CN107698452A - A kind of synthetic method of the hydroxy acetophenone of 3 amino 2 - Google Patents
A kind of synthetic method of the hydroxy acetophenone of 3 amino 2 Download PDFInfo
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- CN107698452A CN107698452A CN201710802846.0A CN201710802846A CN107698452A CN 107698452 A CN107698452 A CN 107698452A CN 201710802846 A CN201710802846 A CN 201710802846A CN 107698452 A CN107698452 A CN 107698452A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
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- 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
- B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
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- 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
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- 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
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/00801—Means to assemble
- B01J2219/0081—Plurality of modules
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- 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
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/00819—Materials of construction
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- 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
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/00851—Additional features
- B01J2219/00867—Microreactors placed in series, on the same or on different supports
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- 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
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/00851—Additional features
- B01J2219/00869—Microreactors placed in parallel, on the same or on different supports
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention provides a kind of synthetic method of the hydroxy acetophenone of 3 amino 2, including the chloro-acetophenone of 2 hydroxyl 5 is added into glacial acetic acid dissolving, fuming nitric aicd is dissolved in glacial acetic acid, the two is blended in reaction generation product in micro passage reaction and the activated carbon for adding 10% (w/w) Pd of load is added after solvent with triethylamine, reacts the generation aminoacetophenone of 2 hydroxyl 3 in micro passage reaction with hydrogen.This method yield is high, purity is high, it is quick, be precisely controlled, can be with continuous production, safe.
Description
Technical field
The invention belongs to anti-asthma and antiallergy the class pharmaceutical synthesis field in organic synthesis, and in particular to a kind of 3- ammonia
The synthetic method of base -2- hydroxy acetophenones.
Background technology
General Leinster is pioneering first LTRA in the world of Japanese little Ye medicine companies Co., Ltd., the medicine
Thing lists in nineteen ninety-five and Japan, is mainly used as anti-asthma and antiallergy in Europe and U.S.'s registration, its clinic within subsequent 1996
Medicine, it is the active drug for treating asthma.Its chemical constitution is as follows：
Because general Leinster has many advantages, such as efficient, low toxicity, left and right scope are wide, adverse reaction is few, city opens from it
Beginning has just captured rapidly antasthmatic market, turns into focus of greatest concern on current international market, has boundless city
Field prospect.Wherein 3- amino -2- hydroxy acetophenones are the critical medication intermediates for synthesizing Pranlukast, are had in terms of new drug research
Very big application value.
Synthetic method at present in document on the intermediate is as follows：
This method generally using parachlorophenol or p bromophenol as initiation material, first at high temperature with acetic anhydride or chloroacetic chloride
Generation acylation reaction, 2- hydroxyl -5- chloro-acetophenones are obtained, then react to obtain nitration product with fuming nitric aicd, finally in Pd/C
Catalysis under occur hydrogenation reduction and obtain 3- amino -2- hydroxy acetophenones.
In said synthesis route using 5- chlorine-2-hydroxyls acetophenone as raw material by nitrification with hydrogenating reduction obtain 3- amino-
2- hydroxy acetophenones, two-step reaction belong to high-risk chemical reaction in industry generates, following production and potential safety hazard be present：
1) nitration reactions speed is fast, and thermal discharge is big, and nitrating agent has severe corrosive and strong oxidizing property, with organic matter
Contact can cause burning or blast, conventional reactor is restricted low with mass-and heat-transfer efficiency, can only temperature control delay within the specific limits
Slow that nitric acid is added dropwise, in the case where stirring is insufficient, formation hot localised points can cause security risk significant increase, while under high temperature
Destruction of the strong oxidizing property of nitric acid to carbonyl is fairly obvious, causes impurity content to raise.
2) catalytic hydrogenation reactions are extremely dangerous in plant-scale production, and the explosion limit of hydrogen is 4%~75%,
Hazard property is fired with height, and traditional stirring technique can not ensure the hybrid switching between airwater mist cooling so that hydrogenation is anti-
Generally it should carry out at high temperature under high pressure, reaction time length, high energy consumption, catalyst recovery efficiency are low, and 3- amino -2- hydroxyls
The stability of benzoylformaldoxime at high temperature is very poor, and the generation of a large amount of degradation impurities causes the purity of product and yield to be greatly reduced.
The content of the invention
To solve, above-mentioned two-step reaction yield present in traditional handicraft operation equipment is low, purity is low, easy generation is violent
The problems such as blast produces potential safety hazard, high temperature lower reaction time length causes degraded, catalyst recovery number low, institute of the present invention
Technical problems to be solved there is provided a kind of essential safety and green 3- amino -2- hydroxy acetophenone synthetic technologys.
In order to realize foregoing invention purpose, following technical scheme is applicant provided：
A kind of synthetic method of 3- amino -2- hydroxy acetophenones, the micro passage reaction used include warm-up block, reaction
Module group and cooling module it is each more than one, warm-up block connect with reaction module group, parallel connection between differential responses module group, is dropped
Warm module is connected with reaction module group；Each reaction module group is in series by 1-6 unit module, cooling module and reaction mould
Block group is in series；
The synthetic method comprises the following steps：
1) glacial acetic acid is dissolved in after 2- hydroxyl -5- chloro-acetophenones are added glacial acetic acid dissolving by as material I, fuming nitric aicd
It is used as material II, material I and material II to be reacted after respectively enteing warm-up block in reaction module group afterwards, then passes through drop
Outflow reactor after warm module, collect reaction solution and obtain 2- hydroxyl -3- nitro -5- chloro-acetophenones after treatment.
2) general-hydroxyls -3- nitro -5- chloro-acetophenones, triethylamine, which add, adds 10% (w/w) of load after dissolving in solvent
Pd activated-carbon catalyst is reacting after warm-up block as material III, material III in reaction module with material hydrogen
Reacted in module group, then pass through outflow reactor after cooling module, collect reaction solution obtain after treatment 2- hydroxyls-
3- aminoacetophenones.
The mol ratio of the step 1) 2- hydroxyls -5- chloro-acetophenones and nitric acid is 1:1.0~1:2.0；It is preferred that 1:1.5；
0.5~the 2mol/L of concentration range of the step 1) 2- hydroxyls -5- chloro-acetophenones in glacial acetic acid；Fuming nitric aicd exists
1~3mol/L of concentration range in glacial acetic acid；
The residence time of the step 1) nitration reaction is 30~120s；
The reaction temperature of the step 1) nitration reaction is 50~80 DEG C, preferably 65 DEG C；
The residence time of the step 2) hydrogenation reduction is 15s~60s；
Hydrogenation reduction temperature described in step 2) is 100~140 DEG C, preferably 120 DEG C；
The concentration of 2- hydroxyl -3- nitro -5- chloro-acetophenones in a solvent described in step 2) is 0.1~1.0mol/L；2-
The mass ratio of hydroxyl -3- nitro -5- chloro-acetophenones and triethylamine is 1:0.5；
2- hydroxyl -3- nitro -5- chloro-acetophenones and 10% (w/w) Pd of load activated-carbon catalyst described in step 2)
Mass ratio is 1:0.01~1:0.10；The mol ratio of 2- hydroxyl -3- nitro -5- chloro-acetophenones and hydrogen is 1:4.0~1:5.0；
The pressure of reaction system is 0.5~1.5MPa.
Solvent described in step 2) is one or two kinds of in ethanol or methanol.
Material I and material II uses mashing pump and gas flow meter respectively come measure control, material III with flow pump with hydrogen
To control；The material of the micro passage reaction be special glass, silicon carbide ceramics, the stainless steel metal for scribbling anti-corrosion layer or
One or more of politef, the Maximum safe pressure that can be born are 1.5~1.8MPa；Described reaction module includes pre-
Thermal modules, reaction module group, cooling module can according to charging rate, reactant concentration, reaction time etc. arbitrarily series connection or simultaneously
Connection combines.When reaction is carried out in micro passage reaction, the warm-up block is straight type structure；The reaction module group
Enter for Two In and One Out or singly the heart-shaped structure module singly gone out, the order of connection be warm-up block, Two In and One Out structure reaction module,
Singly enter the reaction module for singly going out structure, the reaction module of Two In and One Out structure is used for hybrid reaction after preheating, singly enters and singly go out structure
Reaction module be used for extend reaction time；Described cooling module is the heart-shaped structure module for singly entering singly to go out, and material passes through
Connected after crossing warm-up block with reaction module group, reactor, difference preheating are then flowed out into cooling module by reaction module
It is parallel relationship between module, warm-up block is series relationship with reaction module group, and reaction module group is to connect with cooling module
Relation.
Beneficial effect
It is operation difficulty pole in conventional reactor in the method for synthesis 2- hydroxyl -3- aminoacetophenones provided by the invention
Big two classes reaction, using the distinctive heart-shaped structure of micro passage reaction, can improve mass-and heat-transfer efficiency more than 100 times,
The advantages of intrinsic reaction speed is greatly improved, while holds liquid small volume has been greatly reduced the production peace of this kind of high-risk reaction
Full hidden danger.
Traditional Jian Xieshi reactors are low because the relation of equipment size often has reactor mass-and heat-transfer efficiency
Problem, temperature, uneven concentration are easily caused, cause low yield, low production efficiency, intermittently operated product quality stability difference etc.
Shortcoming, especially when handling " dangerous technique ", still reaction process safety hidden danger is big, and is limited to reaction of atomic economy and mistake
The factors such as journey practicality, the alternative of these " dangerous techniques " is often with high costs and route is longer.And micro passage reaction
Contrasting the advantage of traditional reactor can be summarized as follows：
1. rapidity：The characteristics of using micro passage reaction mass-and heat-transfer efficiency high, the reaction time can be greatly shortened,
The several or reaction completed in more than ten hour in traditional reactor, can be complete in only being needed tens seconds in micro passage reaction
Into.
2. it is precisely controlled：The refined control of technological parameter can be achieved, when specifically including reaction temperature, material proportion, stopping
Between etc..
3. continuity：The Automation Design, the production of hitless operation in 24 hours, space-time can be realized by electric terminal manipulation
Ultrahigh in efficiency, reduce cost of labor.
4. security：Online inventory is few, while the intrinsic fire resistance of minim channel, and the destructive power of blast is in geometry radix
Decline, continuous flow process essential safety.
The present invention also creates other beneficial technique effects：
1) the efficient mass-and heat-transfer abilities of ensure that reaction is released substantial amounts of heat and can taken away in time by heat transferring medium, ensure
Reaction is stable in security reaction temperature range, continuously production.
2) batch types mass-transfer efficiency lowly causes hot localised points heat exchange not in time, and system high temperature degradation impurity is more,
Reaction time is grown, and yield is low, and micro passage reaction can realize online fast cooling, fundamentally can effectively control height
The generation of warm degradation impurity.
3) reduces industrial production cost, and urging for 2- hydroxyl -3- nitro -5- chloro-acetophenones is carried out using micro passage reaction
Change hydrogenation reaction, by being adjusted to response parameter, be effectively reduced catalyst Pd/C dosage and Pd/C can be circulated
Apply mechanically number to be significantly increased, the conversion ratio reacted in use by the catalyst Pd/C of multiple recycled does not all go out
It is now obvious to decline, illustrate that still there is very high activity by the catalyst of 8 recycleds.
4) is few in line material, the microchannel of feature inherently fire resistance, can individually be set according to the type of reactor
Explosion-protection equipment is counted, even if the burning or blast of generation a small range can also ensure zero injury to operating personnel, the company of realizing
Afterflow essential safety produces.
5) can continuous production and realizing automate, without enlarge-effect, can directly carry out plant-scale amplification production,
The present invention has mass-and heat-transfer efficiency during 2- hydroxyl -3- aminoacetophenones are prepared with microchannel or micro-reacting tcchnology
It is high, easy to operate, can accurately control the reaction time, be easy to continuous production and control easy to automate, save work money
Source.
Brief description of the drawings
The module material circulation duct shape and structure schematic diagram of Fig. 1 lucite material micro passage reactions, wherein (a) is
Cardioid list enters and singly goes out module, and (b) is cardioid Two In and One Out module, and (c) is straight pattern block.
Fig. 2 step 1) nitration reaction flows and micro passage reaction linking relationship schematic diagram, wherein A, B are respectively material I
With material II fluid discharge pump, 1,2 point of material I and material II Wei not keep straight on warm-up block, and 3~5 be cardioid reaction module group,
6 be cooling module.
Fig. 3 step 2) catalytic hydrogenation reaction flows and micro passage reaction linking relationship schematic diagram, wherein C are material III
Mashing pump, D be hydrogen gas flowmeter, 7 be material III straight trip warm-up block, 8~11 be cardioid reaction module group,
12 be cooling module.
Fig. 4 catalyst Pd/C recycled experimental result.
Embodiment：
This technology invention is furtherd elucidate with reference to specific embodiment；It should be appreciated that it is set forth below for embodiment only use
In the explanation present invention rather than limitation the scope of the present invention；In addition, it is to be understood that after content described in the invention is read,
Those skilled in the art can various modifications may be made or changes to the present invention, but these equivalent form of values equally fall within the appended power of the application
Sharp claim limited range.
Embodiment 1
Weigh in 2- hydroxyl -5- chloro-acetophenones 180.00g additions 1200ml glacial acetic acid and form material I after stirring and dissolving,
Weigh and material II is formed in 100g fuming nitric aicd addition 800ml glacial acetic acid, regulation measuring pump A flow velocity makes material I stream
Speed is 15ml/min, and regulation measuring pump B flow velocity makes material II flow velocity be 7ml/min, and reaction temperature is 65 DEG C, nitric acid and 2-
The mol ratio of hydroxyl -5- chloro-acetophenones is 1.5:1, the residence time of reaction is 95 seconds, collects the reaction solution from outlet outflow, amount
3600ml water is taken to be slowly dropped into reaction system, a large amount of yellow solids separate out, incubation at room temperature stirring 1h, filtering, and filter cake adds
500ml cold ethanol washs, and is dried in vacuo 6h at 50 DEG C, obtains 2- hydroxyl -3- nitro -5- chloro-acetophenone 207.76g, yield
91.33% purity 99.50%.
2- hydroxyl -3- nitro -5- chloro-acetophenone 150.00g are weighed, add absolute ethyl alcohol 3L, add triethylamine 75g, stirring
5.00g 10%Pd/C is added after dissolving, is sufficiently stirring and mixing to form material III；The flow velocity of regulation mashing pump makes material III's
Flow velocity is 22.5g/min, adjusts H2Gas flowmeter flow velocity is 400ml/min, and reaction temperature is 120 DEG C, 2- hydroxyl -3- nitre
Base -5- chloro-acetophenones and H2Mol ratio be 1:4.0, the residence time of reaction is 35 seconds, reaction pressure 1.2Mpa；Collect from
The reaction solution of reactor outlet outflow, is recovered by filtration catalyst Pd/C, and filtrate is distilled to 900ml or so, adds concentrated hydrochloric acid to anti-
The pH=2.0 of system to be answered, incubation at room temperature stirring 1h, is filtered, cold ethanol washs filter cake, and solid is rejoined into 1.2L water,
It is warming up to 50 DEG C of stirrings all to dissolve to solid, adds 50g activated carbons and insulated and stirred decolouring 30min, filtering, filtrate adds
The pH=9.0 of 6mol/L NaOH solution regulation system, insulated and stirred 30min, filtering, obtain 2- hydroxyl -3- aminoacetophenones
92.27g, yield 87.39%, purity 99.78%.
Embodiment 2
Weigh in 2- hydroxyl -5- chloro-acetophenones 150.00g additions 1000ml glacial acetic acid and form material I after stirring and dissolving,
Weigh and material II is formed in the 92g glacial acetic acid for finding nitric acid addition 500ml, regulation measuring pump A flow velocity makes material I flow velocity
For 18ml/min, regulation measuring pump B flow velocity makes material II flow velocity be 9ml/min, and reaction temperature is 60 DEG C, nitric acid and 2- hydroxyls
The mol ratio of base -5- chloro-acetophenones is 1.5:1, the residence time of reaction is 75 seconds, collects the reaction solution from outlet outflow, measures
3000ml water is slowly dropped into reaction system, and a large amount of yellow solids separate out, incubation at room temperature stirring 1h, filtering, and filter cake adds 450ml
The washing of cold ethanol, be dried in vacuo 6h at 50 DEG C, obtain 2- hydroxyl -3- nitro -5- chloro-acetophenone 171.73g, yield 90.59%,
Purity 99.43%.
2- hydroxyl -3- nitro -5- chloro-acetophenone 140.00g are weighed, add absolute methanol 3L, add triethylamine 70g, stirring
7.00g 10%Pd/C is added after dissolving, is sufficiently stirring and mixing to form material III；The flow velocity of regulation mashing pump makes material III's
Flow velocity is 28.2g/min, adjusts H2Gas flowmeter flow velocity is 500ml/min, and reaction temperature is 130 DEG C, 2- hydroxyl -3- nitre
Base -5- chloro-acetophenones and H2Mol ratio be 1:4.0, the residence time of reaction is 30 seconds, reaction pressure 1.5Mpa；Collect from
The reaction solution of reactor outlet outflow, is recovered by filtration catalyst Pd/C, and filtrate is distilled to 840ml or so, adds concentrated hydrochloric acid to anti-
The pH=2.0 of system to be answered, incubation at room temperature stirring 1h, is filtered, cold ethanol washs filter cake, and solid is rejoined into 1.1L water,
It is warming up to 50 DEG C of stirrings all to dissolve to solid, adds 45g activated carbons and insulated and stirred decolouring 30min, filtering, filtrate adds
The pH=9.0 of 6mol/L NaOH solution regulation system, insulated and stirred 30min, filtering, obtain 2- hydroxyl -3- aminoacetophenones
85.59g, yield 82.17%, purity 96.98%.
Embodiment 3
Weigh in 2- hydroxyl -5- chloro-acetophenones 200.00g additions 1600ml glacial acetic acid and form material I after stirring and dissolving,
Weigh and material II is formed in 100g fuming nitric aicd addition 800ml glacial acetic acid, regulation measuring pump A flow velocity makes material I stream
Speed is 12ml/min, and regulation measuring pump B flow velocity makes material II flow velocity be 6ml/min, and reaction temperature is 70 DEG C, nitric acid and 2-
The mol ratio of hydroxyl -5- chloro-acetophenones is 1.2:1, the residence time of reaction is 100 seconds, collects the reaction solution from outlet outflow,
The water for measuring 4800ml is slowly dropped into reaction system, and a large amount of yellow solids separate out, incubation at room temperature stirring 1h, filtering, and filter cake adds
600ml cold ethanol washs, and is dried in vacuo 6h at 50 DEG C, obtains 2- hydroxyl -3- nitro -5- chloro-acetophenone 229.63g, yield
90.85% purity 99.39%.
2- hydroxyl -3- nitro -5- chloro-acetophenone 200.00g are weighed, add absolute ethyl alcohol 4L, triethylamine 100g is added, stirs
The 10%Pd/C that 8.00g is added after dissolving is mixed, is sufficiently stirring and mixing to form material III；The flow velocity of regulation mashing pump makes material III
Flow velocity be 33.8g/min, adjust H2Gas flowmeter flow velocity is 600ml/min, and reaction temperature is 140 DEG C, 2- hydroxyl -3- nitre
Base -5- chloro-acetophenones and H2Mol ratio be 1:4.0, the residence time of reaction is 25 seconds, reaction pressure 1.4Mpa；Collect from
The reaction solution of reactor outlet outflow, is recovered by filtration catalyst Pd/C, and filtrate is distilled to 1200ml or so, adds concentrated hydrochloric acid to anti-
The pH=2.0 of system to be answered, incubation at room temperature stirring 1h, is filtered, cold ethanol washs filter cake, and solid is rejoined into 1.5L water,
It is warming up to 50 DEG C of stirrings all to dissolve to solid, adds 65g activated carbons and insulated and stirred decolouring 30min, filtering, filtrate adds
The pH=9.0 of 6mol/L NaOH solution regulation system, insulated and stirred 30min, filtering, obtain 2- hydroxyl -3- aminoacetophenones
156.72g, yield 82.62%, purity 97.34%.
Embodiment 4
Weigh in 2- hydroxyl -5- chloro-acetophenones 150.00g additions 1000ml glacial acetic acid and form material I after stirring and dissolving,
Weigh and material II is formed in 75g fuming nitric aicd addition 500ml glacial acetic acid, regulation measuring pump A flow velocity makes material I flow velocity
For 15ml/min, regulation measuring pump B flow velocity makes material II flow velocity be 7ml/min, and reaction temperature is 80 DEG C, nitric acid and 2- hydroxyls
The mol ratio of base -5- chloro-acetophenones is 1.2:1, the residence time of reaction is 95 seconds, collects the reaction solution from outlet outflow, measures
3000ml water is slowly dropped into reaction system, and a large amount of yellow solids separate out, incubation at room temperature stirring 1h, filtering, and filter cake adds 400ml
The washing of cold ethanol, be dried in vacuo 6h at 50 DEG C, obtain 2- hydroxyl -3- nitro -5- chloro-acetophenone 173.02g, yield 91.27%,
Purity 99.72%.
2- hydroxyl -3- nitro -5- chloro-acetophenone 150.00g are weighed, add absolute ethyl alcohol 3L, add triethylamine 75g, stirring
10.00g 10%Pd/C is added after dissolving, is sufficiently stirring and mixing to form material III；The flow velocity of regulation mashing pump makes material III
Flow velocity be 25.2g/min, adjust H2Gas flowmeter flow velocity is 450ml/min, and reaction temperature is 120 DEG C, 2- hydroxyl -3- nitre
Base -5- chloro-acetophenones and H2Mol ratio be 1:4.0, the residence time of reaction is 35 seconds, reaction pressure 1.4Mpa；Collect from
The reaction solution of reactor outlet outflow, is recovered by filtration catalyst Pd/C, and filtrate is distilled to 900ml or so, adds concentrated hydrochloric acid to anti-
The pH=2.0 of system to be answered, incubation at room temperature stirring 1h, is filtered, cold ethanol washs filter cake, and solid is rejoined into 1.2L water,
It is warming up to 50 DEG C of stirrings all to dissolve to solid, adds 50g activated carbons and insulated and stirred decolouring 30min, filtering, filtrate adds
The pH=9.0 of 6mol/L NaOH solution regulation system, insulated and stirred 30min, filtering, obtain 2- hydroxyl -3- aminoacetophenones
92.69g, yield 87.77%, purity 99.83%.
Embodiment 5
Weigh in 2- hydroxyl -5- chloro-acetophenones 200.00g additions 1600ml glacial acetic acid and form material I after stirring and dissolving,
Weigh and material II is formed in 90g fuming nitric aicd addition 800ml glacial acetic acid, regulation measuring pump A flow velocity makes material I flow velocity
For 18ml/min, regulation measuring pump B flow velocity makes material II flow velocity be 9ml/min, and reaction temperature is 70 DEG C, nitric acid and 2- hydroxyls
The mol ratio of base -5- chloro-acetophenones is 1.2:1, the residence time of reaction is 70 seconds, collects the reaction solution from outlet outflow, measures
4800ml water is slowly dropped into reaction system, and a large amount of yellow solids separate out, incubation at room temperature stirring 1h, filtering, and filter cake adds 600ml
The washing of cold ethanol, be dried in vacuo 6h at 50 DEG C, obtain 2- hydroxyl -3- nitro -5- chloro-acetophenone 228.04g, yield 90.22%,
Purity 99.44%.
2- hydroxyl -3- nitro -5- chloro-acetophenone 180.00g are weighed, add absolute methanol 3L, add triethylamine 90g, stirring
9.00g 10%Pd/C is added after dissolving, is sufficiently stirring and mixing to form material III；The flow velocity of regulation mashing pump makes material III's
Flow velocity is 26.5g/min, adjusts H2Gas flowmeter flow velocity is 480ml/min, and reaction temperature is 140 DEG C, 2- hydroxyl -3- nitre
Base -5- chloro-acetophenones and H2Mol ratio be 1:4.5, the residence time of reaction is 40 seconds, reaction pressure 1.4Mpa；Collect from
The reaction solution of reactor outlet outflow, is recovered by filtration catalyst Pd/C, and filtrate is distilled to 1000ml or so, adds concentrated hydrochloric acid to anti-
The pH=2.0 of system to be answered, incubation at room temperature stirring 1h, is filtered, cold ethanol washs filter cake, and solid is rejoined into 1.4L water,
It is warming up to 50 DEG C of stirrings all to dissolve to solid, adds 55g activated carbons and insulated and stirred decolouring 30min, filtering, filtrate adds
The pH=9.0 of 6mol/L NaOH solution regulation system, insulated and stirred 30min, filtering, obtain 2- hydroxyl -3- aminoacetophenones
110.04g, yield 82.67%, purity 97.79%.
Embodiment 6
Weigh in 2- hydroxyl -5- chloro-acetophenones 200.00g additions 1600ml glacial acetic acid and form material I after stirring and dissolving,
Weigh and material II is formed in 110g fuming nitric aicd addition 800ml glacial acetic acid, regulation measuring pump A flow velocity makes material I stream
Speed is 20ml/min, and regulation measuring pump B flow velocity makes material II flow velocity be 10ml/min, and reaction temperature is 70 DEG C, nitric acid and
The mol ratio of 2- hydroxyl -5- chloro-acetophenones is 1.5:1, the residence time of reaction is 60 seconds, collects the reaction solution from outlet outflow,
The water for measuring 4800ml is slowly dropped into reaction system, and a large amount of yellow solids separate out, incubation at room temperature stirring 1h, filtering, and filter cake adds
600ml cold ethanol washs, and is dried in vacuo 6h at 50 DEG C, obtains 2- hydroxyl -3- nitro -5- chloro-acetophenone 229.76g, yield
90.90%, purity 99.48%.
2- hydroxyl -3- nitro -5- chloro-acetophenone 200.00g are weighed, add absolute methanol 4L, triethylamine 100g is added, stirs
The 10%Pd/C that 12.00g is added after dissolving is mixed, is sufficiently stirring and mixing to form material III；The flow velocity of regulation mashing pump makes material
III flow velocity is 32.5g/min, adjusts H2Gas flowmeter flow velocity is 650ml/min, and reaction temperature is 120 DEG C, 2- hydroxyls-
3- nitro -5- chloro-acetophenones and H2Mol ratio be 1:4.2, the residence time of reaction is 28 seconds, reaction pressure 1.5Mpa；Receive
Collect the reaction solution from reactor outlet outflow, be recovered by filtration catalyst Pd/C, filtrate is distilled to 1200ml or so, add concentrated hydrochloric acid
Filter cake is washed to the pH=2.0 of reaction system, incubation at room temperature stirring 1h, filtering, cold ethanol, solid is rejoined to 1.5L water
In, it is warming up to 50 DEG C of stirrings and is all dissolved to solid, add 60g activated carbons and insulated and stirred decolouring 30min, filtering, filtrate adds
Enter the pH=9.0 of 6mol/L NaOH solution regulation system, insulated and stirred 30min, filter, obtain 2- hydroxyl -3- aminobenzene second
Ketone 120.21g, yield 87.33%, purity 99.80%.
Embodiment 7-15
Step 1) is carried out by the conditional parameter of embodiment 6, step 2) parameter is shown in Table 1, the undefined same embodiment of parameter in table 1
6。
Table 1
As a result show, step 2) reaction temperature can ensure higher purity and yield when between 100 DEG C -140 DEG C, from whole
Apparently, reaction temperature changes within the range to be influenceed little body rule on purity and yield, but when taking 120 DEG C, reaction product is received
There is very big quantitative change in rate and purity highest and numerical value, do not meet global regularity, the beneficial effect is not learn the skill of the application
It is unpredictable before art scheme and technique effect.
We also examine catalyst Pd/C recovery effect simultaneously, in the experiment for devising recycled 8 times altogether
Hold, wherein ensure that per the catalyst amount of secondary response be 7%, the pressure of reaction is 1.5Mpa, hydrogen usage 3.5eq, 120
Reacted 30 seconds at DEG C, relation of the high spot review between the multiple Pd/C of recycled and reaction conversion ratio, as a result see Fig. 4：Knot
Fruit shows, under the conversion ratio reacted in use by the catalyst Pd/C of multiple recycled is all without occurring significantly
Drop, illustrate that still there is very high activity by the catalyst of 8 recycleds.
Comparative example 1
Nitration reaction：
2- hydroxyl -5- chloro-acetophenone 1Kg are weighed, the stirring and dissolving into 12L glacial acetic acid is added, weighs 600g smoke nitre
Acid instills reaction system after adding 6L glacial acetic acids, is stirred vigorously lower be added dropwise and ensures that the temperature of feed liquid is no more than 30 DEG C, about 3h drops
Complete, subsequent 30 DEG C of insulated and stirred 2h are added, the distilled water for measuring 3L adds reaction system, and a large amount of yellow solids separate out, at room temperature
Insulated and stirred 1h, filtering, filter cake add 300ml cold ethanol washing, are dried in vacuo 6h at 50 DEG C, obtain 2- hydroxyl 3- nitros-
5- chloro-acetophenone 905g, yield 71.60%, purity 97.7%.
Catalytic hydrogenation reaction：
Weigh step product 2- hydroxyl -3- nitro -5- chloro-acetophenones 800g to add in 20L ethanol, add the three of 400g
Ethamine, the 100g palladium charcoal of catalyst 10%, H is passed through into autoclave2, ensure that the pressure in reactor is 2.0~3.0Mpa, rise
Temperature is to 60 DEG C and insulation reaction 10 hours, and reaction, which finishes, is down to room temperature, and catalyst Pd/C is recovered by filtration, and filtrate is distilled left to 4.8L
The right side, add concentrated hydrochloric acid to the pH=2.0 of reaction system, incubation at room temperature stirring 1h, filtering, cold ethanol and wash filter cake, solid is again
Add into 6.5L water, be warming up to 50 DEG C of stirrings and all dissolved to solid, add 300g activated carbons and insulated and stirred is decolourized
30min, filtering, filtrate add pH=9.0, the insulated and stirred 30min of 6mol/L NaOH solution regulation system, filtering, obtained
2- hydroxyl -3- aminoacetophenone 453.30g, yield 80.60%, purity 98.11%.
Result above shows that conventional reactor causes technique mistake compared with micro passage reaction because mass-and heat-transfer efficiency is low
Cheng Wufa is accurately controlled, and has the problems such as reaction time is long, temperature is too high, causes nitration reaction with occurring in catalytic hydrogenation reaction
Substantial amounts of degradation impurity, product quality and purity to two-step reaction all have a great impact.Catalyst Pd/C is being followed simultaneously
Ring set with its activity after 2-3 times there have been significantly declining, it is necessary to add a certain proportion of catalyst during the course of the reaction after
Being smoothed out for reaction is just can guarantee that, cannot make out micro passage reaction compared with batch tank reactor by contrast has reaction
Time is short, safety and environmental protection, catalyst recovery efficiency, high income, product purity are with high advantage.
Claims (9)
- A kind of 1. synthetic method of 3- amino -2- hydroxy acetophenones, it is characterised in that：Comprise the following steps：1) as material I after 2- hydroxyl -5- chloro-acetophenones are added glacial acetic acid dissolving by, fuming nitric aicd is made after being dissolved in glacial acetic acid Pass through the reaction mould after the warm-up block of micro passage reaction in micro passage reaction respectively for material II, material I and material II Reacted in block group, then pass through outflow reactor after the cooling module of micro passage reaction, collect reaction solution by separation 2- hydroxyl -3- nitro -5- chloro-acetophenones are obtained after purification；2) 2- hydroxyl -3- nitro -5- chloro-acetophenones, triethylamine are added to add after dissolving in solvent by loads 10% (w/w) Pd's Activated-carbon catalyst is as material III, and material III is after the warm-up block of micro passage reaction in reaction module group and thing Material hydrogen is reacted, and then passes through outflow reactor after the cooling module of micro passage reaction, collects reaction solution by separation 2- hydroxyl -3- aminoacetophenones are obtained after purification；The micro passage reaction include warm-up block, reaction module group and cooling module it is each more than one, warm-up block with it is anti- Module group is answered to connect, in parallel between differential responses module group, cooling module is connected with reaction module group；Each reaction module group by 1-6 unit module is in series, and cooling module is in series with reaction module group.
- 2. the synthetic method of 3- amino -2- hydroxy acetophenones according to claim 1, it is characterised in that：Step 1) is described The mol ratio of 2- hydroxyl -5- chloro-acetophenones and nitric acid is 1:1.0~1:2.0；It is preferred that 1:1.5；Described 2- hydroxyl -5- chlorobenzene second 0.5~the 2mol/L of concentration range of ketone in glacial acetic acid；1~the 3mol/L of concentration range of fuming nitric aicd in glacial acetic acid.
- 3. the synthetic method of 3- amino -2- hydroxy acetophenones according to claim 2, it is characterised in that：Step 1) is described Reaction time is 30~120s.
- 4. the synthetic method of 3- amino -2- hydroxy acetophenones according to claim 3, it is characterised in that：Step 1) is described Reaction temperature is 50~80 DEG C.
- 5. the synthetic method of 3- amino -2- hydroxy acetophenones according to claim 3, it is characterised in that：Step 1) is described Reaction temperature is 65 DEG C.
- 6. the synthetic method of 3- amino -2- hydroxy acetophenones according to claim 4, it is characterised in that：Step 2) is described Reaction time is 15s~60s.
- 7. the synthetic method of 3- amino -2- hydroxy acetophenones according to claim 6, it is characterised in that：Step 2) is described Reaction temperature be 100~140 DEG C.
- 8. the synthetic method of 3- amino -2- hydroxy acetophenones according to claim 6, it is characterised in that：Step 2) is described 2- hydroxyl -3- nitro -5- chloro-acetophenones with load 10% (w/w) Pd activated-carbon catalyst mass ratio be 1:0.01~1: 0.10；The mol ratio of 2- hydroxyl -3- nitro -5- chloro-acetophenones and hydrogen is 1:4.0~1:5.0；Described 2- hydroxyl -3- nitre The concentration of base -5- chloro-acetophenones in a solvent is 0.1~1.0mol/L；2- hydroxyl -3- nitro -5- chloro-acetophenones and triethylamine Mass ratio is 1:0.5；The pressure of reaction system is 0.5~1.5MPa.
- 9. the synthetic method of 3- amino -2- hydroxy acetophenones according to claim 8, it is characterised in that：Step 2) is described Solvent be one or two kinds of mixture in ethanol or methanol.
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| CN106187993A (en) * | 2016-07-15 | 2016-12-07 | 黑龙江鑫创生物科技开发有限公司 | A kind of micro passage reaction synthesizes the method for 5 chlorine 2 formyl chloride thiophene |
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