CN102260210B - Preparation method of naphthoyl amine derivatives of protein kinase inhibitor and histone deacetylase inhibitor - Google Patents
Preparation method of naphthoyl amine derivatives of protein kinase inhibitor and histone deacetylase inhibitor Download PDFInfo
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Abstract
The invention discloses naphthoyl amine derivatives of protein kinase inhibitor and histone deacetylase inhibitor (N-(2-anilino)-6-(7-substituent quinolyl-4- ether oxy)-2-naphthoyl amine), the structure of which is disclosed as Formula [I] (the 7th position has a substituent group R=F, Cl, Br, I, OCH3, 4-morpholinyl oxyethyl group, 4-morpholinyl methoxyphenyl group, acrylamino group, 2-acryloylamino group). The naphthoyl amine derivatives can treat cardiovascular diseases, metabolic disease, allergy, cancers and hormone-related diseases. The synthesis method of the compounds [I] has the advantage of accessible raw materials, is simple to operate, and is suitable for large-scale industrial production.
Description
Technical field:
The present invention relates to the preparation method of medicine.Be specifically related to the preparation method of the naphthalene amino acid verivate of a kind of kinases inhibitor and NSC 630176.
Background technology:
The naphthalene amino acid verivate of kinases inhibitor and NSC 630176 has treatment and comprises cardiovascular disorder, metabolic disease, allergy, cancer, reaches and the hormone diseases associated.The chemistry of this patent compound I is by name: (7-substd quinolines-4-ether oxygen base)-(7 have substituent R=F to the 2-naphthalene amino acid to N-(2-anilino)-6-, Cl, Br, I, OCH
3, 4-morpholinyl oxyethyl group, 4-morpholinyl methyl phenyl, acrylamido, the rare acid amides of 2-fourth), structural formula is following:
A large amount of clinical trials show that this compounds has protein kinase inhibiting activity simultaneously and histon deacetylase (HDAC) suppresses active; Can be used to treat unusual or the active unusual relevant disease of histon deacetylase (HDAC), comprise inflammation, autoimmune disorder, cancer, nervous system disorders and neurodegenerative disorders, cardiovascular disorder, metabolic disease, allergy, asthma and and hormone-related diseases with protein kinase activity.
International monopoly WO2010139180A1 discloses the compound method of structure of the naphthalene amino acid verivate of some kinases inhibitors and NSC 630176; But the compound structure that does not relate to this patent, the structural formula of this patent are brand-new structure.
Summary of the invention:
The invention provides the preparation method of the naphthalene amino acid verivate of a kind of kinases inhibitor and NSC 630176, its method may further comprise the steps:
A) with formula II compound and formula III compound (R=F, Cl, Br, I, OCH
3, 4-morpholinyl oxyethyl group, 4-morpholinyl methyl phenyl, acrylamido, the rare acid amides of 2-fourth) and reaction:
Formula II compound 1.0 equivalents are dissolved among 10 milliliters of DMF (N, dinethylformamide), and ice bath stirs down, slowly drip the DMF (N that contains 2.5 equivalent NaH (sodium hydride); Dinethylformamide) solution is 5 milliliters, and ice bath stirs half a hour, removes ice bath; Treat that temperature returns to room temperature (25 ℃), slowly splash into to contain compound III (R=F, Cl; Br, I, OCH
3, 4-morpholinyl oxyethyl group, 4-morpholinyl methyl phenyl; Acrylamido, the rare acid amides of 2-fourth) DMF (N, dinethylformamide) solution stirs half a hour for 5 milliliters; 110 ℃ were reacted 6-10 hour down, after the TLC detection reaction is complete, reaction solution were poured in the frozen water; Hydrochloric acid with 5% is regulated about PH=6.5, separates out yellow solid and is formula IV compound;
B) with the formula IV compound (R=F, Cl, Br, I, the OCH that obtain
3, 4-morpholinyl oxyethyl group, 4-morpholinyl methyl phenyl, acrylamido, the rare acid amides of 2-fourth) and carry out acylation reaction:
Formula IV compound (R=F, Cl, Br, I, OCH
3, 4-morpholinyl oxyethyl group, 4-morpholinyl methyl phenyl, acrylamido, the rare acid amides of 2-fourth) and 1.0 equivalents are dissolved in the normal SOCl of 2-5
2In (sulfur oxychloride), backflow 5-7 hour, sulfur oxychloride was removed in underpressure distillation, obtains formula V compound (R=F, Cl, Br, I, OCH
3, 4-morpholinyl oxyethyl group, 4-morpholinyl methyl phenyl, acrylamido, the rare acid amides of 2-fourth);
C) with the formula V compound (R=F, Cl, Br, I, the OCH that obtain
3, 4-morpholinyl oxyethyl group, 4-morpholinyl methyl phenyl, acrylamido, the rare acid amides of 2-fourth) react with O-Phenylene Diamine:
Formula V compound (R=F, Cl, Br, I, OCH
3, 4-morpholinyl oxyethyl group, 4-morpholinyl methyl phenyl, acrylamido; The rare acid amides of 2-fourth) 1.0 equivalents are dissolved in 20 milliliters of THFs, add 1.0 normal O-Phenylene Diamines, stir half a hour, and ice bath drips triethylamine solution 2.0 equivalents that contain 5 milliliters of THFs down; 25 ℃-50 ℃ were reacted 6-8 hour, and TLC detects, and after reacting completely, suction filtration is removed most of salt; Underpressure distillation, solid matter adds 80 milliliters of entry with 50 milliliters of acetic acid ethyl dissolutions, and extracted twice merges organic phase; Anhydrous sodium sulfate drying, underpressure distillation gets bullion, obtains formula I compound with the methylene chloride recrystallization.
Wherein said compound IV (R=F, Cl, Br, I, OCH
3, 4-morpholinyl oxyethyl group, 4-morpholinyl methyl phenyl, acrylamido, the rare acid amides of 2-fourth) prepare through following method: formula II compound 1.0 equivalents are dissolved in 10 milliliters of DMF (N; Dinethylformamide) in, ice bath stirs down, slowly drips 5 milliliters of DMF (N, dinethylformamide) solution that contain 2.5 equivalent NaH (sodium hydride); Ice bath stirs half a hour, removes ice bath, treats that temperature returns to room temperature, slowly drips and contains compound III (R=F; Cl, Br, I, OCH
3, 4-morpholinyl oxyethyl group, 4-morpholinyl methyl phenyl; Acrylamido, the rare acid amides of 2-fourth) DMF (N, dinethylformamide) solution stirs half a hour for 5 milliliters; 110 ℃ were reacted 6-10 hour down, after the TLC detection reaction is complete, reaction solution were poured in the frozen water; Hydrochloric acid with 5% is regulated about PH=6.5, separates out yellow solid and is compound IV;
Wherein said compound V (R=F, Cl, Br, I, OCH
3, 4-morpholinyl oxyethyl group, 4-morpholinyl methyl phenyl, acrylamido, the rare acid amides of 2-fourth) prepare through following method: formula IV compound 1.0 equivalents are dissolved in the normal SOCl of 2-5
2In (sulfur oxychloride), backflow 5-7 hour, sulfur oxychloride was removed in underpressure distillation, obtains formula V compound;
Wherein said compound I (R=F, Cl, Br, I, OCH
3, 4-morpholinyl oxyethyl group, 4-morpholinyl methyl phenyl, acrylamido, the rare acid amides of 2-fourth) prepare through following method: formula V compound (R=F, Cl, Br, I, OCH
3, 4-morpholinyl oxyethyl group, 4-morpholinyl methyl phenyl, acrylamido; The rare acid amides of 2-fourth) 1.0 equivalents are dissolved in 20 milliliters of THFs, add 1.0 normal O-Phenylene Diamines, stir half a hour, and ice bath drips triethylamine solution 2.0 equivalents that contain 5 milliliters of THFs down; 25 ℃-50 ℃ were reacted 6-8 hour, and TLC detects, and after reacting completely, suction filtration is removed most of salt; Underpressure distillation, solid matter adds 80 milliliters of entry with 50 milliliters of acetic acid ethyl dissolutions, and the each 50ml extracted twice of ETHYLE ACETATE merges organic phase; Anhydrous sodium sulfate drying, underpressure distillation gets bullion, with methylene chloride recrystallization material I;
Preparing method of the present invention is simple, and raw material is easy to get, low price.The inventive method is easy and simple to handle, and reaction efficiency is high, is easy to carry out suitability for industrialized production.
Embodiment:
Embodiment 1: the naphthalene amino acid verivate---the preparation (wherein R=Cl) of formula I compound
Formula II compound 1.0 equivalents are dissolved among 10 milliliters of DMF (N, dinethylformamide), and ice bath stirs down; Slowly drip 5 milliliters of DMF (N, dinethylformamide) solution that contain 2.5 equivalent NaH (sodium hydride), ice bath stirs half a hour; Remove ice bath, treat that temperature returns to room temperature (25 ℃), slowly splashes into the DMF (N that contains compound III (R=Cl); Dinethylformamide) solution stirs half a hour for 5 milliliters, and 110 ℃ were reacted 6-10 hour down, after the TLC detection reaction is complete; Reaction solution is poured in the frozen water, and the hydrochloric acid with 5% is regulated about pH=6.5, separates out yellow solid and is formula IV compound;
Formula IV compound (R=Cl) 1.0 equivalents are dissolved in the normal SOCl of 2-5
2In (sulfur oxychloride), backflow 5-7 hour, sulfur oxychloride was removed in underpressure distillation, obtains formula V compound (R=Cl);
Formula V compound (R=Cl) 1.0 equivalents are dissolved in 20 milliliters of THFs, add 1.0 normal O-Phenylene Diamines, stir half a hour; Ice bath drips triethylamine solution 2.0 equivalents that contain 5 milliliters of THFs down, and 25 ℃-50 ℃ were reacted 6-8 hour, and TLC detects; After reacting completely, suction filtration is removed most of salt, underpressure distillation; Solid matter adds 80 milliliters of entry with 50 milliliters of acetic acid ethyl dissolutions, and the each 50ml extracted twice of ETHYLE ACETATE merges organic phase; Anhydrous sodium sulfate drying, underpressure distillation gets bullion, obtains formula I compound with the methylene chloride recrystallization.
Embodiment 2: the naphthalene amino acid verivate---the preparation of formula I compound (R=OCH wherein
3)
Formula II compound 1.0 equivalents are dissolved among 10 milliliters of DMF (N, dinethylformamide), and ice bath stirs down; Slowly drip the DMF (N that contains 2.5 equivalent NaH (sodium hydride); Dinethylformamide) solution is 5 milliliters, and ice bath stirs half a hour, removes ice bath; Treat that temperature returns to room temperature (25 ℃), slowly splashes into and contains compound III (R=OCH
3) 5 milliliters of DMF (N, dinethylformamide) solution stir half a hour, 110 ℃ of reactions 6-10 hour down, the TLC detection reaction fully after, reaction solution is poured in the frozen water, with about 5% hydrochloric acid adjusting pH=6.5, separate out yellow solid and be formula IV compound;
Formula IV compound (R=OCH
3) 1.0 equivalents are dissolved in the normal SOCl of 2-5
2In (sulfur oxychloride), backflow 5-7 hour, sulfur oxychloride was removed in underpressure distillation, obtains formula V compound (R=OCH
3);
Formula V compound (R=OCH
3) 1.0 equivalents are dissolved in 20 milliliters of THFs, add 1.0 normal O-Phenylene Diamines, stir half a hour; Ice bath drips triethylamine solution 2.0 equivalents that contain 5 milliliters of THFs down, and 25 ℃-50 ℃ were reacted 6-8 hour, and TLC detects; After reacting completely, suction filtration is removed most of salt, underpressure distillation; Solid matter adds 80 milliliters of entry with 50 milliliters of acetic acid ethyl dissolutions, and the each 50ml extracted twice of ETHYLE ACETATE merges organic phase; Anhydrous sodium sulfate drying, underpressure distillation gets bullion, obtains formula I compound with the methylene chloride recrystallization.
Embodiment 3: the naphthalene amino acid verivate---the preparation (wherein R=Br) of formula I compound
Formula II compound 1.0 equivalents are dissolved among 10 milliliters of DMF (N, dinethylformamide), and ice bath stirs down; Slowly drip 5 milliliters of DMF (N, dinethylformamide) solution that contain 2.5 equivalent NaH (sodium hydride), ice bath stirs half a hour; Remove ice bath, treat that temperature returns to room temperature (25 ℃), slowly splashes into the DMF (N that contains compound III (R=Br); Dinethylformamide) solution stirs half a hour for 5 milliliters, and 110 ℃ were reacted 6-10 hour down, after the TLC detection reaction is complete; Reaction solution is poured in the frozen water, and the hydrochloric acid with 5% is regulated about pH=6.5, separates out yellow solid and is formula IV compound;
Formula IV compound (R=Br) 1.0 equivalents are dissolved in the normal SOCl of 2-5
2In (sulfur oxychloride), backflow 5-7 hour, sulfur oxychloride was removed in underpressure distillation, obtains formula V compound (R=Br);
Formula V compound (R=Br) 1.0 equivalents are dissolved in 20 milliliters of THFs, add 1.0 normal O-Phenylene Diamines, stir half a hour; Ice bath drips triethylamine solution 2.0 equivalents that contain 5 milliliters of THFs down, and 25 ℃-50 ℃ were reacted 6-8 hour, and TLC detects; After reacting completely, suction filtration is removed most of salt, underpressure distillation; Solid matter adds 80 milliliters of entry with 50 milliliters of acetic acid ethyl dissolutions, and the each 50ml extracted twice of ETHYLE ACETATE merges organic phase; Anhydrous sodium sulfate drying, underpressure distillation gets bullion, obtains formula I compound with the methylene chloride recrystallization.
Embodiment 3: the naphthalene amino acid verivate---the preparation (wherein R=acrylamido) of formula I compound
Formula II compound 1.0 equivalents are dissolved among 10 milliliters of DMF (N, dinethylformamide), and ice bath stirs down; Slowly drip 5 milliliters of DMF (N, dinethylformamide) solution that contain 2.5 equivalent NaH (sodium hydride), ice bath stirs half a hour; Remove ice bath, treat that temperature returns to room temperature (25 ℃), slowly splashes into the DMF (N that contains compound III (R=acrylamido); Dinethylformamide) solution stirs half a hour for 5 milliliters, and 110 ℃ were reacted 6-10 hour down, after the TLC detection reaction is complete; Reaction solution is poured in the frozen water, and the hydrochloric acid with 5% is regulated about pH=6.5, separates out yellow solid and is formula IV compound;
Formula IV compound (R=acrylamido) 1.0 equivalents are dissolved in the normal SOCl of 2-5
2In (sulfur oxychloride), backflow 5-7 hour, sulfur oxychloride was removed in underpressure distillation, obtains formula V compound (R=acrylamido);
Formula V compound (R=acrylamido) 1.0 equivalents are dissolved in 20 milliliters of THFs, add 1.0 normal O-Phenylene Diamines, stir half a hour; Ice bath drips triethylamine solution 2.0 equivalents that contain 5 milliliters of THFs down, and 25 ℃-50 ℃ were reacted 6-8 hour, and TLC detects; After reacting completely, suction filtration is removed most of salt, underpressure distillation; Solid matter adds 80 milliliters of entry with 50 milliliters of acetic acid ethyl dissolutions, and the each 50ml extracted twice of ETHYLE ACETATE merges organic phase; Anhydrous sodium sulfate drying, underpressure distillation gets bullion, obtains formula I compound with the methylene chloride recrystallization.
Embodiment 4: the naphthalene amino acid verivate---the preparation (wherein R=4-morpholinyl oxyethyl group) of formula I compound
Formula II compound 1.0 equivalents are dissolved among 10 milliliters of DMF (N, dinethylformamide), and ice bath stirs down; Slowly drip 5 milliliters of DMF (N, dinethylformamide) solution that contain 2.5 equivalent NaH (sodium hydride), ice bath stirs half a hour; Remove ice bath, treat that temperature returns to room temperature (25 ℃), slowly splashes into the DMF (N that contains compound III (R=4-morpholinyl oxyethyl group); Dinethylformamide) solution stirs half a hour for 5 milliliters, and 110 ℃ were reacted 6-10 hour down, after the TLC detection reaction is complete; Reaction solution is poured in the frozen water, and the hydrochloric acid with 5% is regulated about pH=6.5, separates out yellow solid and is formula IV compound;
Formula IV compound (R=4-morpholinyl oxyethyl group) 1.0 equivalents are dissolved in the normal SOCl of 2-5
2In (sulfur oxychloride), backflow 5-7 hour, sulfur oxychloride was removed in underpressure distillation, obtains formula V (R=4-morpholinyl oxyethyl group);
Formula V compound (R=4-morpholinyl oxyethyl group) 1.0 equivalents are dissolved in 20 milliliters of THFs, add 1.0 normal O-Phenylene Diamines, stir half a hour; Ice bath drips triethylamine solution 2.0 equivalents that contain 5 milliliters of THFs down, and 25 ℃-50 ℃ were reacted 6-8 hour, and TLC detects; After reacting completely, suction filtration is removed most of salt, underpressure distillation; Solid matter adds 80 milliliters of entry with 50 milliliters of acetic acid ethyl dissolutions, and the each 50ml extracted twice of ETHYLE ACETATE merges organic phase; Anhydrous sodium sulfate drying, underpressure distillation gets bullion, obtains formula I compound with the methylene chloride recrystallization.
" reflux " means the boiling point that reacting liquid temperature is risen to solvent among [notes] 1, this paper.
2, " ice bath " means and cools the temperature to about 0 ℃ among this paper.
Claims (1)
1. the preparation method of the naphthalene amino acid verivate of kinases inhibitor and NSC 630176 is characterized in that this method may further comprise the steps:
(a) with formula II compound and the reaction of formula III compound:
Formula II compound 1.0 equivalents are dissolved in 10 milliliters of N, and in the dinethylformamide, ice bath stirs down; Slowly drip the N that contains 2.5 equivalent NaH, 5 milliliters of dinethylformamide solution, ice bath stirs half a hour; Remove ice bath, treat that temperature returns to 25 ℃, slowly splashes into the N that contains the formula III compound; Dinethylformamide solution stirs half a hour for 5 milliliters, and 110 ℃ were reacted 6-10 hour down, after the TLC detection reaction is complete; Reaction solution is poured in the frozen water, regulated about pH=6.5, separate out yellow solid and be formula IV compound with 5% hydrochloric acid
(b) the formula IV compound that obtains is carried out acylation reaction:
Formula IV compound 1.0 equivalents are dissolved in the normal sulfur oxychloride of 2-5, and backflow 5-7 hour, sulfur oxychloride was removed in underpressure distillation, obtains formula V compound
(c) formula V compound that obtains and formula VI O-Phenylene Diamine are reacted:
Formula V compound 1.0 equivalents are dissolved in 20 milliliters of THFs, add 1.0 normal formula VI O-Phenylene Diamines, stir half a hour; Ice bath drips triethylamine solution 2.0 equivalents that contain 5 milliliters of THFs down, and 25 ℃-50 ℃ were reacted 6-8 hour, and TLC detects; After reacting completely, suction filtration is removed inorganic salt, underpressure distillation; Solid matter adds 80 milliliters of entry with 50 milliliters of acetic acid ethyl dissolutions, and the each 50ml extracted twice of ETHYLE ACETATE merges organic phase; Anhydrous sodium sulfate drying, underpressure distillation gets bullion, with obtaining formula I compound N-(2-anilino)-6-(7-substd quinolines-4-ether oxygen base)-2-naphthalene amino acid behind the methylene chloride recrystallization
Wherein the substituent R in formula III compound, formula IV compound, formula V compound, the formula I compound can be F, Cl, Br, I, OCH
3, in the 4-morpholinyl oxyethyl group, 4-morpholinyl methyl phenyl, acrylamido, 2-butylene acid amides any one.
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| CN102603627B (en) * | 2011-05-31 | 2013-02-06 | 王立强 | Naphthlamide derivative used as protein kinase inhibitor and histone deacetylase inhibitor and preparation method of naphthlamide derivative |
| CN102775389B (en) * | 2012-04-05 | 2014-12-17 | 华侨大学 | Preparation method of N-substituted-4-(7-chloro-quinoline -4-amino)-benzamide derivatives, and application thereof |
| CN103288728A (en) * | 2013-05-17 | 2013-09-11 | 华侨大学 | Naphthoyl amine derivative, and preparation method and application thereof |
| CN103351336A (en) * | 2013-06-28 | 2013-10-16 | 华侨大学 | Naphthalenecarboxamide derivative as inhibitors of protein kinase and histone deacetylase and preparation method thereof |
| CN104447534A (en) * | 2014-12-04 | 2015-03-25 | 厦门大学 | 6-[(7-chloroquinoline-4-oxyl) phenolic ether]-2-naphthamide derivative as well as preparation method and application thereof |
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| CN1933839A (en) * | 2004-01-23 | 2007-03-21 | 安进公司 | Compounds and methods of use |
| CN101906076A (en) * | 2009-06-04 | 2010-12-08 | 深圳微芯生物科技有限责任公司 | Naphthaline amide derivative serving as protein kinase inhibitor and histone deacetylase inhibitor and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1933839A (en) * | 2004-01-23 | 2007-03-21 | 安进公司 | Compounds and methods of use |
| CN101906076A (en) * | 2009-06-04 | 2010-12-08 | 深圳微芯生物科技有限责任公司 | Naphthaline amide derivative serving as protein kinase inhibitor and histone deacetylase inhibitor and preparation method and application thereof |
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