CN108358798A - A kind of method of micro passage reaction synthesis Tarceva intermediate - Google Patents
A kind of method of micro passage reaction synthesis Tarceva intermediate Download PDFInfo
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- CN108358798A CN108358798A CN201810145480.9A CN201810145480A CN108358798A CN 108358798 A CN108358798 A CN 108358798A CN 201810145480 A CN201810145480 A CN 201810145480A CN 108358798 A CN108358798 A CN 108358798A
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- WQFOWOANLHERIK-UHFFFAOYSA-N COCCCOc(ccc(N)c1)c1OCCOC Chemical compound COCCCOc(ccc(N)c1)c1OCCOC WQFOWOANLHERIK-UHFFFAOYSA-N 0.000 description 1
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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Abstract
A kind of method of micro passage reaction synthesis Tarceva intermediate belongs to the antitumor drug synthesis field in organic synthesis.The present invention solves the low prior art existing yield when synthesizing Tarceva intermediate, purity difference, high energy consumption, the problems such as heavy explosion generates danger, catalyst recovery number is low, the method for the synthesis Tarceva intermediate easily occurs：1) nitration reaction：It adds raw materials into glacial acetic acid and dissolves, nitration reaction is carried out in micro passage reaction with the mixture of the concentrated sulfuric acid and concentrated nitric acid, collect the reaction solution flowed out from cooling module, post-processing obtains nitration product；2) catalytic hydrogenation reaction：Above-mentioned nitration product is added and is dissolved into organic solvent, the noble metal catalyst and H for loading active charcoal is then added2Hydro-reduction being carried out with nitration product in reaction module to react, collecting the reaction solution flowed out from cooling module, post-processing obtains target product.The present invention is suitable for the production of Tarceva intermediate.
Description
Technical field
The invention belongs to the antitumor drugs in organic synthesis to synthesize field, and in particular to a kind of Tarceva intermediate
Synthetic method.
Background technology
Tarceva is developed by company of Roche Group of Switzerland, trade name Erlotinib, entitled N- (the 3- acetenyls of chemistry
Phenyl) -6,7- is bis--(2- methoxy ethoxies) quinazoline -4- amine, its hydrochloride is clinically used, is a kind of selectively acting
In the selective depressant of the tyrosine kinase of liver EGF-R ELISA, the drug and in November, 2004 obtain FDA in the U.S.
Approval listing is ratified to list for 2006 in China, effective to Patients with Non-small-cell Lung of all categories, and tolerance is good.Together
When the medicine through liver metabolism, no bone marrow suppression and neurotoxicity, the life cycle of patient can be obviously prolonged, improve the life matter of patient
Amount.Therefore, studying a kind of novel synthesis of Tarceva has certain realistic meaning.
The synthetic method of Tarceva mainly has following two at present：
Route one：
Route two：
The synthetic route of above-mentioned two synthesis Tarceva all refers to a key intermediate amino substance before pyrazoles cyclization
Preparation, the introducing process of amino is that nitro is introduced on phenyl ring by nitration reaction first, is then restored by nitro
Amino product is obtained by the reaction, chemical equation can be expressed as follows：
This method introduce amino process be then be reduced to amino by first introducing nitro on phenyl ring to realize, and
Document report two-step reaction realizes the plant-scale production of Tarceva generally by nitric acid nitrating and hydrogenating reduction at present.
Since traditional batch type reaction kettle has that heat transfer and material mixed effect are bad, lead to nitrification mentioned above
Very big with this kind of " high-risk " chemical reaction operation hidden danger of hydro-reduction, temperature runaway, slug caused by local concentration height often occurs are even
The production safeties problem such as combustion explosion.
Invention content
In order to solve low existing yield during traditional stirred autoclave synthesis Tarceva intermediate, purity difference, energy
Consumption is high, heavy explosion easily occurs generates the problems such as dangerous, catalyst recovery number is low, and the present invention provides a kind of microchannels
The method that reactor synthesizes Tarceva intermediate,
The Tarceva intermediate isDescribed method includes following steps：
1) nitration reaction：
By raw material(R=-COOEt ,-CN), which is added in glacial acetic acid, to be dissolved, and mixed solution is as object
Material I enters the warm-up block of micro passage reaction, using the concentrated sulfuric acid and concentrated nitric acid as material II and material III into logical in a subtle way
The warm-up block of road reactor, raw material carry out nitration reaction with the mixture of the concentrated sulfuric acid and concentrated nitric acid, collect from cooling module stream
The reaction solution gone out, post-processing obtain nitration product
(R=-COOEt ,-CN)；
A concentration of 0.1~0.3mol/L of the raw material in glacial acetic acid；The molar ratio of raw material and concentrated nitric acid is (1:1.0)
~(1:2.0)；The concentrated nitric acid is (1 with concentrated sulfuric acid mass ratio:2.0)~(1:5.0).
2) catalytic hydrogenation reaction：
Above-mentioned nitration product is added and is dissolved into organic solvent, the noble metal catalyst for loading active charcoal is then added
As material IV, H2As material V it is preheated after in module with nitration product carry out hydro-reduction react, collect from cooling mould
The reaction solution of block outflow, post-processing obtain target product
A concentration of 0.2~the 0.3mol/L of the nitration product in organic solvent；Nitration product and H2Molar ratio be
(1:3.0)~(1:4.0).
Preferably, the reaction temperature described in step 1) is 40~90 DEG C, and reaction time is 15~60s.
Organic solvent described in step 2) is methanol, ethyl alcohol, one kind in isopropanol or in which several mixing, when organic
When solvent is more than one mixture, mixed with arbitrary proportion between each organic solvent.
The noble metal catalyst of the active charcoal of the step 2) load is one kind in Pd/C, Pt/C, Rh/C or in which several
The mixing of kind；Wherein noble metal quality accounts for the 1%~10% of catalyst gross mass, when noble metal catalyst is more than one,
With arbitrary than mixing between each metallic catalyst.
The mass ratio of the step 2) nitration product and the noble metal catalyst for loading active charcoal is (1:0.01)~(1:
0.10)。
The pressure of reaction described in step 2) is 0.5~1.5Mpa.
Reaction temperature described in step 2) is 60~120 DEG C, total residence time of the material in reaction module group be 15~
50s。
The temperature of step 1), 2) cooling module is 20~30 DEG C.
It is furthermore preferred that the reaction temperature described in step 1) is 70 DEG C.
Total residence time of the step 2) material in reaction module group is 25~35s.
Micro passage reaction used in the present invention includes warm-up block, reaction module group and cooling module, warm-up block
It connects with reaction module group, reaction module group has 1-8 unit module according to charging rate, reactant concentration, reaction time etc.
Arbitrary series connection, cooling module are connected with reaction module group, and the material of reaction module is special glass, silicon carbide ceramics, it is resistance to be coated with
One or more of stainless steel metal or politef of corrosion layer, the Maximum safe pressure that can be born are 1.5~1.8MPa；
The reaction module group has 1-8 unit module according to the arbitrary serial or parallel connection such as charging rate, reactant concentration, reaction time
It is composed.
When reaction carries out in micro passage reaction, the warm-up block is single-entry single-out or Two In and One Out cardioid knot
Structure module；The reaction module and cooling module are Two In and One Out or single-entry single-out heart-shaped structure module, the order of connection are pre-
The reaction module of thermal modules, the reaction module of Two In and One Out structure, the reaction module of single-entry single-out structure, single-entry single-out structure,
The reaction module of Two In and One Out structure stops for hybrid reaction after preheating, the reaction module of single-entry single-out structure for extending reaction
It stays the time and feed liquid is down to room temperature by high temperature, the micro passage reaction used includes warm-up block group and reaction module group, in advance
Thermal modules group is connected with reaction module group, and warm-up block group includes a warm-up block or more than two in parallel warm-up blocks,
Reaction module group includes a reaction module or more than two concatenated reaction modules.
Advantageous effect
Often there is reactor mass-and heat-transfer inefficiency due to the relationship of equipment size in traditional Jian Xieshi reaction kettles
Problem be easy to cause temperature, uneven concentration, leads to low yield, low production efficiency, intermittently operated product quality stability difference etc.
Disadvantage, especially at processing " dangerous technique ", still reaction process safety hidden danger is big, and is limited to reaction of atomic economy and mistake
The alternative of the factors such as journey practicability, these " dangerous techniques " is often with high costs and route is longer.Nitre described herein
Change reaction and catalytic hydrogenation reaction just belong to process control in industrial production it is most complicated in " dangerous technique ", the present invention utilizes one
Kind innovative microchannel or microreactor, provide a kind of essential safety and environmentally protective Tarceva intermediate synthesis side
Method.Using the efficient mass-and heat-transfer efficiency of micro passage reaction itself, this kind of danger technique can pass through micro passage reaction spy
Point design on-line real-time measuremen reaction process, in the preferred range by state modulators such as reaction temperature, reaction time, from basic
Reaction yield can also be further increased while upper control security risk, reduces energy consumption, optimization manufacturing parameter, and advantage is much
Extra current batch type equipment.
The present invention also creates other beneficial technique effects：
1) the efficient mass-and heat-transfer abilities of ensure that reaction is released a large amount of heat and can in time be taken away by heat transferring medium, wherein
The preparation of nitration mixture can be carried out with nitration reaction by the way that the process realization fed online is synchronous, ensure reaction in security reaction temperature
Stablize in section, continuous production.
2) controlling reaction temperature refined and residence time, the online falling temperature technique of complex reaction device can be fundamentally
The stereoselectivity that nitro introduces is controlled, can ensure effectively to control nitration isomer and polynitration impurity at high temperature
Content.
3) time of catalytic hydrogenation reactions can shorten to 20s from ten a few houres, and energy consumption is greatly reduced, save it is economical at
This.
4) the reaction time is short, the surface texture generation of catalyst will not be caused prodigious with high temperature because stirring for a long time
Change, the activity of catalyst can retain to greatest extent, investigate the recycled of catalyst in the present invention by taking Pd/C as an example
As a result, still there is very high activity on experimental data surface by 8 cycle rear catalysts.
5) is few in line material, and the microchannel of feature inherently flame retardant property can individually be set according to the type of reactor
Explosion-protection equipment is counted, even if the burning of a small range occurs or zero injury that can also ensure to operating personnel of exploding, the company of realizing
Afterflow essential safety produces.
6) can continuous production and realizing automate, without enlarge-effect, can directly carry out plant-scale amplification and produce,
It is easy to continuous production and control easy to automate, saves labo r resources.
Description of the drawings
The module material circulation duct shape and structure schematic diagram of Fig. 1 organic glass material micro passage reactions, wherein (a) is
The single-entry single-out module of cardioid (b) is cardioid Two In and One Out module.
Fig. 2 is nitration reaction flow and micro passage reaction connection relationship diagram, and reaction module 1,3 is Two In and One Out mould
Block, reaction module 2,4~8 are single-entry single-out module, and wherein A, B, C is respectively the liquid feedstock of material I, material II and material III
Pump, module 1 are the warm-up block of material II and material III, are used for the mixing and preheating of the concentrated sulfuric acid and concentrated nitric acid, and module 2 is object
The warm-up block of material I is used for the preheating of raw material, and reaction module 3~7 is the reaction module group of nitration reaction, for raw material and is mixed
The nitration reaction of acid, reaction module 8 are cooling module, are used for the cooling of high temperature feed liquid.
Fig. 3 is catalytic hydrogenation reaction flow and micro passage reaction connection relationship diagram, and reaction module 2 is Two In and One Out
Module, module 1,3~7 are single-entry single-out module, and wherein E is gas flowmeter, and H is hydrogenated for the step2Conveying, D is slurry
Pump is used for the conveying of material IV, and module 1 is warm-up block, is used for the preheating of IV Intermediate nitro object of material, reaction module 2~6
For the reaction module group of hydro-reduction reaction, it is used for the reduction reaction of nitration product and hydrogen, reaction module 7 is cooling module,
Cooling for high temperature feed liquid.
Specific implementation mode
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 illustrating the present invention rather than limit the scope of the invention；In addition, it should also be understood that, after reading content described in the invention,
Those skilled in the art can various modifications may be made or changes to the present invention, but such equivalent forms equally fall within the appended power of the application
Sharp claim limited range.
The material of the reaction module for the micro passage reaction that following each embodiments are utilized is special glass, silicon carbide pottery
One or more of porcelain, the stainless steel metal for being coated with anti-corrosion layer or politef, the Maximum safe pressure that can be born are 1.5
~1.8MPa；The reaction module group has 1-8 unit module arbitrary according to charging rate, reactant concentration, reaction time etc.
Serial or parallel connection is composed.
When reaction carries out in micro passage reaction, the warm-up block is single-entry single-out or Two In and One Out cardioid knot
Structure module；The reaction module and cooling module are Two In and One Out or single-entry single-out heart-shaped structure module, the order of connection are pre-
The reaction module of thermal modules, the reaction module of Two In and One Out structure, the reaction module of single-entry single-out structure, single-entry single-out structure,
The reaction module of Two In and One Out structure stops for hybrid reaction after preheating, the reaction module of single-entry single-out structure for extending reaction
It stays the time and feed liquid is down to room temperature by high temperature, the micro passage reaction used includes warm-up block group and reaction module group, in advance
Thermal modules group is connected with reaction module group, and warm-up block group includes a warm-up block or more than two in parallel warm-up blocks,
Reaction module group includes a reaction module or more than two concatenated reaction modules.
The method that 1. micro passage reaction of embodiment synthesizes Tarceva intermediate.
1) nitration reaction：200g dissolution of raw material is dissolved in the glacial acetic acid of 3L and is used as material I, the concentrated sulfuric acid is as material
II, concentrated nitric acid is as material III, and the flow velocity for adjusting flow pump so that the flow velocity of material I is 20ml/min, and the flow velocity of material II is
The flow velocity of 10ml/min, material III are 6ml/min, raw material and HNO3Molar ratio be 1:1.5, the matter of concentrated nitric acid and the concentrated sulfuric acid
Amount is than being 1:3, reaction temperature is 60 DEG C, and the residence time of reaction is 60 seconds, and the temperature of cooling module is 25 DEG C, is collected from cooling
The reaction solution of module outlet outflow, is post-processed, and the post-processing refers to vacuum distillation recycling glacial acetic acid, and residue is added
In 1.2L water, the ethyl acetate that 1L is added is extracted twice, and ethyl acetate 500ml, organic phase saturated sodium bicarbonate are added every time
Solvent is washed to neutrality, anhydrous sodium sulfate drying, and vacuum distillation recovered solvent obtains nitration product 215.21g, yield
93.50%, purity 99.13%.
2) catalytic hydrogenation reaction：The nitration product 200g that upper step obtains is added to the absolute methanol dissolving of 5L, is then added
The Pd/C catalyst that 10g Pd contents are 10% is sufficiently stirring and mixing to form material IV, H2As material V, the stream of mashing pump is adjusted
Speed makes the flow velocity of material IV be 40.0g/min, and adjusting gas flow meter makes H2Flow be 700ml/min, nitro compounds and H2Rub
You are than being 1:3.5, reaction temperature is 90 DEG C, and the temperature of cooling module is 25 DEG C, and the residence time of reaction is 25s, reaction pressure
For 1.5Mpa, the reaction solution from cooling module outlet outflow is collected, is post-processed, the post-processing refers to that catalysis is recovered by filtration
Agent Pd/C, vacuum distillation recycling organic solvent, the acetone that 1.2L is added in residue stir solvent, the concentrated hydrochloric acid of 450ml are added, stirs
Crystallization 1h is mixed, filters, filter cake is put into the water of 2L, the pH value that the NaOH solution regulation system of 2mol/L is added is 8.0 left
The right side, the ethyl acetate that 2L is added are extracted twice, and add 1L ethyl acetate every time, are merged organic phase, are dried by anhydrous sodium sulfate
Vacuum distillation recovered solvent obtains amino product 160.83g, yield 87.79%, purity 99.43% afterwards.
The method that 2. micro passage reaction of embodiment synthesizes Tarceva intermediate.
1) nitration reaction：200g dissolution of raw material is dissolved in the glacial acetic acid of 3L and is used as material I, the concentrated sulfuric acid is as material
II, concentrated nitric acid is as material III, and the flow velocity for adjusting flow pump so that the flow velocity of material I is 20ml/min, and the flow velocity of material II is
The flow velocity of 10ml/min, material III are 6ml/min, raw material and HNO3Molar ratio be 1:1.5, the matter of concentrated nitric acid and the concentrated sulfuric acid
Amount is than being 1:4, reaction temperature is 60 DEG C, and the residence time of reaction is 60 seconds, and the temperature of cooling module is 20 DEG C, is collected from cooling
The reaction solution of module outlet outflow, is post-processed, and the post-processing refers to vacuum distillation recycling glacial acetic acid, and residue is added
In 1.2L water, the ethyl acetate that 1L is added is extracted twice, and ethyl acetate 500ml, organic phase saturated sodium bicarbonate are added every time
Solvent is washed to neutrality, anhydrous sodium sulfate drying, and vacuum distillation recovered solvent obtains nitration product 215.21g, yield
90.58%, purity 98.95%.
2) catalytic hydrogenation reaction：The nitration product 200g that upper step obtains is added to the absolute methanol dissolving of 5L, is then added
The Pd/C catalyst that 15g Pd contents are 10% is sufficiently stirring and mixing to form material IV, H2As material V, the stream of mashing pump is adjusted
Speed makes the flow velocity of material IV be 40.0g/min, and adjusting gas flow meter makes H2Flow be 700ml/min, nitration product and H2's
Molar ratio is 1:3.5 reaction temperature is 100 DEG C, the temperature of cooling module is 25 DEG C, and the residence time of reaction is 25s, reaction pressure
Power is 1.5Mpa, collects the reaction solution from cooling module outlet outflow, is post-processed, the post-processing refers to being recovered by filtration to urge
Agent Pd/C, vacuum distillation recycling organic solvent, the acetone that 1.2L is added in residue stir solvent, the concentrated hydrochloric acid of 450ml are added,
Stirring and crystallizing 1h, filtering, filter cake is put into the water of 2L, and the pH value that the NaOH solution regulation system of 2mol/L is added is 8.0
Left and right, the ethyl acetate that 2L is added are extracted twice, and add 1L ethyl acetate every time, merge organic phase, dry by anhydrous sodium sulfate
Vacuum distillation recovered solvent obtains amino product 160.83g, yield 90.31%, purity 99.61% after dry.
The method that 3. micro passage reaction of embodiment synthesizes Tarceva intermediate.
1) nitration reaction：200g dissolution of raw material is dissolved in the glacial acetic acid of 3L and is used as material I, the concentrated sulfuric acid is as material
II, concentrated nitric acid is as material III, and the flow velocity for adjusting flow pump so that the flow velocity of material I is 30ml/min, and the flow velocity of material II is
The flow velocity of 15ml/min, material III are 12ml/min, raw material and HNO3Molar ratio be 1:2.0, the matter of concentrated nitric acid and the concentrated sulfuric acid
Amount is than being 1:2.0, reaction temperature is 90 DEG C, and the residence time of reaction is 30 seconds, and the temperature of cooling module is 30 DEG C, is collected from drop
The reaction solution of warm module outlet outflow, is post-processed, and the post-processing refers to vacuum distillation recycling glacial acetic acid, and residue is added
In 1.2L water, the ethyl acetate that 1L is added is extracted twice, and ethyl acetate 500ml, organic phase saturated sodium bicarbonate are added every time
Solvent is washed to neutrality, anhydrous sodium sulfate drying, and vacuum distillation recovered solvent obtains nitration product 215.37g, yield
93.36%, purity 99.11%.
2) catalytic hydrogenation reaction：The nitration product 200g that upper step obtains is added to the absolute methanol dissolving of 5L, is then added
The Rh/C catalyst that the Rh contents of 20g are 2% is sufficiently stirring and mixing to form material IV, H2As material V, the stream of mashing pump is adjusted
Speed makes the flow velocity of material IV be 50.0g/min, and adjusting gas flow meter makes H2Flow be 800ml/min, nitration product and H2's
Molar ratio is 1:3.8, reaction temperature is 80 DEG C, and the temperature of cooling module is 20 DEG C, and the residence time of reaction is 15s, reaction pressure
Power is 0.5Mpa, collects the reaction solution from cooling module outlet outflow, is post-processed, the post-processing refers to being recovered by filtration to urge
Agent Rh/C, vacuum distillation recycling organic solvent, the acetone that 1.2L is added in residue stir solvent, the concentrated hydrochloric acid of 450ml are added,
Stirring and crystallizing 1h, filtering, filter cake is put into the water of 2L, and the pH value that the NaOH solution regulation system of 2mol/L is added is 8.0
Left and right, the ethyl acetate that 2L is added are extracted twice, and add 1L ethyl acetate every time, merge organic phase, dry by anhydrous sodium sulfate
Vacuum distillation recovered solvent obtains amino product 151.38g, yield 82.93%, purity 98.11% after dry.
The method that 4. micro passage reaction of embodiment synthesizes Tarceva intermediate.
1) nitration reaction：200g dissolution of raw material is dissolved in the glacial acetic acid of 3L and is used as material I, the concentrated sulfuric acid is as material
II, concentrated nitric acid is as material III, and the flow velocity for adjusting flow pump so that the flow velocity of material I is 25ml/min, and the flow velocity of material II is
The flow velocity of 15ml/min, material III are 6ml/min, raw material and HNO3Molar ratio be 1:1.5, the matter of concentrated nitric acid and the concentrated sulfuric acid
Amount is than being 1:4, reaction temperature is 80 DEG C, and the residence time of reaction is 45 seconds, and the temperature of cooling module is 30 DEG C, is collected from cooling
The reaction solution of module outlet outflow, is post-processed, and the post-processing refers to vacuum distillation recycling glacial acetic acid, and residue is added
In 1.2L water, the ethyl acetate that 1L is added is extracted twice, and ethyl acetate 500ml, organic phase saturated sodium bicarbonate are added every time
Solvent is washed to neutrality, anhydrous sodium sulfate drying, and vacuum distillation recovered solvent obtains nitration product 212.09g, yield
91.17%, purity 98.22%.
2) catalytic hydrogenation reaction：The nitration product 200g that upper step obtains is added to the absolute methanol dissolving of 5L, is then added
The Pd/C catalyst that the Pd contents of 15g are 10% is sufficiently stirring and mixing to form material IV, H2As material V, mashing pump is adjusted
Flow velocity makes the flow velocity of material IV be 40.0g/min, and adjusting gas flow meter makes H2Flow be 700ml/min, nitration product and H2
Molar ratio be 1:3.5, reaction temperature is 120 DEG C, and the temperature of cooling module is 25 DEG C, and the residence time of reaction is 25s, reaction
Pressure is 1.5Mpa, collects the reaction solution from cooling module outlet outflow, is post-processed, the post-processing refers to being recovered by filtration
Catalyst Pd/C, vacuum distillation recycling organic solvent, the acetone that 1.2L is added in residue stir solvent, the dense salt of 450ml are added
Acid, stirring and crystallizing 1h, filtering put into filter cake into the water of 2L, the pH value that the NaOH solution regulation system of 2mol/L is added is
8.0 left and right, the ethyl acetate that 2L is added are extracted twice, 1L ethyl acetate is added every time, merges organic phase, by anhydrous sodium sulfate
Vacuum distillation recovered solvent obtains amino product 160.97g, yield 88.18%, purity 99.51% after drying.
The method that 5. micro passage reaction of embodiment synthesizes Tarceva intermediate.
1) nitration reaction：200g dissolution of raw material is dissolved in the glacial acetic acid of 3L and is used as material I, the concentrated sulfuric acid is as material
II, concentrated nitric acid is as material III, and the flow velocity for adjusting flow pump so that the flow velocity of material I is 35ml/min, and the flow velocity of material II is
The flow velocity of 20ml/min, material III are 18ml/min, raw material and HNO3Molar ratio be 1:1.5, the matter of concentrated nitric acid and the concentrated sulfuric acid
Amount is than being 1:2, reaction temperature is 70 DEG C, and the residence time of reaction is 28s, and the temperature of cooling module is 30 DEG C, is collected from cooling
The reaction solution of module outlet outflow, is post-processed, and the post-processing refers to vacuum distillation recycling glacial acetic acid, and residue is added
In 1.2L water, the ethyl acetate that 1L is added is extracted twice, and ethyl acetate 500ml, organic phase saturated sodium bicarbonate are added every time
Solvent is washed to neutrality, anhydrous sodium sulfate drying, and vacuum distillation recovered solvent obtains nitration product 214.44g, yield
93.17%, purity 99.22%.
2) catalytic hydrogenation reaction：The nitration product 200g that upper step obtains is added to the absolute methanol dissolving of 5L, is then added
The Pt/C catalyst that the Pt contents of 15g are 10% is sufficiently stirring and mixing to form material IV, H2As material V, mashing pump is adjusted
Flow velocity makes the flow velocity of material IV be 42.0g/min, and adjusting gas flow meter makes H2Flow be 600ml/min, nitration product and H2
Molar ratio be 1:3.4, reaction temperature is 90 DEG C, and the temperature of cooling module is 25 DEG C, and the residence time of reaction is 35s, reaction
Pressure is 1.5Mpa, collects the reaction solution from cooling module outlet outflow, is post-processed, the post-processing refers to being recovered by filtration
Catalyst Pt/C, vacuum distillation recycling organic solvent, the acetone that 1.2L is added in residue stir solvent, the dense salt of 450ml are added
Acid, stirring and crystallizing 1h, filtering put into filter cake into the water of 2L, the pH value that the NaOH solution regulation system of 2mol/L is added is
8.0 left and right, the ethyl acetate that 2L is added are extracted twice, 1L ethyl acetate is added every time, merges organic phase, by anhydrous sodium sulfate
Vacuum distillation recovered solvent obtains amino product 161.12g, yield 88.27%, purity 99.59% after drying.
The method that 6. micro passage reaction of embodiment synthesizes Tarceva intermediate.
1) nitration reaction：200g dissolution of raw material is dissolved in the glacial acetic acid of 3L and is used as material I, the concentrated sulfuric acid is as material
II, concentrated nitric acid is as material III, and the flow velocity for adjusting flow pump so that the flow velocity of material I is 32ml/min, and the flow velocity of material II is
The flow velocity of 16ml/min, material III are 12ml/min, raw material and HNO3Molar ratio be 1:1.6, the matter of concentrated nitric acid and the concentrated sulfuric acid
Amount is than being 1:2.0, reaction temperature is 50 DEG C, and the residence time of reaction is 40s, and the temperature of cooling module is 30 DEG C, is collected from drop
The reaction solution of warm module outlet outflow, is post-processed, and the post-processing refers to vacuum distillation recycling glacial acetic acid, and residue is added
In 1.2L water, the ethyl acetate that 1L is added is extracted twice, and ethyl acetate 500ml, organic phase saturated sodium bicarbonate are added every time
Solvent is washed to neutrality, anhydrous sodium sulfate drying, and vacuum distillation recovered solvent obtains nitration product 213.41g, yield
90.50%, purity 98.82%.
2) catalytic hydrogenation reaction：The nitration product 200g that upper step obtains is added to the isopropanol dissolving of 5L, is then added
The Pt/C catalyst that 8gPt contents are 10% is sufficiently stirring and mixing to form material IV, H2As material V, the flow velocity of mashing pump is adjusted
It is 35.0g/min to make the flow velocity of material IV, and adjusting gas flow meter makes H2Flow be 550ml/min, nitration product and H2Rub
You are than being 1:3.0, reaction temperature is 70 DEG C, and the temperature of cooling module is 25 DEG C, and the residence time of reaction is 50s, reaction pressure
For 1.0Mpa, the reaction solution from cooling module outlet outflow is collected, is post-processed, the post-processing refers to that catalysis is recovered by filtration
Agent Pt/C, vacuum distillation recycling organic solvent, the acetone that 1.2L is added in residue stir solvent, the concentrated hydrochloric acid of 450ml are added, stirs
Crystallization 1h is mixed, filters, filter cake is put into the water of 2L, the pH value that the NaOH solution regulation system of 2mol/L is added is 8.0 left
The right side, the ethyl acetate that 2L is added are extracted twice, and add 1L ethyl acetate every time, are merged organic phase, are dried by anhydrous sodium sulfate
Vacuum distillation recovered solvent obtains amino product 151.73g, yield 84.41%, purity 98.02% afterwards.
The method that 7. micro passage reaction of embodiment synthesizes Tarceva intermediate.
1) nitration reaction：200g dissolution of raw material is dissolved in the glacial acetic acid of 3L and is used as material I, the concentrated sulfuric acid is as material
II, concentrated nitric acid is as material III, and the flow velocity for adjusting flow pump so that the flow velocity of material I is 22ml/min, and the flow velocity of material II is
The flow velocity of 10ml/min, material III are 5ml/min, raw material and HNO3Molar ratio be 1:1.1, the matter of concentrated nitric acid and the concentrated sulfuric acid
Amount is than being 1:4.0, reaction temperature is 50 DEG C, and the residence time of reaction is 60 seconds, and the temperature of cooling module is 30 DEG C, is collected from drop
The reaction solution of warm module outlet outflow, is post-processed, and the post-processing refers to vacuum distillation recycling glacial acetic acid, and residue is added
In 1.2L water, the ethyl acetate that 1L is added is extracted twice, and ethyl acetate 500ml, organic phase saturated sodium bicarbonate are added every time
Solvent is washed to neutrality, anhydrous sodium sulfate drying, and vacuum distillation recovered solvent obtains nitration product 201.88g, yield
87.71%, purity 98.52%.
2) catalytic hydrogenation reaction：The nitration product 200g that upper step obtains is added to the absolute methanol dissolving of 5L, is then added
The Pd/C catalyst that 5gPd contents are 10% is sufficiently stirring and mixing to form material IV, H2As material V, the flow velocity of mashing pump is adjusted
It is 30.0g/min to make the flow velocity of material IV, and adjusting gas flow meter makes H2Flow be 650ml/min, nitration product and H2Rub
You are than being 1:4.0, reaction temperature is 80 DEG C, and the temperature of cooling module is 25 DEG C, and the residence time of reaction is 40s, reaction pressure
For 0.8Mpa, the reaction solution from cooling module outlet outflow is collected, is post-processed, the post-processing refers to that catalysis is recovered by filtration
Agent Pd/C, vacuum distillation recycling organic solvent, the acetone that 1.2L is added in residue stir solvent, the concentrated hydrochloric acid of 450ml are added, stirs
Crystallization 1h is mixed, filters, filter cake is put into the water of 2L, the pH value that the NaOH solution regulation system of 2mol/L is added is 8.0 left
The right side, the ethyl acetate that 2L is added are extracted twice, and add 1L ethyl acetate every time, are merged organic phase, are dried by anhydrous sodium sulfate
Vacuum distillation recovered solvent obtains amino product 158.80g, yield 87.00%, purity 98.54% afterwards.
The method that 8. micro passage reaction of embodiment synthesizes Tarceva intermediate.
1) nitration reaction：200g dissolution of raw material is dissolved in the glacial acetic acid of 3L and is used as material I, the concentrated sulfuric acid is as material
II, concentrated nitric acid is as material III, and the flow velocity for adjusting flow pump so that the flow velocity of material I is 30ml/min, and the flow velocity of material II is
The flow velocity of 12ml/min, material III are 10ml/min, raw material and HNO3Molar ratio be 1:1.2, the matter of concentrated nitric acid and the concentrated sulfuric acid
Amount is than being 1:2.0, reaction temperature is 90 DEG C, and the residence time of reaction is 35 seconds, and the temperature of cooling module is 30 DEG C, is collected from drop
The reaction solution of warm module outlet outflow, is post-processed, and the post-processing refers to vacuum distillation recycling glacial acetic acid, and residue is added
1.2L in water, the ethyl acetate that 1L is added is extracted twice, ethyl acetate 500ml, organic phase saturated sodium bicarbonate are added every time
Solvent is washed to neutrality, anhydrous sodium sulfate drying, and vacuum distillation recovered solvent obtains nitration product 212.33g, yield
90.04%, purity 98.19%.
2) catalytic hydrogenation reaction：The nitration product 200g that upper step obtains is added to the absolute methanol dissolving of 5L, is then added
The Pt/C catalyst that 20gPt contents are 5% is sufficiently stirring and mixing to form material IV, H2As material V, the flow velocity of mashing pump is adjusted
It is 38.0g/min to make the flow velocity of material IV, and adjusting gas flow meter makes H2Flow be 600ml/min, nitration product and H2Rub
You are than being 1:3.2, reaction temperature is 100 DEG C, and the temperature of cooling module is 25 DEG C, and the residence time of reaction is 30s, reaction pressure
For 1.2Mpa, the reaction solution from cooling module outlet outflow is collected, is post-processed, the post-processing refers to that catalysis is recovered by filtration
Agent Pt/C, vacuum distillation recycling organic solvent, the acetone that 1.2L is added in residue stir solvent, the concentrated hydrochloric acid of 450ml are added, stirs
Crystallization 1h is mixed, filters, filter cake is put into the water of 2L, the pH value that the NaOH solution regulation system of 2mol/L is added is 8.0 left
The right side, the ethyl acetate that 2L is added are extracted twice, and add 1L ethyl acetate every time, are merged organic phase, are dried by anhydrous sodium sulfate
Vacuum distillation recovered solvent obtains amino product 162.32g, yield 90.30%, purity 99.50% afterwards.
1. investigating influence of the reaction temperature to nitration reaction：It is identical in other technological parameters to attempt different reaction raw materials
In the case of (raw material and HNO3Molar ratio be 1:1.5, the mass ratio of concentrated nitric acid and the concentrated sulfuric acid is 1:4, the residence time of reaction is
60 seconds), variation of the different reaction temperatures to nitration product yield and purity.
Embodiment 9. repeats embodiment 2, is with the difference of embodiment 2, reaction raw materials areNitre
It is 40 DEG C to change reaction temperature.
Embodiment 10. repeats embodiment 2, is with the difference of embodiment 2, reaction raw materials are
Nitration reaction temperature is 50 DEG C.
Embodiment 11. repeats embodiment 2, is with the difference of embodiment 2, reaction raw materials are
Nitration reaction temperature is 70 DEG C.
Embodiment 12. repeats embodiment 2, is with the difference of embodiment 2, reaction raw materials are
Nitration reaction temperature is 80 DEG C.
Embodiment 13. repeats embodiment 2, is with the difference of embodiment 2, reaction raw materials are
Nitration reaction temperature is 90 DEG C.
Embodiment 14. repeats embodiment 2, is with the difference of embodiment 2, and nitration reaction temperature is 40 DEG C.
Embodiment 15. repeats embodiment 2, is with the difference of embodiment 2, and nitration reaction temperature is 50 DEG C.
Embodiment 16. repeats embodiment 2, is with the difference of embodiment 2, and nitration reaction temperature is 60 DEG C.
Embodiment 17. repeats embodiment 2, is with the difference of embodiment 2, and nitration reaction temperature is 70 DEG C.
Embodiment 18. repeats embodiment 2, is with the difference of embodiment 2, and nitration reaction temperature is 80 DEG C.
Embodiment 19. repeats embodiment 2, is with the difference of embodiment 2, and nitration reaction temperature is 90 DEG C.
Nitration product yield and the purity statistics that this method obtains at a temperature of 1 differential responses of table
As shown in Table 1, when reaction temperature is 70 DEG C, the yield and purity of nitration product have exceeded other temperature waters
Flat, reaction temperature can obviously observe that the product of polynitration, the too low raw material of reaction temperature cannot be completely anti-in the case of excessively high
It answers, therefore reaction temperature is most preferably 70 DEG C at present.
2. investigating influence of the reaction time to effect：Using different nitration products as raw material, ensure that reaction temperature is
90 DEG C, the dosage of hydrogen is 3.5eq, reaction pressure 1.5MPa, selects Pd contents for 10% Pd/C catalyst, wherein Pd/C
The mass ratio of catalyst and nitration product is 0.05:1, the different residence times is used on this basis, and then is investigated reaction and stopped
Stay influence of the time to yield and purity.
Embodiment 20. repeats embodiment 1, is with the difference of embodiment 1, and catalysis reaction time is 15s.
Embodiment 21. repeats embodiment 1, is with the difference of embodiment 1, and catalysis reaction time is 20s.
Embodiment 22. repeats embodiment 1, is with the difference of embodiment 1, and catalysis reaction time is 30s.
Embodiment 23. repeats embodiment 1, is with the difference of embodiment 1, and catalysis reaction time is 35s.
Embodiment 24. repeats embodiment 1, is with the difference of embodiment 1, and catalysis reaction time is 40s.
Embodiment 25. repeats embodiment 1, is with the difference of embodiment 1, and catalysis reaction time is 45s.
Embodiment 26. repeats embodiment 1, is with the difference of embodiment 1, and catalysis reaction time is 50s.
Embodiment 27. repeats embodiment 1, is with the difference of embodiment 1, the nitration product isCatalysis reaction time is 15s.
Embodiment 28. repeats embodiment 1, is with the difference of embodiment 1, the nitration product isCatalysis reaction time is 20s.
Embodiment 29. repeats embodiment 1, is with the difference of embodiment 1, the nitration product isCatalysis reaction time is 25s.
Embodiment 30. repeats embodiment 1, is with the difference of embodiment 1, the nitration product isCatalysis reaction time is 30s.
Embodiment 31. repeats embodiment 1, is with the difference of embodiment 1, the nitration product isCatalysis reaction time is 35s.
Embodiment 32. repeats embodiment 1, is with the difference of embodiment 1, the nitration product isCatalysis reaction time is 40s.
Embodiment 33. repeats embodiment 1, is with the difference of embodiment 1, the nitration product isCatalysis reaction time is 45s.
Embodiment 34. repeats embodiment 1, is with the difference of embodiment 1, the nitration product isCatalysis reaction time is 50s.
Comparison result is as shown in table 2.
Final product yield and the purity statistics that this method obtains under the 2 differential responses residence time of table
As shown in Table 2, the residence time of reaction is very big to the yield and impurities affect of reaction, in the situation that the time is too short
Under, reacting has starting material left, and overlong time, is found that the product of side chain ether-oxygen bond fracture under the effect of the catalyst,
Content gradually rises with the extension of time, therefore the key process parameter that the residence time reacted is step reaction, reaction
Residence time is that 25~35s is most suitable.
3. investigating the recycled efficiency of catalyst：The multiple activated carbon supported noble metal of high spot review recycled is urged
Relationship between agent and reaction yield, product purity, the specific method is as follows：
By taking above-mentioned catalytic hydrogenation reaction as an example, Pd/C is catalyst, carries out 8 recycled experiments altogether, i.e.,：By catalyst
The hydrogenation reaction that Pd/C is used in embodiment 1 is to apply mechanically experiment for the first time, then will be recycled after for the first time applying mechanically and to test
Catalyst Pd/C is re-used for embodiment 1 and as applies mechanically experiment for the second time, the catalysis that will be recycled after applying mechanically experiment for the second time
Agent Pd/C is re-used for embodiment 1 and as applies mechanically experiment for the third time, and so on, 8 recycled experiments are carried out altogether；Set every time
Is carried out according to embodiment 1 with experiment, ensures that process that each catalyst circulation is applied mechanically in reaction temperature is 90 DEG C, the use of hydrogen
Amount is 3.5eq, reaction pressure 1.5MPa, residence time 25s, and the mass content of Pd/C catalyst used is 10%, is followed
Ring set experimental result is as shown in table 3：
3 Pd/C catalyst circulations of table apply mechanically experiment
| Catalyst circulation applies mechanically experiment | Purity | Yield |
| Apply mechanically experiment for the first time | 99.46% | 88.23% |
| Experiment is applied mechanically for the second time | 99.41% | 87.96% |
| Third time applies mechanically experiment | 99.52% | 88.13% |
| Apply mechanically experiment 4th time | 99.61% | 88.36% |
| Apply mechanically experiment 5th time | 99.55% | 88.71% |
| Apply mechanically experiment 6th time | 99.49% | 88.18% |
| Apply mechanically experiment 7th time | 99.57% | 88.67% |
| Apply mechanically experiment 8th time | 99.53% | 88.22% |
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.
The method that comparative example popular response equipment produces Tarceva intermediate：
1) concentrated sulfuric acid for measuring 300ml controls in the concentrated nitric acid for instilling 100ml at 0~20 DEG C and prepares nitration mixture, for use,
By 200g dissolution of raw material in the glacial acetic acid of 3L, temperature will be prepared the mixing finished in the case of 10~20 DEG C and be delayed in control system
Slow to instill reaction system, about 2h is added dropwise, then rises at 60 DEG C temperature in reaction and react 1h, is down to room temperature, and decompression is steamed
Recycling glacial acetic acid is evaporated, residue is added in 1.2L water, and the ethyl acetate that 1L is added is extracted twice, and adds 500ml acetic acid second every time
Ester, organic phase are washed with saturated sodium bicarbonate solvent to neutrality, anhydrous sodium sulfate drying, and vacuum distillation recovered solvent obtains nitre
Change product 186.27g, yield 81.37%, purity 98.13%.
2) stirring and dissolving in the absolute methanol of 3.5L is added in upper step nitration product 150g obtained by the reaction, be then added
The Pd/C that 20gPd contents are 10%, H is passed through into autoclave2, ensure that the pressure in reaction kettle is 3.0Mpa or so, be warming up to
120 DEG C and insulation reaction 12 hours, reaction, which finishes, is down to room temperature, excludes the complete H of unreacted2, feed liquid is collected, catalysis is recovered by filtration
Agent Pd/C, vacuum distillation recycling organic solvent, the acetone that 1.2L is added in residue stir solvent, the concentrated hydrochloric acid of 450ml are added, stirs
Crystallization 1h is mixed, filters, filter cake is put into the water of 2L, the pH value that the NaOH solution regulation system of 2mol/L is added is 8.0 left
The right side, the ethyl acetate that 2L is added are extracted twice, and add ethyl acetate 1L every time, merge organic phase, by anhydrous Na2SO4After drying
Vacuum distillation recovered solvent obtains amino product 122.36g, yield 78.92%, purity 98.02%.
By the embodiment of the present invention is compared with comparative example：Nitration mixture may be implemented in micro passage reaction reaction
It prepares and is carried out with the on-line continuous of nitration reaction, nitration mixture is prepared without cumbersome dropwise operation and carry out nitration reaction, save
Operational sequence and operation duration, while the generation of polynitration by-product can be preferably controlled, the yield and purity of nitration product
More preferably；And the catalytic hydrogenation reaction reaction time can be reduced to 20s or so by 12h, reaction kettle liquid holdup big (5L) carries out plus hydrogen
Operate it is abnormally dangerous, it is extremely easy to explode, and micro passage reaction greatly reduces danger since liquid holdup is small (less than 50ml)
Dangerous coefficient, even if there is a small amount of hydrogen leak to there will not be too big danger；Therefore, micro passage reaction is compared with routine operation equipment
Have many advantages, such as that energy consumption of reaction is low, speed is fast, liquid holdup is small, safety and environmental protection, the high incomes of final products, quality are more preferably.
Although the present invention is disclosed as above with preferred embodiment, it is not limited to the present invention, any to be familiar with this
The people of technology can do various changes and modification, therefore the protection of the present invention without departing from the spirit and scope of the present invention
Range should be subject to what claims were defined.
Claims (10)
1. a kind of method of micro passage reaction synthesis Tarceva intermediate, which is characterized in that the Tarceva intermediate
ForDescribed method includes following steps：
1) nitration reaction：By raw material(R=-COOEt ,-CN), which is added in glacial acetic acid, to be dissolved, mixed solution
The warm-up block for entering micro passage reaction as material I, using the concentrated sulfuric acid and concentrated nitric acid as material II and material III into
Enter the warm-up block of micro passage reaction, raw material carries out nitration reaction with the mixture of the concentrated sulfuric acid and concentrated nitric acid, collects from cooling
The reaction solution of module outflow, post-processing are nitrified
Product(R=-COOEt ,-CN)；
A concentration of 0.1~0.3mol/L of the raw material in glacial acetic acid；The molar ratio of raw material and concentrated nitric acid is (1:1.0)~
(1:2.0)；The concentrated nitric acid is (1 with concentrated sulfuric acid mass ratio:2.0)~(1:5.0)；
2) catalytic hydrogenation reaction：Above-mentioned nitration product is added and is dissolved into organic solvent, is then added and loads active charcoal
Noble metal catalyst is as material IV, H2As material V it is preheated after in module with nitration product carry out hydro-reduction react,
The reaction solution flowed out from cooling module is collected, post-processing obtains target product
A concentration of 0.2~the 0.3mol/L of the nitration product in organic solvent；Nitration product and H2Molar ratio be (1:
3.0)~(1:4.0).
2. the method for micro passage reaction synthesis Tarceva intermediate according to claim 1, which is characterized in that step
1) reaction temperature described in is 40~90 DEG C, and reaction time is 15~60s.
3. the method for micro passage reaction synthesis Tarceva intermediate according to claim 2, which is characterized in that step
1) reaction temperature described in is 70 DEG C.
4. the method for micro passage reaction synthesis Tarceva intermediate according to claim 1, which is characterized in that step
2) organic solvent described in is methanol, ethyl alcohol, one kind in isopropanol or in which several mixing.
5. the method for micro passage reaction synthesis Tarceva intermediate according to claim 1, which is characterized in that step
2) noble metal catalyst of the active charcoal of load is one kind or in which several mixing in Pd/C, Pt/C, Rh/C；Wherein
Noble metal quality accounts for the 1%~10% of catalyst gross mass.
6. the method for micro passage reaction synthesis Tarceva intermediate according to claim 1, which is characterized in that step
2) mass ratio of the nitration product and the noble metal catalyst for loading active charcoal is (1:0.01)~(1:0.10).
7. the method for micro passage reaction synthesis Tarceva intermediate according to claim 1, which is characterized in that step
2) pressure of the reaction described in is 0.5~1.5Mpa.
8. the method for micro passage reaction synthesis Tarceva intermediate according to claim 1, which is characterized in that step
2) reaction temperature described in is 60~120 DEG C, and total residence time of the material in reaction module group is 15~50s.
9. the method for micro passage reaction synthesis Tarceva intermediate according to claim 8, which is characterized in that step
2) total residence time of the material in reaction module group is 25~35s.
10. the method for micro passage reaction synthesis Tarceva intermediate according to claim 1, which is characterized in that step
It is rapid that 1), 2) temperature of the cooling module is 20~30 DEG C.
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Citations (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5747498A (en) * | 1996-05-28 | 1998-05-05 | Pfizer Inc. | Alkynyl and azido-substituted 4-anilinoquinazolines |
| EP0790986B1 (en) * | 1994-11-12 | 1999-01-20 | Zeneca Limited | Aniline derivatives |
| WO2002016360A2 (en) * | 2000-08-18 | 2002-02-28 | Cor Therapeutics, Inc. | Nitrogenous heterocyclic compounds |
| EP1614676A1 (en) * | 2003-03-27 | 2006-01-11 | Kirin Beer Kabushiki Kaisha | Compound inhibiting in vivo phosphorus transport and medicine containing the same |
| WO2007138613A2 (en) * | 2006-05-25 | 2007-12-06 | Vittal Mallya Scientific Research Foundation | A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride |
| WO2007138612A2 (en) * | 2006-05-25 | 2007-12-06 | Vittal Mallya Scientific Research Foundation | A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4- yl]-(3-ethynylphenyl)amine hydrochloride |
| WO2008122776A2 (en) * | 2007-04-04 | 2008-10-16 | Cipla Limited | Process for preparation of erlotinib and its pharmaceutically acceptable salts |
| CN101463013A (en) * | 2007-12-21 | 2009-06-24 | 上海百灵医药科技有限公司 | Preparation of erlotinid hydrochloride |
| CN100540539C (en) * | 2003-07-30 | 2009-09-16 | 宇部兴产株式会社 | Preparation 6, the method for 7-two (2-methoxy ethoxy) quinazoline-4-one |
| CN101863844A (en) * | 2009-04-16 | 2010-10-20 | 翔真生物科技股份有限公司 | Synthesis method of 6,7-substituted-4-aniline quinazoline |
| CN102026985A (en) * | 2008-03-17 | 2011-04-20 | 埃姆比特生物科学公司 | Quinazoline derivatives as RAF kinase modulators and methods of use thereof |
| CN102249945A (en) * | 2010-05-21 | 2011-11-23 | 复旦大学 | Salicyloyl anilines compound as well as preparation method and application thereof |
| WO2011147102A1 (en) * | 2010-05-28 | 2011-12-01 | 翔真生物科技股份有限公司 | Synthetic method for 6,7-substituents-4-aniline quinazoline |
| EP2227460B1 (en) * | 2007-10-24 | 2012-06-20 | Cancer Research Technology Limited | Therapeutic oxy-phenyl-aryl compounds and their use |
| CN102584719A (en) * | 2012-02-02 | 2012-07-18 | 瑞阳制药有限公司 | Preparing technology of erlotinib hydrochloride |
| CN102659629A (en) * | 2012-02-14 | 2012-09-12 | 杭州华东医药集团生物工程研究所有限公司 | Compound and application thereof in preparing erlotinib |
| CN102746242A (en) * | 2009-04-16 | 2012-10-24 | 欧美嘉股份有限公司 | Synthesis method of 6, 7-substituted-4-aniline quinazoline |
| CN102827086A (en) * | 2012-08-03 | 2012-12-19 | 浙江理工大学 | Preparation method for 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline |
| CN102887862A (en) * | 2012-07-24 | 2013-01-23 | 连云港盛和生物科技有限公司 | Method for synthesizing erlotinib |
| CN102887835A (en) * | 2012-07-24 | 2013-01-23 | 连云港盛和生物科技有限公司 | Method for synthesizing 2-amino-4,5-bis-(2-methoxyethoxy)cyanophenyl |
| CN102918044A (en) * | 2010-05-21 | 2013-02-06 | 深圳信立泰药业股份有限公司 | Fused quinazoline derivatives and uses thereof |
| CN103070868A (en) * | 2013-01-08 | 2013-05-01 | 复旦大学 | IDO inhibitor containing NH-1,2,3-triazole and preparation method thereof |
| CN103193722A (en) * | 2012-01-10 | 2013-07-10 | 北京师范大学 | Novel quinazoline nitrogen mustard compound, and preparation method and application thereof to treatment of cancer |
| CN103265456A (en) * | 2013-05-15 | 2013-08-28 | 黄山市歙县宏辉化工有限公司 | Preparation method of intermediate of medicament erlotinib for lung cancer targeted therapy |
| WO2013156835A1 (en) * | 2012-04-16 | 2013-10-24 | Laurus Labs Private Limited | An improved process for the preparation of erlotinib hydrochloride form a |
| CN103709110A (en) * | 2013-12-13 | 2014-04-09 | 浙江普洛康裕制药有限公司 | Preparation method of erlotinib hydrochloride key intermediate |
| EP2769723A1 (en) * | 2013-02-22 | 2014-08-27 | Ruprecht-Karls-Universität Heidelberg | Compounds for use in inhibiting HIV capsid assembly |
| CN104725327A (en) * | 2015-03-03 | 2015-06-24 | 山东大学 | Environment-friendly method for preparing high-yield erlotinib hydrochloride |
| CN105130912A (en) * | 2015-08-24 | 2015-12-09 | 海南中化联合制药工业股份有限公司 | Erlotinib preparation method suitable for industrial production |
| CN105646374A (en) * | 2015-12-31 | 2016-06-08 | 山东罗欣药业集团股份有限公司 | Preparation method of erlotinib hydrochloride |
| CN106749047A (en) * | 2015-11-24 | 2017-05-31 | 重庆圣华曦药业股份有限公司 | A kind of method for preparing Tarceva |
| CN106916067A (en) * | 2015-12-24 | 2017-07-04 | 江苏豪森药业集团有限公司 | The preparation method of hydrochloric acid Erlotinib key intermediate |
| CN106957274A (en) * | 2017-04-05 | 2017-07-18 | 盐城师范学院 | Synthetic method of erlotinib hydrochloride |
| CN107382880A (en) * | 2017-07-14 | 2017-11-24 | 连云港恒运药业有限公司 | The preparation method of Tarceva intermediate |
| CN107445907A (en) * | 2016-05-30 | 2017-12-08 | 中国科学院化学研究所 | The method of prepare compound |
-
2018
- 2018-02-12 CN CN201810145480.9A patent/CN108358798A/en active Pending
Patent Citations (36)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0790986B1 (en) * | 1994-11-12 | 1999-01-20 | Zeneca Limited | Aniline derivatives |
| US5747498A (en) * | 1996-05-28 | 1998-05-05 | Pfizer Inc. | Alkynyl and azido-substituted 4-anilinoquinazolines |
| WO2002016360A2 (en) * | 2000-08-18 | 2002-02-28 | Cor Therapeutics, Inc. | Nitrogenous heterocyclic compounds |
| EP1614676A1 (en) * | 2003-03-27 | 2006-01-11 | Kirin Beer Kabushiki Kaisha | Compound inhibiting in vivo phosphorus transport and medicine containing the same |
| CN100540539C (en) * | 2003-07-30 | 2009-09-16 | 宇部兴产株式会社 | Preparation 6, the method for 7-two (2-methoxy ethoxy) quinazoline-4-one |
| WO2007138613A2 (en) * | 2006-05-25 | 2007-12-06 | Vittal Mallya Scientific Research Foundation | A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride |
| WO2007138612A2 (en) * | 2006-05-25 | 2007-12-06 | Vittal Mallya Scientific Research Foundation | A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4- yl]-(3-ethynylphenyl)amine hydrochloride |
| WO2008122776A2 (en) * | 2007-04-04 | 2008-10-16 | Cipla Limited | Process for preparation of erlotinib and its pharmaceutically acceptable salts |
| EP2139868B1 (en) * | 2007-04-04 | 2015-07-29 | Cipla Limited | Process for preparation of erlotinib and its pharmaceutically acceptable salts |
| EP2227460B1 (en) * | 2007-10-24 | 2012-06-20 | Cancer Research Technology Limited | Therapeutic oxy-phenyl-aryl compounds and their use |
| CN101463013A (en) * | 2007-12-21 | 2009-06-24 | 上海百灵医药科技有限公司 | Preparation of erlotinid hydrochloride |
| CN102026985A (en) * | 2008-03-17 | 2011-04-20 | 埃姆比特生物科学公司 | Quinazoline derivatives as RAF kinase modulators and methods of use thereof |
| CN102746242A (en) * | 2009-04-16 | 2012-10-24 | 欧美嘉股份有限公司 | Synthesis method of 6, 7-substituted-4-aniline quinazoline |
| CN101863844A (en) * | 2009-04-16 | 2010-10-20 | 翔真生物科技股份有限公司 | Synthesis method of 6,7-substituted-4-aniline quinazoline |
| CN102249945A (en) * | 2010-05-21 | 2011-11-23 | 复旦大学 | Salicyloyl anilines compound as well as preparation method and application thereof |
| CN102918044A (en) * | 2010-05-21 | 2013-02-06 | 深圳信立泰药业股份有限公司 | Fused quinazoline derivatives and uses thereof |
| WO2011147102A1 (en) * | 2010-05-28 | 2011-12-01 | 翔真生物科技股份有限公司 | Synthetic method for 6,7-substituents-4-aniline quinazoline |
| CN103193722A (en) * | 2012-01-10 | 2013-07-10 | 北京师范大学 | Novel quinazoline nitrogen mustard compound, and preparation method and application thereof to treatment of cancer |
| CN102584719A (en) * | 2012-02-02 | 2012-07-18 | 瑞阳制药有限公司 | Preparing technology of erlotinib hydrochloride |
| CN102659629A (en) * | 2012-02-14 | 2012-09-12 | 杭州华东医药集团生物工程研究所有限公司 | Compound and application thereof in preparing erlotinib |
| WO2013156835A1 (en) * | 2012-04-16 | 2013-10-24 | Laurus Labs Private Limited | An improved process for the preparation of erlotinib hydrochloride form a |
| CN102887862A (en) * | 2012-07-24 | 2013-01-23 | 连云港盛和生物科技有限公司 | Method for synthesizing erlotinib |
| CN102887835A (en) * | 2012-07-24 | 2013-01-23 | 连云港盛和生物科技有限公司 | Method for synthesizing 2-amino-4,5-bis-(2-methoxyethoxy)cyanophenyl |
| CN102827086A (en) * | 2012-08-03 | 2012-12-19 | 浙江理工大学 | Preparation method for 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline |
| CN103070868A (en) * | 2013-01-08 | 2013-05-01 | 复旦大学 | IDO inhibitor containing NH-1,2,3-triazole and preparation method thereof |
| EP2769723A1 (en) * | 2013-02-22 | 2014-08-27 | Ruprecht-Karls-Universität Heidelberg | Compounds for use in inhibiting HIV capsid assembly |
| CN103265456A (en) * | 2013-05-15 | 2013-08-28 | 黄山市歙县宏辉化工有限公司 | Preparation method of intermediate of medicament erlotinib for lung cancer targeted therapy |
| CN103709110A (en) * | 2013-12-13 | 2014-04-09 | 浙江普洛康裕制药有限公司 | Preparation method of erlotinib hydrochloride key intermediate |
| CN104725327A (en) * | 2015-03-03 | 2015-06-24 | 山东大学 | Environment-friendly method for preparing high-yield erlotinib hydrochloride |
| CN105130912A (en) * | 2015-08-24 | 2015-12-09 | 海南中化联合制药工业股份有限公司 | Erlotinib preparation method suitable for industrial production |
| CN106749047A (en) * | 2015-11-24 | 2017-05-31 | 重庆圣华曦药业股份有限公司 | A kind of method for preparing Tarceva |
| CN106916067A (en) * | 2015-12-24 | 2017-07-04 | 江苏豪森药业集团有限公司 | The preparation method of hydrochloric acid Erlotinib key intermediate |
| CN105646374A (en) * | 2015-12-31 | 2016-06-08 | 山东罗欣药业集团股份有限公司 | Preparation method of erlotinib hydrochloride |
| CN107445907A (en) * | 2016-05-30 | 2017-12-08 | 中国科学院化学研究所 | The method of prepare compound |
| CN106957274A (en) * | 2017-04-05 | 2017-07-18 | 盐城师范学院 | Synthetic method of erlotinib hydrochloride |
| CN107382880A (en) * | 2017-07-14 | 2017-11-24 | 连云港恒运药业有限公司 | The preparation method of Tarceva intermediate |
Non-Patent Citations (1)
| Title |
|---|
| 杨光富: "《有机合成》", 31 August 2016 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109096136A (en) * | 2018-08-27 | 2018-12-28 | 山东金城医药化工有限公司 | Tarceva midbody compound and its refining methd |
| CN109096136B (en) * | 2018-08-27 | 2020-11-03 | 山东金城医药化工有限公司 | Erlotinib intermediate compound and refining method thereof |
| CN112812016A (en) * | 2021-01-14 | 2021-05-18 | 山东天铭医药科技有限公司 | Method for preparing 6-nitro veratric acid from veratric acid by using microchannel reactor |
| CN113200861A (en) * | 2021-05-06 | 2021-08-03 | 山东科加工业技术研究院有限公司 | Novel preparation method and application of 6-nitroveratric acid |
| CN113831281A (en) * | 2021-11-18 | 2021-12-24 | 寿光富康制药有限公司 | Industrial method for preparing nitro compound as intermediate of proton pump inhibitor |
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