[go: up one dir, main page]

WO2022061914A1 - 一种3,5-二卤三氟苯乙酮及其衍生物的制备方法 - Google Patents

一种3,5-二卤三氟苯乙酮及其衍生物的制备方法 Download PDF

Info

Publication number
WO2022061914A1
WO2022061914A1 PCT/CN2020/118495 CN2020118495W WO2022061914A1 WO 2022061914 A1 WO2022061914 A1 WO 2022061914A1 CN 2020118495 W CN2020118495 W CN 2020118495W WO 2022061914 A1 WO2022061914 A1 WO 2022061914A1
Authority
WO
WIPO (PCT)
Prior art keywords
nitrite
solution
reaction
preparation
compound
Prior art date
Application number
PCT/CN2020/118495
Other languages
English (en)
French (fr)
Inventor
张凌霄
蔡刚华
唐宏渊
程锦涛
Original Assignee
台州臻挚生物科技有限公司
浙江江北南海药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 台州臻挚生物科技有限公司, 浙江江北南海药业有限公司 filed Critical 台州臻挚生物科技有限公司
Priority to PCT/CN2020/118495 priority Critical patent/WO2022061914A1/zh
Publication of WO2022061914A1 publication Critical patent/WO2022061914A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/20—Diazonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/825—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups all hydroxy groups bound to the ring

Definitions

  • the application relates to the technical field of chemical pharmacy, in particular to a preparation method of 3,5-dihalogenotrifluoroacetophenone and its derivatives.
  • 3,5-Dihalogen-substituted trifluoroacetophenones are important chemical pharmaceutical intermediates and are often used in the preparation of various drugs for killing harmful organisms.
  • various groups are often required to be modified at the para position of the trifluoroacetyl group.
  • the present application provides a preparation method of 3,5-dihalogenotrifluoroacetophenone and derivatives thereof, which has high yield and low cost, and has the advantages of large-scale application in Prospects for industrial production.
  • the present application provides a method for preparing 3,5-dihalotrifluoroacetophenone and derivatives thereof, the method comprising the steps of:
  • R 1 is selected from one of chlorine, bromine and iodine
  • R 2 is selected from one of chlorine and bromine
  • R 3 is selected from one of hydrogen, fluorine, chlorine, bromine and hydroxyl.
  • Compound I is a by-product commonly used in pharmaceutical production, which can be directly purchased, and is also produced during the production process.
  • Compound IV is obtained by reducing compound I to amino group, ortho-halogenation of amino group and substitution of amino group with diazotization through three steps.
  • the above reaction can not only form a substituent at the 4-position of the benzene ring, but also prepare an unsubstituted 3,5-dihalogenotrifluoroacetophenone, which has a wide range of practicability.
  • no harsh reaction conditions are required, and the dissolution and catalyst used in each step are also conventional solvents and catalysts.
  • the production cost is low and the conditions are mild, and can be used in industrial production.
  • the solvent I is selected from at least one or a homogeneous mixed system formed by at least one of the following substances: methanol, ethanol, ethyl acetate, n-butyl acetate, isopropyl acetate, isopropanol , Toluene.
  • R 1 and R 2 are chlorine
  • the halogenated reagent is selected from one of chlorine, sulfonyl chloride, trichloroisocyanuric acid, and NCS.
  • R 3 is a hydrogen atom
  • S 3 specifically includes the following steps:
  • the nitrous acid reagent is selected from one of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite and C1-C6 alkyl nitrite, and the solvent III is selected from toluene, ethanol, One of isopropanol, or a homogeneous system formed by any number of toluene, ethanol, and isopropanol.
  • R 3 is a chlorine atom
  • S 3 specifically includes the following steps:
  • step S3-2-2 prepare a hydrochloric acid solution of cuprous chloride, heat up and mix thoroughly, add the intermediate reaction solution II prepared in step S3-2-1 into the above system, and separate the system after fully reacting and keep the organic phase , dried and distilled under reduced pressure to obtain compound IV;
  • the nitrous acid reagent is selected from one of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite, and C1-C6 alkyl nitrite.
  • R 3 is chlorine
  • the amino group is first acidified with hydrochloric acid to form a salt.
  • hydrochloric acid can make the chloride ion concentration in the system higher, thereby preventing the amino group from being hydrolyzed into phenol or reduced to hydrogen on the benzene ring.
  • the chloride ion replaces the diazo group, so as to realize the chlorination process of the amino group.
  • the acidic system formed by hydrochloric acid and cuprous chloride solution it is helpful to improve the reaction rate and reaction balance, without harsh reaction conditions, and the three wastes treatment is relatively simple, suitable for industrial large-scale production, and has better economic effect.
  • R 3 is a fluorine atom
  • S 3 specifically includes the following steps:
  • the nitrous acid reagent is selected from one of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite, and C1-C6 alkyl nitrite.
  • the reaction system can be rapidly cooled after adding a quenching agent, thereby terminating the reaction, reducing the occurrence of side reactions, and improving the safety of the reaction.
  • the quencher can be further configured as: the quencher is a mixed solution formed by diethyl ether and water in a volume ratio of (0.8-2.5):1.
  • water and ether are selected as quenching agents.
  • Water has a large specific heat capacity, which can quickly cool the system, thereby reducing the occurrence of side reactions.
  • Diethyl ether has a certain miscibility with water, which helps the water to be more uniformly dispersed in the organic solvent, so that the water can realize the process of rapid cooling, so that the reaction can be stopped quickly.
  • diethyl ether can also make water more fully dissolve water-soluble impurities in the organic solvent, which is beneficial to the subsequent separation step.
  • R 3 is a bromine atom
  • S 3 specifically includes the following steps:
  • the nitrous acid reagent is selected from one of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite, and C1-C6 alkyl nitrite
  • the solvent VI is selected from toluene, ethanol, Any one of isopropanol, or a homogeneous mixed system formed by any of them.
  • the amino group is diazotized by hydrobromic acid, and other negative ions will not be introduced into the system, which helps to reduce the occurrence of side reactions.
  • the temperature is raised to 60-80°C, which is conducive to the rapid and smooth progress of the reaction and the rapid discharge of nitrogen gas from the solution.
  • the purity and yield of the obtained target product are high, and the impurities are all water-soluble impurities, which are easy to remove, and have good economic effects and industrial application prospects.
  • R 3 is a hydroxyl group
  • S 3 specifically includes the following steps:
  • the nitrite reagent is selected from the group consisting of sodium nitrite, potassium nitrite, calcium nitrite, barium nitrite, silver nitrite, and C1-C6 alkyl nitrite.
  • the intermediate reaction solution IV is added dropwise to the acidified copper sulfate solution, and the amino group is hydrated into a hydroxyl group under the catalysis of copper ions, and sulfuric acid is used for catalysis in the process, which helps to reduce the occurrence of side reactions.
  • the use of concentrated sulfuric acid will make the sulfate ion less in the system and the hydrogen sulfate concentration increase, which helps to further reduce the reaction of carbocation with other groups except water after the diazo group is removed. The phenomenon occurs, the yield of the reaction and the purity of the target product are improved, and the economic effect is further improved.
  • the present application can be further configured as: the nitrous acid reagent is sodium nitrite or potassium nitrite.
  • sodium nitrite and potassium nitrite have good water solubility, and have low solubility in the organic phase during post-processing, and are easy to separate, which simplifies the separation process.
  • Embodiments 1-16 all relate to the preparation method of 3,5-dihalo-trifluoroacetophenone, comprising the following steps:
  • Step S1 is as follows: take 0.5 mol (127 g) of compound I, dissolve it in 300 m absolute ethanol (solvent I) in a reaction kettle, and add 5.0 g of 5% platinum-carbon catalyst as a catalyst. The inside of the reaction kettle was fully replaced with nitrogen to remove air, and then hydrogen was introduced. After repeated replacement three times, hydrogen was continued to be introduced and stirring was started. During the reaction, the pressure of hydrogen was maintained at 0.1Mpa, and the temperature was controlled at 40°C. After the reaction was completed, the above reaction solution was lowered to room temperature and filtered. After the filtrate was evaporated to dryness with ethanol, 150.0 ml of toluene was added, the temperature was raised to 40° C. and fully stirred to dissolve the system into a clear and transparent solution, and then the temperature was lowered to -20° C. Set to crystallize, filter and keep the filter cake without drying to obtain compound II.
  • Step S2 is as follows, take 0.2 mol (44.7 g) of compound I obtained in step S1, dissolve it in 200 mL of toluene, heat it up to 50° C., stir well until the solution is clear, and then weigh 33.7 g of sulfonyl chloride (0.25 mol) as halogen. Substitute the reagent and complete the dropwise addition within 90 min. After the dropwise addition, the reaction was continued for 8 h, then cooled to 20 °C naturally, rinsed with 200 mL of water, retained the organic phase, and evaporated to dryness to obtain compound III.
  • Step S3 specifically includes the following steps:
  • the above process The temperature of the control system is lower than 0 °C, and the reaction is continued for 1 h after the dropwise addition; after the reaction is completed, 87 g of sodium nitrite solution with a mass fraction of 33% (containing 0.41 mol of sodium nitrite) is added dropwise to the system within 30 minutes as a nitration reagent , and keep the temperature of the system below 0°C during the dropwise addition, and keep the reaction for 2h after the dropwise addition to obtain the intermediate reaction solution I;
  • the intermediate reaction solution was heated to 20°C, 83.0 g of 50% hypophosphorous acid was added, and 0.5 g of cuprous oxide was added, and the reaction was kept for 2 h. After the reaction, the layers were separated and 5% aqueous sodium bicarbonate solution was used The organic layer was washed and adjusted to neutral pH, the organic phase was dried over anhydrous magnesium sulfate, and the compound 3,5-dichloro-trifluoroacetophenone was obtained after distillation under reduced pressure.
  • Step S2 is specifically as follows:
  • step S1 Take 0.2 mol (44.7 g) of compound I obtained in step S1, dissolve it in 150 mL of chloroform, raise the temperature to 70°C, dissolve 0.22 mol of NBS (39.2 g) and 0.02 mol of AIBN (3.3 g) in 50 mL of chloroform, and add it within 30 min.
  • the reaction was incubated for 2 h, 100 mL of sodium hydroxide solution was added for quenching and the system was lowered to room temperature, and the organic phase was separated and obtained, and the solvent was evaporated to obtain compound II.
  • Step S2 is specifically as follows:
  • step S1 Take 0.2 mol (53.4 g) of compound I obtained in step S1, dissolve it in 150 mL of chloroform, raise the temperature to 70°C, dissolve 0.22 mol of NBS (39.2 g) and 0.02 mol of AIBN (3.3 g) in 50 mL of chloroform, and add it within 30 min. After the dropwise addition, the reaction was incubated for 2 hours, 100 mL of 5% sodium hydroxide solution was added for quenching, and the system was cooled to room temperature. The organic phase was separated and the solvent was evaporated to obtain compound II.
  • step S2 is as follows:
  • step S2 Take 0.2 mol (44.7 g) of compound I obtained in step S1, dissolve it in 200 mL of acetonitrile, stir at room temperature until the solution is clear, then weigh 30.7 g of NCS (0.23 mol) as a halogenated reagent, heat to reflux and react for 2 h, After the reaction, the solvent was concentrated and dried to obtain compound III.
  • step S2 is as follows:
  • step S1 Take 0.2 mol (44.7 g) of compound I obtained in step S1, dissolve it in 500 mL of glacial acetic acid, heat up to 40 ° C, slowly introduce 17.04 g of chlorine gas (0.24 mol) in 3 h to react and monitor until the raw material point disappears, continue Nitrogen was introduced to remove excess chlorine and hydrogen chloride. After suction filtration, the filter cake was washed twice with glacial acetic acid and dried under vacuum at 60°C to obtain compound III.
  • a preparation method of 3,5-dihalogenotrifluoroacetophenone is different from Example 1 in that, in step S1, an equal amount of 5% palladium carbon is used as a catalyst.
  • a preparation method of 3,5-dihalogenotrifluoroacetophenone is different from Example 1 in that, in step S1, an equivalent amount of Raney nickel is selected as a catalyst.
  • a preparation method of 3,5-dihalogenotrifluoroacetophenone, the difference from Example 1 is that in step S1, the hydrogen pressure is 1.0 mPa, and the reaction temperature is 50°C.
  • step S1 A preparation method of 3,5-dihalogenotrifluoroacetophenone, the difference from Example 1 is that in step S1, solvent I is selected from toluene.
  • a preparation method of 3,5-dihalogenotrifluoroacetophenone, the difference from Example 1 is that in step S3, solvent III is a mixed solvent formed by ethanol and isopropanol in a volume ratio of 1:1.
  • a preparation method of 3,5-dihalogenotrifluoroacetophenone, the difference from Example 1 is that in step S3, the nitrous acid reagent is prepared with potassium nitrite in an equivalent amount and the mass fraction obtained is 30% of aqueous solution.
  • a preparation method of 3,5-dihalogenotrifluoroacetophenone, the difference from Example 1 is that, in step S3, the nitrous acid reagent selects methyl nitrite in an equivalent amount.
  • a preparation method of 3,5-dihalogenotrifluoroacetophenone, the method in embodiment 8 is carried out amplifying treatment, wherein the usage amount of each substance is 10 times of the usage amount in embodiment 8, other conditions and Example 8 remains the same.
  • a preparation method of 3,5-dihalogenotrifluoroacetophenone, the method in embodiment 5 is carried out amplifying treatment, wherein the usage amount of each material is 10 times of the usage amount in embodiment 5, other conditions and Example 5 remains the same.
  • step S1 using palladium carbon and Raney nickel can improve the conversion rate of raw materials, adding The high hydrogen pressure also helps to improve the conversion of the feedstock.
  • R 1 and R 2 can be reasonably selected from halogen, and when the electron donating ability of R 1 and R 2 is enhanced, the yields of steps S1, S2 and S3 are all improved.
  • step S3 when calcium nitrite is selected as the nitroso reagent, the yield of step S3 will be slightly reduced, and the use of methyl nitrite will help to improve the yield of S3.
  • methyl nitrite has good oil solubility, and is likely to remain in the system during final separation, which will lead to a decrease in the purity of the final product.
  • Example 16 and Example 17 carried out a large-scale reaction, and the reaction yield and purity did not change significantly, which proved that the above method has the potential for industrial production and has a good industrial application prospect.
  • step S3 is as follows: S3-2-1, take 51.6g (0.2mol) of compound III, add 300mL of concentrated hydrochloric acid was heated to 60°C, stirred for 1h, then cooled to -10°C, and 50.3g of sodium nitrite (nitrous acid reagent) solution with a content of 33% was added dropwise within one hour (containing 0.24mol of sodium nitrite), After the dropwise addition, the reaction was continued for 30 min to obtain intermediate reaction solution II;
  • step S3-2-2 Weigh 29.7 g of cuprous chloride and dissolve it in 300 mL of hydrochloric acid to prepare a hydrochloric acid solution of cuprous chloride, heat up to 60°C and stir for 1 h, and then add the intermediate prepared in step S3-2-1.
  • the reaction solution II was evenly added dropwise to the above-mentioned cuprous chloride hydrochloric acid solution within 1 h. After the dropwise addition, the reaction was continued for 1 h and cooled to room temperature, extracted twice with dichloromethane, and the organic phases were combined, dried with sewage magnesium chloride, and reduced pressure. The solvent is distilled to obtain compound IV in which R3 is chlorine.
  • step S3 is as follows:
  • step S3-2-2 Weigh 29.7 g of cuprous chloride and dissolve it in 300 mL of hydrochloric acid to prepare a hydrochloric acid solution of cuprous chloride, heat up to 60°C and stir for 1 h, and then add the intermediate prepared in step S3-2-1.
  • the reaction solution II was evenly added dropwise to the above-mentioned cuprous chloride hydrochloric acid solution within 1 h. After the dropwise addition, the reaction was continued for 1 h and cooled to room temperature, extracted twice with dichloromethane, and the organic phases were combined, dried with sewage magnesium chloride, and reduced pressure. The solvent is distilled to obtain compound IV in which R3 is chlorine.
  • a preparation method of 3,5-dihalo-trifluoroacetophenone derivatives the difference from Example 18 is that the method in step S18 is processed in an enlarged amount, wherein, step S1 and step S2 are the same as the embodiment Steps S1 and S2 in Step 16 are the same, and the amount of each material used in Step S3 is 10 times the amount used in Step S3 in Example 18, and other conditions are the same as in Example 18.
  • a preparation method of a 3,5-dihalo-trifluoroacetophenone derivative the difference from Example 19 is that the method in step S19 is processed in an enlarged amount, wherein step S1 and step S2 are the same as those in Example 19. Steps S1 and S2 in 17 are the same, the amount of each material used in step S3 is 10 times the amount used in step S3 in embodiment 19, and other conditions are the same as in embodiment 19.
  • step S3 is as follows:
  • compound IV is 3,5-dichloro-4-bromotrifluoroacetophenone.
  • a preparation method of 3,5-dihalo-trifluoroacetophenone derivatives is subjected to a large amount of processing, wherein, step S1 and step S2 are the same as those in embodiment 22, and each step in step S3 is the same as that of embodiment 22.
  • the amount of material used is 10 times the amount used in step S3 in Example 24, and the remaining conditions are the same as in Example 24.
  • a kind of preparation method of 3,5-dihalogen-trifluoroacetophenone derivative the difference with embodiment 24 is, in step S3-4-1, solvent IV selects the ethanol and isopropyl alcohol that the volume ratio is 0.4:1 Propanol blend system.
  • step S3 is as follows:
  • the intermediate reaction solution III was heated to 60°C and continued to react for 3 hours, 200 mL of quenching agent was added, and the quenching agent was a mixed solution formed by mixing ether and water in a volume of 1.6:1, and the organic layer was obtained by separation, and washed with saturated sodium chloride solution, eluted with 200 mL of toluene, and dried to obtain compound IV.
  • a preparation method of 3,5-dihalo-trifluoroacetophenone derivatives, the difference from Example 27 is that in step S3-2-2, the quenching agents are: ether and water in a ratio of 0.8:1
  • the mixed solution formed by the volume ratio of ether and water is the mixed solution formed by the volume ratio of 2.5:1, ether and water.
  • a preparation method of 3,5-dihalo-trifluoroacetophenone derivatives, the method in Example 27 has been processed in a large amount, wherein, step S1 and step S2 are the same as those in embodiment 22, and each step in step S3 is the same as that of embodiment 22.
  • the amount of materials used is 10 times the amount used in step S3 of Example 33, and the remaining conditions are the same as those of Example 27.
  • step S3 is as follows:
  • step S3-5-2 take 71.5g anhydrous copper sulfate (0.286mol), add 123.5g pure water to prepare a copper sulfate solution, then add 52.7g concentrated sulfuric acid dropwise to acidify, stir evenly and heat up to 110°C to reflux the above solution , the intermediate reaction solution V obtained in step S3-5-1 is added dropwise to the above solution, the product is steamed while the dropwise addition is made, and the volume is kept constant, and the steamed product is extracted with dichloromethane and then merged with the organic phase, Drying gave compound IV.
  • compound IV is 3,5-dichloro-4-hydroxytrifluoroacetophenone.
  • Embodiment 34 a preparation method of 3,5-dihalo-trifluoroacetophenone derivatives, the method in embodiment 33 is amplified, wherein, step S1 and step S2 are the same as embodiment 22, step In S3, the usage amount of each material is 10 times the amount used in step S3 of Example 33, and the remaining conditions are the same as those of Example 33.
  • the comparative example is set as follows.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本申请涉及化工制药的技术领域，尤其是涉及一种3,5-二卤三氟苯乙酮及其衍生物的制备方法，以3-卤素-4-硝基三氟苯乙酮为原料，经过还原反应、卤代反应和氨基取代反应，最终得到3,5-二卤三氟苯乙酮的衍生物，其原料便宜易得，工艺简单，条件温和，具有大规模生产的前景，具有较好的经济效应。

Description

一种3,5-二卤三氟苯乙酮及其衍生物的制备方法 技术领域
本申请涉及化工制药的技术领域，尤其是涉及一种3,5-二卤三氟苯乙酮及其衍生物的制备方法。
背景技术
3,5-二卤取代的三氟苯乙酮类化合物是一种重要的化学制药中间体，常用于制备各种用于杀灭有害生物的药物。出于药物改性和修饰的目的，常需要在三氟乙酰基的对位上进行各种基团的修饰。
由于三氟乙酰基和卤原子均为强吸电子基团，因此三氟乙酰基的对位反应较难发生，目前尚缺少一种制备4位取代的一种3,5-二卤三氟苯乙酮及其衍生物的制备方法。
发明内容
针对现有技术存在的不足，本申请提供了一种3,5-二卤三氟苯乙酮及其衍生物的制备方法，具有较高的产率和较低的成本，具有大规模运用于工业生产的前景。
在一个实施方案中，本申请提供了一种3,5-二卤三氟苯乙酮及其衍生物的制备方法，所述方法包括如下步骤：
S1、将化合物Ⅰ经过还原反应，得到化合物Ⅱ；
S2、将化合物Ⅱ通过卤代反应，得到化合物Ⅲ；
S3、将化合物Ⅲ通过氨基取代反应，得到化合物Ⅳ；
Figure PCTCN2020118495-appb-000001
Figure PCTCN2020118495-appb-000002
其中，R 1选自氯、溴、碘中的一种，R 2选自氯、溴中的一种，R 3选自氢、氟、氯、溴、羟基中的一种。
化合物Ⅰ是一种药物生产中常用的副产物，可直接购买得到，在进行生产过程中也均有产出。对化合物Ⅰ经硝基还原至氨基、氨基邻位卤代、氨基重氮化取代三步，制得化合物Ⅳ。上述反应既可以在苯环的4位上形成取代基，也可以制备无取代基的3,5-二卤三氟苯乙酮，具有较为广泛的实用性。且在上述过程中，无需使用苛刻的反应条件，各个步骤中使用的溶解和催化剂也均为常规溶剂和催化剂，其生产成本较低，条件温和，可运用于工业生产。
本申请在一较佳示例中可以进一步配置为：所述步骤S1中，将化合物Ⅰ溶解于溶剂Ⅰ中，采用铂碳、钯碳、Raney镍中的一种作为催化剂，在氢气作用下对硝基进行还原。在一个实施方案中，溶剂Ⅰ选自以下物质中的至少一种或两种及以上形成的均相混合体系：甲醇、乙醇、乙酸乙酯、乙酸正丁酯、乙酸异丙酯、异丙醇、甲苯。
本申请在一较佳示例中可以进一步配置为：R 1、R 2为氯，在步骤S2中卤代试剂选自氯气、磺酰氯、三氯异氰尿酸、NCS中的一种。
本申请在一较佳示例中可以进一步配置为：R 3为氢原子，S3具体包括如下步骤：
S3-1-1、将化合物Ⅲ溶解于溶剂Ⅲ中，并降温至-10～0℃，加入硫酸酸化后，滴加亚硝酸试剂溶液使氨基重氮化，充分反应得到中间反应液Ⅰ；
S3-1-2、将中间反应液Ⅰ升温至20～30℃，并加入次磷酸溶液和氧化亚铜，继续反应至完全，随后用碱性无机盐溶液洗涤并保留有机相，干燥后即得到化合物Ⅳ；
其中，亚硝酸试剂选自亚硝酸钠、亚硝酸钾、亚硝酸钙、亚硝酸钡、亚硝酸银、亚硝酸C1～C6烷基酯中的一种，所述溶剂Ⅲ选自甲苯、乙醇、异丙醇中的一种，或甲苯、乙醇、异丙醇中任意数种形成的均相体系。
在上述技术方案中，反应过程中副反应较少，且体系中产生的杂质均能较好地溶解于水中，在后续分离时，加水萃取即可快速完成除杂工作，生产成本较低，产率较高，具有良好的经济效应。
本申请在一较佳示例中可以进一步配置为：R 3为氯原子，S3具体包括如下步骤：
S3-2-1、将化合物Ⅲ加入到盐酸进行酸化，酸化完毕后加入亚硝酸试剂溶液使氨基重氮化，反应完全后得到中间反应液Ⅱ；
S3-2-2、配制氯化亚铜的盐酸溶液，升温并充分混合后将步骤S3-2-1中制得的中间反应液Ⅱ加入上述体系中，充分反应后对体系分离并保留有机相、干燥并减压蒸馏，得到化合物Ⅳ；
其中，亚硝酸试剂选自亚硝酸钠、亚硝酸钾、亚硝酸钙、亚硝酸钡、亚硝酸银、亚硝酸C1～C6烷基酯中的一种。
当R 3为氯时，先通过盐酸对氨基进行酸化成盐，此时使用盐酸可以使体系内的氯离子浓度较高，从而抑制氨基脱离后苯环上水解成酚或被还原为氢。随后通过亚铜离子的催化，使氯离子替换重氮基团，从而实现氨基的氯代过程。在该过程中，在盐酸和氯化亚铜溶液形成的酸性体系中，有助于提高反应速率和反应平衡，无需苛刻的反应条件，三废处理也较为简单，适用于工业大规模生产，且具有较好的经济效应。
本申请在一较佳示例中可以进一步配置为：R 3为氟原子，S3具体包括如下步骤：
S3-3-1、将化合物Ⅲ溶解于含有氟化氢的吡啶溶液中，控制温度为-5～5℃，充分混合并使氨基和氟化氢成盐后加入亚硝酸试剂溶液使氨基重氮化，反应完全后得到中间反应液Ⅲ；
S3-3-2、将中间反应液Ⅲ升温至60～90℃并继续反应，充分反应后，加入淬灭剂，洗涤干燥并进一步分离后得到化合物Ⅳ；
其中，亚硝酸试剂选自亚硝酸钠、亚硝酸钾、亚硝酸钙、亚硝酸钡、亚硝酸银、亚硝酸C1～C6烷基酯中的一种。
升温反应完毕后，加入淬灭剂后可以快速对反应体系进行降温，从而终止反应，减少副反应发生，并提高反应的安全性。
本申请在一较佳示例中可以进一步配置为：所述淬灭剂为乙醚和水以(0.8～2.5):1的体积比形成的混合液。
在上述技术方案中，选用水和乙醚作为淬灭剂。水具有较大的比热容，可以使体系快速冷却，从而降低副反应的发生。乙醚与水有一定的混溶性，有助于水在有机溶剂中更加均匀地分散，使水可以实现快速降温的过程，从而使反应快速停止。另外，乙醚也可以使水可以更加充分地溶解有机溶剂中的水溶性杂质，有利于后续的分离步骤。
本申请在一较佳示例中可以进一步配置为：R 3为溴原子，S3具体包括如下步骤：
S3-4-1、将化合物Ⅲ溶解于溶剂Ⅵ中，升温后加入氢溴酸并充分反应，随后降温至-10～0℃并滴加亚硝酸试剂溶液，充分反应使氨基重氮化，得到中间反应液Ⅳ；
S3-4-2、向中间反应液Ⅳ中加入溴化亚酮，随后升温至60～80℃，继续充分反应，随后萃取、保留有机相并进一步分离得到化合物Ⅵ；
其中，亚硝酸试剂选自亚硝酸钠、亚硝酸钾、亚硝酸钙、亚硝酸钡、亚硝酸银、亚硝酸C1～C6烷基酯中的一种，所述溶剂Ⅵ选自甲苯、乙醇、异丙醇中的任意一种，或其中任意多种形成的均相混合体系。
通过氢溴酸使氨基重氮化，体系中不会引入其他负离子，有助于减少副反应的发生。在溴代过程中，升温至60～80℃，有利于反应快速顺利进行，并使氮气快速排出溶液中。另外，在该温度范围下副反应较少，得到目标产物的纯度和产率均较高，杂质均为水溶性杂质，方便去除，具有较好的经济效应和工业化运用前景。
本申请在一较佳示例中可以进一步配置为：R 3为羟基，S3具体包括如下步骤：
S3-5-1、将硫酸水溶液升温至80℃，并加入化合物Ⅲ，充分反应后，降温至0℃并加入亚硝酸试剂溶液，使氨基重氮化，得到中间反应液Ⅴ；
S3-5-2、配制硫酸铜溶液，并加入浓硫酸酸化，升温至110℃，将中间反应液Ⅴ滴加至上述溶液中，将产品蒸出，并提纯干燥，得到化合物Ⅳ；
亚硝酸试剂选自亚硝酸钠、亚硝酸钾、亚硝酸钙、亚硝酸钡、亚硝酸银、亚硝酸C1～C6烷基酯中的一种。
上述技术方案中，将中间反应液Ⅳ滴加入酸化的硫酸铜溶液中，在铜离子的催化下使氨基被水化为羟基，在过程中使用硫酸催化，有助于减少副反应的发生。此外，在上述反应中，使用浓硫酸会使体系中硫酸根离子少而硫酸氢根的浓度增大，有助于进一步降低重氮基团脱离后碳正离子与除水以外的其他基团反应的现象发生，提高该反应的收率和目标产物的纯度，进一步提高经济效应。
本申请在一较佳示例中可以进一步配置为：所述亚硝酸试剂为亚硝酸钠或亚硝酸钾。
在上述技术方案中，亚硝酸钠和亚硝酸钾具有良好的水溶性，后处理时在有机相中溶解性较小，容易分离，简化了分离的工艺。
具体实施方式
实施例1～16均涉及3,5-二卤-三氟苯乙酮的制备方法，包括如下步骤：
S1、将化合物Ⅰ经过还原反应，得到化合物Ⅱ；
S2、将化合物Ⅱ通过卤代反应，得到化合物Ⅲ；
S3、将化合物Ⅲ通过氨基取代反应，得到化合物Ⅳ；
Figure PCTCN2020118495-appb-000003
实施例1
一种3,5-二卤-三氟苯乙酮的制备方法，R 1和R 2均为氯。
步骤S1具体如下：取化合物Ⅰ0.5mol(127g)，在反应釜内溶解于300m无水乙醇(溶剂Ⅰ)中，加入5％铂碳催化剂5.0g作为催化剂。反应釜内先用氮气充分置换除去空气，再通入氢气，反复置换三次后，继续通入氢气并开启搅拌。反应过程中氢气的压力维持于0.1Mpa，控制温度为40℃。反应结束后，将上述反应液降至室温并过滤，滤液经将乙醇蒸干后，加入甲苯150.0ml，升温至40℃并充分搅拌使体系溶解为澄清透明溶液，再降温至-20℃，静置结晶，过滤保留滤饼没干燥后得到化合物Ⅱ。
步骤S2具体如下，取步骤S1中得到的化合物Ⅰ0.2mol(44.7g)，溶解于200mL甲苯中，升温至50℃，充分搅拌直至溶液澄清，随后称取33.7g磺酰氯(0.25mol)作为卤代试剂并在90min内滴加完毕，滴加完毕后继续保温反应8h，随后自然降温至20℃，加水200mL漂洗，保留有机相，蒸干后得到化合物Ⅲ。
步骤S3具体包括如下步骤：
S3-1-1、取步骤S2中得到的化合物Ⅲ0.19mol(49.1g)溶解于150mL甲苯中，降温至-10℃，在30min内向体系中滴加浓度为92.5％的浓硫酸80g，上述过程中控制体系温度低于0℃，滴加完毕后继续反应1h；反应完毕后，在30min内向体系中滴加质量分数为33％的亚硝酸钠溶液87g(含亚硝酸钠0.41mol)作为硝化试剂，并在滴加过程中并保持体系温度低于0℃，滴加完毕后保温反应2h，得到中间反应液Ⅰ；
S3-1-2，将中间反应液升温至20℃，加入50％的次磷酸83.0g，并加入0.5g氧化亚铜，保温反应2h，反应结束后分层并使用5％的碳酸氢钠水溶液清洗有机层并调剂pH至中性，通过无水硫酸镁对有机相进行干燥，减压蒸馏后得到化合物3,5-二氯-三氟苯乙酮。
实施例2
一种3,5-二卤-三氟苯乙酮的制备方法，与实施例1的区别在于，化合物Ⅰ选用等物质的量的3-溴-4-氨基-三氟苯乙酮。
实施例3
一种3,5-二卤-三氟苯乙酮的制备方法，与实施例1的区别在于，化合物Ⅰ选用等物质的量的3-碘-4-氨基-三氟苯乙酮。
实施例4
一种3,5-二卤三氟苯乙酮的制备方法，与实施例1的区别在于，R 2为溴。步骤S2具体如下：
取步骤S1中得到的化合物Ⅰ0.2mol(44.7g)，溶解于150mL氯仿中，升温至70℃，将0.22molNBS(39.2g)和0.02molAIBN(3.3g)溶解于50mL氯仿中，在30min内加入到体系中，滴加完毕后保温反应2h，加入100mL氢氧化钠溶液进行淬灭并使体系降至室温，分离得到有机相，蒸干溶剂后得到化合物Ⅱ。
实施例5
一种3,5-二卤三氟苯乙酮的制备方法，与实施例2的区别在于，R 2为溴。步骤S2具体如下：
取步骤S1中得到的化合物Ⅰ0.2mol(53.4g)，溶解于150mL氯仿中，升温至70℃，将0.22molNBS(39.2g)和0.02molAIBN(3.3g)溶解于50mL氯仿中，在30min内加入到体系中，滴加完毕后保温反应2h，加入100mL质量分数为5％的氢氧化钠溶液进行淬灭并使体系降至室温，分离得到有机相，蒸干溶剂后得到化合物Ⅱ。
实施例6
一种3,5-二卤三氟苯乙酮的制备方法，与实施例1的区别在于，步骤S2具体如下：
S2、取步骤S1中得到的化合物Ⅰ0.2mol(44.7g)，溶解于200mL乙腈，室温搅拌直至溶液澄 清，随后称取30.7gNCS(0.23mol)作为卤代试剂投入，加热至回流并反应2h，反应结束后浓缩溶剂并烘干，得到化合物Ⅲ。
实施例7
一种3,5-二卤三氟苯乙酮的制备方法，与实施例1的区别在于，步骤S2具体如下：
取步骤S1中得到的化合物Ⅰ0.2mol(44.7g)，溶解于500mL冰醋酸，升温至40℃，在3h内缓慢通入17.04g氯气(0.24mol)反应并点板监测直至原料点消失，继续通入氮气除去多余的氯气和氯化氢，抽滤后滤饼用冰醋酸洗涤两次，在60℃下真空干燥，得到化合物Ⅲ。
实施例8
一种3,5-二卤三氟苯乙酮的制备方法，与实施例1的区别在于，在步骤S1中，选用等量5％钯碳作为催化剂。
实施例9
一种3,5-二卤三氟苯乙酮的制备方法，与实施例1的区别在于，在步骤S1中，选用等量Raney镍作为催化剂。
实施例10
一种3,5-二卤三氟苯乙酮的制备方法，与实施例1的区别在于，在步骤S1中，氢气压力为1.0mPa，反应温度为50℃。
实施例11
一种3,5-二卤三氟苯乙酮的制备方法，与实施例1的区别在于，在步骤S1中，溶剂Ⅰ选用甲苯。
实施例12
一种3,5-二卤三氟苯乙酮的制备方法，与实施例1的区别在于，在步骤S3中，溶剂Ⅲ为乙醇和异丙醇以体积比1:1形成的混合溶剂。
实施例13
一种3,5-二卤三氟苯乙酮的制备方法，与实施例1的区别在于，在步骤S3中，亚硝酸试剂选用等物质的量的亚硝酸钾配制得到的质量分数为30％的水溶液。
实施例14
一种3,5-二卤三氟苯乙酮的制备方法，与实施例1的区别在于，在步骤S3中，亚硝酸试剂选用等物质的量的亚硝酸甲酯。
实施例15
一种3,5-二卤三氟苯乙酮的制备方法，与实施例1的区别在于，在步骤S3中，亚硝酸试剂为 等物质的量的亚硝酸钙，亚硝酸钙配制成质量分数35％的水溶液加入。
实施例16
一种3,5-二卤三氟苯乙酮的制备方法，对实施例8中的方法进行放大量处理，其中各物质的使用量均为实施例8中使用量的10倍，其他条件与实施例8保持一致。
实施例17
一种3,5-二卤三氟苯乙酮的制备方法，对实施例5中的方法进行放大量处理，其中各物料的使用量均为实施例5中使用量的10倍，其他条件与实施例5保持一致。
通过实施例1～17中的方法生产3,5-二卤-三氟苯乙酮，其产率和纯度如表1所示。
Figure PCTCN2020118495-appb-000004
其中，以实施例1为例，最终得到产物核磁数据为1H-NMR(360MHz,CDCl 3):δ＝7.7(s,1H),7.9(s,2H)。
通过上述实验数据可知，通过本申请中的方法可以实现3,5-二卤-三氟苯乙酮的制备，其中，在步骤S1中，使用钯碳和Raney镍能够提高原料的转化率，加大氢气的压强也有助于提高原料的转化率。R 1和R 2可以在卤素中合理选择，且当R 1、R 2的给电子能力增强时，对步骤S1、S2和S3的产率均有提升的效果。
在步骤S3中，选用亚硝酸钙作为亚硝基试剂时，会稍稍降低步骤S3的产率，而采用亚硝酸甲酯则有助于提升S3的产率。但是亚硝酸甲酯油溶性较好，在最后分离时容易残留于体系中，因此会导致最终产物纯度降低。
实施例16和实施例17进行了放大量的反应，其反应产率和纯度均没有明显的改变， 证明了上述方法具有进行工业化生产的潜质，具有较好的工业运用前景。
实施例18
一种3,5-二卤-三氟苯乙酮衍生物的制备方法，与实施例8的区别在于，步骤S3具体如下：S3-2-1、取化合物Ⅲ51.6g(0.2mol)，加入300mL浓盐酸，升温至60℃，搅拌1h，随后降温至-10℃，一小时内均匀滴加含量为33％的亚硝酸钠(亚硝酸试剂)溶液50.3g(含亚硝酸钠0.24mol)，滴加完毕后继续反应30min，得到中间反应液Ⅱ；
S3-2-2、称取29.7g氯化亚铜溶解于300mL盐酸中配制呈氯化亚铜的盐酸溶液，升温至60℃并搅拌1h，之后将步骤S3-2-1中制得的中间反应液Ⅱ在1h内均匀滴加到上述氯化亚铜盐酸溶液中，滴加完毕后继续保温反应1h降温至室温，用二氯甲烷萃取两次，合并有机相，并用污水氯化镁干燥，减压蒸馏溶剂，得到化合物Ⅳ，化合物Ⅳ中R 3为氯。
实施例19
一种3,5-二卤-三氟苯乙酮衍生物的制备方法，与实施例5的区别在于，步骤S3具体如下：
S3-2-1、取化合物Ⅲ69.4g(0.2mol)，加入300mL浓盐酸，升温至60℃，搅拌1h，随后降温至-10℃，一小时内均匀滴加含量为33％的亚硝酸钠(亚硝酸试剂)溶液50.3g(含亚硝酸钠0.24mol)，滴加完毕后继续反应30min，得到中间反应液Ⅱ；
S3-2-2、称取29.7g氯化亚铜溶解于300mL盐酸中配制呈氯化亚铜的盐酸溶液，升温至60℃并搅拌1h，之后将步骤S3-2-1中制得的中间反应液Ⅱ在1h内均匀滴加到上述氯化亚铜盐酸溶液中，滴加完毕后继续保温反应1h降温至室温，用二氯甲烷萃取两次，合并有机相，并用污水氯化镁干燥，减压蒸馏溶剂，得到化合物Ⅳ，化合物Ⅳ中R 3为氯。
实施例20
一种3,5-二卤-三氟苯乙酮衍生物的制备方法，与实施例18的区别在于，在步骤S3中，在步骤S3中，亚硝酸试剂选用等物质的量的亚硝酸甲酯。
实施例21
一种3,5-二卤-三氟苯乙酮衍生物的制备方法，与实施例18的区别在于，亚硝酸试剂为等物质的量的亚硝酸钙，亚硝酸钙配制成质量分数35％的水溶液加入。
实施例22
一种3,5-二卤-三氟苯乙酮衍生物的制备方法，与实施例18的区别在于，将步骤S18中的方法进行了放大量处理，其中，步骤S1和步骤S2与实施例16中的步骤S1和S2相同，步骤S3中各物料的使用量为实施例18中步骤S3中所使用的的量的10倍，其余条件与实施例18相同。
实施例23
一种3,5-二卤-三氟苯乙酮衍生物的制备方法，与实施例19的区别在于，将步骤S19中的方法进行了放大量处理，其中，步骤S1和步骤S2与实施例17中的步骤S1和S2相同，步骤S3中各物料的使用量为实施例19中步骤S3中所使用的的量的10倍，其余条件与实施例19相同。
实施例18～23中，其各步骤收率和纯度如表2所示。
Figure PCTCN2020118495-appb-000005
通过上述实验数据可知，当采用实施例18～23中的方法在三氟乙酰基的对位上用氯取代，同样具有较好的收率好较高的最终产物纯度。实施例22和23分别对3，4，5-三氯-三氟苯乙酮(核磁共振氢谱数据为1HNMR(300MHz,CDCl3):δ＝8.05(d,J＝0.8Hz,2H))和3,5-二溴-4-氯三氟苯乙酮(核磁共振氢谱数据为1HNMR(300MHz,CDCl3):δ＝8.24(s,2H))进行了放大合成的实验，证明了上述方法具有较好的工业运用前景。
实施例24
一种3,5-二卤-三氟苯乙酮衍生物的制备方法，与实施例18的区别在于，步骤S3具体如下：
S3-4-1、取化合物Ⅲ51.6g(0.2mol)溶解于300mL乙腈(溶剂Ⅳ)中，加热至50℃，随后加入浓度为47％的溴化氢300mL，保温反应1h，随后降温至-10℃并在1h内均匀滴加质量分数为33％的亚硝酸钠溶液50mL(含亚硝酸钠0.24mol)，滴加完毕后继续反应30min，得到中间反应液Ⅳ。
S3-4-2、在30min内向中间反应液Ⅳ中分批均匀加入43.0g(0.3mol)溴化亚酮，随后升温至60℃，搅拌反应1h，反应完毕后用二氯甲烷萃取并保留有机相，使用无水硫酸镁干燥后，减压蒸馏得到化合物Ⅳ。
在上述过程中，化合物Ⅳ为3,5-二氯-4-溴三氟苯乙酮。
实施例25
一种3,5-二卤-三氟苯乙酮衍生物的制备方法，对实施例24中的制备方法进行放大量处理，其中，步骤S1和步骤S2与实施例22相同，步骤S3中各物料的使用量为实施例24中步骤S3中所使用的的量的10倍，其余条件与实施例24相同。
实施例26
一种3,5-二卤-三氟苯乙酮衍生物的制备方法，与实施例24的区别在于，在步骤S3-4-1中，溶剂Ⅳ选用体积比为0.4:1的乙醇和异丙醇混合体系。
实施例27
一种3,5-二卤-三氟苯乙酮衍生物的制备方法，与实施例18的区别在于，步骤S3具体如下：
S3-3-1、取化合物Ⅲ51.6g，在30min内加入到已降温至0℃的300mL氟化氢吡啶溶液中(氟化氢质量分数为70％)，保持温度在0±5℃并搅拌1h，之后再在1h内滴加质量分数为33％的亚硝酸钠溶液50.3g(含亚硝酸钠0.24mol)，继续反应30min，得到中间反应液Ⅲ；
S3-3-2、将中间反应液Ⅲ升温至60℃并继续反应3h，加入200mL淬灭剂，淬灭剂为乙醚和水以1.6:1的体积混合形成的混合液，分离得到有机层，并用饱和氯化钠溶液洗涤，用200mL甲苯洗脱，干燥后得到化合物Ⅳ。
上述过程中，化合物Ⅳ中R 3为氟，其核磁共振氢谱数据为1HNMR(400MHz,CDCl3)δ＝8.06(dd,J＝0.8,6.1Hz,2H)。
实施例28～31
一种3,5-二卤-三氟苯乙酮衍生物的制备方法，与实施例27的区别在于，在步骤S3-2-2中,淬灭剂分别为：乙醚和水以0.8:1的体积比形成的混合溶液，乙醚和水以2.5:1的体积比形成的混合溶液，乙醚，水。
实施例32
一种3,5-二卤-三氟苯乙酮衍生物的制备方法，对实施例27中的方法进行了放大量处理，其中，步骤S1和步骤S2与实施例22相同，步骤S3中各物料的使用量为实施例33步骤S3中所使用的的量的10倍，其余条件与实施例27相同。
实施例33
一种3,5-二卤-三氟苯乙酮衍生物的制备方法，与实施例27区别在于，步骤S3具体如下：
S3-5-1、向150mL纯水中滴加46.0g浓硫酸，并控温于80℃，再将51.6g化合物Ⅲ加入到上述体系中，搅拌1h后，降温至0℃，在1h内均匀滴加50.3g质量分数为33％的亚硝酸钠溶液(含亚硝酸钠0.24mol)，滴加完毕后继续保温反应1h，得到中间反应液Ⅴ；
S3-5-2、取71.5g无水硫酸铜(0.286mol)，加入123.5g纯水配制成硫酸铜溶液，再滴加52.7g浓硫酸进行酸化，搅拌均匀后升温至110℃使上述溶液回流，将步骤S3-5-1中得到的中间反应液Ⅴ滴加至上述溶液中，一边滴加一边将产品蒸出，保持体积不变，蒸出的产品用二氯甲烷萃取后合并有机相，干燥得到化合物Ⅳ。
在上述过程中，化合物Ⅳ为3,5-二氯-4-羟基三氟苯乙酮。
实施例34，一种3,5-二卤-三氟苯乙酮衍生物的制备方法，对实施例33中的方法进行了放大处理，其中，步骤S1和步骤S2与实施例22相同，步骤S3中，各物料的使用量为实施例33步骤S3中所使用的的量的10倍，其余条件与实施例33相同。
实施例24～34中，其各步骤收率和纯度如表3所示。
Figure PCTCN2020118495-appb-000006
通过上述实验数据可知，通过本申请中的方法，同样可以实现对3,5-二氯-三氟苯乙酮及其衍生物的制备，且均具有较好的工业运用前景。在制备过程中，选用乙醚和水的混合体系可以有效减少反应结束后副反应发生的可能性，提高步骤S3的产率和纯度。
对于上述实施例,现设置对比例如下。
对比例1
一种3,5-二氯-三氟苯乙酮的制备方法，以3,5-二氯溴苯为原料，将5.0g3,5-二氯溴苯(22.1mmol)溶解于50mL四氢呋喃中，在氮气保护下，将18.7ml1.3M的叔丁基锂滴加到上述溶液中，30min内滴加完毕，混合反应2h后，将3.30g三氟乙酸乙酯(23.2mmol)滴加到上述体系中，继续反应2h，反应完毕后升至室温继续保温反应4h。室温反应完成后，加入50mL饱和氯化铵溶液终止反应，并用乙醚萃取，合并有机相，用饱和食盐水洗涤，并用无水硫酸镁干燥，旋蒸除去溶剂得到无色液体即为3,5-二氯-三氟苯乙酮，产率38.4％，纯度为99.4％。
在采用上述对比例对3,5-二卤-三氟苯乙酮进行合成时，由于卤原子的选择性，其只能对3位和5位均为氯的化合物进行合成，适用性较窄，且容易发生一系列副反应，产率较低。在反应过程中，需要使用-78℃的超低温状态，生产成本较高，且在反应完毕后，由于三氟甲基的强吸电子效应，其对位难以继续发生反应，因此不能用于合成4取代的3,5-二卤-三氟苯乙酮衍生物，在工业运用中有着较大的限制。

Claims (10)

  1. 一种3,5-二卤三氟苯乙酮及其衍生物的制备方法，其特征在于：包括如下步骤：
    S1、将化合物Ⅰ经过还原反应，得到化合物Ⅱ；
    S2、将化合物Ⅱ通过卤代反应，得到化合物Ⅲ；
    S3、将化合物Ⅲ通过氨基取代反应，得到化合物Ⅳ；
    Figure PCTCN2020118495-appb-100001
    其中，R 1选自氯、溴、碘中的一种，R 2为氯、溴中的一种，R 3选自氢、氟、氯、溴、羟基中的一种。
  2. 根据权利要求1所述的一种3,5-二卤三氟苯乙酮及其衍生物的制备方法，其特征在于：所述步骤S1中，将化合物Ⅰ溶解于溶剂Ⅰ中，采用铂碳、钯碳、Raney镍中的一种作为催化剂，在氢气作用下对硝基进行还原，溶剂Ⅰ选自以下物质中的至少一种或两种及以上形成的均相混合体系：甲醇、乙醇、乙酸乙酯、乙酸正丁酯、乙酸异丙酯、异丙醇、甲苯。
  3. 根据权利要求1所述的一种3,5-二卤三氟苯乙酮及其衍生物的制备方法，其特征在于：R 1、R 2为氯，在步骤S2中卤代试剂选自氯气、磺酰氯、三氯异氰尿酸、NCS中的一种。
  4. 根据权利要求1所述的一种3,5-二卤三氟苯乙酮及其衍生物的制备方法，其特征在于：R 3为氢原子，S3具体包括如下步骤：
    S3-1-1、将化合物Ⅲ溶解于溶剂Ⅲ中，并降温至-10～0℃，加入硫酸酸化后，滴加亚硝酸试剂溶液使氨基重氮化，充分反应得到中间反应液Ⅰ；
    S3-1-2、将中间反应液Ⅰ升温至20～30℃，并加入次磷酸溶液和氧化亚铜，继续反应至完全，随后用碱性无机盐溶液洗涤并保留有机相，干燥后即得到化合物Ⅳ；
    其中，亚硝酸试剂选自亚硝酸钠、亚硝酸钾、亚硝酸钙、亚硝酸钡、亚硝酸银、亚硝酸C1～C6烷基酯中的一种，所述溶剂Ⅲ选自甲苯、乙醇、异丙醇中的一种，或甲苯、乙醇、异丙醇中任意数种形成的均相体系。
  5. 根据权利要求1所述的一种3,5-二卤三氟苯乙酮及其衍生物的制备方法，其特征在于：R 3为氯原子，S3具体包括如下步骤：
    S3-2-1、将化合物Ⅲ加入到盐酸进行酸化，酸化完毕后加入亚硝酸试剂溶液使氨基重氮化，反应完全后得到中间反应液Ⅱ；
    S3-2-2、配制氯化亚铜的盐酸溶液，升温并充分混合后将步骤S3-2-1中制得的中间反应液Ⅱ加入上述体系中，充分反应后对体系分离并保留有机相、干燥并减压蒸馏，得到化合物Ⅳ；其中，亚硝酸试剂选自亚硝酸钠、亚硝酸钾、亚硝酸钙、亚硝酸钡、亚硝酸银、亚硝酸C1～C6烷基酯中的一种。
  6. 根据权利要求1所述的一种3,5-二卤三氟苯乙酮及其衍生物的制备方法，其特征在于：R 3为氟原子，S3具体包括如下步骤：
    S3-3-1、将化合物Ⅲ溶解于含有氟化氢的吡啶溶液中，控制温度为-5～5℃，充分混合并使氨基和氟化氢成盐后加入亚硝酸试剂溶液使氨基重氮化，反应完全后得到中间反应液Ⅲ；
    S3-3-2、将中间反应液Ⅲ升温至60～90℃并继续反应，充分反应后，加入淬灭剂，洗涤干燥并进一步分离后得到化合物Ⅳ；
    其中，亚硝酸试剂为亚硝酸钠、亚硝酸钾、亚硝酸钙、亚硝酸钡、亚硝酸银、亚硝酸C1～C6烷基酯中的一种。
  7. 根据权利要求6所述的一种3,5-二卤三氟苯乙酮及其衍生物的制备方法，其特征在于：所述淬灭剂为乙醚和水以(0.8～2.5):1的体积比形成的混合液。
  8. 根据权利要求1所述的一种3,5-二卤三氟苯乙酮及其衍生物的制备方法，其特征在于：R 3为溴原子，S3具体包括如下步骤：
    S3-4-1、将化合物Ⅲ溶解于溶剂Ⅵ中，升温后加入氢溴酸并充分反应，随后降温至-10～0℃并 滴加亚硝酸试剂溶液，充分反应使氨基重氮化，得到中间反应液Ⅳ；
    S3-4-2、向中间反应液Ⅳ中加入溴化亚酮，随后升温至60～80℃，继续充分反应，随后萃取、保留有机相并进一步分离得到化合物Ⅵ；
    其中，亚硝酸试剂选自亚硝酸钠、亚硝酸钾、亚硝酸钙、亚硝酸钡、亚硝酸银、亚硝酸C1～C6烷基酯中的一种，所述溶剂Ⅵ选自甲苯、乙醇、异丙醇中的任意一种，或其中任意多种形成的均相混合体系。
  9. 根据权利要求1所述的一种3,5-二卤三氟苯乙酮及其衍生物的制备方法，其特征在于：R 3为羟基，S3具体包括如下步骤：
    S3-5-1、将硫酸水溶液升温至80℃，并加入化合物Ⅲ，充分反应后，降温至0℃并加入亚硝酸试剂溶液，使氨基重氮化，得到中间反应液Ⅴ；
    S3-5-2、配制硫酸铜溶液，并加入浓硫酸酸化，升温至110℃，将中间反应液Ⅴ滴加至上述溶液中，将产品蒸出，并提纯干燥，得到化合物Ⅳ；
    亚硝酸试剂选自亚硝酸钠、亚硝酸钾、亚硝酸钙、亚硝酸钡、亚硝酸银、亚硝酸C1～C6烷基酯中的一种。
  10. 根据权利要求4～9中任意一项所述的一种3,5-二卤三氟苯乙酮及其衍生物的制备方法，其特征在于：所述亚硝酸试剂为亚硝酸钠或亚硝酸钾。
PCT/CN2020/118495 2020-09-28 2020-09-28 一种3,5-二卤三氟苯乙酮及其衍生物的制备方法 WO2022061914A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2020/118495 WO2022061914A1 (zh) 2020-09-28 2020-09-28 一种3,5-二卤三氟苯乙酮及其衍生物的制备方法

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2020/118495 WO2022061914A1 (zh) 2020-09-28 2020-09-28 一种3,5-二卤三氟苯乙酮及其衍生物的制备方法

Publications (1)

Publication Number Publication Date
WO2022061914A1 true WO2022061914A1 (zh) 2022-03-31

Family

ID=80846133

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/118495 WO2022061914A1 (zh) 2020-09-28 2020-09-28 一种3,5-二卤三氟苯乙酮及其衍生物的制备方法

Country Status (1)

Country Link
WO (1) WO2022061914A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116903445A (zh) * 2023-07-27 2023-10-20 江苏乾元生物科技有限公司 一种2-氟-6-氯苯酚的制备方法

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101827521A (zh) * 2007-10-17 2010-09-08 先正达参股股份有限公司 双酰胺衍生物及其作为杀昆虫化合物的用途
WO2012161313A1 (ja) * 2011-05-26 2012-11-29 日産化学工業株式会社 １－（２－アミノ－置換フェニル）－２－ハロ－２，２－ジフルオロエタノン化合物及び１－（置換フェニル）－２－ハロ－２，２－ジフルオロエタノン化合物の製造方法
JP2013006820A (ja) * 2011-05-26 2013-01-10 Nissan Chem Ind Ltd １−（４−アミノ−置換フェニル）−２−ハロ−２，２−ジフルオロエタノン化合物及び１−（置換フェニル）−２−ハロ−２，２−ジフルオロエタノン化合物の製造方法
WO2015005408A1 (ja) * 2013-07-08 2015-01-15 住友化学株式会社 ヒドラジド化合物及びその有害節足動物防除用途
CN104812758A (zh) * 2012-08-31 2015-07-29 硕腾有限责任公司 1-(5′-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-3′h-螺[氮杂环丁烷-3,1′-异苯并呋喃]-1-基)-2-(甲基磺酰基)乙酮的晶型
WO2016058881A2 (en) * 2014-10-14 2016-04-21 Syngenta Participations Ag Process for the preparation of halo-substituted benzenes
CN106518636A (zh) * 2016-10-18 2017-03-22 浙江天宇药业股份有限公司 4‑氯‑2‑（三氟乙酰基）苯胺盐酸盐水合物及其游离碱的制备方法
CN106795080A (zh) * 2014-10-14 2017-05-31 先正达参股股份有限公司 用于制备卤代三氟苯乙酮的方法
CN106795082A (zh) * 2014-10-14 2017-05-31 先正达参股股份有限公司 用于制备1‑(3,5‑二氯‑4‑氟‑苯基)‑2,2,2‑三氟‑乙酮的方法
CN107353189A (zh) * 2017-07-06 2017-11-17 荆门医药工业技术研究院 制备3, 5‑二氯‑a‑（三氟甲基）苯乙烯的方法

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101827521A (zh) * 2007-10-17 2010-09-08 先正达参股股份有限公司 双酰胺衍生物及其作为杀昆虫化合物的用途
WO2012161313A1 (ja) * 2011-05-26 2012-11-29 日産化学工業株式会社 １－（２－アミノ－置換フェニル）－２－ハロ－２，２－ジフルオロエタノン化合物及び１－（置換フェニル）－２－ハロ－２，２－ジフルオロエタノン化合物の製造方法
JP2013006820A (ja) * 2011-05-26 2013-01-10 Nissan Chem Ind Ltd １−（４−アミノ−置換フェニル）−２−ハロ−２，２−ジフルオロエタノン化合物及び１−（置換フェニル）−２−ハロ−２，２−ジフルオロエタノン化合物の製造方法
CN104812758A (zh) * 2012-08-31 2015-07-29 硕腾有限责任公司 1-(5′-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-3′h-螺[氮杂环丁烷-3,1′-异苯并呋喃]-1-基)-2-(甲基磺酰基)乙酮的晶型
WO2015005408A1 (ja) * 2013-07-08 2015-01-15 住友化学株式会社 ヒドラジド化合物及びその有害節足動物防除用途
WO2016058881A2 (en) * 2014-10-14 2016-04-21 Syngenta Participations Ag Process for the preparation of halo-substituted benzenes
CN106795080A (zh) * 2014-10-14 2017-05-31 先正达参股股份有限公司 用于制备卤代三氟苯乙酮的方法
CN106795093A (zh) * 2014-10-14 2017-05-31 先正达参股股份有限公司 用于制备1‑(3,5‑二氯苯基)‑2,2,2‑三氟乙酮及其衍生物的方法
CN106795082A (zh) * 2014-10-14 2017-05-31 先正达参股股份有限公司 用于制备1‑(3,5‑二氯‑4‑氟‑苯基)‑2,2,2‑三氟‑乙酮的方法
CN106518636A (zh) * 2016-10-18 2017-03-22 浙江天宇药业股份有限公司 4‑氯‑2‑（三氟乙酰基）苯胺盐酸盐水合物及其游离碱的制备方法
CN107353189A (zh) * 2017-07-06 2017-11-17 荆门医药工业技术研究院 制备3, 5‑二氯‑a‑（三氟甲基）苯乙烯的方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHAO, HAOYU: "Synthesis of 2,4,5-Trifluoroacetophenone", CHINESE JOURNAL OF PHARMACEUTICALS, vol. 42, no. 4, 31 December 2011 (2011-12-31), pages 254 - 255, XP055915604 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116903445A (zh) * 2023-07-27 2023-10-20 江苏乾元生物科技有限公司 一种2-氟-6-氯苯酚的制备方法

Similar Documents

Publication Publication Date Title
CN112110804B (zh) 一种3,5-二卤三氟苯乙酮及其衍生物的制备方法
CN112851646A (zh) 特戈拉赞的制备方法
CN109320496B (zh) 硒氰化试剂及其制备方法与应用
CN112645826A (zh) 一种乙炔基苯胺的制备方法
WO2022061914A1 (zh) 一种3,5-二卤三氟苯乙酮及其衍生物的制备方法
CN103102264B (zh) 一类水杨酸类化合物的制备方法
CN106699559A (zh) 一种洛索洛芬钠的制备工艺
CN105175317B (zh) 一种制备匹可硫酸钠的方法
CN118530215A (zh) 一种(2-溴-5-氯-4-((5-乙基噻吩-2-基)甲基)苯基)甲醇的制备方法
CN115536536B (zh) 一种间二烷胺基苯酚的制备方法
CN104370738B (zh) 木豆素结构类似物及其在制备抗菌药物中的应用
CN106167459A (zh) 一种合成烯基硫氰酸酯衍生物的新方法
CN116554014A (zh) 一种非诺贝特及其杂质的制备方法
CN112778109B (zh) 1-[3-氯-5-(三氟甲基)苯基]-2,2,2-三氟乙酮及其衍生物的制备方法
CN117209504A (zh) 一种普拉洛芬中间体的合成方法及其中间体合成普拉洛芬的方法
CN104803846B (zh) 制备双[4-(6-丙烯酰氧己基)苯基]环己烷-1,4-二羧酸酯的方法
CN113149879B (zh) 一种4-硒代萘酯或4-硒代萘酰胺的制备方法
CN112110803B (zh) 一种3’,5’-二氯-2,2,2-三氟苯乙酮的制备方法
WO2022061920A1 (zh) 一种3'，5'-二氯-2，2，2-三氟苯乙酮的制备方法
CN114890902B (zh) 2-甲基-3-三氟甲基苯胺的制备方法
CN111909057A (zh) 一种环戊烯基芳基酮肟类化合物的制备方法
CN111349012B (zh) 一种卤代芳烃类化合物的制备方法及其中间体
CN118125928B (zh) 一种2-氨基-3,5-二溴苯甲醛的制备方法
CN112209814B (zh) 一种合成维生素k2的新方法
CN116903471B (zh) 一种单氟/二氟氧代烯丙基酯类化合物及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20954762

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20954762

Country of ref document: EP

Kind code of ref document: A1