6的后续反应，实施例12为实施例7的后续反应，实施例13为实施例8的后续反应；其不同点在于步骤B)中第二反应溶剂，第二反应温度和/或第二反应时间的差异，详见表14。
实施例9～13中，步骤B)反应24小时(第二反应时间)后，检测反应液中相关物质的含量，结果见表14。
表14
实施例 第二反应溶剂 第二反应温度 化合物IV含量 化合物II含量 化合物I含量
实施例9 四氢呋喃 -5℃ 7％ 22％ 66％
实施例10 四氢呋喃 10℃ 5％ 2％ 87％
实施例11 四氢呋喃 35℃ 14％ 0.1％ 75％
实施例12 甲苯 10℃ 68％ 5％ 16％
实施例13 乙腈 10℃ 12％ 1％ 79％
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。

Claims (22)

  1. 一种莱博雷生的制备方法，其特征在于包括以下步骤：
    B)化合物II和化合物III在第二反应溶剂中发生反应，得到式I所示的莱博雷生；
    Figure PCTCN2022083178-appb-100001
  2. 根据权利要求1所述的制备方法，其特征在于所述第二反应溶剂选自有机溶剂，所述有机溶剂选自乙腈、二氧六环、乙二醇二甲醚、吡啶、甲苯、乙酸乙酯、四氢呋喃中的至少一种，优选为四氢呋喃或乙腈。
  3. 根据权利要求1或2所述的制备方法，其特征在于所述反应的反应温度为-5℃-40℃，优选为10℃-35℃。
  4. 根据权利要求1-3任一项所述的制备方法，其特征在于所述反应的反应时间为1h-48h，优选12-24h。
  5. 一种如式II所示的化合物：
    Figure PCTCN2022083178-appb-100002
  6. 一种化合物II的制备方法，其特征在于包括以下步骤：
    A)化合物IV、化合物V和化合物VI在第一反应溶剂中发生反应，得到化合物II；
    Figure PCTCN2022083178-appb-100003
  7. 根据权利要求6所述的制备方法，其特征在于所述第一反应溶剂选自有机溶剂，所述有机溶剂选自乙腈、二氧六环、乙二醇二甲醚、吡啶、甲苯、乙酸乙酯、四氢呋喃中的至少一种，优选为四氢呋喃或乙腈。
  8. 根据权利要求6或7所述的制备方法，其特征在于所述反应的反应温度为-15℃-10℃，优选为-10℃-5℃。
  9. 根据权利要求6-8任一项所述的制备方法，其特征在于所述反应的反应时间为1h-48h，优选为4-24h。
  10. 一种化合物IV的制备方法，其特征在于包括以下步骤：
    A)以化合物VII为原料，在催化剂和氧化剂作用下，在叔丁醇和水的混合溶剂中发生氧化反应，生成化合物IV；
    Figure PCTCN2022083178-appb-100004
  11. 根据权利要求10所述的制备方法，其特征在于所述催化剂选自2,2,6,6,-四甲基哌啶-氮-氧化物或4-羟基-2,2,6,6,-四甲基哌啶-1-氧自由基中的至少一种。
  12. 根据权利要求10所述的制备方法，其特征在于所述催化剂的用量为化合物VII的摩尔量的1％-25％。
  13. 根据权利要求10所述的制备方法，其特征在于所述混合溶剂中叔丁醇和水的体积比为4∶1-3∶2。
  14. 根据权利要求10所述的制备方法，其特征在于所述氧化剂为次氯酸钠。
  15. 根据权利要求10所述的制备方法，其特征在于所述氧化剂的用量为化合物VII的摩尔量的2.0eq-5.0eq。
  16. 根据权利要求10所述的制备方法，其特征在于所述氧化反应的pH值范围为6-12。
  17. 根据权利要求10所述的制备方法，其特征在于所述混合溶剂中还加入碳酸氢钠和/或碳酸钠。
  18. 根据权利要求10所述的制备方法，其特征在于所述氧化反应的反应温度为-10℃～45℃，优选为-3℃～3℃。
  19. 根据权利要求10所述的制备方法，其特征在于所述氧化反应的反应时间为1h-96h，优选为1h-24h。
  20. 一种莱博雷生的制备方法，其特征在于包括以下步骤：
    通过如权利要求6～9任一项所述的步骤A)制备得到化合物II；
    通过如权利要求1～4任一项所述的步骤B)制备得到式I所示的莱博雷生；
    Figure PCTCN2022083178-appb-100005
  21. 根据权利要求20所述的制备方法，其特征在于通过如权利要求10～19任一项所述的步骤A)制备得到化合物IV。
  22. 根据权利要求20或21所述的制备方法，其特征在于包括以下步骤：
    步骤A)制备得到化合物II不经分离直接用于步骤B)。
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