WO2020248126A1 - 1,1'-二环[1.1.1]戊烷-1,3-二乙基酮类有机物的连续化合成方法 - Google Patents

1,1'-二环[1.1.1]戊烷-1,3-二乙基酮类有机物的连续化合成方法 Download PDF

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WO2020248126A1
WO2020248126A1 PCT/CN2019/090736 CN2019090736W WO2020248126A1 WO 2020248126 A1 WO2020248126 A1 WO 2020248126A1 CN 2019090736 W CN2019090736 W CN 2019090736W WO 2020248126 A1 WO2020248126 A1 WO 2020248126A1
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continuous
reaction
synthesis method
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pentane
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PCT/CN2019/090736
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English (en)
French (fr)
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洪浩
张恩选
卢江平
魏福亮
杨思航
车冠达
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吉林凯莱英医药化学有限公司
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Priority to AU2019450898A priority Critical patent/AU2019450898B2/en
Priority to US17/433,826 priority patent/US20220144744A1/en
Priority to JP2021570238A priority patent/JP7405871B2/ja
Priority to EP19933011.9A priority patent/EP3912968A4/en
Priority to CA3131419A priority patent/CA3131419C/en
Priority to KR1020227000989A priority patent/KR20220019803A/ko
Priority to PCT/CN2019/090736 priority patent/WO2020248126A1/zh
Priority to BR112021016976-8A priority patent/BR112021016976B1/pt
Publication of WO2020248126A1 publication Critical patent/WO2020248126A1/zh

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    • 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
    • C07C45/67—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 isomerisation; by change of size of the carbon skeleton
    • C07C45/68—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 isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0053—Details of the reactor
    • B01J19/0066—Stirrers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/08—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor
    • B01J19/12—Processes employing the direct application of electric or wave energy, or particle radiation; Apparatus therefor employing electromagnetic waves
    • B01J19/121—Coherent waves, e.g. laser beams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/29—Saturated compounds containing keto groups bound to rings
    • C07C49/313—Saturated compounds containing keto groups bound to rings polycyclic
    • C07C49/323—Saturated compounds containing keto groups bound to rings polycyclic having keto groups bound to condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/29—Saturated compounds containing keto groups bound to rings
    • C07C49/35—Saturated compounds containing keto groups bound to rings containing ether groups, groups, groups, or groups
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00002—Chemical plants
    • B01J2219/00027—Process aspects
    • B01J2219/00033—Continuous processes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/38—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing five carbon atoms

Definitions

  • the present invention relates to the field of the synthesis of pharmaceutical intermediates, and in particular to a continuous synthesis method of 1,1'-bicyclo[1.1.1]pentane-1,3-diethyl ketone organic compounds.
  • 1-Aminobicyclo[1.1.1]pentane-1-carboxylic acid as an unnatural amino acid, has great potential in the field of medicinal chemistry research, and its price is expensive.
  • 1,1'-Bicyclo[1.1.1]pentane-1,3-diethyl ketone is an important intermediate for the synthesis of 1-aminobicyclo[1.1.1]pentane-1-carboxylic acid, and it is also the synthesis of various types of symmetry
  • propane derivatives can be further functionalized to obtain a series of propane derivatives such as acids, esters, alcohols and amides. Due to the particularity of the substrate, there are few reports on the synthesis of 1,1'-bicyclo[1.1.1]pentane-1,3-diethyl ketone.
  • the existing synthesis methods are all batch synthesis methods, using propane and 2,3-butanedione as substrates, through long-term light, a free radical addition reaction occurs to prepare 1,1'-bicyclo[1.1. 1] Pentane-1,3-diethyl ketone.
  • the existing literature reported a kind of 1,1-dibromo-2,2-dichloromethylcyclopropane as the starting material, first reacted with methyl lithium and then distilled, and then the distillate was mixed with 2,3-butane Under the condition of diketone ice-water bath, it was illuminated for 8 hours to obtain the target. The total yield of the two steps was 58%. However, this reaction requires a long time of illumination, and the reaction conversion is slow.
  • the existing synthesis methods have the problems of low reaction efficiency and poor yield.
  • it also has the instability of the reaction substrate propane and the product.
  • the propane will slowly decompose and deteriorate under light, and effective conversion cannot be achieved.
  • the product will deteriorate under light.
  • the main purpose of the present invention is to provide a continuous synthesis method of 1,1'-bicyclo[1.1.1]pentane-1,3-diethyl ketones to solve the existing 1,1'- During the synthesis of bicyclo[1.1.1]pentane-1,3-diethyl ketone, the reaction raw materials and products are unstable, which in turn leads to the problems of low conversion rate of reaction raw materials and low product yield.
  • the above-mentioned continuous synthesis method includes: under the irradiation of a light source, raw material A and raw material B are continuously transported to a continuous reaction device for continuous photochemical reaction to obtain 1,1'-bicyclo[1.1.1]pentane-1 , 3-Diethyl ketone organics, and in the continuous photochemical reaction process, the temperature control device is used to control the reaction temperature in the continuous reaction device, wherein the raw material A has the structure shown in formula (I), and the raw material B has The structure shown in formula (II):
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, benzyl, alkyl, aryl, halogen, ester, carboxy, or hydroxyl, and at least one of R 1 , R 2 , and R 3 is not hydrogen;
  • R 4 and R 5 are each independently selected from hydrogen, alkyl, or aryl.
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, benzyl, methyl, phenyl or hydroxyl; R 4 and R 5 are each independently selected from hydrogen, methyl, benzyl, or phenyl.
  • the continuous synthesis method further includes: mixing the raw material A with the solvent to form a mixed liquid, and then transporting the mixed liquid to the continuous reaction device;
  • the solvent is selected from one or more of the group consisting of n-hexane, n-heptane, n-butyl ether, cyclohexane and cyclopentane.
  • the light source is an LED lamp with a wavelength of 300-350 nm.
  • reaction temperature of the continuous photochemical reaction is 0-30°C, preferably 0-5°C.
  • reaction time of the continuous photochemical reaction is 10-20 min.
  • the continuous synthesis method further includes: continuously transporting the cosolvent to the continuous reaction device.
  • the co-solvent is selected from one or more of the group consisting of methanol, ethanol, ethyl acetate, ethyl formate, acetone, methyl ethyl ketone and acetonitrile.
  • the ratio of the number of moles of the raw material A and the raw material B is 1:(1.0-1.5).
  • the continuous reaction device is selected from a continuous reaction coil or a columnar reactor.
  • the free radicals formed by the substituted propanes have high stability. Therefore, using the substituted propanes as the reaction raw materials can greatly improve the stability of the reaction raw materials and reduce their exposure to light.
  • the probability of slow decomposition and deterioration which can improve the conversion rate of the reaction raw materials and the target product (1,1'-bicyclo[1.1.1]pentane-1,3-diethyl ketone organic matter) to a certain extent The yield.
  • the reaction raw materials are continuously transported to the continuous reaction device, the reaction time is short, and the product output is large. This can reduce the probability of the reaction raw materials and products being destroyed, and greatly improve the conversion rate of the reaction raw materials and the product yield.
  • the above-mentioned continuous synthesis method also effectively solves the problems (such as feasibility and efficiency) of the reaction amplification process, which is 1,1'-bicyclo[1.1.1]pentane-1,3-diethyl ketone
  • the industrialization and commissioning of organic matter provides the possibility.
  • Figure 1 shows a schematic structural diagram of a preferred continuous synthesis device for 1,1'-bicyclo[1.1.1]pentane-1,3-diethyl ketones according to the present invention.
  • the above-mentioned continuous synthesis method includes: under the irradiation of a light source, raw material A and raw material B are continuously transported to a continuous reaction device for continuous photochemical reaction to obtain 1,1'-bicyclo[1.1.1]pentane- 1,3-Diethyl ketone organics, and in the continuous photochemical reaction process, the temperature control device is used to control the reaction temperature in the continuous reaction device, wherein the raw material A has the structure shown in formula (I), and the raw material B It has the structure shown in formula (II):
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, benzyl, alkyl, aryl, halogen, ester, carboxy, or hydroxyl, and at least one of R 1 , R 2 , and R 3 is not hydrogen; R 4 and R 5 are each independently selected from hydrogen, alkyl, or aryl.
  • the free radicals formed by substituted propanes have high stability. Therefore, using substituted propanes as raw materials can greatly improve the stability of the reaction raw materials and reduce the probability of slow decomposition and deterioration under light. , Which can improve the conversion rate of the reaction raw materials and the yield of the target product (1,1'-bicyclo[1.1.1]pentane-1,3-diethyl ketone organics) to a certain extent.
  • the reaction raw materials are continuously transported to the continuous reaction device, the reaction time is short, and the product output is large. This can reduce the probability of the reaction raw materials and products being destroyed, and greatly improve the conversion rate of the reaction raw materials and the product yield.
  • the above-mentioned continuous synthesis method also effectively solves the problems (such as feasibility and efficiency) of the reaction amplification process, which is 1,1'-bicyclo[1.1.1]pentane-1,3-diethyl ketone Industrialization has provided the possibility.
  • the continuous synthesis method before performing the continuous photochemical reaction, further includes: mixing the raw material A with the solvent to form a mixed liquid, and then transporting the mixed liquid to the continuous reaction device.
  • the raw material A is mixed with the solvent to form a mixed liquid and then is transported to the continuous reaction device, which is beneficial to further improve the stability of the reaction raw materials, and in turn, is beneficial to increase the conversion rate of the reaction raw materials and the yield of the target product.
  • the solvent includes, but is not limited to, one or more of the group consisting of n-hexane, n-heptane, n-butyl ether, cyclohexane and cyclopentane.
  • the above-mentioned solvents have better compatibility with raw material A, which is beneficial to further improve the stability of raw material A.
  • the existing photochemical reaction process usually uses a high-pressure mercury lamp for strong light irradiation, and the equipment will emit a large amount of heat after long-term operation, which causes a huge safety hazard in the kettle-type reaction.
  • the light source is an LED lamp with a wavelength of 300-350 nm. Compared with traditional high-pressure mercury lamps, the use of LED lamps with the above wavelengths as light sources can reduce equipment risk and equipment investment.
  • the reaction temperature of the continuous photochemical reaction is 0-30°C.
  • the reaction temperature of the continuous photochemical reaction includes but is not limited to the above range, and limiting it to the above range is beneficial to improve the conversion rate of the reaction raw materials and the yield of the target product during the continuous photochemical reaction. More preferably, the reaction temperature of the continuous photochemical reaction is 0-5°C.
  • the reaction time of the continuous photochemical reaction is 10-20 min.
  • the continuous synthesis method further includes: continuously transporting the cosolvent to the continuous reaction device.
  • a co-solvent in the continuous photochemical reaction process can not only improve the compatibility of raw material A and raw material B, but also dissolve the target product (1,1'-bicyclo[1.1.1]pentane-1, 3-diethyl ketone organic matter), which can be better discharged and reduce the probability of side reactions.
  • the co-solvent includes but is not limited to one or more of the group consisting of methanol, ethanol, ethyl acetate, ethyl formate, acetone, methyl ethyl ketone and acetonitrile.
  • the ratio of the number of moles of the raw material A to the raw material B is 1:(1.0-1.5).
  • the ratio of the number of moles of raw material A to raw material B includes but is not limited to the above range, and limiting it to the above range is beneficial to further improve the target product (1,1'-bicyclo[1.1.1]pentane-1, 3-Diethyl ketone organics) yield.
  • the existing batch reaction process adopts a kettle-type reaction device, which has high requirements on the material of the equipment, and is affected by the material and cannot be mass-produced.
  • the continuous reaction device is selected from a continuous reaction coil or a columnar reactor.
  • the continuous chemical synthesis device includes: a first feeding device 10, a second feeding device 20, an automatic feeding system 30, a mixer 40, a first plunger pump 50, and a second plunger
  • the first feeding device 10 is provided with a raw material A inlet, a solvent inlet, and a mixed liquid outlet
  • the second feeding device 20 is provided with a raw material B inlet and a raw material B outlet
  • the mixer 40 is provided with a feed inlet and a reaction raw material outlet
  • the above The feed port and the mixed liquid outlet are communicated through a mixed liquid conveying pipeline
  • the first plunger pump 50 is arranged on the mixed liquid conveying pipeline.
  • the above-mentioned feed port and the outlet of the raw material B are communicated through the raw material B delivery pipeline
  • the second plunger pump 51 is arranged on the raw material B delivery pipeline.
  • the automatic feeding system 30 is used to control the feeding rate of the first plunger pump 50 and the second plunger pump 51.
  • the continuous photochemical reaction device 60 is provided with a reaction raw material inlet and a product system outlet, and the reaction raw material inlet and the reaction raw material outlet are connected through a reaction raw material delivery pipeline.
  • the first plunger pump 50 is arranged on the delivery pipeline, and the product system outlet is connected to the rear
  • the inlet end of the processing device 80 is connected; in the post-processing device 80, the product system is processed by the thin film evaporator 81, the continuous crystallizer 82, and the filter 83 to obtain the required 1,1'-bicyclic ring [1.1.1 ] Pentane-1,3-diethyl ketone organic matter; the light source 70 acts on the irradiation continuous photochemical reaction device.
  • equiv means a multiple of the number of moles.
  • the amount of 2,3-butanedione required for 1 mol of propane is 1.1 mol, which can also be expressed as 1.1 equiv.
  • the apparatus shown in FIG. 1 was used to synthesize 1,1'-bicyclo[1.1.1]pentane-1,3-diethyl ketone organic compounds.
  • the temperature of the outer bath is controlled at 0 ⁇ 5°C, the retention time is 15min, and the discharge port is connected to the film concentration device for continuous concentration.
  • the concentrated liquid enters the oscillator to control the temperature -55 ⁇ -60°C, online crystallizing and filtering the product, the white solid is 195.67g, the yield is 85%.
  • the temperature of the outer bath is controlled at 0 ⁇ 5°C, and the retention time is 15min, the discharge port is connected to the film concentration device for continuous concentration, the concentrated liquid enters the oscillator to control the temperature -55 ⁇ -60°C online crystallizing and filtering the product, the white solid is 145.8g, the yield is 94%.
  • Example 1 The difference from Example 1 is that the temperature of the outer bath is 20°C.
  • the temperature of the outer bath is controlled at 20°C and the retention time is 15min.
  • the discharging port is connected to the thin film concentration device for continuous concentration, and the concentrated liquid enters the oscillator to control the temperature -55 ⁇ -60°C on-line crystallizing and filtering the product, the white solid 120.98g, the yield is 78%.
  • Example 1 The difference from Example 1 is that the ratio of the number of moles of raw material A and raw material B is 1:2.0.
  • the temperature of the outer bath is controlled at 0 ⁇ 5°C, keep After 15 minutes, the discharge port is connected to the thin film concentration device for continuous concentration, and the concentrated liquid enters the oscillator to control the temperature -55 ⁇ -60°C and online crystallize and filter the product.
  • the white solid is 108.57g, the yield is 70%.
  • Example 2 The difference from Example 1 is that the continuous reaction device is a columnar reactor.
  • the temperature of the external bath is controlled at 0 ⁇ 5°C, the retention time is 15min, and the discharge port Connected with a thin film concentration device for continuous concentration, and the concentrated liquid enters the oscillator to control the temperature -55 ⁇ 60°C and online crystallize and filter the product.
  • the white solid is 122.52g, the yield is 79%.
  • R 1 , R 2 , and R 3 in the raw material A are hydrogen, hydrogen, and benzyl, respectively.
  • the temperature of the external bath is controlled at 0 ⁇ 5°C, and the retention time is 15min.
  • the discharge port is connected to the thin film concentration device for continuous concentration, and the concentrated liquid enters the oscillator to control the temperature -55 ⁇ -60°C on-line crystallizing and filtering the product, the white solid is 146.6g, the yield is 94.5%.
  • R 1 , R 2 , and R 3 in the raw material A are hydrogen, hydrogen, and p-methoxybenzyl, respectively.
  • R 1 , R 2 , and R 3 in the raw material A are hydrogen, hydrogen, and p-methoxyphenyl respectively.
  • Example 2 The difference from Example 1 is that the solvent used is n-hexane
  • the temperature of the outer bath is controlled at 0 ⁇ 5°C, and the retention time is 15min, the discharge port is connected to the thin film concentration device for continuous concentration, and the concentrated liquid enters the oscillator to control the temperature -55 ⁇ -60 °C online crystallizing and filtering the product, the white solid is 141.14g, the yield is 91%.
  • Example 1 The difference from Example 1 is that the wavelength of the light source used is 365nm
  • the temperature of the outer bath is controlled at 0 ⁇ 5°C, and the retention time is 15min, the discharge port is connected to the thin film concentration device for continuous concentration, and the concentrated liquid enters the oscillator to control the temperature -55 ⁇ -60°C online crystallizing and filtering the product, the white solid is 131.85g, the yield is 85%.
  • the temperature of the outer bath is controlled at 0 ⁇ 5°C, and the retention time is 30min, the discharge port is connected to the thin film concentration device for continuous concentration, and the concentrated liquid enters the oscillator to control the temperature -55 ⁇ -60°C online crystallizing and filtering the product, the white solid is 136.48g, the yield is 88%.
  • Example 1 The difference from Example 1 is that the added co-solvent is acetonitrile
  • the temperature of the outer bath is controlled at 0 ⁇ 5°C, and the retention time is 15min.
  • the discharge port is connected to the thin film concentration device for continuous concentration, and the concentrated liquid enters the oscillator to control the temperature -55 ⁇ -60°C online crystallization filtration product, the white solid is 131.83g, the yield is 85%.
  • the use of the above-mentioned substituted propane as the reaction raw material can greatly improve the stability of the reaction raw material, reduce the probability of its slow decomposition and deterioration under light, and thus can improve to a certain extent
  • the conversion rate of the reaction raw materials and the yield of the target product (1,1'-bicyclo[1.1.1]pentane-1,3-diethyl ketone organics).

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Abstract

一种1,1'-二环[1.1.1]戊烷-1,3-二乙基酮类有机物的连续化合成方法。该连续化合成方法包括：在光源照射下，原料A和原料B连续输送至连续化反应装置中进行连续化光化学反应，得到1,1'-二环[1.1.1]戊烷-1,3-二乙基酮类有机物，采用控温装置控制连续化反应装置中的反应温度。以具有取代基的螺桨烷作为反应原料并在连续化反应装置中进行上述光化学反应能够降低其在光照下缓慢分解和变质的几率，并极大地提高反应原料的转化率和产品收率。

Description

1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物的连续化合成方法 技术领域
本发明涉及药物中间体合成领域，具体而言，涉及一种1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物的连续化合成方法。
背景技术
1-氨基双环[1.1.1]戊烷-1-甲酸作为非天然的氨基酸在药物化学研究领域发挥着巨大的潜力，其价格昂贵。1,1'-二环[1.1.1]戊烷-1,3-二乙基酮是合成1-氨基双环[1.1.1]戊烷-1-甲酸的重要中间体，也是合成各类对称螺桨烷衍生物的砌块，通过进一步官能团化，可得到一系列酸、酯、醇、酰胺等螺浆烷衍生物。由于底物的特殊性，1,1'-二环[1.1.1]戊烷-1,3-二乙基酮的合成报道较少。
现有的合成方法均是批次合成法，以螺桨烷与2，3-丁二酮为底物，通过长时间光照，发生自由基加成反应制备1,1'-二环[1.1.1]戊烷-1,3-二乙基酮。比如现有文献报道了一种以1，1-二溴-2，2-二氯甲基环丙烷为起始原料，先与甲基锂反应后进行蒸馏，再使馏分与2，3-丁二酮冰水浴条件下光照8h，得到目标物，两步总收率58％。但该反应所需的光照时间较长，反应转化较慢，只能实验室小规模制备1,1'-二环[1.1.1]戊烷-1,3-二乙基酮，无法进行放大生产。后续也有相似文献报道，但其始终没能解决反应效率低的问题，使得该类化合物的成本及下游产品价格极其昂贵。
在此基础上，现有的合成方法存在反应效率低和收率差的问题。此外，其还存在反应底物螺桨烷及产品的不稳定性，在光照下螺桨烷会自身缓慢分解变坏，无法实现有效转化，同时产品也会在光照下变质。
鉴于上述问题的存在，有必要提供一种新的1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物的合成方法，以提高其转化率和反应速率。
发明内容
本发明的主要目的在于提供一种1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物的连续化合成方法，以解决现有的1,1'-二环[1.1.1]戊烷-1,3-二乙基酮合成过程中存在反应原料和产品不稳定，进而导致反应原料的转化率低和产品收率低的问题。
为了实现上述目的，根据本发明提供了一种1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物的连续化合成方法，1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物具有式(Ⅲ)所示的结构：
Figure PCTCN2019090736-appb-000001
上述连续化合成方法包括：在光源的照射下，原料A和原料B连续地输送至连续化反应装置中进行连续化光化学反应，得到1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物，且在连续化光化学反应过程中，采用控温装置控制连续化反应装置中的反应温度，其中，原料A具有式(Ⅰ)所示的结构，原料B具有式(Ⅱ)所示的结构：
Figure PCTCN2019090736-appb-000002
R 1、R 2、R 3分别独立地选自氢、苄基、烷基、芳基、卤素、酯基、羧基或羟基，且R 1、R 2、R 3中至少一个不为氢；
Figure PCTCN2019090736-appb-000003
R 4和R 5分别独立地选自氢、烷基或芳基。
进一步地，R 1、R 2、R 3分别独立地选自氢、苄基、甲基、苯基或羟基；R 4和R 5分别独立地选自氢、甲基、苄基或苯基。
进一步地，在进行连续化光化学反应之前，连续化合成方法还包括：将原料A与溶剂混合形成混合液，然后将混合液输送至连续化反应装置中；
优选地，溶剂选自正己烷、正庚烷、正丁醚、环己烷和环戊烷组成的组中的一种或多种。
进一步地，光源为波长300～350nm的LED灯。
进一步地，连续化光化学反应的反应温度为0～30℃，优选为0～5℃。
进一步地，连续化光化学反应的反应时间为10～20min。
进一步地，在进行连续化光化学反应的过程，连续化合成方法还包括：将助溶剂连续地输送至连续化反应装置中。
进一步地，助溶剂选自甲醇、乙醇、乙酸乙酯、甲酸乙酯、丙酮、丁酮和乙腈组成的组中的一种或多种。
进一步地，原料A和原料B的摩尔数之比为1:(1.0～1.5)。
进一步地，连续化反应装置选自连续化反应盘管或柱状反应器。
应用本发明的技术方案，具有取代基的螺桨烷形成的自由基具有较高的稳定性，因而以具有取代基的螺桨烷作为反应原料能够大幅提高反应原料的稳定性，降低其在光照下缓慢分解和变质的几率，从而能够在一定程度上提高反应原料的转化率和目标产物(1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物)的收率。同时上述光化学反应过程中，反应原料连续输送至连续化反应装置中，反应所需时间短，产品产量大。这能够降低反应原料及产品被破坏的几率，并极大地提高反应原料的转化率和产品的收率。此外上述连续化合成方法还有效解决了反应放大过程存在的问题(如可行性及效率性)，为1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物的工业化投产提供了可能性。
附图说明
构成本申请的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。在附图中：
图1示出了根据本发明的一种优选的1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物的连续化合成装置的结构示意图。
其中，上述附图包括以下附图标记：
10、第一打料装置；20、第二打料装置；30、自动进料系统；40、混合器；50、第一柱塞泵；51、第二柱塞泵；60、连续化光化学反应装置；70、光源；80、后处理装置；81、薄膜蒸发器；82、连续结晶器；83、过滤器。
具体实施方式
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将结合实施例来详细说明本发明。
正如背景技术所描述的，现有的1,1'-二环[1.1.1]戊烷-1,3-二乙基酮合成过程中存在反应原料和产品不稳定，进而导致反应原料的转化率低和产品收率低的问题。为了解决上述技术问题，本申请提供了一种1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物的连续化合成方法，1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物具有式(Ⅲ)所示的结构：
Figure PCTCN2019090736-appb-000004
上述连续化合成方法包括：在光源的照射下，将原料A和原料B连续地输送至连续化反应装置中进行连续化光化学反应，得到1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物，且在连续化光化学反应过程中，采用控温装置控制连续化反应装置中的反应温度，其中，原料A具有式(Ⅰ)所示的结构，原料B具有式(Ⅱ)所示的结构：
Figure PCTCN2019090736-appb-000005
R 1、R 2、R 3分别独立地选自氢、苄基、烷基、芳基、卤素、酯基、羧基或羟基，且R 1、R 2、R 3中至少一个不为氢；
Figure PCTCN2019090736-appb-000006
Figure PCTCN2019090736-appb-000007
R 4和R 5分别独立地选自氢、烷基或芳基。
具有取代基的螺桨烷形成的自由基具有较高的稳定性，因而以具有取代基的螺桨烷作为反应原料能够大幅提高反应原料的稳定性，降低其在光照下缓慢分解和变质的几率，从而能够在一定程度上提高反应原料的转化率和目标产物(1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物)的收率。同时上述光化学反应过程中，反应原料连续输送至连续化反应装置中，反应所需时间短，产品产量大。这能够降低反应原料及产品被破坏的几率，并极大地提高反应原料的转化率和产品的收率。此外上述连续化合成方法还有效解决了反应放大过程存在的问题(如可行性及效率性)，为1,1'-二环[1.1.1]戊烷-1,3-二乙基酮的工业化投产提供了可能性。
为了进一步提高连续化光化学反应的转化率，优选地，R 1、R 2、R 3分别独立地选自氢、苄基、甲基、苯基或羟基；R 4和R 5分别独立地选自氢、甲基、苄基或苯基。在一种优选的实施例中，在进行连续化光化学反应之前，连续化合成方法还包括：将原料A与溶剂混合形成混合液，然后将混合液输送至连续化反应装置中。将原料A与溶剂混合形成混合液后在输送至连续化反应装置中，这有利于进一步提高反应原料的稳定性，进而有利于提高反应原料的转化率和目标产品的收率。更优选地，溶剂包括但不限于正己烷、正庚烷、正丁醚、环己烷和环戊烷组成的组中的一种或多种。相比于其它溶剂，上述几种溶剂与原料A具有更好的相容性，进而有利于更进一步提高原料A的稳定性。
现有的光化学反应过程通常使用高压汞灯进行强光照射，而设备长时间运行后会放出大量的热，在釜式反应中，产生巨大安全隐患。为了解决上述技术问题，在一种优选的实施例中，光源为波长300～350nm的LED灯。相比于传统的高压汞灯，采用上述波长的LED灯做光源能够降低设备使用风险，减少设备投资。
在一种优选的实施例中，连续化光化学反应的反应温度为0～30℃。连续化光化学反应的反应温度包括但不限于上述范围，而将其限定在上述范围内有利于提高连续化光化学反应过 程中反应原料的转化率和目标产品的收率。更优选地，连续化光化学反应的反应温度为0～5℃。
为了提高反应原料A和原料B的充分反应程度以进一步提高目标产物的收率，优选地，连续化光化学反应的反应时间为10～20min。
在一种优选的实施例中，在进行连续化光化学反应的过程，连续化合成方法还包括：将助溶剂连续地输送至连续化反应装置中。在连续化光化学反应过程中加入助溶剂不仅能够提高原料A和原料B的相容性，而且还能够溶解反应生成的目标产品(1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物)，从而能够使其更好地排出，降低副反应的发生几率。更优选地，助溶剂包括但不限于甲醇、乙醇、乙酸乙酯、甲酸乙酯、丙酮、丁酮和乙腈组成的组中的一种或多种。
在一种优选的实施例中，原料A和原料B的摩尔数之比为1:(1.0～1.5)。将原料A和原料B的摩尔数之比包括但不限于上述范围，而将其限定在上述范围内有利于进一步提高目标产品(1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物)的收率。
现有的批次性反应工艺中采用釜式反应装置，其对设备的材质要求较高，受材质影响，无法大规模生产。为了解决上述问题，在一种优选的实施例中，连续化反应装置选自连续化反应盘管或柱状反应器。
为了更好地理解上述技术方案，本申请还提供了一种优选的用于合成1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物的连续化合成装置，如图1所示，该连续化合成装置包括：第一打料装置10、第二打料装置20、自动进料系统30、混合器40、第一柱塞泵50、第二柱塞泵51、连续化光化学反应装置60(反应盘管)、光源70和后处理装置80(连续化浓缩结晶装置)，且后处理装置80包括薄膜蒸发器81、连续结晶器82和过滤器83。其中第一打料装置10设置有原料A入口和溶剂入口以及混合液出口，第二打料装置20设置原料B入口和原料B出口，混合器40设置有进料口和反应原料出口，且上述进料口与混合液出口通过混合液输送管路连通，且第一柱塞泵50设置在混合液输送管路上。上述进料口与原料B出口通过原料B输送管路连通，且第二柱塞泵51设置在原料B输送管路上。同时使用自动进料系统30控制第一柱塞泵50和第二柱塞泵51的进料速率。连续化光化学反应装置60设置有反应原料入口和产物体系出口，且反应原料入口与反应原料出口通过反应原料输送管路相连通，第一柱塞泵50设置在输送管路上，产物体系出口与后处理装置80的入口端相连通；在后处理装置80中，产物体系依次经薄膜蒸发器81、连续结晶器82、过滤器83处理，得到所需的1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物；光源70作用于照射连续化光化学反应装置。
以下结合具体实施例对本申请作进一步详细描述，这些实施例不能理解为限制本申请所要求保护的范围。
本申请中“equiv.”表示摩尔数的倍数，比如1mol螺桨烷所需的2，3-丁二酮的用量为1.1mol，也可表示为1.1equiv.。
实施例中采用图1所示的装置合成1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物。
对比例1
自制[1.1.1]螺桨烷的正丁醚溶液1.5kg，(NMR含量6.7％，折算原料100g)加入到第一打料装置中；2，3-丁二酮143g(1.1equiv.)，200ml助溶剂乙醇加入到第二打料装置中，配制成均一溶液；打开光源(波长为313nm的LED灯)，开启自动进料系统，控制柱塞泵原料A溶液以10g/min，2，3-丁二酮乙醇溶液以2g/min进入在线混合器然后进入连续化反应装置(盘管)中反应，外浴控温为0～5℃，保留时间15min，出料口连接薄膜浓缩装置连续浓缩，浓缩液进入振荡器控温-55～-60℃在线析晶过滤产品，白色固体195.67g，收率85％。
实施例1
自制2-甲基-2苯基[1.1.1.0 1,3]螺桨烷正丁醚溶液1.56kg，(NMR含量5.0％，折算原料78g)加入到第一打料装置中；2，3-丁二酮143g(1.1equiv.)，200ml助溶剂乙醇加入到第二打料装置中，配制成均一溶液；打开光源(波长为313nm的LED灯)，开启自动进料系统，控制柱塞泵原料A溶液以10g/min，2，3-丁二酮乙醇溶液以1.93g/min进入在线混合器然后进入连续化反应装置(盘管)中反应，外浴控温为0～5℃，保留时间15min，出料口连接薄膜浓缩装置连续浓缩，浓缩液进入振荡器控温-55～-60℃在线析晶过滤产品，白色固体145.8g，收率94％。
实施例2
与实施例1的不同之处在于：外浴的温度为20℃。
自制2-甲基-2苯基[1.1.1.0 1,3]螺桨烷正丁醚溶液1.56kg，(NMR含量5.0％，折算原料78g)加入到第一打料装置中；2，3-丁二酮143g(1.1equiv.)，200ml助溶剂乙醇加入到第二打料装置中，配制成均一溶液；打开光源(波长为313nm的LED灯)，开启自动进料系统，控制柱塞泵原料A溶液以10g/min，2，3-丁二酮乙醇溶液以1.93g/min进入在线混合器然后进入连续化反应装置(盘管)中反应，外浴控温为20℃，保留时间15min，出料口连接薄膜浓缩装置连续浓缩，浓缩液进入振荡器控温-55～-60℃在线析晶过滤产品，白色固体120.98g，收率78％。
实施例3
与实施例1的不同之处在于：原料A和原料B的摩尔数之比为1:2.0。
自制2-甲基-2苯基[1.1.1.0 1,3]螺桨烷正丁醚溶液1.56kg，(NMR含量5.0％，折算原料78g)加入到第一打料装置中；2，3-丁二酮260.5g(2.0equiv.)，200ml助溶剂乙醇加入到第二打料装置中，配制成均一溶液；打开光源(波长为313nm的LED灯)，开启自动进料系统，控制柱塞泵原料A溶液以10g/min，2，3-丁二酮乙醇溶液以4.18g/min进入在线混合器然后进入连续化反应装置(盘管)中反应，外浴控温为0～5℃，保留时间15min，出料口连接薄膜浓缩装置连续浓缩，浓缩液进入振荡器控温-55～-60℃在线析晶过滤产品，白色固体108.57g，收率70％。
实施例4
与实施例1的不同之处在于：连续化反应装置为柱状反应器。
自制2-甲基-2苯基[1.1.1.0 1,3]螺桨烷正丁醚溶液1.56kg，(NMR含量5.0％，折算原料78g)加入到第一打料装置中；2，3-丁二酮143g(1.1equiv.)，200ml助溶剂乙醇加入到第二打料装置中，配制成均一溶液；打开光源(波长为313nm的LED灯)，开启自动进料系统，控制柱塞泵原料A溶液以10g/min，2，3-丁二酮乙醇溶液以1.93g/min进入在线混合器然后进入柱状反应器中反应，外浴控温为0～5℃，保留时间15min，出料口连接薄膜浓缩装置连续浓缩，浓缩液进入振荡器控温-55～60℃在线析晶过滤产品，白色固体122.52g，收率79％。
实施例5
与实施例1的不同之处在于：原料A中R 1、R 2、R 3的分别为氢、氢、苄基。
自制2-苄基三环[1.1.1.0 1,3]戊烷正丁醚溶液1.5kg，(NMR含量6.7％，折算原料100g)加入到第一打料装置中；2，3-丁二酮60.6g(1.1equiv.)，200ml助溶剂乙醇加入到第二打料装置中，配制成均一溶液；打开光源(波长为313nm的LED灯)，开启自动进料系统，控制柱塞泵原料A溶液以10g/min，2，3-丁二酮乙醇溶液以1.46g/min进入在线混合器然后进入连续化反应装置(盘管)中反应，外浴控温为0～5℃，保留时间15min，出料口连接薄膜浓缩装置连续浓缩，浓缩液进入振荡器控温-55～-60℃在线析晶过滤产品，白色固体146.6g，收率94.5％。
实施例6
与实施例1的不同之处在于：原料A中R 1、R 2、R 3的分别为氢、氢、对甲氧基苄基。
自制2-对甲氧基苄基三环[1.1.1.0 1,3]戊烷正丁醚溶液1.5kg，(NMR含量6.7％，折算原料100g)加入到第一打料装置中；2，3-丁二酮50.8g(1.1equiv.)，200ml助溶剂乙醇加入到第二打料装置中，配制成均一溶液；打开光源(波长为313nm的LED灯)，开启自动进料系统，控制柱塞泵原料A溶液以10g/min，2，3-丁二酮乙醇溶液以1.39g/min进入在线混合器然后进入连续化反应装置(盘管)中反应，外浴控温为0～5℃，保留时间15min，出料口连接薄膜浓缩装置连续浓缩，浓缩液进入振荡器控温-55～-60℃在线析晶过滤产品，白色固体138.6g，收率94.8％。
实施例7
与实施例1的不同之处在于：原料A中R 1、R 2、R 3的分别为氢、氢、对甲氧基苯基。
自制2-对甲氧基苯基三环[1.1.1.0 1,3]戊烷正丁醚溶液1.5kg，(NMR含量6.7％，折算原料100g)加入到第一打料装置中；2，3-丁二酮55.0g(1.1equiv.)，200ml助溶剂乙醇加入到第二打料装置中，配制成均一溶液；打开光源(波长为313nm的LED灯)，开启自动进料系统，控制柱塞泵原料A溶液以10g/min，2，3-丁二酮乙醇溶液以1.42g/min进入在线混合器然后进入连续化反应装置(盘管)中反应，外浴控温为0～5℃，保留时间15min，出料口连接薄膜 浓缩装置连续浓缩，浓缩液进入振荡器控温-55～-60℃在线析晶过滤产品，白色固体141g，收率94％。
实施例8
与实施例1的不同之处在于：所用溶剂为正己烷
自制2-甲基-2苯基[1.1.1.0 1,3]螺桨烷的正己烷溶液1.5kg，(NMR含量6.7％，折算原料78g)加入到第一打料装置中；2，3-丁二酮143g(1.1equiv.)，200ml助溶剂乙醇加入到第二打料装置中，配制成均一溶液；打开光源(波长为313nm的LED灯)，开启自动进料系统，控制柱塞泵原料A溶液以10g/min，2，3-丁二酮乙醇溶液以1.93g/min进入在线混合器然后进入连续化反应装置(盘管)中反应，外浴控温为0～5℃，保留时间15min，出料口连接薄膜浓缩装置连续浓缩，浓缩液进入振荡器控温-55～-60℃在线析晶过滤产品，白色固体141.14g，收率91％。
实施例9
与实施例1的不同之处在于：所用光源波长为365nm
自制2-甲基-2苯基[1.1.1.0 1,3]螺桨烷正丁醚溶液1.56kg，(NMR含量5.0％，折算原料78g)加入到第一打料装置中；2，3-丁二酮143g(1.1equiv.)，200ml助溶剂乙醇加入到第二打料装置中，配制成均一溶液；打开光源(波长为365nm的LED灯)，开启自动进料系统，控制柱塞泵原料A溶液以10g/min，2，3-丁二酮乙醇溶液以1.93g/min进入在线混合器然后进入连续化反应装置(盘管)中反应，外浴控温为0～5℃，保留时间15min，出料口连接薄膜浓缩装置连续浓缩，浓缩液进入振荡器控温-55～-60℃在线析晶过滤产品，白色固体131.85g，收率85％。
实施例10
与实施例1的不同之处在于：保留时间为30min
自制2-甲基-2苯基[1.1.1.0 1,3]螺桨烷正丁醚溶液1.56kg，(NMR含量5.0％，折算原料78g)加入到第一打料装置中；2，3-丁二酮143g(1.1equiv.)，200ml助溶剂乙醇加入到第二打料装置中，配制成均一溶液；打开光源(波长为313nm的LED灯)，开启自动进料系统，控制柱塞泵原料A溶液以5.0g/min，2，3-丁二酮乙醇溶液以1g/min进入在线混合器然后进入连续化反应装置(盘管)中反应，外浴控温为0～5℃，保留时间30min，出料口连接薄膜浓缩装置连续浓缩，浓缩液进入振荡器控温-55～-60℃在线析晶过滤产品，白色固体136.48g，收率88％。
实施例11
与实施例1的不同之处在于：所加助溶剂为乙腈
自制2-甲基-2苯基[1.1.1.0 1,3]螺桨烷正丁醚溶液1.56kg，(NMR含量5.0％，折算原料78g)加入到第一打料装置中；2，3-丁二酮143g(1.1equiv.)，200ml助溶剂乙腈加入到第二打料装置中，配制成均一溶液；打开光源(波长为313nm的LED灯)，开启自动进料系统，控制柱塞泵原料A溶液以10g/min，2，3-丁二酮乙醇溶液以2g/min进入在线混合器然后进入连续化反 应装置(盘管)中反应，外浴控温为0～5℃，保留时间15min，出料口连接薄膜浓缩装置连续浓缩，浓缩液进入振荡器控温-55～-60℃在线析晶过滤产品，白色固体131.83g，收率85％。
从以上的描述中，可以看出，本发明上述的实施例实现了如下技术效果：
相比于现有的制备方法，采用上述以具有取代基的螺桨烷作为反应原料能够大幅提高反应原料的稳定性，降低其在光照下缓慢分解和变质的几率，从而能够在一定程度上提高反应原料的转化率和目标产物(1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物)的收率。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物的连续化合成方法，其特征在于，所述1,1’-二环[1.1.1]戊烷-1,3-二乙基酮类有机物具有式(Ⅲ)所示的结构：
    Figure PCTCN2019090736-appb-100001
    所述连续化合成方法包括：
    在光源的照射下，原料A和原料B连续地输送至连续化反应装置中进行连续化光化学反应，得到所述1,1'-二环[1.1.1]戊烷-1,3-二乙基酮类有机物，且在所述连续化光化学反应过程中，采用控温装置控制所述连续化反应装置中的反应温度，其中，所述原料A具有式(Ⅰ)所示的结构，所述原料B具有式(Ⅱ)所示的结构：
    Figure PCTCN2019090736-appb-100002
    所述R 1、所述R 2、所述R 3分别独立地选自氢、苄基、烷基、芳基、卤素、酯基、羧基或羟基，且所述R 1、所述R 2、所述R 3中至少一个不为氢；
    Figure PCTCN2019090736-appb-100003
    所述R 4和所述R 5分别独立地选自氢、烷基或芳基。
  2. 根据权利要求1所述的连续化合成方法，其特征在于，所述R 1、所述R 2、所述R 3分别独立地选自氢、苄基、甲基、苯基或羟基；所述R 4和所述R 5分别独立地选自氢、甲基、苄基或苯基。
  3. 根据权利要求1或2所述的连续化合成方法，其特征在于，在进行所述连续化光化学反应之前，所述连续化合成方法还包括：将所述原料A与溶剂混合形成混合液，然后将所述混合液输送至所述连续化反应装置中；
    优选地，所述溶剂选自正己烷、正庚烷、正丁醚、环己烷和环戊烷组成的组中的一种或多种。
  4. 根据权利要求1至3中任一项所述的连续化合成方法，其特征在于，所述光源为波长300～350nm的LED灯。
  5. 根据权利要求1或2所述的连续化合成方法，其特征在于，所述连续化光化学反应的反应温度为0～30℃，优选为0～5℃。
  6. 根据权利要求1或2所述的连续化合成方法，其特征在于，所述连续化光化学反应的反应时间为10～20min。
  7. 根据权利要求1或2所述的连续化合成方法，其特征在于，在进行所述连续化光化学反应的过程，所述连续化合成方法还包括：将助溶剂连续地输送至所述连续化反应装置中。
  8. 根据权利要求7所述的连续化合成方法，其特征在于，所述助溶剂选自甲醇、乙醇、乙酸乙酯、甲酸乙酯、丙酮、丁酮和乙腈组成的组中的一种或多种。
  9. 根据权利要求1至3中任一项所述的连续化合成方法，其特征在于，所述原料A和所述原料B的摩尔数之比为1:(1.0～1.5)。
  10. 根据权利要求1至3中任一项所述的连续化合成方法，其特征在于，所述连续化反应装置选自连续化反应盘管或柱状反应器。
PCT/CN2019/090736 2019-06-11 2019-06-11 1,1'-二环[1.1.1]戊烷-1,3-二乙基酮类有机物的连续化合成方法 WO2020248126A1 (zh)

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