CN102718749A - Preparation method of antitumor drug Nuonatini - Google Patents
Preparation method of antitumor drug Nuonatini Download PDFInfo
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- CN102718749A CN102718749A CN2011100787140A CN201110078714A CN102718749A CN 102718749 A CN102718749 A CN 102718749A CN 2011100787140 A CN2011100787140 A CN 2011100787140A CN 201110078714 A CN201110078714 A CN 201110078714A CN 102718749 A CN102718749 A CN 102718749A
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Abstract
The invention discloses a preparation method of an antitumor drug Nuonatini, comprising the following steps of: performing a reaction between a compound I, a compound II and triethyl orthoformate in an organic solvent to obtain an intermediate III; and carrying out cyclization on the compound III to obtain Nuonatini.
Description
Technical field
The present invention relates to antitumor drug promise that preparation method and key intermediate thereof for the Buddhist nun.
Background technology
That replaces the Buddhist nun promise, and chemistry (2E)-N-[4-[[3-chloro-4-[(pyridine-2-yl) methoxyl group] phenyl] amino]-3-cyanic acid-7-ethoxyquinoline-6-yl] by name-4-(dimethyl amido) but-2-enamides is the Urogastron tyrosine kinase inhibitor.In recent years,, found many new treatment target spots based on research to the molecular level at tumor focus position, for the new drug of the high-efficiency low-toxicity of development of new provides maybe.Urogastron (EGFR) acceptor is a kind of membrane receptor; In multiple malignant tumour such as neurogliocytoma, mammary cancer, lung cancer, ovarian cancer, Head and Neck squama cancer, cervical cancer, the esophageal carcinoma, prostate cancer, liver cancer, colorectal carcinoma, cancer of the stomach etc., over-expresses is arranged all; Activation also can be accelerated the tumour cell breeding; Promote tumor-blood-vessel growth, quicken metastases, hinder tumor death.The EGFR Tyrosylprotein kinase is that the antineoplaston of target spot has become one of field very active in the cancer research at present; Through further research; Along with further illustrating of mechanism of action, increasing this type of medicine can go through to be applied to clinical, becomes the effective weapon of control cancer.
Summary of the invention
The object of the present invention is to provide a kind of that preparation method for the Buddhist nun of new promise, this preparation method can obvious improved promise that productive rate and quality for the Buddhist nun.
That preparation method of the disclosed promise of the present invention for the Buddhist nun, it comprises following step:
1. in organic solvent, compound I, compound I I, triethyl orthoformate reaction obtain intermediate III.
2. compound III cyclization, that replaces the Buddhist nun to obtain promise.
Reaction equation is following:
Wherein, compound I is (E)-N-(4-amino-2-ethoxyl phenenyl)-4-(dimethylamino) but-2-enamides.
Compound I I is N-[3-chloro-4-(pyridine-2-ylmethoxy) phenyl]-2-itrile group-ethanamide.
Compound III is (E)-N-(4-((E)-3-(3-chloro-4-(pyridine-2-base-methoxyl group) aniline)-2-itrile group-3-acrylic amide)-2-oxyethyl group)-4-(n n dimetylaniline) but-2-enamides.
Compound TM be promise that for the Buddhist nun.
The temperature of reaction of step (1) or step (2) is-50～150 ℃.
Reaction medium in step (1) or the step (2) is THF, methylene dichloride, toluene, N, one or more in dinethylformamide, acetonitrile, acetone, chloroform, pyridine, tetracol phenixin, Virahol, acetic anhydride, ether, isopropyl ether, methyl alcohol and the ethanol.
The mol ratio of compound I and compound I I is 1:2.2 in the step (1).
The described cyclizing agent of step (3) is POCl3, Vanadium Pentoxide in FLAKES or the vitriol oil.
1. step can adopt method and the condition of the conventional oxidizing reaction in this area to carry out preferred following condition: step temperature of reaction 1. is preferable to be-15～150 ℃, and better is 50～80 ℃; Reaction times preferable with detection reaction fully till, be generally 2～22 h, that better is 6～10 h.Described organic solvent is conventional ability dissolved compound I that uses in this area and the solvent of compound I I; That preferable is THF, methylene dichloride, toluene, N; In dinethylformamide, acetonitrile, acetone, chloroform, pyridine, tetracol phenixin, Virahol, acetic anhydride, ether, isopropyl ether, methyl alcohol and the ethanol one or more; Preferred THF, acetic anhydride, acetonitrile, N, dinethylformamide; The consumption of solvent is 1～10 times of compound I, and better is 5～6 times (the ratio here is the volume mass ratio).
2. step is ring-closing condensation reaction, preferred following condition: compound III is carried out ring-closing condensation reaction under the effect of dewatering agent, and what the temperature of reaction was preferable is 20～150 ℃, and better is 50～70 ℃; The time of reaction is preferable be (with detection reaction complete till), is generally 2～24h, preferred 15～20h.Described organic solvent is the solvent of the conventional ability dissolved compound III that uses in this area; That preferable is THF, methylene dichloride, toluene, acetone, chloroform, tetracol phenixin, pyridine, acetonitrile, methyl alcohol and N; In the dinethylformamide one or more, preferred acetonitrile, methyl alcohol; The consumption of solvent is 3～10 times of compound I, and better is 3～5 times.Dewatering agent is the vitriol oil, acetic anhydride, Vanadium Pentoxide in FLAKES, POCl3, and preferable is POCl3.
But each the optimum condition arbitrary combination among the preparation method of the present invention promptly gets each preferred embodiment of the present invention.
Reagent that the present invention is used and raw material are all commercially available to be got.
Beneficial effect of the present invention has been to provide a kind of that preparation method for the Buddhist nun of new promise, and that replaces Buddhist nun's yield of product the obvious improved promise of this method ability, reduces production costs.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Embodiment 1: (E)-preparation of N-(4-((E)-3-(3-chloro-4-(pyridine-2-base-methoxyl group) aniline)-2-itrile group-3-acrylic amide)-2-oxyethyl group)-4-(n n dimetylaniline) but-2-enamides (compound III).
In the 500ml there-necked flask, add 25 gram triethyl orthoformates and 5 and digest compound II (16.7mmol), stir, be heated to 55 ℃, add the 40mL acetic anhydride, be heated to 100 ℃, reaction at least 4 h.Be cooled to 70-75 ℃, add the aqueous isopropanol 60mL contain compound I 5.3 grams (16.7 mmol), continue to be cooled to room temperature, add 100ml water, ethyl acetate extraction twice, each 30mL 70-75 ℃ of stirring reaction 3 hours.Organic phase is used the saturated nacl aqueous solution washed twice, and anhydrous sodium sulfate drying 2h, elimination siccative, resistates are dissolved in acetonitrile (50mL), obtains white solid 5.7 g, yield: 58.53%.
MS(+1):575。
1HNMR：δ?(ppm，CDCl
3)，8.65-8.67(d，1H)，?8.05-8.09?(q，1H)，8.01?(br,?2H?),?7.89-7.91?(d，1H)，7.75-7.78(d，1H)，7.54-7.56?(s，1H)，7.40-7.43?(m，2H)，?7.28-7.29?(d，1H)，6.69(s，1H)，6.75-6.78?(m，1H)，6.38-6.39?(d，1H),?6.12-6.14?(m，2H)，5.53(s，2H)，?4.02(brs，1H)，3.96-3.98?(q，2H)，?3.04-3.06(d，2H)，2.28-2.29?(d，6H)，1.35-1.37?(t，3H)。
Embodiment 2: the preparation of chemistry (2E)-N-[4-[[3-chloro-4-[(pyridine-2-yl) methoxyl group] phenyl] amino]-3-cyanic acid-7-ethoxyquinoline-6-yl] by name-4-(dimethyl amido) but-2-enamides (compound TM, that replaces the Buddhist nun promise)
In the 250ml there-necked flask, add compound III 5.7 gram (10mmol), 60mL acetonitriles.2mL methyl alcohol, nitrogen protection is stirred, and is heated to 60-65 ℃, and (100mmol 9.8mL), continues to be cooled to 0 ℃ at 60-65 ℃ of reaction 18h, adds water 40 mL, uses ammoniacal liquor to regulate the pH value to 8-10 to drip POCl3 15.5 grams., separate out solid, filter, (3 * 10mL), the solid of acquisition obtains off-white color solid 4.6 g, yield: 82.73% 60 ℃ of vacuum-dryings to filter cake with water washing.
MS（+1）：557。
1HNMR：δ?(ppm，CDCl
3)，9.05.?-9.06(s，1H)，865-8.67?(d，1H)，8.05-8.07?(q，1H?)，8.01?(br,?2H?),7.75-7.78(d，1H)，7.54-7.56?(s，1H)，7.40-7.43?(t，1H)，?7.13-7.15?(s，1H)，6.75-6.78(m，1H)，6.72?(s，1H)，6.46-6.47?(t，1H),?6.36?(s，1H)，6.23?(d，1H)，5.53(s，2H)，?4.02(brs，1H)，3.96-3.98?(q，2H)，?3.04-3.06(d，2H)，2.28-2.29?(d，6H)，1.33-1.35?(t，3H)。
Embodiment 3: (E)-preparation of N-(4-((E)-3-(3-chloro-4-(pyridine-2-base-methoxyl group) aniline)-2-itrile group-3-acrylic amide)-2-oxyethyl group)-4-(n n dimetylaniline) but-2-enamides (compound III).
In the 500ml there-necked flask, add the aqueous isopropanol 60mL that compound I 5.3 grams (16.7mmol), 5 digest compound II (16.7 mmol), stir, be heated to 55 ℃, be heated to 70 ℃, 10 gram triethyl orthoformates and reaction at least 4 h.Be heated to 95-100 ℃, reaction 2h adds 10 gram triethyl orthoformates, continues to add 5 gram triethyl orthoformates 95-100 ℃ of stirring reaction 2 hours, continues reaction 10h, and cooling is only to 10 ℃.Separate out solid, suction filtration, filtrating is with the cold isopropanol washing, and the solid of acquisition obtains white solid 6.3g, yield 60 ℃ of vacuum-dryings: 64.69 %.
1HNMR：δ?(ppm，CDCl
3)，8.65-8.67(d，1H)，?8.05-8.09?(q，1H)，8.01?(br,?2H?),?7.89-7.91?(d，1H)，7.75-7.78(d，1H)，7.54-7.56?(s，1H)，7.40-7.43?(m，2H)，?7.28-7.29?(d，1H)，6.69(s，1H)，6.75-6.78?(m，1H)，6.38-6.39?(d，1H),?6.12-6.14?(m，2H)，5.53(s，2H)，?4.02(brs，1H)，3.96-3.98?(q，2H)，?3.04-3.06(d，2H)，2.28-2.29?(d，6H)，1.35-1.37?(t，3H)。
Embodiment 4:The preparation of chemistry (2E)-N-[4-[[3-chloro-4-[(pyridine-2-yl) methoxyl group] phenyl] amino]-3-cyanic acid-7-ethoxyquinoline-6-yl] by name-4-(dimethyl amido) but-2-enamides (compound TM, that replaces the Buddhist nun promise)
In the 250ml there-necked flask, adding compound III 5.7 grams (10mmol),, Vanadium Pentoxide in FLAKES 14.2 grams (100mmol), 70mL acetonitrile.5mL methyl alcohol, nitrogen protection is stirred, and is heated to 60-65 ℃ of reaction 18h, is cooled to 0 ℃, adds water 40 mL, uses ammoniacal liquor to regulate the pH value to 8-10., separate out solid, filter, (3 * 10mL), the solid of acquisition obtains off-white color solid 3.2 g, yield: 57.53% 60 ℃ of vacuum-dryings to filter cake with water washing.
1HNMR：δ?(ppm，CDCl
3)，9.05.?-9.06(s，1H)，865-8.67?(d，1H)，8.05-8.07?(q，1H?)，8.01?(br,?2H?),7.75-7.78(d，1H)，7.54-7.56?(s，1H)，7.40-7.43?(t，1H)，?7.13-7.15?(s，1H)，6.75-6.78(m，1H)，6.72?(s，1H)，6.46-6.47?(t，1H),?6.36?(s，1H)，6.23?(d，1H)，5.53(s，2H)，?4.02(brs，1H)，3.96-3.98?(q，2H)，?3.04-3.06(d，2H)，2.28-2.29?(d，6H)，1.33-1.35?(t，3H)。
Embodiment 5:The preparation of chemistry (2E)-N-[4-[[3-chloro-4-[(pyridine-2-yl) methoxyl group] phenyl] amino]-3-cyanic acid-7-ethoxyquinoline-6-yl] by name-4-(dimethyl amido) but-2-enamides (compound TM, that replaces the Buddhist nun promise)
In the 250ml there-necked flask, add compound III 5.7 grams (10mmol), the vitriol oil 9.8 grams (100mmol), the 60mL acetonitrile.3mL methyl alcohol, nitrogen protection is stirred, and is heated to 60-65 ℃ of reaction 18h, is cooled to 0 ℃, adds water 40 mL, uses 10% sodium hydroxide to regulate the pH value to 8-10., separate out solid, filter, (3 * 10mL), the solid of acquisition obtains off-white color solid 3.6g, yield: 64.72% 60 ℃ of vacuum-dryings to filter cake with water washing.
1HNMR：δ?(ppm，CDCl
3)，9.05.?-9.06(s，1H)，865-8.67?(d，1H)，8.05-8.07?(q，1H?)，8.01?(br,?2H?),7.75-7.78(d，1H)，7.54-7.56?(s，1H)，7.40-7.43?(t，1H)，?7.13-7.15?(s，1H)，6.75-6.78(m，1H)，6.72?(s，1H)，6.46-6.47?(t，1H),?6.36?(s，1H)，6.23?(d，1H)，5.53(s，2H)，?4.02(brs，1H)，3.96-3.98?(q，2H)，?3.04-3.06(d，2H)，2.28-2.29?(d，6H)，1.33-1.35?(t，3H)。
Claims (5)
- The antitumor drug promise that for preparation method of Buddhist nun, it comprises following steps:(1) compound I, compound I I and triethyl orthoformate reaction obtain intermediate III;(2) compound III that makes of step (1) under the effect of cyclization reagent through cyclization obtain promise that for the Buddhist nun;。
- 2. preparation method according to claim 1 is characterized in that, the temperature of reaction of step (1) or step (2) is-50～150 ℃.
- 3. preparation method according to claim 1; It is characterized in that; Reaction medium in step (1) or the step (2) is THF, methylene dichloride, toluene, N, one or more in dinethylformamide, acetonitrile, acetone, chloroform, pyridine, tetracol phenixin, Virahol, acetic anhydride, ether, isopropyl ether, methyl alcohol and the ethanol.
- 4. preparation method according to claim 1 is characterized in that, the mol ratio of compound I and compound I I is 1:2.2 in the step (1).
- 5. preparation method according to claim 1 is characterized in that, the described cyclizing agent of step (3) is POCl3, Vanadium Pentoxide in FLAKES or the vitriol oil.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103788067A (en) * | 2014-01-14 | 2014-05-14 | 北京万全德众医药生物技术有限公司 | Preparation method of 3-[3-ethoxy-4-(N-phthaloyl)]phenylamino-N-[3-chloro-4-(2-pyridylmethoxyl]phenyl-2-cyano-2-acrylamide |
| CN106831710A (en) * | 2015-12-07 | 2017-06-13 | 常州爱诺新睿医药技术有限公司 | A kind of solid dispersions of unformed HKI-272 or its pharmaceutically acceptable salt and pharmaceutic adjuvant and preparation method thereof |
| CN113135852A (en) * | 2021-04-30 | 2021-07-20 | 中国科学院长春应用化学研究所 | Preparation method of 4-aminoquinoline compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101180269A (en) * | 2005-05-25 | 2008-05-14 | 惠氏公司 | Method of preparing 3-cyano-quinolines and intermediates made thereby |
| CN101203494A (en) * | 2005-05-25 | 2008-06-18 | 惠氏公司 | Methods of synthesizing substituted 3-cyanoquinolines and intermediates thereof |
-
2011
- 2011-03-30 CN CN2011100787140A patent/CN102718749A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101180269A (en) * | 2005-05-25 | 2008-05-14 | 惠氏公司 | Method of preparing 3-cyano-quinolines and intermediates made thereby |
| CN101203494A (en) * | 2005-05-25 | 2008-06-18 | 惠氏公司 | Methods of synthesizing substituted 3-cyanoquinolines and intermediates thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103788067A (en) * | 2014-01-14 | 2014-05-14 | 北京万全德众医药生物技术有限公司 | Preparation method of 3-[3-ethoxy-4-(N-phthaloyl)]phenylamino-N-[3-chloro-4-(2-pyridylmethoxyl]phenyl-2-cyano-2-acrylamide |
| CN106831710A (en) * | 2015-12-07 | 2017-06-13 | 常州爱诺新睿医药技术有限公司 | A kind of solid dispersions of unformed HKI-272 or its pharmaceutically acceptable salt and pharmaceutic adjuvant and preparation method thereof |
| CN113135852A (en) * | 2021-04-30 | 2021-07-20 | 中国科学院长春应用化学研究所 | Preparation method of 4-aminoquinoline compound |
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Application publication date: 20121010 |