CN108610308A - The method that one kettle way prepares Nintedanib intermediate - Google Patents
The method that one kettle way prepares Nintedanib intermediate Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
The present invention relates to the methods that " one kettle way " prepares Nintedanib (Nintedanib, I) key intermediate N (4 aminophenyl) N methyl 2 (4 methyl piperazine, 1 base) acetamide.Method is as follows：It is realized especially by following technical scheme：The aqueous solution that 4 nitroaniline of N methyl is dissolved in organic solvent and alkali mixes, then chloracetyl chloride or bromoacetyl bromide is added dropwise, at 0 70 degree, the progress first stage reacts 0.1 3 hours, branch vibration layer is added N methyl piperazines and carries out second stage reaction, and 0 75 degree are reacted 2 10 hours, then go back original reagent is added, 0 75 degree, pressure 15 100psi progress phase III reactions, 8 36 hours.Filtering removal go back original reagent after reaction, reaction solution concentrates, reverse phase solvent crystallization is added and obtains Nintedanib (Nintedanib, I) key intermediate N (4 aminophenyl) N methyl 2 (4 methyl piperazine, 1 base) acetamide (formula B).The preparation method raw material is easy to get, and concise in technology is economic and environment-friendly, is suitble to industrialized production.
Description
Technical field：
The invention belongs to organic synthesis and the preparing technical field of bulk pharmaceutical chemicals intermediate, more particularly to a kind of " one kettle way " system
It is ready for use on key intermediate N- (the 4- aminobenzenes of the drug Nintedanib (nintedanib, I) for the treatment of idiopathic pulmonary fibrosis
Base)-N- methyl -2- (4- methylpiperazine-1-yls) acetamide (formula B) method.
Background technology：
Nintedanib (nintedanib, I) is a kind of novel for treating special hair of Boehringer Ingelheim company exploitation
The oral drugs of property pulmonary fibrosis.Idiopathic pulmonary fibrosis is a kind of to the serious lethal lung disease of mankind's harm, patient
Median survival interval after diagnosis is only 2 to 3 years.Nintedanib can vegf blocker receptor, blood be small simultaneously
Plate source property growth factor receptors and fibroblast growth factor acceptor.The blocking of these receptors can lead to the suppression of angiogenesis
System.Nintedanib is first and only one is approved the tyrosine kinase inhibitor for treating idiopathic pulmonary fibrosis.
The chemistry of Nintedanib is entitled：Z- [1- (4- (N- ((4- thyl-piperazin -1- bases)-methyl carbonyl)-N- methyl-ammonia
Base)-anilino-) -1- phenyi-methylenes] -2- oxo -2,3- dihydro -1H- indoles 6- methyl formates, structural formula is as follows (I)：
The preparation method of Nintedanib is it has been reported that original grinds compound patent WO2001027081 and prepares patent
WO2009071523, WO 2009071524 gives the synthetic method of Nintedanib and the like.Its main synthesis side
Method is condensed to yield by two key intermediates A and B in following formula.
Patent CN104262232A reports another synthetic method of Nintedanib, but is equally used in committed step
Key intermediate B.Therefore intermediate B is a necessary key intermediate in Nintedanib industrialization, therefore among this
The industrialization research of body has great realistic meaning.
But pass through investigation, it has been found that relatively fewer, main source is reported for the main synthetic route of the intermediate
In the preparation patent that original is ground, specifically prepared through following formula method：
Use B-1 (N- methyl-4-nitrophenylamines) for starting material, by with chloracetyl chloride or bromoacetyl bromide alkali work
Amidation process is first carried out with lower, substitution reaction then occurs with methyl piperazine, finally obtains intermediate B by reduction；Due to
In original grinds technique, which often walks reaction and substep is required for carry out, and intermediate is required for Crystallization Separation, entire process cycle
It is long, and mixed solvent is often used in crystallization process, cause solvent recovery difficulty big, route yield is low, not green.Therefore anxious
Simplification of flowsheet is needed, three waste discharge is reduced so that entire technique is more green, more economically, is more applicable in industrial metaplasia
Production.
Invention content：
For current present situation, the present invention is realized using craftsmenship using single organic solvent by the change of feed way
Series connection to entire technique, " one kettle way " linearly synthesize Nintedanib (Nintedanib, I) key intermediate B, i.e. N- (4- ammonia
Base phenyl)-N- methyl -2- (4- methylpiperazine-1-yls) acetamide.The preparation method concise in technology, the period is short, more economically,
It is more environmentally-friendly, it is suitble to industrialized production.
It is realized especially by following technical scheme：N- methyl-4-nitrophenylamines are dissolved in the water of organic solvent and alkali
Solution mixes, and chloracetyl chloride or bromoacetyl bromide is then added dropwise, and carries out first stage reaction 0.1-3 hours in 0-75 degree, divides and go
Water layer is added N methyl piperazine and carries out second stage reaction, and 0-75 degree reacts 2-10 hours, and go back original reagent, 0-75 is then added
Degree, pressure 15-100psi progress phase III reactions, 8-36 hours.Filtering removal go back original reagent, reaction solution are dense after reaction
Contracting is added reverse phase solvent crystallization and obtains Nintedanib (Nintedanib, I) key intermediate B
The wherein described organic solvent includes ethyl acetate, dichloromethane, isopropyl acetate, toluene, tetrahydrofuran and 2- first
Base tetrahydrofuran.Reverse phase solvent includes normal heptane, n-hexane, hexamethylene, methyl tertiary butyl ether(MTBE).
The wherein described alkali includes sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, bicarbonate
Sodium, saleratus；
The wherein described go back original reagent includes：Hydrogen, palladium/carbon, platinum/charcoal, Raney's nickel.
Wherein main three kinds of reaction reagents N- methyl-4-nitrophenylamines, chloracetyl chloride or bromoacetyl bromide and N- methyl piperazines
The molar ratio of piperazine is 1：1.5~3:1.5~3, base amount is 1-3 times of key reaction reagent chloracetyl chloride or bromoacetyl bromide
The reaction principle be first stage N- methyl-4-nitrophenylamine in the presence of alkali with chloracetyl chloride or bromoacetyl bromide
Amidation process occurs, substitution reaction occurs with N methyl piperazine again for the chlorine or bromine substituent group on α carbon of second stage amide, the
Three stages were that nitro substituent is reduced to aniline by reducing agent on phenyl ring.
Reaction is by following course (alkali is by taking sodium carbonate is alkali as an example)：
The chloracetic acid and hydrochloric acid that side reaction generates in reaction process in the first stage are dissolved at salt in the presence of alkali
In water phase, and product is maintained at organic phase, the influence for dividing water layer that can remove reaction of these by-products to second stage well.
Excessive N methyl piperazine can be with the hydrochloric acid that generates during the reaction at salt during second stage, and these salt will not be to
Triphasic reduction reaction impacts, and salt is not dissolved in organic solvent, can be together with reduction after reduction reaction
Reagent filtering removal, by concentration be added reverse phase solvent crystallization can high yield obtain Nintedanib key intermediate B (N-
(4- aminophenyls)-N- methyl -2- (4- methylpiperazine-1-yls) acetamide), and then eliminated well in mother liquor it is excessive not
At the N methyl piperazine and some related impurities of salt, 97% or more product purity is obtained, total recovery is 85% or more.
Compared to prior art, the method for " one kettle way " according to the present invention preparation Nintedanib (I) key intermediate B
Have many advantages, such as concise in technology, it is economic and environment-friendly, it is suitble to industrialized production.
Embodiment：
Unrestricted illustrate is carried out to technical scheme of the present invention below by way of several specific embodiments.Wherein,
Raw material N- methyl-4-nitrophenylamines, chloracetyl chloride, bromoacetyl bromide and N methyl piperazine can bulk purchases.
Embodiment 1：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 18.2g potassium carbonate and
55mL water adjusts 20-25 DEG C of temperature, 12.5g chloracetyl chlorides is added dropwise in reaction bulb, and 20-25 DEG C is stirred 0.5 hour, is divided and is gone
15.8gN- methyl piperazines are added in water layer, and 20-25 DEG C is stirred 5 hours, and 0.5g Pd/C, hydrogen displacement adjustment pressure is then added
40-45psi, 40-55 DEG C are stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, and filter to obtain production
Product, yield 91.5%.1H NMR(400MHz,CDCl3):δ 6.88 (d, J=8.4,2H), 6.54 (d, J=8.4,2H), δ 5.22
(s, 2H), 3.03 (s, 3H), 2.35~2.27 (M, 4H), 2.27~2.19 (m, 4H), 2.10 (s, 3H) Mass:263.2[M+H+]。
Embodiment 2：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 150mL ethyl acetate, 18.2g potassium carbonate with
And 55mL water, 20-25 DEG C of temperature is adjusted, 12.5g chloracetyl chlorides are added dropwise in reaction bulb, 20-25 DEG C is stirred 0.5 hour, point
Water layer is removed, 15.8gN- methyl piperazines are added, 20-25 DEG C is stirred 5 hours, and 0.5g Pd/C, hydrogen displacement adjustment pressure is then added
Power 40-45psi, 40-55 DEG C is stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, filter
Product, yield 92.3%.
Embodiment 3
10g N- methyl-4-nitrophenylamines, 150mL isopropyl acetates, 18.2g potassium carbonate are added in 250mL reaction bulbs
And 55mL water, 20-25 DEG C of temperature is adjusted, 12.5g chloracetyl chlorides are added dropwise in reaction bulb, 20-25 DEG C is stirred 0.5 hour,
15.8gN- methyl piperazines are added in branch vibration layer, and 20-25 DEG C is stirred 5 hours, and 0.5g Pd/C, hydrogen displacement adjustment is then added
Pressure 40-45psi, 40-55 DEG C is stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes, filtering is added
Obtain product, yield 90.4%.
Embodiment 4：
10g N- methyl-4-nitrophenylamines, 100mL2- methyltetrahydrofurans, 18.2g carbon are added in 250mL reaction bulbs
Sour potassium and 55mL water adjust 20-25 DEG C of temperature, 12.5g chloracetyl chlorides are added dropwise in reaction bulb, and 20-25 DEG C of stirring 0.5 is small
When, 15.8gN- methyl piperazines are added in branch vibration layer, and 20-25 DEG C is stirred 5 hours, and 0.5g Pd/C are then added, and hydrogen displacement is adjusted
Seamless power 40-45psi, 40-55 DEG C is stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes, mistake is added
Filter to obtain product, yield 86.4%.
Embodiment 5：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 100mL tetrahydrofurans, 18.2g potassium carbonate with
And 55mL water, 20-25 DEG C of temperature is adjusted, 12.5g chloracetyl chlorides are added dropwise in reaction bulb, 20-25 DEG C is stirred 0.5 hour, point
Water layer is removed, 15.8gN- methyl piperazines are added, 20-25 DEG C is stirred 5 hours, and 0.5g Pd/C, hydrogen displacement adjustment pressure is then added
Power 40-45psi, 40-55 DEG C is stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, filter
Product, yield 89.7%.
Embodiment 6：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 150mL toluene, 18.2g potassium carbonate and
55mL water adjusts 20-25 DEG C of temperature, 12.5g chloracetyl chlorides is added dropwise in reaction bulb, and 20-25 DEG C is stirred 0.5 hour, is divided and is gone
15.8gN- methyl piperazines are added in water layer, and 20-25 DEG C is stirred 5 hours, and 0.5g Pd/C, hydrogen displacement adjustment pressure is then added
40-45psi, 40-55 DEG C are stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, and filter to obtain production
Product, yield 86.9%.
Embodiment 7：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 18.2g potassium carbonate and
55mL water adjusts 20-25 DEG C of temperature, 22.4g bromoacetyl bromides is added dropwise in reaction bulb, and 20-25 DEG C is stirred 0.5 hour, is divided and is gone
15.8gN- methyl piperazines are added in water layer, and 20-25 DEG C is stirred 5 hours, and 0.5g Pd/C, hydrogen displacement adjustment pressure is then added
40-45psi, 40-55 DEG C are stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, and filter to obtain production
Product, yield 90.1%.
Embodiment 8：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 18.2g potassium carbonate and
55mL water adjusts 20-25 DEG C of temperature, 12.5g chloracetyl chlorides is added dropwise in reaction bulb, and 20-25 DEG C is stirred 0.5 hour, is divided and is gone
15.8gN- methyl piperazines are added in water layer, and 20-25 DEG C is stirred 5 hours, and 0.5g platinum/carbon, hydrogen displacement adjustment pressure is then added
40-45psi, 40-55 DEG C are stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, and filter to obtain production
Product, yield 90.7%.
Embodiment 9：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 18.2g potassium carbonate and
55mL water adjusts 20-25 DEG C of temperature, 12.5g chloracetyl chlorides is added dropwise in reaction bulb, and 20-25 DEG C is stirred 0.5 hour, is divided and is gone
15.8gN- methyl piperazines are added in water layer, and 20-25 DEG C is stirred 5 hours, and 0.5g Raney's nickels, hydrogen displacement adjustment pressure is then added
40-45psi, 40-55 DEG C are stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, and filter to obtain production
Product, yield 90.3%.
Embodiment 10：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 18.2g potassium carbonate and
55mL water adjusts 20-25 DEG C of temperature, 12.5g chloracetyl chlorides is added dropwise in reaction bulb, and 20-25 DEG C is stirred 0.5 hour, is divided and is gone
15.8gN- methyl piperazines are added in water layer, and 20-25 DEG C is stirred 5 hours, and 0.5g palladium dydroxides, hydrogen displacement adjustment pressure is then added
Power 40-45psi, 40-55 DEG C is stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, filter
Product, yield 90.3%.
Embodiment 11：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 100mL ethyl acetate, 18.2g potassium carbonate with
And 55mL water, 0 DEG C of temperature is adjusted, 12.5g chloracetyl chlorides are added dropwise in reaction bulb, 20-25 DEG C is stirred 0.5 hour, is divided and is removed water
15.8gN- methyl piperazines are added in layer, and 0-5 DEG C is stirred 10 hours, and 0.5g Pd/C, hydrogen displacement adjustment pressure 40- is then added
45psi, 40-55 DEG C are stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, filter to obtain product,
Yield 88.3%.
Embodiment 12：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 100mL ethyl acetate, 18.2g potassium carbonate with
And 55mL water, temperature 70 C is adjusted, 12.5g chloracetyl chlorides are added dropwise in reaction bulb, 70-75 DEG C is stirred 0.5 hour, is divided and is removed water
15.8gN- methyl piperazines are added in layer, and 70-75 DEG C is stirred 2 hours, and 0.5g Pd/C, hydrogen displacement adjustment pressure 40- is then added
45psi, 40-55 DEG C are stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, filter to obtain product,
Yield 86.3%.
Embodiment 13：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 14.0g sodium carbonate and
55mL water adjusts 20-25 DEG C of temperature, 12.5g chloracetyl chlorides is added dropwise in reaction bulb, and 20-25 DEG C is stirred 0.5 hour, is divided and is gone
15.8gN- methyl piperazines are added in water layer, and 20-25 DEG C is stirred 5 hours, and 0.5g palladiums/carbon, hydrogen displacement adjustment pressure is then added
40-45psi, 40-55 DEG C are stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, and filter to obtain production
Product, yield 91.3%.
Embodiment 14：Nintedanib (I)
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 10.5g sodium hydroxides with
And 100mL water, 20-25 DEG C of temperature is adjusted, 12.5g chloracetyl chlorides are added dropwise in reaction bulb, 20-25 DEG C is stirred 0.5 hour, point
Water layer is removed, 15.8gN- methyl piperazines are added, 20-25 DEG C is stirred 5 hours, and 0.5g palladiums/carbon, hydrogen displacement adjustment pressure is then added
Power 40-45psi, 40-55 DEG C is stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, filter
Product, yield 88.7%.
Embodiment 15：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 14.7g potassium hydroxide with
And 100mL water, 20-25 DEG C of temperature is adjusted, 12.5g chloracetyl chlorides are added dropwise in reaction bulb, 20-25 DEG C is stirred 0.5 hour, point
Water layer is removed, 15.8gN- methyl piperazines are added, 20-25 DEG C is stirred 5 hours, and 0.5g palladiums/carbon, hydrogen displacement adjustment pressure is then added
Power 40-45psi, 40-55 DEG C is stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, filter
Product, yield 86.9%.
Embodiment 16：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 29.4g sodium bicarbonates with
And 150mL water, 20-25 DEG C of temperature is adjusted, 12.5g chloracetyl chlorides are added dropwise in reaction bulb, 20-25 DEG C is stirred 0.5 hour, point
Water layer is removed, 15.8gN- methyl piperazines are added, 20-25 DEG C is stirred 5 hours, and 0.5g palladiums/carbon, hydrogen displacement adjustment pressure is then added
Power 40-45psi, 40-55 DEG C is stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, filter
Product, yield 89.9%.
Embodiment 17：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 35g saleratus and
150mL water adjusts 20-25 DEG C of temperature, 12.5g chloracetyl chlorides is added dropwise in reaction bulb, and 20-25 DEG C is stirred 0.5 hour, is divided and is gone
15.8gN- methyl piperazines are added in water layer, and 20-25 DEG C is stirred 5 hours, and 0.5g palladiums/carbon, hydrogen displacement adjustment pressure is then added
40-45psi, 40-55 DEG C are stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, and filter to obtain production
Product, yield 88.1%.
Embodiment 18：
In 500mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 38.4g lithium hydroxides with
And 150mL water, 20-25 DEG C of temperature is adjusted, 12.5g chloracetyl chlorides are added dropwise in reaction bulb, 20-25 DEG C is stirred 0.5 hour, point
Water layer is removed, 15.8gN- methyl piperazines are added, 20-25 DEG C is stirred 5 hours, and 0.5g palladiums/carbon, hydrogen displacement adjustment pressure is then added
Power 40-45psi, 40-55 DEG C is stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, filter
Product, yield 90.9%.
Embodiment 19：
In 500mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 113.5g cesium carbonates with
And 200mL water, 20-25 DEG C of temperature is adjusted, 12.5g chloracetyl chlorides are added dropwise in reaction bulb, 20-25 DEG C is stirred 0.5 hour, point
Water layer is removed, 15.8gN- methyl piperazines are added, 20-25 DEG C is stirred 5 hours, and 0.5g palladiums/carbon, hydrogen displacement adjustment pressure is then added
Power 40-45psi, 40-55 DEG C is stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, filter
Product, yield 85.7%.
Embodiment 20：
In 500mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 113.5g sodium carbonate with
And 200mL water, 20-25 DEG C of temperature is adjusted, 8.8g chloracetyl chlorides are added dropwise in reaction bulb, 20-25 DEG C is stirred 0.5 hour, point
Water layer is removed, 15.8gN- methyl piperazines are added, 20-25 DEG C is stirred 5 hours, and 0.5g palladiums/carbon, hydrogen displacement adjustment pressure is then added
Power 40-45psi, 40-55 DEG C is stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, filter
Product, yield 85.1%.
Embodiment 21：
In 500mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 113.5g sodium carbonate with
And 200mL water, 20-25 DEG C of temperature is adjusted, 22.1g chloracetyl chlorides are added dropwise in reaction bulb, 20-25 DEG C is stirred 0.5 hour, point
Water layer is removed, 15.8gN- methyl piperazines are added, 20-25 DEG C is stirred 5 hours, and 0.5g palladiums/carbon, hydrogen displacement adjustment pressure is then added
Power 40-45psi, 40-55 DEG C is stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, filter
Product, yield 92.1%.
Embodiment 22：
In 500mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 15.5g potassium carbonate and
200mL water adjusts 20-25 DEG C of temperature, 12.5g chloracetyl chlorides is added dropwise in reaction bulb, and 20-25 DEG C is stirred 0.5 hour, is divided and is gone
15.8gN- methyl piperazines are added in water layer, and 20-25 DEG C is stirred 5 hours, and 0.5g palladiums/carbon, hydrogen displacement adjustment pressure is then added
40-45psi, 40-55 DEG C are stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, and filter to obtain production
Product, yield 86.2%.
Embodiment 23：
In 500mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 46.5g potassium carbonate and
200mL water adjusts 20-25 DEG C of temperature, 12.5g chloracetyl chlorides is added dropwise in reaction bulb, and 20-25 DEG C is stirred 0.5 hour, is divided and is gone
15.8gN- methyl piperazines are added in water layer, and 20-25 DEG C is stirred 5 hours, and 0.5g palladiums/carbon, hydrogen displacement adjustment pressure is then added
40-45psi, 40-55 DEG C are stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL normal heptanes are added, and filter to obtain production
Product, yield 89.8%.
Embodiment 24：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 18.2g potassium carbonate and
55mL water adjusts 20-25 DEG C of temperature, 12.5g chloracetyl chlorides is added dropwise in reaction bulb, and 20-25 DEG C is stirred 0.5 hour, is divided and is gone
15.8gN- methyl piperazines are added in water layer, and 20-25 DEG C is stirred 5 hours, and 0.5g Pd/C, hydrogen displacement adjustment pressure is then added
40-45psi, 40-55 DEG C are stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL n-hexanes are added, and filter to obtain production
Product, yield 90.8%.
Embodiment 25：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 18.2g potassium carbonate and
55mL water adjusts 20-25 DEG C of temperature, 12.5g chloracetyl chlorides is added dropwise in reaction bulb, and 20-25 DEG C is stirred 0.5 hour, is divided and is gone
15.8gN- methyl piperazines are added in water layer, and 20-25 DEG C is stirred 5 hours, and 0.5g Pd/C, hydrogen displacement adjustment pressure is then added
40-45psi, 40-55 DEG C are stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL hexamethylenes are added, and filter to obtain production
Product, yield 90.8%.
Embodiment 26：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 18.2g potassium carbonate and
55mL water adjusts 20-25 DEG C of temperature, 12.5g chloracetyl chlorides is added dropwise in reaction bulb, and 20-25 DEG C is stirred 0.5 hour, is divided and is gone
15.8gN- methyl piperazines are added in water layer, and 20-25 DEG C is stirred 5 hours, and 0.5g Pd/C, hydrogen displacement adjustment pressure is then added
40-45psi, 40-55 DEG C are stirred 18 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL methyl tertiary butyl ether(MTBE)s, mistake is added
Filter to obtain product, yield 89.8%.
Embodiment 27：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 18.2g potassium carbonate and
55mL water adjusts 20-25 DEG C of temperature, 12.5g chloracetyl chlorides is added dropwise in reaction bulb, and 20-25 DEG C is stirred 0.5 hour, is divided and is gone
15.8gN- methyl piperazines are added in water layer, and 20-25 DEG C is stirred 5 hours, and 0.5g Pd/C, hydrogen displacement adjustment pressure is then added
15-20psi, 40-55 DEG C are stirred 36 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL methyl tertiary butyl ether(MTBE)s, mistake is added
Filter to obtain product, yield 85.7%.
Embodiment 28：
In 250mL reaction bulbs be added 10g N- methyl-4-nitrophenylamines, 50mL dichloromethane, 18.2g potassium carbonate and
55mL water adjusts 20-25 DEG C of temperature, 12.5g chloracetyl chlorides is added dropwise in reaction bulb, and 20-25 DEG C is stirred 0.5 hour, is divided and is gone
15.8gN- methyl piperazines are added in water layer, and 20-25 DEG C is stirred 5 hours, and 0.5g Pd/C, hydrogen displacement adjustment pressure is then added
90-100psi, 40-55 DEG C are stirred 8 hours, and filtering, filtrate is concentrated into 1-2 times of volume, and 100mL methyl tertiary butyl ether(MTBE)s, mistake is added
Filter to obtain product, yield 91.7%.
Claims (6)
1. a kind of " one kettle way " prepares Nintedanib (nintedanib, I) key intermediate N- (4- aminophenyls)-N- methyl-
The method of 2- (4- methylpiperazine-1-yls) acetamide (formula B)：
Step in the preparation method includes：N- methyl-4-nitrophenylamines are dissolved in the water of organic solvent and alkali by the first stage
Solution mixes, and chloracetyl chloride or bromoacetyl bromide is then added dropwise, and reaction 0.1-3 hours, branch vibration layer are carried out in 0-75 degree；It is organic
N methyl piperazine is added in phase and carries out second stage reaction, 0-75 degree reacts 2-10 hours, and reduction examination is directly added into reaction solution
Agent, adjustment temperature 0-75 degree, reactor pressure 15-100psi progress phase III reactions, 8-36 hours.It filters after reaction
Go back original reagent is removed, reaction solution concentration is added reverse phase solvent crystallization and obtains Nintedanib (Nintedanib, I) key intermediate
N- (4- aminophenyls)-N- methyl -2- (4- methylpiperazine-1-yls) acetamide (formula B).
2. organic solvent described in method includes ethyl acetate, dichloromethane, isopropyl acetate, first as described in the appended claim 1
Benzene, tetrahydrofuran and 2- methyltetrahydrofurans.The reverse phase solvent includes normal heptane, n-hexane, hexamethylene, methyl tertbutyl
Ether.
3. as described in the appended claim 1 in method alkali include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate,
Cesium carbonate, sodium bicarbonate, saleratus.
4. go back original reagent includes described in method as described in claim 1：Hydrogen, palladium/carbon, platinum/charcoal, Raney's nickel.
5. " one kettle way " preparation method is it is characterized in that, 0-75 DEG C of first stage reaction temperature, reaction as described in the appended claim 1
Time 0.1-3 hour；0-75 DEG C of second stage reaction temperature, reaction time 3-10 hour；0-70 DEG C of phase III reaction temperature,
Reaction pressure 15-100psi, reaction time 8-36 hour.
6. in " one kettle way " preparation method as described in claim 1, main material N- methyl-4-nitrophenylamines, chlorine are reacted
The molar ratio of chloroacetic chloride or bromoacetyl bromide and N methyl piperazine is 1：1.5~3:1.5~3, base amount is key reaction reagent
1-3 times of chloracetyl chloride or bromoacetyl bromide.
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