CN108484579A - A kind of micro passage reaction synthesis uncommon method for Buddhist nun's intermediate difficult to understand - Google Patents
A kind of micro passage reaction synthesis uncommon method for Buddhist nun's intermediate difficult to understand Download PDFInfo
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- CN108484579A CN108484579A CN201810264348.XA CN201810264348A CN108484579A CN 108484579 A CN108484579 A CN 108484579A CN 201810264348 A CN201810264348 A CN 201810264348A CN 108484579 A CN108484579 A CN 108484579A
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- YULLUIVOKRZUNM-UHFFFAOYSA-N CCCCN(C)c1cc(OC)c(C)cc1N Chemical compound CCCCN(C)c1cc(OC)c(C)cc1N YULLUIVOKRZUNM-UHFFFAOYSA-N 0.000 description 1
- LRDIIEXOYSOATQ-FMIVXFBMSA-N Cc1ccccc1/C(/c1nc(N)ncc1)=C\NC Chemical compound Cc1ccccc1/C(/c1nc(N)ncc1)=C\NC LRDIIEXOYSOATQ-FMIVXFBMSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
A kind of micro passage reaction synthesis uncommon method for Buddhist nun's intermediate difficult to understand, belongs to the anticancer drug synthesis technical field in organic synthesis.For yield in traditional Hydrogenation reaction kettle building-up process, low, purity difference, easily generation heavy explosion generate the problems such as dangerous, catalyst recovery number is low, provide a kind of micro passage reaction synthesis uncommon method for Buddhist nun's intermediate difficult to understand, the Ao Xi is 5 methoxyl group N1 methyl Ns of N 1 [2 (dimethylamino) ethyl], 4 [4 (1 methyl 1H indoles, 3 base) 2 pyrimidine radicals] 1 for Buddhist nun's intermediate, 2,4 benzene triamines, synthesis step are as follows：In micro passage reaction, by 5 nitrobenzenes 1 of N (2 dimethyl aminoethyl) 2 methoxyl group N ﹝ 4 (1 methyl, 1 indoles, 3 base) 2 Ji ﹞ of pyrimidine, 4 diamines are added in the mixture of organic solvent and concentrated hydrochloric acid, then the catalyst of activated carbon supported noble metal is added, preheating is used as material I；Hydrogen is reacted with the material I after preheating, is obtained difficult to understand uncommon for Buddhist nun's intermediate, synthesis of the present invention suitable for anticancer drug.
Description
Technical field
The present invention relates to a kind of micro passage reaction synthesis uncommon methods for Buddhist nun's intermediate difficult to understand, belong to anti-in organic synthesis
Cancer drug synthesis technical field.
Background technology
Ao Xi is for entitled N- { 2- { [2- (dimethylamino) ethyl] (methyl) amino } -4- methoxyl group-the 5- { [4- of Buddhist nun's chemistry
(l- methyl-lH-indol -3- bases) pyrimidine -2-base] amino } phenyl) 2 acrylamide of propyl-, single mesylate is AstraZeneca public affairs
In 3rd generation of department's research and development, takes orally epidermal growth factor receptor inhibitor, and 60% asian patients can effectively be overcome to receive preceding two generations drug
Medicament-resistant mutation caused by treatment, while reducing the risk that hyperglycemia, gastrointestinal tract and skin adverse reaction occur.FDA in
Accelerate within 2015 examination ＆ approval methanesulfonic acid Austria is uncommon to be listed for Buddhist nun, is third ground targeted therapy for treating metastatic lung Small Cell Lung Cancer
Drug, trade name Tagrisso, chemical constitution are as follows：
Wherein compound N -1- [2- (dimethylamino) ethyl] -5- methoxyl group-N1- methyl-N4- [4- (1- methyl-1s H-
Indol-3-yl) -2- pyrimidine radicals] -1,2,4- benzene triamines are the synthesis key intermediate for Buddhist nun difficult to understand uncommon, the conjunction about the intermediate
At being mainly to be obtained by hydrogenating reduction by its precursor nitro compound, chemical equation is as follows：
Mainly have about the common method of step nitro reduction at present following several：1) catalytic hydrogenations method：With Pd, Ni, Pt
Equal heavy metals are catalyst, and hydrogen is that reducing agent carries out hydro-reduction reaction under high temperature and high pressure；2) metal deoxidizations：
Iron is added under strong acid condition, zinc etc. has and restores nitro under the metallic high temperature of reproducibility；3) hydrazine hydrate reductions method：In graphite powder or
In the presence of person's Raney's nickel using be hydrazine hydrate reproducibility reduction nitro be amido.Mentioned above is several about nitro
The method of reduction the shortcomings of there are high pollution, high energy consumption, high risk, low economic value addeds, most production methods and production equipment
All suffer from the risk being eliminated.
Invention content
In order to solve low yield in traditional Hydrogenation reaction kettle building-up process, purity difference, easily occur acutely it is quick-fried
Fried to generate the problems such as dangerous, high temperature lower reaction time length causes degradation, catalyst recovery number is low, the present invention provides one
The kind micro passage reaction synthesis uncommon method for Buddhist nun's intermediate difficult to understand, chemical equation are as follows：
The Ao Xi is N-1- [2- (dimethylamino) ethyl] -5- methoxyl group-N1- methyl-N4- [4- for Buddhist nun's intermediate
(1- Methyl-1H-indole -3- bases) -2- pyrimidine radicals] -1,2,4- benzene triamines, synthesis step is as follows：
1) will add hydrogen precursor nitro compounds N- (2- dimethylarnino-ethyls) -2- methoxyl group-N- ﹝ 4- (1- methyl-1s-Yin
Diindyl -3- bases)-pyrimidine -2- Ji ﹞ -5- nitros-benzene-Isosorbide-5-Nitrae-diamines is added in organic solvent, concentrated hydrochloric acid dissolving is added, then plus
Enter the catalyst of activated carbon supported noble metal, material I is delivered to micro passage reaction by the mixture of acquisition as material I
It is preheated in warm-up block, reaction module group is entered after preheating；
The described plus a concentration of 0.1mol/L~0.15mol/L of hydrogen precursor nitro compounds in organic solvent；
The mass ratio of described plus hydrogen precursor nitro compounds and concentrated hydrochloric acid is 1:0.5；
The mass ratio of described plus hydrogen precursor nitro compounds and the catalyst of activated carbon supported noble metal is 1：(0.01~
0.10)；
2) hydrogen is delivered to the material I of the reaction module group of micro passage reaction and step 1) after preheating anti-by
It answers module group to be reacted, collects the reaction solution flowed out from cooling module, post-processing obtains difficult to understand uncommon for Buddhist nun intermediate N 1- [2-
(dimethylamino) ethyl] -5- methoxyl group-N1- methyl-N4- [4- (1- Methyl-1H-indole -3- bases) -2- pyrimidine radicals] -1,2,
4- benzene triamines, in the material I plus the molar ratio of hydrogen precursor nitro compounds and hydrogen is 1:(3.0~4.0).
Preferably：Organic solvent described in step 1) is one kind in methanol, ethyl alcohol, isopropanol.
Preferably：The catalyst of activated carbon supported noble metal described in step 1) be Pd/C, Pt/C, Rh/C in one kind or
Two or more compositions, when the catalyst of activated carbon supported noble metal is two or more composition, between each component with
Arbitrary ratio mixing；Wherein noble metal quality accounts for the 1%~10% of catalyst gross mass.
Preferably：The pressure of the step 2) reaction is 0.5MPa~1.5MPa.
Preferably：Reaction temperature described in step 2) is 60 DEG C~120 DEG C, more preferably 90 DEG C.
Preferably：The temperature of cooling module described in step 2) is 20 DEG C~30 DEG C.
Preferably：The total residence time of material I and hydrogen in reaction module group described in step 2) is 10s~50s.
Micro passage reaction of the present invention, also referred to as microreactor.Including warm-up block, reaction module group and cooling mould
Block, warm-up block are connected with reaction module group, and reaction module group is connected with cooling module, the unit process module of reaction module group
It is composed according to the arbitrary serial or parallel connection such as charging rate, reactant concentration, reaction time, if reaction module group is by there is 1-8
A unit module is arbitrarily connected in series according to charging rate, reactant concentration, reaction time etc.；Such as the connection type in Fig. 1-2,
By taking four unit process module composition reaction module groups as an example, material I enters the of reaction module group after the preheating of warm-up block 1
One group of unit process module 2, and the not preheated first group of unit process module 2 for being directly entered reaction module group of hydrogen,
Hybrid concurrency life reaction is carried out in first group of unit process module 2, and with the continuous entrance of hydrogen and material I, hydrogen and
Material I flows to last group of unit process module from first group of unit process module, reacts in flow process, finally from
Cooling module 6 flows out, and the reaction solution of outflow is that can be obtained by purifying difficult to understand uncommon for Buddhist nun containing the uncommon solution for Buddhist nun's intermediate of Austria
Intermediate, i.e. N-1- [2- (dimethylamino) ethyl] -5- methoxyl group-N1- methyl-N4- [4- (1- Methyl-1H-indoles -3-
Base) -2- pyrimidine radicals] -1,2,4- benzene triamines.Cooling module is in order to which the feed liquid of high temperature is down to room temperature by module in the present invention
Facilitate processing.
The heart-shaped structure module of straight type structure or Two In and One Out may be used in warm-up block in micro passage reaction of the present invention,
As shown in Figure 1, the microchannel with two entrances and one outlet may be used in first group of unit process module in reaction module
Unit process module, referred to as Two In and One Out construction module, two of which entrance are respectively used to the entrance of hydrogen and entering for material I
Mouthful, tool may be used in second group of unit module to last group of unit module, and there are one the micro-channel units of entrance and one outlet
Reaction module (referred to as single-entry single-out construction module), wherein：Two In and One Out construction module is mainly used for hybrid reaction, Dan Jindan
Go out construction module for extending reaction time and pyroreaction feed liquid being down to room temperature.Above-mentioned warm-up block and reaction module
The order of connection of (Two In and One Out construction module+single-entry single-out construction module) is：Warm-up block, Two In and One Out construction module, list
Into singly going out construction module.Micro passage reaction further includes mashing pump and gas flow meter in the present invention, and mashing pump is for conveying object
Material I enters warm-up block 1, and hydrogen enters first group of unit process module of reaction module by gas flowmeter A.
The material of the reaction module of the present invention can be special glass, silicon carbide ceramics, the stainless steel for being coated with anti-corrosion layer
One or more of metal, politef, the Maximum safe pressure that can be born are 1.5~1.8MPa.
Advantageous effect
It is uncommon for Buddhist nun's intermediate catalytic hydrogenation synthetic technology that the present invention provides a kind of essential safeties and environmentally protective Austria, should
It is difficult to understand that method completes a kind of catalytic hydrogenation reaction synthesis clarke using micro passage reaction (being also called microreactor) technology for the first time
Uncommon Buddhist nun's intermediate N 1- [2- (dimethylamino) ethyl] -5- methoxyl group-N1- methyl-N4- [4- (1- Methyl-1H-indoles -3-
Base) -2- pyrimidine radicals] -1,2,4- benzene triamines.
Heretofore described catalytic hydrogenation reaction due to the use of inflammable and explosive hydrogen as reducing agent, therefore in industry
Belong to " high-risk " chemical reaction in the production of scale, usually this kind of reaction needs under the action of the precious metal catalysts such as Pd, Pt, Ni
It could complete, and this kind of catalyst can not dissolve in the reaction system under normal circumstances, therefore catalytic hydrogenation reaction belongs to typical
Airwater mist cooling hybrid reaction, traditional mixing plant gradually amplify in the case of, three-phase mixing efficiency is very low, therefore
Catalytic hydrogenation reaction must carry out under long-time high temperature and pressure mostly, otherwise it is difficult to ensure that raw material reacts completely.In this process
If leakage occurs for middle hydrogen or temperature control is easy to that combustion explosion occurs.The reaction time long under high temperature can also lead simultaneously
A large amount of product degradation in cause system influences the purity and yield of final products, and on the activated carbon expensive is adhered in reaction process
As the reasons activity such as excessive friction constantly reduces, recovery difficulty becomes larger metallic catalyst.
Micro passage reaction set forth in the present invention can be very due to the difference of design concept and stock size operation equipment
Good overcomes disadvantage mentioned above, advantage that can be summarized as follows：
1) micro passage reactions vapor-liquid-solid three-phase hybrid switching efficiency during continuous operation adds hydrogen than tradition stirring
Reaction kettle improves 100 times or more, in a short period of time and completes three and mixes, substantially increases intrinsic reaction speed, instead
It can be shorten to from 10 hours less than 20 seconds between seasonable, energy consumption can be greatly reduced；
2) can effectively inhibit the over-hydrogenation by-product generated under lower high temperature for a long time, and the yield and purity of product have
Prodigious raising；
3) residence time shorter makes the surface texture of catalyst that prodigious change not occur, and retains to greatest extent
The activity of catalyst, experimental result show that catalyst still has very high activity, the economy of catalyst after recycled 8 times
Cost is greatly reduced；
4) holds only tens to hundreds of milliliters of liquid product, and can substantially reduce hydrogen in the case where there is safeguard protection lets out
Reveal the security risk of combustion explosion；
5) occupation area of equipment is small, easy to operate, and cooperation electronics charging terminal may be implemented prolonged safe and stable
Online production and post-processing, operation recruitment can reduce 50% to 70%, production cost is minimized, and production economy is protected
Barrier.
Description of the drawings
Fig. 1 is the module material circulation duct shape and structure schematic diagram of organic glass material micro passage reaction, wherein (a)
For the single-entry single-out module of cardioid, it is (b) cardioid Two In and One Out module, is (c) straight pattern block.
Fig. 2 is catalytic hydrogenation reaction flow and micro passage reaction connection relationship diagram, and wherein A is mashing pump, and B is gas
Flowmeter body, 1 is straight type warm-up block, and 2 be cardioid Two In and One Out reaction module, and for hybrid reaction after preheating, 3-6 is respectively
The single-entry single-out reaction module of cardioid, 6 be the single-entry single-out module of heart-shaped structure, is used for the cooling of pyroreaction feed liquid.
Specific implementation mode
In following embodiments, used micro passage reaction includes warm-up block, reaction module group and cooling module, such as
Shown in Fig. 1 and Fig. 2, wherein：Warm-up block is connected with reaction module group, and cooling module is connected with reaction module group, reaction module
Group includes 1 unit process module or is composed of more than two unit process block coupled in series.
Material I is controlled with hydrogen with mashing pump and gas flow meter in the present invention.When reaction is in micro passage reaction
When progress, warm-up block is the heart-shaped structure module of straight type structure or Two In and One Out；The reaction module is Two In and One Out or list
Into the heart-shaped structure module singly gone out, the order of connection is warm-up block, the reaction module of Two In and One Out structure, single-entry single-out structure
Reaction module, for hybrid reaction after preheating, the reaction module of single-entry single-out structure is used for the reaction module of Two In and One Out structure
Extend reaction time.The micro passage reaction used includes warm-up block group, reaction module group and cooling module, pre- hot-die
Block is connected with reaction module group, and reaction module group is connected with cooling module, and warm-up block group includes a warm-up block or two
The warm-up block of more parallel, reaction module group include a reaction module or more than two concatenated reaction modules, and cool down mould
Block is single-entry single-out individual module；Material 1 enters warm-up block 1 by mashing pump, and warm-up block 1 is connected with reaction module 2；
Material 2 enters reaction module 2 by gas flowmeter A.
The micro passage reaction synthesis uncommon method for Buddhist nun's intermediate difficult to understand is detailed below.
1. micro passage reaction of the embodiment synthesis uncommon method for Buddhist nun's intermediate difficult to understand.
1) it weighs raw material and adds hydrogen precursor nitro compounds 200g, be then added to the mixed liquor of the methanol and 100g concentrated hydrochloric acids of 4L
In, the Pd/C catalyst that 10g Pd mass contents are 5% is added after stirring and dissolving, material I is sufficiently stirring and mixing to form, by material
I is delivered in the warm-up block 1 of micro passage reaction and preheats, and the reaction module group of micro passage reaction is entered after preheating.
2) the reaction module group that hydrogen is delivered to micro passage reaction is being reacted with material I of the step 1) after preheating
Module group is reacted, wherein：Adjusting the flow velocity of mashing pump makes the flow velocity of material I be 40.0g/min, adjusts H2Gas flowmeter
Flow velocity be 500ml/min, raw material add the molar ratio of hydrogen precursor nitro compounds and hydrogen be 1:3.5, reaction temperature is 90 DEG C, cooling
The temperature of module is 20 DEG C, and the residence time of reaction is 25s, reaction pressure 1.5Mpa, collects to export from cooling module 6 and flow out
Reaction solution, post-processed, the post-processing refers to that catalyst is recovered by filtration, vacuum distillation recovered solvent, residue be added
Stirring and dissolving after 1L water is then added with pH value=9.0~10.0 for the NaOH solution regulation system that mass fraction is 20%
Ethyl acetate extraction, the liquid separation of 500ml, organic phase discard, water phase insulated and stirred crystallization 1 hour at 10 DEG C, filtering, Shao Liangyi
Alcohol cleaning product obtains difficult to understand uncommon replacing Buddhist nun intermediate target product 159.69g, yield after being dried in vacuo 8 hours at 50 DEG C
85.22%, purity 99.70%.
2. micro passage reaction of the embodiment synthesis uncommon method for Buddhist nun's intermediate difficult to understand.
1) it weighs raw material and adds hydrogen precursor nitro compounds 200g, be then added to the mixed liquor of the ethyl alcohol and 100g concentrated hydrochloric acids of 4L
In, the Pd/C catalyst of 7g Pd mass contents 8% is added after stirring and dissolving, is sufficiently stirring and mixing to form material I, material I is defeated
It send into the warm-up block 1 of micro passage reaction and preheats, the reaction module group of micro passage reaction is entered after preheating.
2) the reaction module group that hydrogen is delivered to micro passage reaction is being reacted with material I of the step 1) after preheating
Module group is reacted, wherein：Adjusting the flow velocity of mashing pump makes the flow velocity of material I be 35.0g/min, adjusts H2Gas flowmeter
Flow velocity be 400ml/min, raw material add the molar ratio of hydrogen precursor nitro compounds and hydrogen be 1:3.2, reaction temperature is 70 DEG C, cooling
The temperature of module is 20 DEG C, and the residence time of reaction is 32s, reaction pressure 1.2Mpa, collects to export from cooling module 6 and flow out
Reaction solution, post-processed, the post-processing refers to that catalyst is recovered by filtration, vacuum distillation recovered solvent, residue be added
Stirring and dissolving after 1L water is then added with pH value=9.0~10.0 for the NaOH solution regulation system that mass fraction is 20%
Ethyl acetate extraction, the liquid separation of 500ml, organic phase discard, water phase insulated and stirred crystallization 1 hour at 10 DEG C, filtering, Shao Liangyi
Alcohol cleaning product obtains difficult to understand uncommon replacing Buddhist nun intermediate target product 144.05g, yield after being dried in vacuo 8 hours at 50 DEG C
76.87%, purity 97.09%.
3. micro passage reaction of the embodiment synthesis uncommon method for Buddhist nun's intermediate difficult to understand.
1) it weighs raw material and adds hydrogen precursor nitro compounds 300g, be then added to the mixed liquor of the ethyl alcohol and 150g concentrated hydrochloric acids of 5L
In, the Pt/C catalyst of 10g Pt mass contents 10% is added after stirring and dissolving, material I is sufficiently stirring and mixing to form, by material I
It is delivered in the warm-up block 1 of micro passage reaction and preheats, the reaction module group of micro passage reaction is entered after preheating.
2) the reaction module group that hydrogen is delivered to micro passage reaction is being reacted with material I of the step 1) after preheating
Module group is reacted, wherein：Adjusting the flow velocity of mashing pump makes the flow velocity of material I be 25.0g/min, adjusts H2Gas flowmeter
Flow velocity be 300ml/min, raw material add the molar ratio of hydrogen precursor nitro compounds and hydrogen be 1:3.8, reaction temperature is 100 DEG C, drop
The temperature of warm module is 25 DEG C, and the residence time of reaction is 50s, reaction pressure 0.8Mpa, is collected from 6 outlet stream of cooling module
The reaction solution gone out, is post-processed, and the post-processing refers to that catalyst is recovered by filtration, and vacuum distillation recovered solvent, residue adds
Stirring and dissolving is then added with pH value=9.0~10.0 for the NaOH solution regulation system that mass fraction is 20% after entering 1.5L water
Enter ethyl acetate extraction, the liquid separation of 750ml, organic phase discards, water phase insulated and stirred crystallization 1 hour at 10 DEG C, filtering, on a small quantity
Ethyl alcohol cleaning product obtains difficult to understand uncommon replacing Buddhist nun intermediate target product 235.75g, yield after being dried in vacuo 8 hours at 50 DEG C
83.87%, purity 98.85%.
4. micro passage reaction of the embodiment synthesis uncommon method for Buddhist nun's intermediate difficult to understand.
1) it weighs raw material and adds hydrogen precursor nitro compounds 300g, be then added to the mixed liquor of the isopropanol and 150g concentrated hydrochloric acids of 5L
In, the Pt/C catalyst of 20g Pt mass contents 3% is added after stirring and dissolving, material I is sufficiently stirring and mixing to form, by material I
It is delivered in the warm-up block 1 of micro passage reaction and preheats, the reaction module group of micro passage reaction is entered after preheating.
2) the reaction module group that hydrogen is delivered to micro passage reaction is being reacted with material I of the step 1) after preheating
Module group is reacted, wherein：Adjusting the flow velocity of mashing pump makes the flow velocity of material I be 35.0g/min, adjusts H2Gas flowmeter
Flow velocity be 320ml/min, raw material add the molar ratio of hydrogen precursor nitro compounds and hydrogen be 1:3.0, reaction temperature is 80 DEG C, cooling
The temperature of module 6 is 30 DEG C, and the residence time of reaction is 35s, reaction pressure 1.0Mpa, is collected from 6 outlet stream of cooling module
The reaction solution gone out, is post-processed, and the post-processing refers to that catalyst is recovered by filtration, and vacuum distillation recovered solvent, residue adds
Stirring and dissolving is then added with pH value=9.0~10.0 for the NaOH solution regulation system that mass fraction is 20% after entering 1.5L water
Enter ethyl acetate extraction, the liquid separation of 750ml, organic phase discards, water phase insulated and stirred crystallization 1 hour at 10 DEG C, filtering, on a small quantity
Ethyl alcohol cleaning product obtains difficult to understand uncommon replacing Buddhist nun intermediate target product 226.25g, yield after being dried in vacuo 8 hours at 50 DEG C
80.49%, purity 99.00%.
5. micro passage reaction of the embodiment synthesis uncommon method for Buddhist nun's intermediate difficult to understand.
1) it weighs raw material and adds hydrogen precursor nitro compounds 200g, be then added to the mixed liquor of the methanol and 100g concentrated hydrochloric acids of 4L
In, the Rh/C catalyst of 20g Rh mass contents 5% is added after stirring and dissolving, material I is sufficiently stirring and mixing to form, by material I
It is delivered in the warm-up block 1 of micro passage reaction and preheats, the reaction module group of micro passage reaction is entered after preheating.
2) the reaction module group that hydrogen is delivered to micro passage reaction is being reacted with material I of the step 1) after preheating
Module group is reacted, wherein：Adjusting the flow velocity of mashing pump makes the flow velocity of material I be 42.0g/min, adjusts H2Gas flowmeter
Flow velocity be 450ml/min, raw material add the molar ratio of hydrogen precursor nitro compounds and hydrogen be 1:3.0, reaction temperature is 90 DEG C, cooling
The temperature of module is 30 DEG C, and the residence time of reaction is 20s, reaction pressure 1.0Mpa, collects to export from cooling module 6 and flow out
Reaction solution, post-processed, the post-processing refers to that catalyst is recovered by filtration, vacuum distillation recovered solvent, residue be added
Stirring and dissolving after 1.0L water is then added with pH value=9.0~10.0 for the NaOH solution regulation system that mass fraction is 20%
Ethyl acetate extraction, the liquid separation of 500ml, organic phase discard, water phase insulated and stirred crystallization 1 hour at 10 DEG C, filtering, Shao Liangyi
Alcohol cleaning product obtains difficult to understand uncommon replacing Buddhist nun intermediate target product 151.82g, yield after being dried in vacuo 8 hours at 50 DEG C
81.02%, purity 99.26%.
6. micro passage reaction of the embodiment synthesis uncommon method for Buddhist nun's intermediate difficult to understand.
1) it weighs raw material and adds hydrogen precursor nitro compounds 250g, be then added to the mixed liquor of the methanol and 125g concentrated hydrochloric acids of 5L
In, the Pd/C catalyst of 15g Pd mass contents 8% is added after stirring and dissolving, material I is sufficiently stirring and mixing to form, by material I
It is delivered in the warm-up block 1 of micro passage reaction and preheats, the reaction module group of micro passage reaction is entered after preheating.
2) the reaction module group that hydrogen is delivered to micro passage reaction is being reacted with material I of the step 1) after preheating
Module group is reacted, wherein：Adjusting the flow velocity of mashing pump makes the flow velocity of material I be 50.0g/min, adjusts H2Gas flowmeter
Flow velocity be 600ml/min, raw material add the molar ratio of hydrogen precursor nitro compounds and hydrogen be 1:3.4, reaction temperature is 60 DEG C, cooling
The temperature of module is 30 DEG C, and the residence time of reaction is 10s, reaction pressure 0.5Mpa, collects to export from cooling module 6 and flow out
Reaction solution, post-processed, the post-processing refers to that catalyst is recovered by filtration, vacuum distillation recovered solvent, residue be added
Stirring and dissolving after 1.25L water is then added with pH value=9.0~10.0 for the NaOH solution regulation system that mass fraction is 20%
Enter ethyl acetate extraction, the liquid separation of 600ml, organic phase discards, water phase insulated and stirred crystallization 1 hour at 10 DEG C, filtering, on a small quantity
Ethyl alcohol cleaning product obtains difficult to understand uncommon replacing Buddhist nun intermediate target product 160.80g, yield after being dried in vacuo 8 hours at 50 DEG C
68.65%, purity 95.52%.
7. micro passage reaction of the embodiment synthesis uncommon method for Buddhist nun's intermediate difficult to understand.
1) it weighs raw material and adds hydrogen precursor nitro compounds 200g, be then added to the mixed liquor of the methanol and 100g concentrated hydrochloric acids of 4L
In, the Pd/C catalyst of 10g Pd mass contents 5% is added after stirring and dissolving, material I is sufficiently stirring and mixing to form, by material I
It is delivered in the warm-up block 1 of micro passage reaction and preheats, the reaction module group of micro passage reaction is entered after preheating.
2) the reaction module group that hydrogen is delivered to micro passage reaction is being reacted with material I of the step 1) after preheating
Module group is reacted, wherein：Adjusting the flow velocity of mashing pump makes the flow velocity of material I be 30.0g/min, adjusts H2Gas flowmeter
Flow velocity be 480ml/min, raw material add the molar ratio of hydrogen precursor nitro compounds and hydrogen be 1:4.0, reaction temperature is 120 DEG C, drop
The temperature of warm module is 25 DEG C, and the residence time of reaction is 42s, reaction pressure 0.6Mpa, is collected from 6 outlet stream of cooling module
The reaction solution gone out, is post-processed, and the post-processing refers to that catalyst is recovered by filtration, and vacuum distillation recovered solvent, residue adds
Stirring and dissolving is then added with pH value=9.0~10.0 for the NaOH solution regulation system that mass fraction is 20% after entering 1.0L water
Enter ethyl acetate extraction, the liquid separation of 600ml, organic phase discards, water phase insulated and stirred crystallization 1 hour at 10 DEG C, filtering, on a small quantity
Ethyl alcohol cleaning product obtains difficult to understand uncommon replacing Buddhist nun intermediate target product 146.33g, yield after being dried in vacuo 8 hours at 50 DEG C
78.09%, purity 97.11%.
8. micro passage reaction of the embodiment synthesis uncommon method for Buddhist nun's intermediate difficult to understand.
1) it weighs raw material and adds hydrogen precursor nitro compounds 250g, be then added to the mixed liquor of the methanol and 125g concentrated hydrochloric acids of 5L
In, the Pt/C catalyst of 15g Pt mass contents 8% is added after stirring and dissolving, material I is sufficiently stirring and mixing to form, by material I
It is delivered in the warm-up block 1 of micro passage reaction and preheats, the reaction module group of micro passage reaction is entered after preheating.
2) the reaction module group that hydrogen is delivered to micro passage reaction is being reacted with material I of the step 1) after preheating
Module group is reacted, wherein：Adjusting the flow velocity of mashing pump makes the flow velocity of material I be 38.0g/min, adjusts H2Gas flowmeter
Flow velocity be 450ml/min, raw material add the molar ratio of hydrogen precursor nitro compounds and hydrogen be 1:3.3, reaction temperature is 110 DEG C, drop
The temperature of warm module is 25 DEG C, and the residence time of reaction is 28s, reaction pressure 1.5Mpa, is collected from 6 outlet stream of cooling module
The reaction solution gone out, is post-processed, and the post-processing refers to that catalyst is recovered by filtration, and vacuum distillation recovered solvent, residue adds
Enter stirring and dissolving after 1.25L water, with pH value=9.0~10.0 for the NaOH solution regulation system that mass fraction is 20%, then
Ethyl acetate extraction, the liquid separation of 600ml is added, organic phase discards, and water phase insulated and stirred crystallization 1 hour at 10 DEG C is filtered, few
Ethyl alcohol cleaning product is measured, is obtained after being dried in vacuo 8 hours at 50 DEG C difficult to understand uncommon for Buddhist nun intermediate target product 190.39g, yield
81.28%, purity 98.27%.
1, illustrate the advantageous effect that the method for the present invention can obtain through the following experiment：
9. micro passage reaction of the embodiment synthesis uncommon method for Buddhist nun's intermediate difficult to understand.
1) it weighs raw material and adds hydrogen precursor nitro compounds 200g, be then added to the mixed liquor of the methanol and 100g concentrated hydrochloric acids of 4L
In, the Pd/C catalyst that 10g Pd mass contents are 10% is added after stirring and dissolving, material I is sufficiently stirring and mixing to form, by object
Material I, which is delivered in the warm-up block 1 of micro passage reaction, to be preheated, and the reaction module group of micro passage reaction is entered after preheating.
2) the reaction module group that hydrogen is delivered to micro passage reaction is being reacted with material I of the step 1) after preheating
Module group is reacted, wherein：Adjusting the flow velocity of mashing pump makes the flow velocity of material I be 40.0g/min, adjusts H2Gas flowmeter
Flow velocity be 500ml/min, raw material add the molar ratio of hydrogen precursor nitro compounds and hydrogen be 1:3.5, reaction temperature is 90 DEG C, cooling
The temperature of module is 20 DEG C, and the residence time of reaction is 25s, reaction pressure 1.5Mpa, collects to export from cooling module and flow out
Reaction solution, post-processed, the post-processing refers to that catalyst is recovered by filtration, vacuum distillation recovered solvent, residue be added
Stirring and dissolving after 1L water is then added with pH value=9.0~10.0 for the NaOH solution regulation system that mass fraction is 20%
Ethyl acetate extraction, the liquid separation of 500ml, organic phase discard, water phase insulated and stirred crystallization 1 hour at 10 DEG C, filtering, Shao Liangyi
Alcohol cleaning product obtains difficult to understand uncommon replacing Buddhist nun intermediate target product 160.65g, yield after being dried in vacuo 8 hours at 50 DEG C
85.73%, purity 99.68%.
10. the present embodiment of embodiment and the difference of embodiment 9 are that the step 2) reaction temperature is 60 in the present embodiment
℃。
11. the present embodiment of embodiment and the difference of embodiment 9 are that the step 2) reaction temperature is 70 in the present embodiment
℃。
12. the present embodiment of embodiment and the difference of embodiment 9 are that the step 2) reaction temperature is 80 in the present embodiment
℃。
13. the present embodiment of embodiment and the difference of embodiment 9 are that the step 2) reaction temperature is in the present embodiment
100℃。
14. the present embodiment of embodiment and the difference of embodiment 9 are that the step 2) reaction temperature is in the present embodiment
110℃。
15. the present embodiment of embodiment and the difference of embodiment 9 are that the step 2) reaction temperature is in the present embodiment
120℃。
This method obtains uncommon yield and purity statistics for Buddhist nun's intermediate difficult to understand at a temperature of 1 differential responses of table
| Experimental group | Reaction temperature | Yield (%) | Purity (%) |
| Embodiment 9 | 90℃ | 85.73 | 99.68 |
| Embodiment 10 | 60℃ | 69.88 | 94.98 |
| Embodiment 11 | 70℃ | 75.21 | 97.16 |
| Embodiment 12 | 80℃ | 80.62 | 99.04 |
| Embodiment 13 | 100℃ | 84.09 | 98.77 |
| Embodiment 14 | 110℃ | 81.33 | 98.12 |
| Embodiment 15 | 120℃ | 77.76 | 96.94 |
As shown in Table 1, reaction temperature is very big to the yield and impurities affect of target product, in the relatively low feelings of reaction temperature
Raw material has a residue under condition, and temperature is excessively high that there will be the appearance of a large amount of over-hydrogenation impurity, therefore reaction temperature is step reaction
Key process parameter, the reaction time is 90 DEG C the most suitable.
2, it is the recycled efficiency for investigating catalyst, this experiment is embodiment 1 on the basis of, high spot review circulating sleeve
With the relationship between multiple Pd/C and reaction yield, product purity, the specific method is as follows：
Using Pd/C as catalyst, 8 recycled experiments are carried out altogether, i.e.,：It is first that catalyst Pd/C, which is used for embodiment 1,
Secondary to apply mechanically experiment, it is second that the catalyst Pd/C recycled after applying mechanically experiment for the first time, which is then re-used for embodiment 1,
Secondary to apply mechanically experiment, it is that third time covers that the catalyst Pd/C recycled after applying mechanically experiment for the second time, which is re-used for embodiment 1,
With experiment, and so on, eight recycleds experiments are carried out altogether；Experiment is applied mechanically every time to carry out according to embodiment 1, is ensured each
The process that catalyst circulation is applied mechanically is 90 DEG C in reaction temperature, and the dosage of hydrogen is 3.5eq, reaction pressure 1.5MPa, is stopped
Time is 25s, and the Pd mass contents of Pd/C catalyst used are 5%, and recycled experimental result is as shown in table 2：
Table 2Pd/C catalyst circulations apply mechanically experiment
The results show that the conversion ratio reacted in use by the catalyst Pd/C of multiple recycled does not all go out
It is now apparent to decline, illustrate that catalyst still has very high activity by 8 recycleds, can ensure higher product yield
And purity.
1. conventional high-pressure reaction kettle of the comparative example production uncommon method for Buddhist nun's intermediate difficult to understand.
Addition plus hydrogen precursor nitro compounds 150g into the high-pressure stirring reaction kettle of 5L, the subsequent methanol that 3L is added and 75g's
Concentrated hydrochloric acid, it is 10%Pd/C catalyst that 30g Pd contents are added after stirring and dissolving, and H is passed through into autoclave2, ensure in reaction kettle
Pressure be 3.0Mpa, be warming up to 120 DEG C and insulation reaction 12 hours, reaction, which finishes, is down to room temperature, after feed liquid is released out of kettle
Catalyst, vacuum distillation recovered solvent is recovered by filtration, stirring and dissolving after 1.2L water is added in residue, is 20% with mass fraction
PH value=9.0~10.0 of NaOH solution regulation system, are then added ethyl acetate extraction, the liquid separation of 375ml, and organic phase is abandoned
It goes, water phase insulated and stirred crystallization 1 hour at 10 DEG C, filters, a small amount of ethyl alcohol cleaning product, after being dried in vacuo 8 hours at 50 DEG C
It obtains difficult to understand uncommon for Buddhist nun intermediate target product 95.89g, yield 68.23%, purity 96.12%.
By the embodiment of the present invention is compared with comparative example：The micro passage reaction reaction time only needs deficiency
1min, and the reaction time of autoclave needs 12h；Synthesize target product N-1- [2- (dimethylamino) ethyl] -5- methoxyl groups -
During N1- methyl-N4- [4- (1- Methyl-1H-indole -3- bases) -2- pyrimidine radicals] -1,2,4- benzene triamines, reaction kettle holds liquid
It is abnormally dangerous that amount big (5L) carries out hydroprocessing, extremely easy to explode, and micro passage reaction due to liquid holdup it is small (less than
50ml), danger coefficient is greatly reduced, even if there is a small amount of hydrogen leak to there will not be too big danger；Since the reaction time is long
Over-hydrogenation impurity content is caused to increase, reaction yield is obviously relatively low, and micro passage reaction is controlled very due to the reaction time
Accurately, the case where capable of fundamentally controlling over-hydrogenation, the yield and purity of product all have been improved.Therefore, microchannel plate is answered
Device has many advantages, such as that reaction speed is fast, liquid holdup is small, safety and environmental protection compared with conventional high-pressure reaction kettle, during the reaction excessively
The content of hydrogenated by-product can greatly reduce, and the high incomes of final products, quality are more preferably.
Claims (8)
1. a kind of micro passage reaction synthesis uncommon method for Buddhist nun's intermediate difficult to understand, the Ao Xi is N-1- [2- (two for Buddhist nun's intermediate
Methylamino) ethyl] -5- methoxyl group-N1- methyl-N4- [4- (1- Methyl-1H-indole -3- bases) -2- pyrimidine radicals] -1,2,4-
Benzene triamine, which is characterized in that include the following steps：
1) hydrogen precursor nitro compounds N- (2- dimethylarnino-ethyls) -2- methoxyl group-N- ﹝ 4- (1- methyl-1s-indoles -3- will be added
Base)-pyrimidine -2- Ji ﹞ -5- nitros-benzene-Isosorbide-5-Nitrae-diamines is added in organic solvent, and concentrated hydrochloric acid dissolving is added, activity is then added
Material I is delivered to the pre- hot-die of micro passage reaction by the mixture of the catalyst of charcoal carried noble metal, acquisition as material I
It is preheated in block, reaction module group is entered after preheating；
The described plus a concentration of 0.1mol/L~0.15mol/L of hydrogen precursor nitro compounds in organic solvent；
The mass ratio of described plus hydrogen precursor nitro compounds and concentrated hydrochloric acid is 1:0.5；
The mass ratio of described plus hydrogen precursor nitro compounds and the catalyst of activated carbon supported noble metal is 1：(0.01~0.10)；
2) hydrogen is delivered to the reaction module group of micro passage reaction with material I of the step 1) after preheating in reaction module
Group is reacted, and the reaction solution flowed out from cooling module is collected, and post-processing obtains difficult to understand uncommon for Buddhist nun's intermediate N 1- [2- (dimethyl
Amino) ethyl] -5- methoxyl group-N1- methyl-N4- [4- (1- Methyl-1H-indole -3- bases) -2- pyrimidine radicals] -1,2,4- benzene three
Amine, in the material I plus the molar ratio of hydrogen precursor nitro compounds and hydrogen is 1:(3.0~4.0).
2. the micro passage reaction synthesis uncommon method for Buddhist nun's intermediate difficult to understand according to claim 1, which is characterized in that step
1) organic solvent described in is one kind in methanol, ethyl alcohol, isopropanol.
3. the micro passage reaction synthesis uncommon method for Buddhist nun's intermediate difficult to understand according to claim 1, which is characterized in that step
1) catalyst of the activated carbon supported noble metal described in is the composition of one or more of Pd/C, Pt/C, Rh/C；Its
Middle noble metal quality accounts for the 1%~10% of catalyst gross mass.
4. the micro passage reaction synthesis uncommon method for Buddhist nun's intermediate difficult to understand according to claim 1, which is characterized in that step
2) pressure of the reaction is 0.5MPa~1.5MPa.
5. the micro passage reaction synthesis uncommon method for Buddhist nun's intermediate difficult to understand according to claim 1, which is characterized in that step
2) reaction temperature described in is 60 DEG C~120 DEG C.
6. the micro passage reaction synthesis uncommon method for Buddhist nun's intermediate difficult to understand according to claim 5, which is characterized in that step
2) reaction temperature described in is 90 DEG C.
7. the micro passage reaction synthesis uncommon method for Buddhist nun's intermediate difficult to understand according to claim 1, which is characterized in that step
2) temperature of the cooling module described in is 20 DEG C~30 DEG C.
8. the micro passage reaction synthesis uncommon method for Buddhist nun's intermediate difficult to understand according to claim 1, which is characterized in that step
2) total residence time of material I and hydrogen in reaction module group described in is 10s~50s.
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| CN113061135A (en) * | 2021-03-16 | 2021-07-02 | 河北广祥制药有限公司 | Method for continuously synthesizing xanthinol nicotinate by micro-channel |
| CN115504937A (en) * | 2022-10-17 | 2022-12-23 | 喆鹿(山东)新材料有限公司 | Method for synthesizing axitinib intermediate 6-aminoindazole by tubular reactor |
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