CN105418478B - A kind of method for producing 4- oxyindoles - Google Patents

A kind of method for producing 4- oxyindoles Download PDF

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CN105418478B
CN105418478B CN201410471023.0A CN201410471023A CN105418478B CN 105418478 B CN105418478 B CN 105418478B CN 201410471023 A CN201410471023 A CN 201410471023A CN 105418478 B CN105418478 B CN 105418478B
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tower
solvent
reaction
catalyst
fixed bed
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CN105418478A (en
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高爽
张毅
李国松
吕迎
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Dalian Institute of Chemical Physics of CAS
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Dalian Institute of Chemical Physics of CAS
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Abstract

The present invention provides a kind of method of 4 oxyindole of continuous production, in fixed bed reactors, 1,5,6,7 tetrahydrochysene 4H indoles, 4 ketone, solvent, Pd/C catalyst carry out dehydroisomerization reaction, output material is reacted to be evaporated under reduced pressure by solvent destilling tower, tower top obtains circulation solvent, and solvent distillation tower bottoms obtains indoles by product destilling tower vacuum distillation tower top, and tower reactor obtains 4 oxyindoles.The problems such as work efficiency that the production technology overcomes current Batch Process is low, reaction and separation process are tediously long, and accessory substance separation is difficult, realizes continuous production, simplifies production technology, accessory substance has been effectively separated.

Description

A kind of method for producing 4- oxyindoles
Technical field
The present invention relates to a kind of method for producing 4- oxyindoles, belong to technical field of fine.
Background technology
4- oxyindoles are a kind of fine chemical products of high added value, can be used to synthesize the side such as medicine, spices, additive Face.The currently used synthetic method of 4- oxyindoles be by 1,5,6,7- tetrahydrochysene -4H- indoles -4- ketone, Pd/C catalyst, Solvent is added in autoclave, and heating heating carries out catalytic dehydrogenation isomerization reaction, cools down after reaction, filters to isolate Pd/C catalyst, filtrate obtain 4- oxyindoles by condensation-crystallization.Synthetically produced process used by 4- oxyindoles at present For Batch reaction processes, reaction process is relatively continuous, and reaction work efficiency is low, and needs to heat up and cooled down in reaction process Journey, pressure can produce fluctuation therewith；The Pd/C catalyst filtration separation process times are longer, and catalyst rapid wear in transfer process Lose；Accessory substance indoles is not easy to separate from crystalline product in product.
The content of the invention
In order to overcome relatively low current 4- oxyindoles synthetic method production process work efficiency, reaction and separation process superfluous The deficiencies of length, accessory substance indoles can not separate, the present invention provides a kind of continuous production processes of 4- oxyindoles.
The technical scheme is that：
A kind of production technology of 4- oxyindoles, the catalyst used is Pd/C catalyst, 1,5,6,7- tetrahydrochysene -4H- Yin Diindyl -4- ketone carries out dehydroisomerization reaction on fixed bed reactors, and reaction output material is evaporated under reduced pressure by solvent destilling tower, tower Top obtains circulation solvent mesitylene and returns in fixed bed reactors that the reaction was continued, and solvent distillation tower bottoms passes through product destilling tower Tower top obtains indoles, tower reactor obtains 4- oxyindoles for vacuum distillation.
Synthetic route reaction equation is：
Operating procedure is：
1) Pd/C catalyst is added by charge door a3 in fixed bed reactors internal catalyst bed layer, is led to by charge door a2 Enter hydrogen to be activated, after the completion of activation of catalyst, then nitrogen is continually fed into by charge door a2, tail gas passes through tail gas buffer Periodic off-gases are discharged, reaction temperature is adjusted the temperature to after nitrogen is full of reactor, pressure are adjusted to reaction pressure, by 1,5,6,7- Tetrahydrochysene -4H- indoles -4- ketone and mesitylene according to required mass ratio by charge door a1 the continuous feed into reactor, material Dehydroisomerization reaction is carried out on catalyst in reactor bed；
2) reactor outlet reaction product flows to the material inlet in the middle part of solvent destilling tower, subtracts by solvent destilling tower (T1) Pressure distillation, tower top obtain recyclable solvent mesitylene, and solvent mesitylene, which is back in fixed bed reactors, to be continued to participate in Reaction；
3) kettle liquid in solvent destilling tower is flowed out by tower bottom, flows to the material inlet in the middle part of product destilling tower, by production Product destilling tower is evaporated under reduced pressure, and tower top obtains indoles, 4- oxyindoles are obtained in the tower reactor of tower bottom.
In step 1) of the present invention, before fixed bed reactors internal catalyst bed layer adds Pd/C catalyst, nitrogen is first carried out Purging, nitrogen purging temperature is 20~50 DEG C, and nitrogen purging pressure is 0.1~0.5MPa, when purge time is 0.1~1 small.
In step 1) of the present invention, the mass ratio of 1,5,6,7- tetrahydrochysene -4H- indoles -4- ketone and mesitylene solvent is 1：2~ 25。
The load capacity of Pd is 1~10% in the Pd/C catalyst, and catalyst particle size is 0.5~60 mesh.
After Pd/C activation of catalyst in the fixed bed reactors, the reaction pressure of dehydroisomerization reaction is 0.3 ~2.5MPa, reaction temperature are 150~270 DEG C, and reaction velocity is controlled in 0.02~1.0h-1。
Shell and tube condenser is equipped with the top of fixed bed reactors, upper end of condenser is equipped with spherical surge tank, surge tank upper end Equipped with exhaust emissions pipeline.
Solvent destilling tower bottom temperature is at 60~185 DEG C, and tower top pressure is 0.001~0.05MPa, solvent overhead Equipped with condenser and surge tank, the circulation solvent mesitylene that tower top obtains is recycled in fixed bed reactors by charge door a1 The reaction was continued.
Product destilling tower bottom temperature is at 150~250 DEG C, and tower top pressure is 0.001~0.05MPa, product destilling tower tower Top is equipped with condenser and surge tank, and tower top obtains byproduct indoles, and tower reactor obtains product 4- oxyindoles.
Pd/C catalyst carries out activation process, when activation 4-16 is small in 200-400 DEG C of hydrogen atmosphere, Pd/C catalyst Filler blade diameter length ratio is 1:6~12, Pd/C catalyst filling amount and the volume ratio of fixed bed reactors inner cavity are 1:2.5~10.
Advantageous effects
The production technology of the present invention, temperature, pressure stability in reaction process, catalyst not easily run off in fixed bed, produce Accessory substance indoles in product can be effectively separated, and the present invention realizes continuous production, simplify production technology, effectively divide Accessory substance is separated out.
Brief description of the drawings
Fig. 1 is the technological process of production schematic diagram of 4- oxyindoles.
Marked in wherein Fig. 1 as follows：R1- fixed bed reactors；T1- solvent destilling towers；T2- product destilling towers；E1- tail gas Surge tank；E2- solvent destilling tower surge tanks；E3- product destilling tower surge tanks；
A1- charge doors, add 1,5,6,7- tetrahydrochysene -4H- indoles -4- ketone and solvent mesitylene；A2- charge doors, for gas The entrance of body, is passed through hydrogen and nitrogen；A3- charge doors, add Pd/C catalyst.
Embodiment
Following embodiments are used to the present invention be described in further detail, but are not construed as limiting the invention, tool of the invention Volume data is only limitted to absolutely not these embodiments.
As shown in Figure 1, being passed through nitrogen by the charge door a2 of reactor R1 first carries out nitrogen purging, tail gas passes through tail gas Surge tank E1 carries out periodic off-gases, and by charge door a3, into fixed bed reactors R1, catalyst bed adds Pd/C catalyst, leads to Cross charge door a2 and be passed through hydrogen into fixed bed reactors R1, in hydrogen atmosphere after activated catalyst, stopping is passed through hydrogen, holds It is continuous to be passed through nitrogen, the temperature of reactor R1 is adjusted to reaction temperature, adjusts pressure to reaction pressure, and regulate tail gas buffer E1 carries out periodic off-gases, and 1,5,6,7- tetrahydrochysene -4H- indoles -4- ketone and mesitylene are passed through charge door a1 according to certain mass ratio The continuous feed into reactor R1, material carry out dehydroisomerization reaction in R1 on catalyst bed, reaction product passes through reaction The outlet of device R1 is flowed in solvent destilling tower T1, and by vacuum distillation, solvent destilling tower T1 tower tops obtain the circulation equal front three of solvent Benzene, circulation solvent is back in reactor R1 by charge door a1 continues to participate in reaction, and solvent destilling tower T1 tower reactors flow to product Destilling tower T2, by vacuum distillation, product destilling tower T2 tower tops obtain indoles, and product destilling tower T2 tower reactors obtain 4- hydroxyls Yin Diindyl.
Embodiment 1
0.25MPa nitrogen is continually fed into by reactor R1 by charge door a2 first, it is small that 0.2 is purged under the conditions of 45 DEG C When, then, the Pd/C catalyst that Pd loadings are 5%, Pd/C catalysis are added into fixed bed reactors R1 by charge door a3 The amount of filler of agent is 1 with the volume ratio of fixed bed reactors R1 inner cavities:4, catalyst filling blade diameter length ratio is 1:6, pass through charge door A2 is passed through hydrogen into fixed bed reactors R1, when activation 4 is small in 200 DEG C of hydrogen atmospheres, after catalyst completes activation, holds It is continuous to be passed through nitrogen, in 160 DEG C, reaction pressure 0.5MPa, reaction velocity 0.025h of reaction temperature-1Under the conditions of, by 1,5,6,7- Tetrahydrochysene -4H- indoles -4- ketone is 1 according to mass ratio with mesitylene:10 are transported to fixed bed reactors R1 by charge door a1 Middle to carry out dehydroisomerization reaction, reaction product is flowed in solvent destilling tower T1 in fixed bed reactors R1, and solvent destilling tower T1 exists Temperature is 160 DEG C, and in the case of pressure is 0.02MPa, tower top obtains pure mesitylene, and solvent mesitylene is back to fixed bed again Reaction is continued to participate in reactor R1, solvent destilling tower T1 tower kettle products flow to product destilling tower T2, and product destilling tower T2 is in temperature Spend for 220 DEG C, in the case of pressure is 0.02MPa, product destilling tower T2 tower tops obtain the accessory substance Yin that mass yield is 0.9% Diindyl, product destilling tower T2 tower reactors obtain the product 4- oxyindoles that mass yield is 5.7%.
Embodiment 2
0.25MPa nitrogen is continually fed into by reactor R1 by charge door a2 first, it is small that 0.2 is purged under the conditions of 45 DEG C When, then, the Pd/C catalyst that Pd loadings are 10%, Pd/C catalysis are added into fixed bed reactors R1 by charge door a3 The amount of filler of agent is 1 with the volume ratio of fixed bed reactors R1 inner cavities:4, catalyst filling blade diameter length ratio is 1:6, pass through charge door A2 is passed through hydrogen into fixed bed reactors R1, when activation 10 is small in 400 DEG C of hydrogen atmospheres, after catalyst completes activation, Nitrogen is continually fed into, in 180 DEG C, reaction pressure 0.5MPa, reaction velocity 0.25h of reaction temperature-1Under the conditions of, by 1,5,6,7- Tetrahydrochysene -4H- indoles -4- ketone is 1 according to mass ratio with mesitylene:10 are transported to fixed bed reactors R1 by charge door a1 Middle to carry out dehydroisomerization reaction, reaction product is flowed in solvent destilling tower T1 in fixed bed reactors R1, and solvent destilling tower T1 exists Temperature is 160 DEG C, and tower top obtains pure mesitylene in the case of pressure is 0.02MPa, and solvent mesitylene is back to fixed bed again Reaction is continued to participate in reactor R1, solvent destilling tower T1 tower kettle products flow to product destilling tower T2, and product destilling tower T2 is in temperature Spend for 220 DEG C, in the case of pressure is 0.02MPa, product destilling tower T2 tower tops obtain the accessory substance Yin that mass yield is 0.8% Diindyl, product destilling tower T2 tower reactors obtain the product 4- oxyindoles that mass yield is 8.7%.
Embodiment 3
0.25MPa nitrogen is continually fed into by reactor R1 by charge door a2 first, it is small that 0.2 is purged under the conditions of 45 DEG C When, then, the Pd/C catalyst that Pd loadings are 10%, Pd/C catalysis are added into fixed bed reactors R1 by charge door a3 The amount of filler of agent is 1 with the volume ratio of fixed bed reactors R1 inner cavities:6, catalyst filling blade diameter length ratio is 1:5, pass through charge door A2 is passed through hydrogen into fixed bed reactors R1, when activation 12 is small in 400 DEG C of hydrogen atmospheres, after catalyst completes activation, Nitrogen is continually fed into, in 185 DEG C, reaction pressure 2.5MPa, reaction velocity 0.17h of reaction temperature-1Under the conditions of, by 1,5,6,7- Tetrahydrochysene -4H- indoles -4- ketone is 1 according to mass ratio with mesitylene:10 are transported to fixed bed reactors R1 by charge door a1 Middle to carry out dehydroisomerization reaction, reaction product is flowed in solvent destilling tower T1 in fixed bed reactors R1, and solvent destilling tower T1 exists Temperature is 180 DEG C, and tower top obtains pure mesitylene in the case of pressure is 0.02MPa,Solvent mesitylene is back to fixed bed again Reaction is continued to participate in reactor R1, solvent destilling tower T1 tower kettle products flow to product destilling tower T2, and product destilling tower T2 is in temperature Spend for 250 DEG C, in the case of pressure is 0.02MPa, product destilling tower T2 tower tops obtain the accessory substance Yin that mass yield is 0.7% Diindyl, product destilling tower T2 tower reactors obtain the product 4- oxyindoles that mass yield is 11.7%.
The method for proving a kind of continuous production 4- oxyindoles provided by the invention by above-described embodiment overcomes at present The problems such as work efficiency of Batch Process is low, reaction and separation process are tediously long, and accessory substance separation is difficult, realizes continuous production, letter Production technology is changed, accessory substance has been effectively separated.

Claims (6)

  1. A kind of 1. method for producing 4- oxyindoles, it is characterised in that
    Operating procedure is：
    1) Pd/C catalyst is added in fixed bed reactors (R1), hydrogen is passed through and is activated, after the completion of activation of catalyst, then Nitrogen is continually fed into, tail gas adjusts the temperature to anti-by tail gas buffer (E1) discharge periodic off-gases after nitrogen is full of reactor Temperature is answered, pressure is adjusted to reaction pressure, by 1,5,6,7- tetrahydrochysene -4H- indoles -4- ketone and mesitylene according to required mass ratio The continuous feed into reactor (R1), material carry out dehydroisomerization reaction on reactor (R1) internal catalyst bed layer；
    2) reactor (R1) outlet reaction product flows to the material inlet in the middle part of solvent destilling tower (T1), by solvent destilling tower (T1) it is evaporated under reduced pressure, tower top obtains recyclable solvent mesitylene, and solvent mesitylene is back to fixed bed reactors (R1) In continue to participate in reaction；
    3) kettle liquid in solvent destilling tower (T1) is flowed out by tower bottom, flows to the material inlet in the middle part of product destilling tower (T2), warp Product destilling tower (T2) vacuum distillation is crossed, tower top obtains indoles, 4- oxyindoles are obtained in the tower reactor of tower bottom；
    In step 1), before fixed bed reactors (R1) internal catalyst bed layer adds Pd/C catalyst, nitrogen purging, nitrogen are first carried out Air-blowing sweeps temperature as 20~50 DEG C, and nitrogen purging pressure is 0.1~0.5MPa, when purge time is 0.1~1 small；
    In step 1), the mass ratio of 1,5,6,7- tetrahydrochysene -4H- indoles -4- ketone and mesitylene solvent is 1：2~25；
    After Pd/C activation of catalyst in the fixed bed reactors (R1), the reaction pressure of dehydroisomerization reaction is 0.3 ~2.5MPa, reaction temperature are 150~270 DEG C, and reaction velocity is controlled in 0.02~1.0h-1；
    Pd/C catalyst carries out activation process, when activation 4-16 is small in 200-400 DEG C of hydrogen atmosphere.
  2. 2. according to the method described in claim 1, it is characterized in that：The load capacity of Pd is 1~10% in the Pd/C catalyst, Catalyst particle size is 0.5~60 mesh.
  3. 3. according to the method described in claim 1, it is characterized in that：Shell and tube is equipped with the top of fixed bed reactors (R1) to condense Device, upper end of condenser are equipped with spherical surge tank (E1), and surge tank (E1) upper end is equipped with exhaust emissions pipeline.
  4. 4. according to the method described in claim 1, it is characterized in that：Solvent destilling tower (T1) bottom temperature is at 60~185 DEG C, tower Pressure on top surface is 0.001~0.05MPa, and solvent destilling tower (T1) tower top is equipped with condenser and surge tank (E2), and what tower top obtained follows Ring solvent mesitylene is recycled in fixed bed reactors (R1) that the reaction was continued by charge door (a1).
  5. 5. according to the method described in claim 1, it is characterized in that：Product destilling tower (T2) bottom temperature at 150~250 DEG C, Tower top pressure is 0.001~0.05MPa, and product destilling tower (T2) tower top is equipped with condenser and surge tank (E3), and tower top obtains pair Product indoles, tower reactor obtain product 4- oxyindoles.
  6. 6. according to the method described in claim 1, it is characterized in that：Pd/C catalyst fillings blade diameter length ratio is 1:6~12, Pd/C are urged Agent amount of filler and the volume ratio of fixed bed reactors R1 inner cavities are 1:2.5~10.
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CN107954917A (en) * 2017-11-03 2018-04-24 苏州艾缇克药物化学有限公司 A kind of preparation method of 4- oxyindoles
CN115466207B (en) * 2022-09-19 2023-09-12 浙江华伟医药科技有限公司 Method for synthesizing 6-hydroxy indole by tubular fixed bed hydrogenation

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JPS60146870A (en) * 1984-01-06 1985-08-02 Kanegafuchi Chem Ind Co Ltd Production of 4-hydroxyindole
JPH07103103B2 (en) * 1990-11-30 1995-11-08 日本ゼオン株式会社 Process for producing 4-hydroxyindoles
JP2000044555A (en) * 1998-07-31 2000-02-15 Nippon Zeon Co Ltd Production of 4-hydroxyindole compound and its intermediate

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