CN106467500A - A kind of one pot synthesis synthesize the new method of Nintedanib key intermediate - Google Patents
A kind of one pot synthesis synthesize the new method of Nintedanib key intermediate Download PDFInfo
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- CN106467500A CN106467500A CN201510512164.7A CN201510512164A CN106467500A CN 106467500 A CN106467500 A CN 106467500A CN 201510512164 A CN201510512164 A CN 201510512164A CN 106467500 A CN106467500 A CN 106467500A
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- sodium hydrosulfite
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- XZXHXSATPCNXJR-ZQHSETAFSA-N CN(C(CN1CCN(C)CC1)=O)c(cc1)ccc1N/C(/c1ccccc1)=C(\c(c(N1)c2)ccc2C(OC)=O)/C1=O Chemical compound CN(C(CN1CCN(C)CC1)=O)c(cc1)ccc1N/C(/c1ccccc1)=C(\c(c(N1)c2)ccc2C(OC)=O)/C1=O XZXHXSATPCNXJR-ZQHSETAFSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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 a kind of one pot synthesis synthesize the new method of Nintedanib key intermediate, the method is reacted with chloracetyl chloride from N- methyl -4- aminonitrobenzene using one pot synthesis, react with N methyl piperazine again, sodium hydrosulfite reduction synthesis N- (4- aminophenyl)-N again, 4- dimethyl -1- piperazineacetamide, centre no purification or separation of intermediates operation, in solvent, organic solvent used is single solvent system, and its reaction equation is：The method substantially reduces reaction man-hour, simplifies operation, and reaction condition is gentle, simple to operate, low production cost, environmental friendliness, be especially suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of one pot synthesis synthesize the new method of Nintedanib key intermediate.
Background technology
Nintedanib (Intedanib), chemical name is (3Z)-[1- [4- [N- methyl-N- [2- (4- methylpiperazine-1-yl) acetyl
Base] amino] anilino-] -1- benzylidene] -2- oxo -2,3- dihydro -1H- indole -6-carboxylic methyl ester, its structural formula is as follows：
The treatment idiopathic pulmonary fibrosises medicine that Nintedanib is developed by Boehringer Ingelheim drugmaker is first, be also only one obtains
The mutatis mutandis tyrosine kinase inhibitor in treatment IPF, lists in the U.S. and European Union, and indication is idiopathic pulmonary fibrosises.
Wherein N- (4- aminophenyl)-N, 4- dimethyl -1- piperazineacetamide is one of key intermediate of synthesis Nintedanib, presently relevant system
Preparation Method report is as follows：
1.Journal of Medicinal Chemistry；vol.52；nb.14；(2009)；And Journal of the American p.4466-4488.
ChemicalSociety；vol.125；nb.40；(2003)；p.12084-12085；With N- methyl -4- aminonitrobenzene as raw material, through reacting with chloracetyl chloride
Generate amide, after process, then hydro-reduction obtains compound to gained amide again with N methyl piperazine effect again：
2.WO200971524 being disclosed directly below preparation method, reaction equation is as follows：
The subject matter of this synthetic method is：
1) N- methyl -4- aminonitrobenzene is raw material, and through reacting generation amide with chloracetyl chloride, main material is first added by this step reaction with solvent
Heat arrives nearly reflux temperature, then Deca chloracetyl chloride, and industrial operation is more inconvenient, is not suitable for commercial production；
2) N- methyl -4- aminonitrobenzene and chloracetyl chloride react gained amide through isolating and purifying operation and drying operation, considerably increase
Production hour and labor intensity, and increase energy consumption, it is unfavorable for energy-saving, be not suitable for industrialized production；
3) N- methyl -4- aminonitrobenzene is raw material, through reacting generation amide with chloracetyl chloride, after the completion of reaction, need to cool to 60 DEG C,
Add poor solvent hexahydrotoluene, be then chilled to 0 DEG C of crystallize again 1 hour, operation is cumbersome, and solvent cannot reclaim for mixed solvent, become
This is higher, is not suitable for industrialized production；
4) after first step gained amide and solvent are heated to 40 DEG C, instill N methyl piperazine, be then warmed up to 50 DEG C of reactions again, operation is relatively
Loaded down with trivial details, be not suitable for industrialized production；Isopropanol is added after replacement, under Pd/C catalysis, hydrogenating reduction.After filling into isopropanol, solvent is mixed
Bonding solvent, it is impossible to be reclaimed, is not suitable for industrialized production；
5) after reacting with N methyl piperazine, washing, organic faciess add isopropanol, under Pd/C catalysis, hydrogenating reduction.Fill into isopropyl
After alcohol, solvent is not suitable for industrialized production for mixed solvent it is impossible to be reclaimed；
Content of the invention
It is an object of the invention to provide a kind of new method of synthesis Nintedanib key intermediate, overcoming defect and the deficiency of prior art
Part.
The technical solution used in the present invention is as follows：
Using one pot synthesis, N- methyl -4- aminonitrobenzene is reacted with chloracetyl chloride in a solvent, then washed reaction liquid, then organic
It is added to N methyl piperazine and continues reaction, be subsequently adding sodium hydrosulfite reduction and obtain target product, reaction equation is：
In the present invention, N- methyl -4- aminonitrobenzene is initiation material, the then dilute solution of Deca chloracetyl chloride, then insulation reaction,
Reaction finishes, washing；Organic faciess instill N methyl piperazine, then insulation reaction, and reaction finishes, and take a policy powder and ammonia, and heating and thermal insulation is anti-
Target compound should be obtained.
The present invention can be ethyl acetate, isopropyl acetate using solvent.It is preferably ethyl acetate, solvent volume with reactant quality ratio is
4～20, preferably 8～10.
In the present invention, chloracetyl chloride and RM-1 mol ratio are 1.00～1.50, and preferred molar ratio is 1.05～1.10；
In the present invention, N methyl piperazine and RM-1 mol ratio are 1.00～4.00, and preferred molar ratio is 2.50～3.00；
In the present invention, sodium hydrosulfite and RM-1 mol ratio are 2.00～7.00, and preferred molar ratio is 3.00～3.50；
In the present invention, chloracetyl chloride dropping temperature is 20～50 DEG C, preferably 20～25 DEG C；
In the present invention, after dripping chloracetyl chloride, reaction temperature is 40～70 DEG C, preferably 50～55 DEG C；
In the present invention, N methyl piperazine dropping temperature is 20～50 DEG C, preferably 20～25 DEG C；
In the present invention, after dripping N methyl piperazine, reaction temperature is 20～70 DEG C, preferably 45～50 DEG C；
In the present invention, sodium hydrosulfite adds temperature to be 0～30 DEG C, preferably 10～15 DEG C；
In the present invention, after adding sodium hydrosulfite, reaction temperature is 20～70 DEG C, preferably 50～55 DEG C；
The present invention provides a kind of method that one pot synthesis synthesize Nintedanib key intermediate, and centre no recrystallization etc. isolates and purifies middle gymnastics
Make, Deca chloracetyl chloride and N methyl piperazine temperature are relatively low, reaction dissolvent is single solvent, substantially reduce reaction man-hour, simplify reaction behaviour
Make, the method reaction condition is gentle, simple to operate, low production cost, environmental friendliness, be especially suitable for industrialized production.
Specific embodiment
Below with reference to embodiment, technical scheme and its produced technique effect are described further, understand this with sufficient
The purpose of invention, technical characteristic and effect.
Embodiment 1：The preparation of compound TM
10 grams of N- methyl -4- aminonitrobenzenes, 80 milliliters of ethyl acetate are added in 250 milliliters of there-necked flasks, in 20～25 DEG C, 30 minutes
The interior mixed solution by 7.8 grams of (1.05eq) chloracetyl chlorides and 20 milliliters of ethyl acetate is added drop-wise in reactant liquor.Completion of dropping, is heated to 50～55 DEG C,
Insulation reaction 2 hours, TLC monitoring reaction raw materials point disappearance (developing solvent is ethyl acetate: petroleum ether=2: 1, Rf=0.42), cool to 20～25 DEG C,
10 milliliters of water are added in reactant liquor, stir 10 minutes, point liquid, and organic faciess are poured in 250 milliliters of there-necked flasks.Control temperature at 20～25 DEG C,
16.45 grams of (2.5eq) N methyl piperazines are added dropwise in reaction bulb, completion of dropping, are heated to 45～50 DEG C, insulation reaction 4 hours, TLC monitors
Reaction raw materials point disappear (developing solvent be dichloromethane: methanol=2: 1, Rf=0.61), cool to 10～15 DEG C, add 30 milliliter of 28% ammonia and
30 milliliters of water, are dividedly in some parts 35 grams of (3.0eq) sodium hydrosulfites, finish, be warmed up to 50～55 DEG C, insulation reaction 2.5 hours, and TLC monitors reaction raw materials
Point disappearance (developing solvent is dichloromethane: methanol=2: 1, Rf=0.46), cool to 20～25 DEG C, point liquid, and 10 milliliters of washings of ethyl acetate phase,
10 milliliters of saturated common salt washings, anhydrous sodium sulfate drying, concentrate, in residual liquid, add 20 milliliters of re-crystallizing in ethyl acetate, sucking filtration, 45 DEG C of drums of filter cake
Air-dry dry, obtain 13.48 grams of off-white powder, yield 78.2%.Purity：98.62%.
Embodiment 2：The preparation of compound TM
10 grams of N- methyl -4- aminonitrobenzenes, 80 milliliters of isopropyl acetates are added in 250 milliliters of there-necked flasks, in 20～25 DEG C, 30 points
In clock, the mixed profit solution of 7.8 grams of (1.05eq) chloracetyl chlorides and 20 milliliters of isopropyl acetates is added drop-wise in reactant liquor.Completion of dropping, is heated to 50～55 DEG C,
Insulation reaction 2 hours, TLC monitoring reaction raw materials point disappearance (developing solvent is ethyl acetate: petroleum ether=2: 1, Rf=0.42), cool to 20～25 DEG C,
10 milliliters of water are added in reactant liquor, stir 10 minutes, point liquid, and organic faciess are poured in 250 milliliters of there-necked flasks.Control temperature at 20～25 DEG C,
16.45 grams of (2.5eq) N methyl piperazines are added dropwise in reaction bulb, completion of dropping, are heated to 45～50 DEG C, insulation reaction 4 hours, TLC monitors
Reaction raw materials point disappear (developing solvent be dichloromethane: methanol=2: 1, Rf=0.61), cool to 10～15 DEG C, add 30 milliliter of 28% ammonia and
30 milliliters of water, are dividedly in some parts 35 grams of (3.0eq) sodium hydrosulfites, finish, be warmed up to 50～55 DEG C, insulation reaction 2.5 hours, and TLC monitors reaction raw materials
Point disappearance (developing solvent is dichloromethane: methanol=2: 1, Rf=0.46), cool to 20～25 DEG C, point liquid, and the 10 milliliters of washings of isopropyl acetate phase,
10 milliliters of saturated common salt washings, anhydrous sodium sulfate drying, concentrate, in residual liquid, add 20 milliliters of isopropyl acetate recrystallization, sucking filtration, 45 DEG C of filter cake
Forced air drying, obtains 13.28 grams of off-white powder, yield 77.03%.Purity：97.86%.
Embodiment 3：The preparation of compound TM
40 grams of N- methyl -4- aminonitrobenzenes, 320 milliliters of ethyl acetate are added in 1 liter of there-necked flask, in 20～25 DEG C, will in 30 minutes
The mixed solution of 31.2 grams of (1.05eq) chloracetyl chlorides and 80 milliliters of ethyl acetate is added drop-wise in reactant liquor.Completion of dropping, is heated to 50～55 DEG C, protects
Temperature reaction 2 hours, TLC monitoring reaction raw materials point disappearance (developing solvent is ethyl acetate: petroleum ether=2: 1, Rf=0.42), cool to 20～25 DEG C,
40 milliliters of water are added in reactant liquor, stir 15 minutes, point liquid, and organic faciess are poured in 1 liter of there-necked flask.Control temperature at 20～25 DEG C, by 65.80
Gram (2.5eq) N methyl piperazine is added dropwise in reaction bulb, and completion of dropping is heated to 45～50 DEG C, insulation reaction 4.5 hours, and TLC monitoring reaction is former
Shots disappear, and (developing solvent is dichloromethane: methanol=2: 1, Rf=0.61), cools to 10～15 DEG C, adds 120 milliliter of 28% ammonia and 120 millis
Rise water, be dividedly in some parts 140 grams of (3.0eq) sodium hydrosulfites, finish, be warmed up to 50～55 DEG C, insulation reaction 2.5 hours, TLC monitors reaction raw materials point
Disappear (developing solvent is dichloromethane: methanol=2: 1, Rf=0.46), cool to 20～25 DEG C, point liquid, and 50 milliliters of washings of ethyl acetate phase, 50
Milliliter saturated common salt washing, anhydrous sodium sulfate drying, concentrate, in residual liquid, add 80 milliliters of re-crystallizing in ethyl acetate, sucking filtration, 45 DEG C of air blast of filter cake
It is dried, obtain 54.67 grams of off-white powder, yield 79.27%.Purity：98.91%.
Claims (12)
1. a kind of synthesis Nintedanib intermediate method it is characterised in that being reacted with chloracetyl chloride from N- methyl -4- aminonitrobenzene using one pot synthesis,
React with N methyl piperazine again, then sodium hydrosulfite reduction synthesis N- (4- aminophenyl)-N, 4- dimethyl -1- piperazineacetamide, centre no purification or point
In middlebox operation, solvent, organic solvent used is single solvent system, and its reaction equation is：
2. method according to claim 1 is it is characterised in that described dicyandiamide solution can be ethyl acetate, isopropyl acetate, preferably acetic acid
Ethyl ester.
3. method according to claim 1 is it is characterised in that described solvent volume and reactant quality are than for 4～20, preferably 8～10.
4. it is characterised in that described chloracetyl chloride and RM-1 mol ratio are 1.00～1.50, preferred molar ratio is method according to claim 1
1.05～1.10.
5. method according to claim 1 is it is characterised in that described N monomethyl piperazine and RM-1 mol ratio are 1.00～4.00, preferred molar ratio
For 2.50～3.00.
6. it is characterised in that described sodium hydrosulfite and RM-1 mol ratio are 2.00～7.00, preferred molar ratio is method according to claim 1
3.00～3.50.
7. method according to claim 1 it is characterised in that described chloracetyl chloride dropping temperature be 20～50 DEG C, preferably 20～25 DEG C.
8. method according to claim 1 is it is characterised in that described drip reaction temperature after chloracetyl chloride and be 40～70 DEG C, preferably 50～55 DEG C.
9. method according to claim 1 it is characterised in that described N methyl piperazine dropping temperature be 20～50 DEG C, preferably 20～25 DEG C.
10. method according to claim 1 is it is characterised in that described drip reaction temperature after N methyl piperazine and be 20～70 DEG C, preferably
45～50 DEG C.
11. methods according to claim 1 it is characterised in that described sodium hydrosulfite add temperature be 0～30 DEG C, preferably 10～15 DEG C.
12. methods according to claim 1 it is characterised in that described add reaction temperature after sodium hydrosulfite and be 20～70 DEG C, preferably 50～55 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106841495A (en) * | 2017-04-21 | 2017-06-13 | 常州佳德医药科技有限公司 | The high-sensitivity analysis method of genotoxicity impurity in ethyl sulfonic acid Nintedanib |
| US11261158B2 (en) | 2017-11-17 | 2022-03-01 | Fermion Oy | Synthesis of 2-indolinone derivatives |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1391557A (en) * | 1999-10-13 | 2003-01-15 | 贝林格尔英格海姆法玛公司 | 6-position substituted indoline, production and use thereof as medicament |
| CN101883756A (en) * | 2007-12-03 | 2010-11-10 | 贝林格尔.英格海姆国际有限公司 | Process for the manufacture of an indolinone derivative |
| WO2012068441A2 (en) * | 2010-11-19 | 2012-05-24 | Ratiopharm Gmbh | Intedanib salts and solid state forms thereof |
-
2015
- 2015-08-14 CN CN201510512164.7A patent/CN106467500A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1391557A (en) * | 1999-10-13 | 2003-01-15 | 贝林格尔英格海姆法玛公司 | 6-position substituted indoline, production and use thereof as medicament |
| CN101883756A (en) * | 2007-12-03 | 2010-11-10 | 贝林格尔.英格海姆国际有限公司 | Process for the manufacture of an indolinone derivative |
| WO2012068441A2 (en) * | 2010-11-19 | 2012-05-24 | Ratiopharm Gmbh | Intedanib salts and solid state forms thereof |
Non-Patent Citations (5)
| Title |
|---|
| GERALD J. ROTH等: "Design, Synthesis, and Evaluation of Indolinones as Triple Angiokinase Inhibitors and the Discovery of a Highly Specific 6-Methoxycarbonyl-Substituted Indolinone (BIBF 1120)", 《J. MED. CHEM.》 * |
| RUIXUE XU等: "Design, synthesis and biological evaluation of deuterated nintedanib for improving pharmacokinetic properties", 《JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS》 * |
| 姚其正: "《药物合成反应》", 30 September 2012, 中国医药科技出版社 * |
| 薛永强等: "《现代有机合成方法与技术》", 31 May 2003, 化学工业出版社 * |
| 郑端文: "《生产工艺防火》", 31 July 1998, 化学工业出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106841495A (en) * | 2017-04-21 | 2017-06-13 | 常州佳德医药科技有限公司 | The high-sensitivity analysis method of genotoxicity impurity in ethyl sulfonic acid Nintedanib |
| US11261158B2 (en) | 2017-11-17 | 2022-03-01 | Fermion Oy | Synthesis of 2-indolinone derivatives |
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