WO2021051275A1 - 乙炔与酮类化合物进行加成反应的方法 - Google Patents

乙炔与酮类化合物进行加成反应的方法 Download PDF

Info

Publication number
WO2021051275A1
WO2021051275A1 PCT/CN2019/106220 CN2019106220W WO2021051275A1 WO 2021051275 A1 WO2021051275 A1 WO 2021051275A1 CN 2019106220 W CN2019106220 W CN 2019106220W WO 2021051275 A1 WO2021051275 A1 WO 2021051275A1
Authority
WO
WIPO (PCT)
Prior art keywords
acetylene
bubbling
reaction
ketone compound
gas
Prior art date
Application number
PCT/CN2019/106220
Other languages
English (en)
French (fr)
Inventor
洪浩
卢江平
丰惜春
张欣
颜博
Original Assignee
凯莱英生命科学技术(天津)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 凯莱英生命科学技术(天津)有限公司 filed Critical 凯莱英生命科学技术(天津)有限公司
Priority to PT199461351T priority Critical patent/PT4032873T/pt
Priority to CA3150254A priority patent/CA3150254C/en
Priority to KR1020227012829A priority patent/KR102656545B1/ko
Priority to JP2022517223A priority patent/JP7350998B2/ja
Priority to US17/642,937 priority patent/US20220380280A1/en
Priority to PCT/CN2019/106220 priority patent/WO2021051275A1/zh
Priority to HUE19946135A priority patent/HUE066856T2/hu
Priority to EP19946135.1A priority patent/EP4032873B1/en
Publication of WO2021051275A1 publication Critical patent/WO2021051275A1/zh

Links

Images

Classifications

    • 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
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C07C29/42—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing triple carbon-to-carbon bonds, e.g. with metal-alkynes
    • 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
    • B01J10/00—Chemical processes in general for reacting liquid with gaseous media other than in the presence of solid particles, or apparatus specially adapted therefor
    • B01J10/002—Chemical processes in general for reacting liquid with gaseous media other than in the presence of solid particles, or apparatus specially adapted therefor carried out in foam, aerosol or bubbles
    • 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
    • B01J19/0006—Controlling or regulating processes
    • B01J19/0013—Controlling the temperature of the process
    • 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
    • B01J19/24—Stationary reactors without moving elements inside
    • B01J19/2415—Tubular reactors
    • B01J19/242—Tubular reactors in series
    • 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
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/04—Acyclic alcohols with carbon-to-carbon triple bonds
    • C07C33/042—Acyclic alcohols with carbon-to-carbon triple bonds with only one triple bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/48—Preparation of compounds having groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14—Unsaturated ethers
    • C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
    • C07C43/1785—Unsaturated ethers containing hydroxy or O-metal groups having more than one ether bound
    • 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
    • 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
    • B01J2219/00049—Controlling or regulating processes
    • B01J2219/00051—Controlling the temperature
    • B01J2219/00074—Controlling the temperature by indirect heating or cooling employing heat exchange fluids
    • B01J2219/00087—Controlling the temperature by indirect heating or cooling employing heat exchange fluids with heat exchange elements outside the reactor
    • B01J2219/00094—Jackets

Definitions

  • the invention relates to the technical field of organic synthesis, in particular to a method for the addition reaction of acetylene and ketone compounds.
  • Acetylene is a flammable gas with a colorless aromatic odor.
  • the flash point is -17.78°C
  • the spontaneous ignition point is 305°C.
  • the explosion limit in the air is 2.3% to 72.3%.
  • acetylene and ketone compounds are very important type of reaction in the field of organic synthesis.
  • a potential anti-HIV agent 3',4'-Di-O-(-)-camphanoyl-(+)-cis-khellacton (DCK, deoxycytidine kinase)
  • DCK deoxycytidine kinase
  • acetylene gas with ketone under the action of strong alkali.
  • Acetylene is an extremely flammable gas, and there is a danger of violent explosion under a certain pressure. Due to the great potential safety hazards, it is difficult for acetylene to be directly used in industrial production.
  • acetylene gas is usually firstly reacted with a strong base, for example, acetylene and Grignard reagent are used to prepare ethynyl Grignard reagent, and then ethynyl Grignard reagent is used to complete the addition reaction with ketone.
  • a strong base for example, acetylene and Grignard reagent are used to prepare ethynyl Grignard reagent, and then ethynyl Grignard reagent is used to complete the addition reaction with ketone.
  • acetylene and Grignard reagent are used to prepare ethynyl Grignard reagent, and then ethynyl Grignard reagent is used to complete the addition reaction with ketone.
  • the following document Organic Letters2013vol.15#2p.238-241.
  • this process method still requires the use of acetylene gas, so there are also great safety hazards in the scale-up production
  • the reactor in industrial production, the reactor is usually over several thousand liters, and the reaction volume is huge.
  • the structural design of the traditional batch reactor is not suitable for gas-liquid two-phase reaction under normal pressure, and acetylene gas needs to be vented into the reaction system all the time during the reaction process. Acetylene gas is greatly excessive, the utilization rate is low, and it is easy to cause acetylene to accumulate in the reactor and reaction pipeline, which poses great safety risks.
  • the present invention aims to provide a method for the addition reaction of acetylene and ketone compounds to realize the safe progress of the addition reaction of acetylene and ketone compounds.
  • a method for the addition reaction of acetylene and ketone compounds includes the following steps: S1, a continuous reaction device is provided, the continuous reaction device includes a plurality of bubbling tubular reactors arranged in series, and the plurality of bubbling tubular reactors are connected by a connecting pipe; S2, a ketone compound and The raw material solution of the base is sent to a plurality of bubble tube reactors; and S3, under normal pressure, acetylene is bubbled from the bottom of the first bubble tube reactor for addition reaction.
  • the raw material solution is contained in a raw material tank, and the raw material solution is pumped into a plurality of bubbling tubular reactors through a raw material pump.
  • a temperature control jacket is provided on the periphery of the multiple bubbling tubular reactors.
  • the method further includes: S4, sending the reaction product discharged from the bubbling tubular reactor into a gas-liquid separator for gas-liquid separation.
  • the acetylene separated in the gas-liquid separator is diluted with nitrogen and emptied.
  • the ketone compound is an alkyl ketone compound, a ketone compound with a halogen or alkoxy functional group; preferably, the base is potassium/sodium tert-butoxide or potassium/sodium tert-pentoxide.
  • ketone compound when the ketone compound is When, control the reaction temperature of the bubbling tubular reactor to be 0 ⁇ 5°C, and the reaction time to be 0.5 ⁇ 4h, The molar ratio with acetylene is (1.0 ⁇ 0.2):1.
  • ketone compound when the ketone compound is When, control the reaction temperature of the bubbling tubular reactor to be 10-15°C, and the reaction time to be 0.5-4h, The molar ratio with acetylene is (1.0 ⁇ 0.2):1.
  • the reaction time is 0.5 ⁇ 4h
  • the molar ratio with acetylene is (1.0 ⁇ 0.2):1.
  • acetylene and ketone compounds are reacted in multiple bubbling tubular reactors arranged in series, which can ensure sufficient gas-liquid contact time, which can make full use of acetylene gas and improve the utilization rate of acetylene gas , Effectively reduce the amount of acetylene, reduce costs, and further increase safety.
  • Fig. 1 shows a schematic structural diagram of a continuous reaction device according to an embodiment of the present invention.
  • this application provides a gas-liquid two-phase continuous reaction process, which can realize the efficient utilization of acetylene gas under normal pressure, and can avoid the accumulation of a large amount of acetylene gas during the reaction process. Dangerous, so that the safety of the process is greatly improved, so that the process is more suitable for industrial production.
  • a method for the addition reaction of acetylene and ketone compounds includes the following steps: S1, a continuous reaction device is provided, the continuous reaction device includes a plurality of bubbling tubular reactors arranged in series, and the plurality of bubbling tubular reactors are connected by a connecting pipe; S2, a ketone compound and The raw material solution of the base is sent to a plurality of bubble tube reactors; and S3, under normal pressure, acetylene is bubbled from the bottom of the first bubble tube reactor for addition reaction.
  • acetylene and ketone compounds are reacted in multiple bubbling tubular reactors arranged in series, which can ensure sufficient gas-liquid contact time, which can make full use of acetylene gas and improve the utilization rate of acetylene gas , Effectively reduce the amount of acetylene, reduce costs, and further increase safety.
  • the present invention uses a continuous reaction device, a small reactor volume can complete the production of thousands of liters of reaction system, for example, the reactor volume of the production level can be only 100L, and can be reacted according to production requirements
  • the volume of the device is reduced to a smaller size, which effectively avoids the accumulation of acetylene gas and a large amount of solution after dissolving the acetylene gas, thereby making the risk more controllable.
  • the number of bubbling tubular reactors can be increased or decreased according to process requirements in order to ensure sufficient gas-liquid contact time to maximize the utilization of acetylene.
  • the raw material solution is contained in a raw material tank, and the raw material solution is pumped into a plurality of bubbling tubular reactors through a raw material pump, which is convenient for industrial production.
  • a temperature control jacket is provided on the periphery of the multiple bubbling tubular reactors.
  • the method further includes: S4, sending the reaction product discharged from the bubbling tubular reactor into a gas-liquid separator for gas-liquid separation, and a small amount of acetylene tail gas produced during the operation of the process can be used in the gas-liquid separator , After being fully diluted with nitrogen, it is emptied to maximize process safety.
  • the technical scheme of the present invention can be applied to ketone compounds compatible with strong alkaline reagents, such as potassium tert-butoxide and potassium acetylene.
  • the ketone compounds include alkyl ketone compounds, and ketones with halogen or alkoxy functional groups. Compound etc.
  • the reaction temperature of the bubbling tubular reactor is controlled to be 0-5°C, and the reaction time is 0.5-4h, preferably 2h,
  • the molar ratio with acetylene is (1.0 ⁇ 0.2):1; when the ketone compound is At this time, the reaction temperature of the bubbling tubular reactor is controlled to be 10-15°C, and the reaction time is 0.5-4h, preferably 30 minutes,
  • the molar ratio with acetylene is (1.0 ⁇ 0.2):1; preferably, when the ketone compound is When controlling the reaction temperature of the bubbling tubular reactor to be -40 to 30°C, and the reaction time to be 0.5 to 4 hours, preferably 3 hours,
  • the molar ratio with acetylene is (1.0 ⁇ 0.2):1.
  • the continuous reaction device is shown in Figure 1 and includes: a power system: a raw material pump 21, a continuous reactor: a first bubbling tubular reactor 31, a second bubbling tubular reactor and a third drum
  • the bubble tube reactor together constitutes a continuous gas-liquid two-phase reactor; it also includes a raw material tank 11, an acetylene gas cylinder 12, a nitrogen gas cylinder 13, a receiving tank 14, and a temperature control jacket 41 for controlling the temperature of the reactor.
  • the first bubbling tubular reactor 31, the second bubbling tubular reactor and the third bubbling tubular reactor with a larger diameter are connected in series via a connecting pipe with a smaller diameter.
  • the raw material tank 11 is used to store the prepared main raw material/strong alkali solution.
  • the feed liquid is pumped into the reactor by the feed pump 21.
  • the acetylene flow rate in the acetylene gas cylinder 12 can be controlled by any gas flow rate controller, such as a gas mass flow meter.
  • the acetylene gas emitted from the acetylene gas cylinder 12 is combined with the raw material solution, it enters from the lower end of the first bubbling tubular reactor 31.
  • the temperature required for the first bubbling tubular reactor 31, the second bubbling tubular reactor and the third bubbling tubular reactor is controlled by the temperature control jacket 41.
  • acetylene gas flows upward in a bubbling shape.
  • the raw material solution flows upward as a continuous phase.
  • the reaction system reaches the upper end of the tubular reactor, it passes through the thinner connecting pipe 32 between the first bubbling tubular reactor 31 and the second bubbling tubular reactor to reach the bottom of the next second bubbling tubular reactor.
  • the reaction system continuously flows back and forth to the outlet end of the reactor in this way.
  • the acetylene gas is bubbled in the first bubbling tubular reactor 31, and its flow rate is greater than the liquid flow rate.
  • the acetylene gas and the liquid flow in stages, and the gas-liquid flow rate is the same.
  • the number of bubbling tubular reactors can be adjusted according to the required reaction time (gas-liquid contact time). Since this set of reactors can ensure sufficient gas-liquid contact time, acetylene gas can be fully utilized instead of requiring a large excess of acetylene gas as in traditional batch reaction processes.
  • a large number of acetylene gas bubbles exist in the first bubbling tubular reactor 31, a large number of acetylene gas bubbles exist. As the gas and liquid flow backward, the number of bubbles in the second bubbling tubular reactor and the third bubbling tubular reactor gradually decreases.
  • the outlet of the third bubbling tubular reactor is connected to the gas-liquid separator 33. Excess acetylene gas can be evacuated after being diluted by nitrogen to comply with regulations. The finally reacted system is received by the receiving tank 14.
  • the raw material ketone and potassium tert-butoxide are dissolved in 10 times the volume of the raw material ketone in tetrahydrofuran, and the resulting solution is called the SM solution.
  • Connect the SM solution to the feed pump in the reaction device. Adjust the temperature of the reaction device to the specified temperature. According to the size of the reactor and the required reaction time, the SM solution feed rate is calculated. According to the SM solution feed rate and the required acetylene equivalent, the acetylene feed rate is calculated. Simultaneously turn on the SM solution feed pump and the acetylene steel cylinder, and feed materials into the reaction device simultaneously according to the set flow rate. Take samples at the sampling point at the outlet of the reaction device to track and monitor the reaction. After the SM solution is completely pumped into the reaction device, continue to pump the solvent tetrahydrofuran into the reaction device to replace all the reaction system into the receiving flask or the receiving kettle.
  • the device shown in FIG. 1 was used to carry out the reaction.
  • the volume of the reactor is small, which can effectively avoid the accumulation of a large amount of acetylene, and can minimize the risk during the reaction;

Landscapes

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

Abstract

本发明公开了一种乙炔与酮类化合物进行加成反应的方法。该方法包括以下步骤：S1，提供连续反应装置，连续反应装置包括串联设置的多个鼓泡管状反应器，多个鼓泡管状反应器之间通过连接管连接；S2，将含有酮类化合物和碱的原料溶液送入多个鼓泡管状反应器中；以及S3，在常压下，将乙炔从首个鼓泡管状反应器的底部鼓入进行加成反应。应用本发明的技术方案，乙炔与酮类化合物在串联设置的多个鼓泡管状反应器中反应，可以保证充足的气液接触时间，这就可以使乙炔气得到充分利用，提高乙炔气利用率，有效减少乙炔用量，降低成本的同时，进一步增加安全性。

Description

乙炔与酮类化合物进行加成反应的方法 技术领域
本发明涉及有机合成技术领域，具体而言，涉及一种乙炔与酮类化合物进行加成反应的方法。
背景技术
乙炔为无色芳香气味的易燃气体。闪点-17.78℃，自燃点305℃。在空气中爆炸极限2.3％～72.3％。在液态和固态下，或在气态和一定压力下有猛烈爆炸的危险，受热、震动、电火花等因素都可以引发爆炸。
乙炔与酮类化合物之间的加成反应，在有机合成领域，是一类非常重要的反应。例如，一种潜在的抗HIV试剂，3',4'-Di-O-(-)-camphanoyl-(+)-cis-khellacton(DCK，脱氧胞苷激酶)，其合成中的关键一步，就是乙炔气在强碱作用下与酮的加成反应。而乙炔是一种极易燃气体，且在一定压力下有猛烈爆炸的危险。由于存在极大的安全隐患，这使乙炔很难被直接用于工业化生产。例如文献Bioorganic and Medicinal Chemistry Letters2004vol.14#23p.5855-5857中记载，在实验室研究过程中，使用叔丁醇钾作为强碱，直接使用乙炔气与酮进行加成反应，制取所需化合物。但是这种方法仅限于实验室制备使用，无法进行工业化放大。
因此在有机合成领域，通常是先将乙炔气与强碱反应，例如利用乙炔和格式试剂反应制备乙炔基格式试剂，然后再利用乙炔基格式试剂完成与酮的加成反应。例如如下文献：Organic Letters2013vol.15#2p.238-241。但是这种工艺方法依然需要使用乙炔气，因此在放大生产过程中，同样存在极大的安全隐患。而如果直接采购使用乙炔基格式试剂，则由于乙炔基格式试剂的高昂成本，必然导致工艺成本成倍增加。
另外，传统的批次反应工艺，在进行工业化生产时，其反应釜通常在几千升以上，反应体积巨大。且传统的批次反应釜，其结构设计并不适合于常压下的气液两相反应，反应过程中需要一直向反应体系中通乙炔气。乙炔气大大过量，利用率低，且很容易使乙炔在反应釜，反应管路中形成蓄积，存在极大安全隐患。
发明内容
本发明旨在提供一种乙炔与酮类化合物进行加成反应的方法，以实现乙炔与酮类化合物加成反应的安全进行。
为了实现上述目的，根据本发明的一个方面，提供了一种乙炔与酮类化合物进行加成反应的方法。该方法包括以下步骤：S1，提供连续反应装置，连续反应装置包括串联设置的多个鼓泡管状反应器，多个鼓泡管状反应器之间通过连接管连接；S2，将含有酮类化合物和碱的原料溶液送入多个鼓泡管状反应器中；以及S3，在常压下，将乙炔从首个鼓泡管状反应器 的底部鼓入进行加成反应。
进一步地，S2中，原料溶液盛放在原料罐中，通过原料泵将原料溶液泵入多个鼓泡管状反应器中。
进一步地，多个鼓泡管状反应器的外围设置有控温夹套。
进一步地，该方法进一步包括：S4，将从鼓泡管状反应器排出的反应产物送入气液分离器进行气液分离。
进一步地，气液分离器中分离出的乙炔由氮气稀释后排空。
进一步地，酮类化合物为烷基酮类化合物，带有卤素或烷氧基官能团的酮类化合物；优选的，碱为叔丁醇钾/钠或叔戊醇钾/钠。
进一步地，当酮类化合物为
Figure PCTCN2019106220-appb-000001
时，控制鼓泡管状反应器的反应温度为0～5℃，反应时间为0.5～4h，
Figure PCTCN2019106220-appb-000002
与乙炔的摩尔比为(1.0～0.2)：1。
进一步地，当酮类化合物为
Figure PCTCN2019106220-appb-000003
时，控制鼓泡管状反应器的反应温度为10～15℃，反应时间为0.5～4h，
Figure PCTCN2019106220-appb-000004
与乙炔的摩尔比为(1.0～0.2)：1。
进一步地，当酮类化合物为
Figure PCTCN2019106220-appb-000005
时，控制鼓泡管状反应器的反应温度为-40～30℃，反应时间为0.5～4h，
Figure PCTCN2019106220-appb-000006
与乙炔的摩尔比为(1.0～0.2)：1。
应用本发明的技术方案，乙炔与酮类化合物在串联设置的多个鼓泡管状反应器中反应，可以保证充足的气液接触时间，这就可以使乙炔气得到充分利用，提高乙炔气利用率，有效减少乙炔用量，降低成本的同时，进一步增加安全性。
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示出了本发明一实施方式的连续反应装置的结构示意图。
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。下面将参考附图并结合实施例来详细说明本发明。
针对背景技术中描述的一系列技术问题，本申请提供了一种气液两相连续反应工艺，该工艺可在常压下实现乙炔气的高效利用，可避免反应过程中，大量乙炔气蓄积的危险，使工艺安全性得到极大提高，从而使该工艺更加适合于工业化生产。
根据本发明一种典型的实施方式，提供一种乙炔与酮类化合物进行加成反应的方法。该方法包括以下步骤：S1，提供连续反应装置，连续反应装置包括串联设置的多个鼓泡管状反应器，多个鼓泡管状反应器之间通过连接管连接；S2，将含有酮类化合物和碱的原料溶液送入多个鼓泡管状反应器中；以及S3，在常压下，将乙炔从首个鼓泡管状反应器的底部鼓入进行加成反应。
应用本发明的技术方案，乙炔与酮类化合物在串联设置的多个鼓泡管状反应器中反应，可以保证充足的气液接触时间，这就可以使乙炔气得到充分利用，提高乙炔气利用率，有效减少乙炔用量，降低成本的同时，进一步增加安全性。另外，本发明采用的是连续反应装置，较小的反应器体积即可完成数千升反应体系的生产，例如，其生产级别的反应器体积可仅为100L，并且可根据生产需求，将反应器体积减至更小，这有效避免了乙炔气，及溶解乙炔气后的溶液的大量蓄积，从而使危险更加可控。
鼓泡管状反应器数量，可根据工艺需要增减，目的是确保足够的气液接触时间，使乙炔利用率达到最大。优选的，S2中，原料溶液盛放在原料罐中，通过原料泵将原料溶液泵入多个鼓泡管状反应器中，这样便于工业化生产的进行。
为了方便温度的控制，多个鼓泡管状反应器的外围设置有控温夹套。
优选的，该方法进一步包括：S4，将从鼓泡管状反应器排出的反应产物送入气液分离器进行气液分离，工艺运行过程中，产生的少量乙炔尾气，可在气液分离器中，经过氮气的充分稀释后排空，使工艺安全达到最大化。
本发明的技术方案可以应用于可与强碱性试剂，例如叔丁醇钾，乙炔钾兼容的酮类化合物，酮类化合物包括烷基酮类化合物，带有卤素或烷氧基官能团的酮类化合物等。
应用本发明的技术方案，需要根据具体的酮类化合物确定具体的反应条件，例如，当酮类化合物为
Figure PCTCN2019106220-appb-000007
时，控制鼓泡管状反应器的反应温度为0～5℃，反应时间为0.5～4h，优选为2h，
Figure PCTCN2019106220-appb-000008
与乙炔的摩尔比为(1.0～0.2)：1；当酮类化合物为
Figure PCTCN2019106220-appb-000009
时，控制鼓 泡管状反应器的反应温度为10～15℃，反应时间为0.5～4h，优选为30分钟，
Figure PCTCN2019106220-appb-000010
与乙炔的摩尔比为(1.0～0.2)：1；优选的，当酮类化合物为
Figure PCTCN2019106220-appb-000011
时，控制鼓泡管状反应器的反应温度为-40～30℃，反应时间为0.5～4h，优选为3h，
Figure PCTCN2019106220-appb-000012
与乙炔的摩尔比为(1.0～0.2)：1。
在本发明一实施方式中，连续反应装置如图1所示，包括：动力系统：原料泵21，连续反应器：第一鼓泡管状反应器31、第二鼓泡管状反应器和第三鼓泡管状反应器共同组成连续气液两相反应器；还包括原料罐11，乙炔气体钢瓶12、氮气气体钢瓶13、接收罐14以及用于控制反应器温度的控温夹套41。整套反应器中，直径较粗的第一鼓泡管状反应器31、第二鼓泡管状反应器和第三鼓泡管状反应器经由直径较细的连接管串联连接。其中，原料罐11用于存储配制好的主原料/强碱溶液。工艺流程启动后由原料泵21将料液泵入反应器。乙炔气体钢瓶12中乙炔流速可由任意气体流速控制器进行控制，例如气体质量流量计。由乙炔气体钢瓶12放出的乙炔气与原料溶液会和后，从第一根鼓泡管状反应器31下端进入。第一鼓泡管状反应器31、第二鼓泡管状反应器和第三鼓泡管状反应器所需温度由控温夹套41控制。在第一鼓泡管状反应器31中，乙炔气成鼓泡状向上流动。原料溶液作为连续相向上流动。当反应体系到达管状反应器上端时，通过第一鼓泡管状反应器31和第二鼓泡管状反应器间较细的连接管32到达下一根第二鼓泡管状反应器的底部。反应体系如此往复连续的向反应器的出口端流动。乙炔气在第一鼓泡管状反应器31中呈鼓泡状，其流速大于液体流速。在第二鼓泡管状反应器中，乙炔气与液体呈分段式流动，气液流速相同。整套反应器，可根据所需反应时间(气液接触时间)来调整鼓泡管状反应器数量。由于该套反应器可以保证充足的气液接触时间，这就可以使乙炔气得到充分利用，而不用像传统批次反应工艺中，需要乙炔气大大过量。如图1所示，在第一鼓泡管状反应器31中，乙炔气气泡大量存在。而随着气体及液体向后流动，第二鼓泡管状反应器和第三鼓泡管状反应器中气泡数量逐渐减少。第三鼓泡管状反应器出口与气液分离器33连接。过量的乙炔气可在此处由氮气稀释至合规后排空。最后反应完的体系由接收罐14接收。
下面将结合实施例进一步说明本发明的有益效果。
实施例1
Figure PCTCN2019106220-appb-000013
根据上述反应式，采用如图1所示的装置(连续反应装置)及批次反应工艺进行反应，具体参数及结果如表1所示。
将原料酮和叔丁醇钾溶于10倍原料酮体积量的四氢呋喃中，所形成溶液称为SM溶液。将SM溶液与反应装置中的进料泵相连接。将反应装置温度调至指定温度。根据反应器大小及所需反应时间，计算SM溶液进料速率。根据SM溶液进料速率，及所需乙炔当量，计算乙炔进料速率。同时开启SM溶液进料泵及乙炔钢瓶，按照设定流速同时向反应装置中进料。在反应装置出口处取样点取样，跟踪监测反应情况。待SM溶液全部泵入反应装置后，继续向反应装置中泵入溶剂四氢呋喃，以将反应体系全部置换到接收瓶或接收釜中。
表1
Figure PCTCN2019106220-appb-000014
实施例2
Figure PCTCN2019106220-appb-000015
根据上述反应式，采用如图1所示的装置进行反应，步骤参见实施例1，具体参数及结果 如表2所示。
表2
Figure PCTCN2019106220-appb-000016
实施例3
Figure PCTCN2019106220-appb-000017
根据上述反应式，采用如图1所示的装置进行反应，步骤参见实施例1，具体参数及结果如表3所示。
表3
Figure PCTCN2019106220-appb-000018
Figure PCTCN2019106220-appb-000019
以上实施例说明，该反应可成功应用于100Kg级以上的放大生产，不仅没有放大效应，且工艺安全，可靠。成功实现了在生产级别的合成中直接应用乙炔气。除此之外，相较批次工艺，乙炔利用率大大提升，进一步节省了成本及提高了工艺安全性。
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：
1)反应器体积小，可有效避免大量乙炔的蓄积，可将反应过程中的危险降至最低；
2)可提高乙炔利用率，有效减小乙炔用量，节省成本，同时进一步提高安全性；
3)稍过量的乙炔气不存在蓄积现象，而是在工艺运行过程中，在气液分离器处，由稀释氮气连续稀释后排空。
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 (9)

  1. 一种乙炔与酮类化合物进行加成反应的方法，其特征在于，包括以下步骤：
    S1，提供连续反应装置，所述连续反应装置包括串联设置的多个鼓泡管状反应器，多个所述鼓泡管状反应器之间通过连接管连接；
    S2，将含有所述酮类化合物和碱的原料溶液送入多个所述鼓泡管状反应器中；以及
    S3，在常压下，将乙炔从首个所述鼓泡管状反应器的底部鼓入进行所述加成反应。
  2. 根据权利要求1所述的方法，其特征在于，所述S2中，所述原料溶液盛放在原料罐中，通过原料泵将所述原料溶液泵入多个所述鼓泡管状反应器中。
  3. 根据权利要求1所述的方法，其特征在于，多个所述鼓泡管状反应器的外围设置有控温夹套。
  4. 根据权利要求1所述的方法，其特征在于，所述方法进一步包括：S4，将从所述鼓泡管状反应器排出的反应产物送入气液分离器进行气液分离。
  5. 根据权利要求4所述的方法，其特征在于，所述气液分离器中分离出的乙炔由氮气稀释后排空。
  6. 根据权利要求1所述的方法，其特征在于，所述酮类化合物为烷基酮类化合物，带有卤素或烷氧基官能团的酮类化合物；
    优选的，所述碱为叔丁醇钾/钠或叔戊醇钾/钠。
  7. 根据权利要求6所述的方法，其特征在于，当所述酮类化合物为
    Figure PCTCN2019106220-appb-100001
    时，控制所述鼓泡管状反应器的反应温度为0～5℃，反应时间为0.5～4h，
    Figure PCTCN2019106220-appb-100002
    与乙炔的摩尔比为(1.0～0.2)：1。
  8. 根据权利要求1所述的方法，其特征在于，当所述酮类化合物为
    Figure PCTCN2019106220-appb-100003
    时，控制所述鼓泡管状反应器的反应温度为10～15℃，反应时间为0.5～4h，
    Figure PCTCN2019106220-appb-100004
    与乙炔的摩尔比为(1.0～0.2)：1。
  9. 根据权利要求1所述的方法，其特征在于，当所述酮类化合物为
    Figure PCTCN2019106220-appb-100005
    时，控制所述鼓泡管状反应器的反应温度为-40～30℃，反应时间为0.5～4h，
    Figure PCTCN2019106220-appb-100006
    与乙炔的摩尔比为(1.0～0.2)：1。
PCT/CN2019/106220 2019-09-17 2019-09-17 乙炔与酮类化合物进行加成反应的方法 WO2021051275A1 (zh)

Priority Applications (8)

Application Number Priority Date Filing Date Title
PT199461351T PT4032873T (pt) 2019-09-17 2019-09-17 Método para efectuar a reacção de adição entre acetileno e um composto de cetona
CA3150254A CA3150254C (en) 2019-09-17 2019-09-17 Method for addition reaction of acetylene and ketone compound
KR1020227012829A KR102656545B1 (ko) 2019-09-17 2019-09-17 아세틸렌과 케톤계 화합물의 부가 반응 방법
JP2022517223A JP7350998B2 (ja) 2019-09-17 2019-09-17 アセチレンとケトン系化合物との付加反応方法
US17/642,937 US20220380280A1 (en) 2019-09-17 2019-09-17 Method for addition reaction of acetylene and ketone compound
PCT/CN2019/106220 WO2021051275A1 (zh) 2019-09-17 2019-09-17 乙炔与酮类化合物进行加成反应的方法
HUE19946135A HUE066856T2 (hu) 2019-09-17 2019-09-17 Módszer az acetilén és ketonvegyület közötti addíciós reakció végrehajtására
EP19946135.1A EP4032873B1 (en) 2019-09-17 2019-09-17 Method for performing addition reaction between acetylene and ketone compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2019/106220 WO2021051275A1 (zh) 2019-09-17 2019-09-17 乙炔与酮类化合物进行加成反应的方法

Publications (1)

Publication Number Publication Date
WO2021051275A1 true WO2021051275A1 (zh) 2021-03-25

Family

ID=74883429

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/106220 WO2021051275A1 (zh) 2019-09-17 2019-09-17 乙炔与酮类化合物进行加成反应的方法

Country Status (8)

Country Link
US (1) US20220380280A1 (zh)
EP (1) EP4032873B1 (zh)
JP (1) JP7350998B2 (zh)
KR (1) KR102656545B1 (zh)
CA (1) CA3150254C (zh)
HU (1) HUE066856T2 (zh)
PT (1) PT4032873T (zh)
WO (1) WO2021051275A1 (zh)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1312784A (zh) * 1998-08-17 2001-09-12 巴斯福股份公司 炔二醇的制备方法
WO2010119448A1 (en) * 2009-04-17 2010-10-21 Hindustan Organic Chemicals Limited An 'in-situ' prepared, improved catalyst for low pressure continuous butynediol synthesis
CN102076701A (zh) * 2008-07-01 2011-05-25 莫门蒂夫性能材料股份有限公司 用于气态不饱和烃的氢化硅烷化方法
CN109796304A (zh) * 2019-02-22 2019-05-24 重庆弛源化工有限公司 一种bed的合成方法
CN109897010A (zh) * 2019-03-04 2019-06-18 天津凯莱英制药有限公司 一种1,2,3-三氮唑类化合物的连续合成方法
CN110540489A (zh) * 2019-09-17 2019-12-06 凯莱英生命科学技术(天津)有限公司 乙炔与酮类化合物进行加成反应的方法

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL7414755A (nl) * 1973-11-20 1975-05-22 Basf Ag Werkwijze voor het ethynyleren.
JPS516123A (zh) * 1974-07-06 1976-01-19 Nippon Steel Corp
JPS5911569B2 (ja) * 1980-03-14 1984-03-16 株式会社クラレ プロパルギル型アルコ−ルおよびその製法
JPS56156226A (en) * 1980-05-08 1981-12-02 Dainippon Ink & Chem Inc Treating method of ethynylcarbinol compound solution
JPS5955840A (ja) * 1982-09-24 1984-03-31 Ube Ind Ltd 光学活性プロパルギルアルコ−ル類の製法
JPS6379852A (ja) * 1986-09-24 1988-04-09 Idemitsu Petrochem Co Ltd トリメリツト酸の製造方法
DE19907532A1 (de) * 1999-02-22 2000-08-31 Basf Ag Verfahren zur Herstellung von Acetylenalkoholen und deren Folgeprodukten
JP3659109B2 (ja) 2000-01-19 2005-06-15 三菱化学株式会社 エチレングリコールと炭酸エステルの併産方法
DE10123066A1 (de) * 2001-05-11 2002-11-14 Basf Ag Verfahren zur Herstellung von höheren alpha,beta-ungesättigten Alkoholen
KR100880081B1 (ko) 2001-09-28 2009-01-23 디에스엠 아이피 어셋츠 비.브이. 에티닐화 방법

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1312784A (zh) * 1998-08-17 2001-09-12 巴斯福股份公司 炔二醇的制备方法
CN102076701A (zh) * 2008-07-01 2011-05-25 莫门蒂夫性能材料股份有限公司 用于气态不饱和烃的氢化硅烷化方法
WO2010119448A1 (en) * 2009-04-17 2010-10-21 Hindustan Organic Chemicals Limited An 'in-situ' prepared, improved catalyst for low pressure continuous butynediol synthesis
CN109796304A (zh) * 2019-02-22 2019-05-24 重庆弛源化工有限公司 一种bed的合成方法
CN109897010A (zh) * 2019-03-04 2019-06-18 天津凯莱英制药有限公司 一种1,2,3-三氮唑类化合物的连续合成方法
CN110540489A (zh) * 2019-09-17 2019-12-06 凯莱英生命科学技术(天津)有限公司 乙炔与酮类化合物进行加成反应的方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 14, no. 23, 2004, pages 5855 - 5857
ORGANIC LETTERS, vol. 15, no. 2, 2013, pages 238 - 241

Also Published As

Publication number Publication date
KR102656545B1 (ko) 2024-04-09
CA3150254A1 (en) 2021-03-25
EP4032873B1 (en) 2024-02-21
HUE066856T2 (hu) 2024-09-28
CA3150254C (en) 2024-01-02
EP4032873A1 (en) 2022-07-27
US20220380280A1 (en) 2022-12-01
PT4032873T (pt) 2024-06-14
EP4032873A4 (en) 2023-06-28
KR20220065015A (ko) 2022-05-19
JP2022548164A (ja) 2022-11-16
JP7350998B2 (ja) 2023-09-26

Similar Documents

Publication Publication Date Title
CN103232382B (zh) 一种乙基咔唑的加氢方法及其产物的脱氢方法
CN108586203A (zh) 一种制备高反/反异构物比例的氢化型丙二酚的氢化方法
CN106588735A (zh) 一种双（叔丁基过氧化异丙基）苯的生产方法
WO2021114460A1 (zh) 基于连续流反应的双温区两段法生产对乙酰胺基苯磺酰氯的方法
CN110540489B (zh) 乙炔与酮类化合物进行加成反应的方法
WO2021051275A1 (zh) 乙炔与酮类化合物进行加成反应的方法
CN104557536B (zh) 一种丁二酸单甲酯的制备方法
CN105330693B (zh) 一种烃基二卤化磷的制备方法
CN113754512A (zh) 邻溴三氟甲苯的制备方法
CN106279097A (zh) 一种丙烯基‑1,3‑磺酸内酯的制备方法
CN111825705B (zh) 一种三氟化硼二甲基硫醚络合物的制备方法
CN109265384B (zh) 一种制备过氧化二碳酸二(2-乙基己基)酯的方法
CN103102369B (zh) 一种乙基膦酸二乙酯的生产方法
CN106187993A (zh) 一种微通道反应器合成5‑氯‑2‑甲酰氯噻吩的方法
CN210584939U (zh) 格氏试剂的生产装置
CN106518595B (zh) 一种四氢三环戊二烯的连续异构化的方法
CN110372462B (zh) 连续化合成-纯化一体装置及含有其的连续化反应系统
CN114426501A (zh) 基于水相反应的溴代沙坦联苯的制备方法
CN113264819A (zh) 一种基于连续流反应技术快速合成3-溴-2-氟苯甲醛的方法
CN113150021A (zh) 一种采用微通道反应器合成三氟化硼络合物的方法
CN115724788A (zh) 一种阻聚剂702的微通道合成方法
CN110845504A (zh) 合成赞布替尼的新方法
CN216756367U (zh) 2-羟基四氢呋喃连续生产装置
CN219942788U (zh) 一种芳基硼酸及其衍生物合成装置
CN108793198B (zh) 一种氟化氢钾的制备方法及其制备系统

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: 19946135

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3150254

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2022517223

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20227012829

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2019946135

Country of ref document: EP

Effective date: 20220419