CN103788067A - Preparation method of 3-[3-ethoxy-4-(N-phthaloyl)]phenylamino-N-[3-chloro-4-(2-pyridylmethoxyl]phenyl-2-cyano-2-acrylamide - Google Patents
Preparation method of 3-[3-ethoxy-4-(N-phthaloyl)]phenylamino-N-[3-chloro-4-(2-pyridylmethoxyl]phenyl-2-cyano-2-acrylamide Download PDFInfo
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- CN103788067A CN103788067A CN201410014877.6A CN201410014877A CN103788067A CN 103788067 A CN103788067 A CN 103788067A CN 201410014877 A CN201410014877 A CN 201410014877A CN 103788067 A CN103788067 A CN 103788067A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention belongs to the field of medicinal chemistry, and discloses a preparation method of 3-[3-ethoxy-4-(N-phthaloyl)]phenylamino-N-[3-chloro-4-(2-pyridylmethoxyl]phenyl-2-cyano-2-acrylamide serving as a key intermediate of neratinib. The method comprises the following steps: dissolving 3-ethoxy-4-(N-phthaloyl)-phenylamino into a polar aprotic solvent of a certain temperature; dropwise adding a certain molar ratio of formic ether R slowly; and adding 3-chloro-4-(pyridine-2-methoxyl)-phenyl)-2-cyanoacetamide in batch, and docking to obtain a target product. The preparation method is quick in reaction and high in yield.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, be specifically related to the key intermediate 3-[3-oxyethyl group-4-(N-O-phthalic first imido grpup) of medicine HKI-272] the chloro-4-of phenylamino-N-[3-(2-pyridyl methoxyl group)] synthetic method of phenyl-2-cyano group-2-acrylamide (I).
Background technology
HKI-272 is a kind of irreversible ErbB receptor tyrosine kinase inhibitors, can effectively suppress ErbB1 and ErbB2 tyrosine kinase activity, is a kind of oral anti-breast cancer medicines, at present in three phase clinical stages.
3-[3-oxyethyl group-4-(the first imido grpup of N-O-phthalic)] the chloro-4-of phenylamino-N-[3-(2-pyridyl methoxyl group)] phenyl-2-cyano group-2-acrylamide (I)
beimportant intermediate during HKI-272 is synthetic.Existing three synthetic methods of this intermediate, specific as follows:
Route one (CN1144786):
Route two (CN1930128A):
Above-mentioned two lines are reacted as intermediate (being generated with raw material reaction by ortho-formiate) by aryl azomethine ester compound or alkoxyl group methylene compound, in reaction process, adopt triethyl orthoformate as solvent, cost improves, and speed of response is slow.
Route three (CN1835923A)
Above-mentioned route adopts Virahol as solvent, and poor for the solvability of raw material, speed of response is slower, and yield is not high.
Summary of the invention
In order to overcome the defect existing in above-mentioned preparation method, the invention discloses a kind of key intermediate 3-[3-oxyethyl group-4-(N-O-phthalic first imido grpup) of synthetic HKI-272] the chloro-4-of phenylamino-N-[3-(2-pyridyl methoxyl group)] method of phenyl-2-cyano group-2-acrylamide (I), it is fast that this preparation method reacts, yield is high, can reach 80%.Its route is as follows:
Wherein: R is the straight or branched alkyl such as H or methyl, ethyl, propyl group, sec.-propyl, benzyl, the phenyl that phenyl or alkyl replace.
3-oxyethyl group-4-(the first imido grpup of N-O-phthalic)-aniline (II) is dissolved in to the polar aprotic solvent of certain temperature, slowly drip the formic acid R ester (IV) of certain mol proportion, then add [the chloro-4-(pyridine-2-methoxyl group of 3-)-phenyl]-2-malonamide nitrile (III) docking to obtain target product (I) in batches.
Described non-proton property polar solvent is selected from acetone, DMF, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO), preferably N-Methyl pyrrolidone;
Described certain temperature is selected from T=50 ℃ ~ 100 ℃, preferably 70 ℃ ~ 80 ℃;
Described certain mol proportion is selected from V (IV)/V (III)/V (II)=1.1/1/1, V (IV)/V (III)/V (II)=1.1/1/0.9, V (IV)/V (III)/V (II)=1.1/0.9/1, preferably V (IV)/V (III)/V (II)=1.1/0.9/1.
Embodiment
Embodiment 1
Take 28.3g(0.1mol) 3-oxyethyl group-4-(the first imido grpup of N-O-phthalic)-aniline immigration 500ml there-necked flask, pour 300ml acetone into, open mechanical stirring, be heated to 60 ℃, slowly drip 8.14g(0.11mol) ethyl formate, after 1h, add 30.1g(0.1mol) [the chloro-4-(pyridine-2-methoxyl group of 3-)-phenyl]-2-malonamide nitrile.After reaction 24h, raw material reaction is complete, naturally cools to room temperature, adds 1.5L water stirring and crystallizing 2h, and suction filtration obtains khaki color solid 49.2g, yield 82.8%,
1h NMR: δ (DMSO-d
6) 11.45 (d, 1H), 9.58 (d, 1H), 8.59 (m, 1H), 8.54 (d, 1H), 8.00-7.84 (m, 6H), 7.57 (d, 1H), 7.52 (dd, 1H), 7.39-7.34 (m, 3H), 7.21 (d, 1H), 7.11 (dd, 1H), 5.27 (s, 2H), 4.11 (q, 2H), 1.16 (t, 3H). MS:597.0 [M-H]
+
Embodiment 2
Take 28.3g(0.1mol) 3-oxyethyl group-4-(the first imido grpup of N-O-phthalic)-aniline immigration 500ml there-necked flask, pour 300ml N into, dinethylformamide, open mechanical stirring, be heated to 80 ℃, slowly drip 8.14g(0.11mol) ethyl formate, after 1h, add 30.1g(0.1mol) [the chloro-4-(pyridine-2-methoxyl group of 3-)-phenyl]-2-malonamide nitrile.After reaction 5h, raw material reaction is complete, naturally cools to room temperature, adds 1.5L water stirring and crystallizing 2h, and suction filtration obtains khaki color solid 48.7g, yield 81.9%.
Embodiment 3
Take 28.3g(0.1mol) 3-oxyethyl group-4-(the first imido grpup of N-O-phthalic)-aniline immigration 500ml there-necked flask, pour 300ml dimethyl sulfoxide (DMSO) into, open mechanical stirring, be heated to 80 ℃, slowly drip 8.14g(0.11mol) ethyl formate, after 1h, add 30.1g(0.1mol) [the chloro-4-(pyridine-2-methoxyl group of 3-)-phenyl]-2-malonamide nitrile.After reaction 4.5h, raw material reaction is complete, naturally cools to room temperature, adds 1.5L water stirring and crystallizing 2h, and suction filtration obtains khaki color solid 49.7g, yield 83.6%.
Embodiment 4
Take 28.3g(0.1mol) 3-oxyethyl group-4-(the first imido grpup of N-O-phthalic)-aniline immigration 500ml there-necked flask, pour 300ml N-Methyl pyrrolidone into, open mechanical stirring, be heated to 70 ℃, slowly drip 8.14g(0.11mol) ethyl formate, after 1h, add 30.1g(0.1mol) [the chloro-4-(pyridine-2-methoxyl group of 3-)-phenyl]-2-malonamide nitrile.After reaction 4h, raw material reaction is complete, naturally cools to room temperature, adds 1.5L water stirring and crystallizing 2h, and suction filtration obtains khaki color solid 50.8g, yield 85.5%.
Embodiment 5
Take 25.5g(0.09mol) 3-oxyethyl group-4-(the first imido grpup of N-O-phthalic)-aniline immigration 500ml there-necked flask, pour 300ml N-Methyl pyrrolidone into, open mechanical stirring, be heated to 70 ℃, slowly drip 8.14g(0.11mol) ethyl formate, after 1h, add 30.1g(0.1mol) [the chloro-4-(pyridine-2-methoxyl group of 3-)-phenyl]-2-malonamide nitrile.After reaction 4h, raw material reaction reacts completely, and naturally cools to room temperature, adds 1.5L water stirring and crystallizing 2h, and suction filtration obtains khaki color solid 49.8g, yield 83.8%.
Embodiment 6
Take 28.3g(0.1mol) 3-oxyethyl group-4-(the first imido grpup of N-O-phthalic)-aniline immigration 500ml there-necked flask, pour 300ml N-Methyl pyrrolidone into, open mechanical stirring, be heated to 80 ℃, slowly drip 8.14g(0.11mol) ethyl formate, after 1h, add 27.1g(0.09mol) [the chloro-4-(pyridine-2-methoxyl group of 3-)-phenyl]-2-malonamide nitrile.After reaction 4h, raw material reaction is complete, naturally cools to room temperature, adds 1.5L water stirring and crystallizing 2h, and suction filtration obtains khaki color solid 52.1g, yield 87.7%.
Embodiment 7
Take 25.5g(0.09mol) 3-oxyethyl group-4-(the first imido grpup of N-O-phthalic)-aniline immigration 500ml there-necked flask, pour 300ml N-Methyl pyrrolidone into, open mechanical stirring, be heated to 80 ℃, slowly drip 7.4g(0.1mol) ethyl formate, after 1h, add 30.1g(0.1mol) [the chloro-4-(pyridine-2-methoxyl group of 3-)-phenyl]-2-malonamide nitrile.After reaction 8h, raw material reaction is complete, naturally cools to room temperature, adds 1.5L water stirring and crystallizing 2h, and suction filtration obtains khaki color solid 48.5g, yield 81.6%.
Claims (8)
1. 3-[3-oxyethyl group-4-(N-O-phthalic first imido grpup)] the chloro-4-of phenylamino-N-[3-(2-pyridyl methoxyl group)] preparation method of phenyl-2-cyano group-2-acrylamide (I), reaction equation is as follows:
Wherein: R is H or straight or branched alkyl, benzyl, the phenyl that phenyl or alkyl replace.
2. according to the preparation method described in claims 1, it is characterized in that described preparation method comprises the steps:
3-oxyethyl group-4-(the first imido grpup of N-O-phthalic)-aniline (II) is dissolved in to the polar aprotic solvent of certain temperature, slowly drip the formic acid R ester (IV) of certain mol proportion, then add [the chloro-4-(pyridine-2-methoxyl group of 3-)-phenyl]-2-malonamide nitrile (III) docking to obtain target product (I) in batches.
3. according to the method described in claims 2, it is characterized in that described non-proton property polar solvent is selected from acetone, DMF, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO).
4. according to the method described in claims 2, it is characterized in that the preferred N-Methyl pyrrolidone of described non-proton property polar solvent.
5. according to the method described in claims 2, it is characterized in that described certain temperature is 50 ℃ ~ 100 ℃.
6. according to the method described in claims 2, it is characterized in that described certain temperature is 70 ℃ ~ 80 ℃.
7. according to the method described in claims 2, it is characterized in that described certain mol proportion is selected from V (IV)/V (III)/V (II)=1.1/1/1, V (IV)/V (III)/V (II)=1.1/1/0.9, V (IV)/V (III)/V (II)=1.1/0.9/1.
8. according to the method described in claims 2, it is characterized in that the preferred V of described certain mol proportion (IV)/V (III)/V (II)=1.1/0.9/1.
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| CN201410014877.6A CN103788067A (en) | 2014-01-14 | 2014-01-14 | Preparation method of 3-[3-ethoxy-4-(N-phthaloyl)]phenylamino-N-[3-chloro-4-(2-pyridylmethoxyl]phenyl-2-cyano-2-acrylamide |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1616417A (en) * | 1996-11-29 | 2005-05-18 | 巴斯福股份公司 | Photo-stable cosmetic and pharmaceutical formulations containing UV-filters |
| CN101180269A (en) * | 2005-05-25 | 2008-05-14 | 惠氏公司 | Method of preparing 3-cyano-quinolines and intermediates made thereby |
| US20120219522A1 (en) * | 2011-02-28 | 2012-08-30 | Dr. Ning XI | Substituted quinoline compounds and methods of use |
| CN102718749A (en) * | 2011-03-30 | 2012-10-10 | 北京德众万全药物技术开发有限公司 | Preparation method of antitumor drug Nuonatini |
-
2014
- 2014-01-14 CN CN201410014877.6A patent/CN103788067A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1616417A (en) * | 1996-11-29 | 2005-05-18 | 巴斯福股份公司 | Photo-stable cosmetic and pharmaceutical formulations containing UV-filters |
| CN101180269A (en) * | 2005-05-25 | 2008-05-14 | 惠氏公司 | Method of preparing 3-cyano-quinolines and intermediates made thereby |
| US20120219522A1 (en) * | 2011-02-28 | 2012-08-30 | Dr. Ning XI | Substituted quinoline compounds and methods of use |
| CN102718749A (en) * | 2011-03-30 | 2012-10-10 | 北京德众万全药物技术开发有限公司 | Preparation method of antitumor drug Nuonatini |
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