CN103145709A - Synthesis process for 4-chloro-1,6-naphthyridine - Google Patents
Synthesis process for 4-chloro-1,6-naphthyridine Download PDFInfo
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- CN103145709A CN103145709A CN2013101258266A CN201310125826A CN103145709A CN 103145709 A CN103145709 A CN 103145709A CN 2013101258266 A CN2013101258266 A CN 2013101258266A CN 201310125826 A CN201310125826 A CN 201310125826A CN 103145709 A CN103145709 A CN 103145709A
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Abstract
The invention discloses a novel synthesis process for 4-chloro-1,6-naphthyridine. The novel synthesis process for the 4-chloro-1,6-naphthyridine comprises the following steps of: performing a condensation reaction by taking Meldrum's acid as a starting raw material; then, performing high-temperature cyclization to obtain a key intermediate: 5,7-dichloro-1,6-naphthyridine-4(1H)-ketone; then, performing catalytic hydrogenation dechloridation; and chloridizing to obtain the 4-chloro-1,6-naphthyridine. The novel synthesis process for the 4-chloro-1,6-naphthyridine is mild and simple in reaction condition, low in cost, high in yield and easy and simple in operation, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of 4-chloro-1, the new synthesis process of 6-naphthyridines belongs to medicine, chemical technology field.
Background technology
Naphthyridines and derivative thereof are widely used in field of medicaments, have good anti-tumor activity (WO2007113565; EP1724268).
The synthetic method of bibliographical information has as follows:
Route A (WO20042992; Synlett2007,14,2205-2208; JOC1971,36,1720; JCS1960,1790-1793)
Route B (Justus Liebigs Annalen der Chemie1958,612,153-157)
Route C (EP1724268)
In route A, the second step reaction needed is used Dowtherm A, reaction high temperature (600 ℃), and reaction product is complicated, and productive rate is low, and poor reproducibility as a result.
In route B, raw material is not easy to obtain, depickling reaction needed high temperature, and productive rate is on the low side.
In route C, through attempting discovery, during the dechlorination of second step catalytic hydrogenation, use 20%Pd (OH)
2Make catalyzer, solvent is DMF, and product is complicated; The 3rd one-step chlorination reaction adds diisopropylethylamine, and productive rate is extremely low, almost can not get product.
Comprehensive more above-mentioned three routes, reaction needed high temperature, wayward, productive rate is low, and starting raw material is difficult for preparation, can't repeat.
Summary of the invention
The present invention seeks to a kind of new synthesis technique, optimize and improved operational path C and prepare 4-chloro-1, the 6-naphthyridines, the method productive rate is high, and reaction conditions is gentle, and good reproducibility is suitable for industrial production.
Reaction scheme is as follows:
4-chloro-1 of the present invention, the new synthesis process of 6-naphthyridines is at synthetic 5-((2,6-dichloropyridine-4-is amino) methylene radical)-2,2-dimethyl-1,3-dioxan-4, in 6-diketone (compound 3): the temperature of Michaelis acid and triethyl orthoformate generation condensation reaction is at 120 ℃; Then the gained intermediate is direct with 2 without separating, 6-dichloropyridine-4-amine condensation, and the temperature of reaction is at 70 to 75 ℃.
4-chloro-1 of the present invention, the new synthesis process of 6-naphthyridines is synthetic 5,7-two chloro-1, in 6-naphthyridines-4 (1H)-ketone (compound 4): the first step gained intermediate high temperature closes ring, and reaction solvent can be phenyl ether, can be also the mixture of the biphenyl-biphenyl ether such as Dowtherm A; Temperature of reaction is at 220 ℃.
4-chloro-1 of the present invention, the new synthesis process of 6-naphthyridines, in synthetic 1,6-naphthyridines-4 (1H)-ketone (compound 5): the catalyzer that the catalytic hydrogenation dechlorination is used, including but not limited to 10% palladium carbon, 5% palladium carbon, 20% palladium hydroxide and 10% palladium hydroxide etc.; Alkali used is including but not limited to triethylamine, diisopropylethylamine, sodium carbonate, salt of wormwood, sodium-acetate, Potassium ethanoate, sodium hydroxide and potassium hydroxide etc.; Reaction solvent is tetrahydrofuran (THF)-methyl alcohol, also can be DMF, methyl alcohol, tetrahydrofuran (THF), tetrahydrofuran-ethyl alcohol and ethanol etc.; Temperature of reaction is in room temperature.
4-chloro-1 of the present invention, the new synthesis process of 6-naphthyridines, at synthetic 4-chloro-1, in 6-naphthyridines (compound 6): chlorination reagent used is including but not limited to mixture of phosphorus oxychloride, phosphorus pentachloride, phosphorus oxychloride and phosphorus pentachloride etc.; Alkali used, including but not limited to triethylamine, diisopropylethylamine, DMA and N, N-Diethyl Aniline etc.; The temperature of reaction is at 100 to 105 ℃.
The present invention compared with prior art has following beneficial effect:
1, synthetic key intermediate 1,6-naphthyridines-4 (1H)-ketone adopt the dechlorination of palladium carbon catalytic hydrogenation to reduce cost, and product purity is high, need not purifying and is directly used in the next step; Solvents tetrahydrofurane-methyl alcohol is than DMF convenient post-treatment, and productive rate is high.
2, chlorination reaction has solved because adding diisopropylethylamine, and causes the problem that productive rate is extremely low, can't repeat, and has improved the purity of productive rate and product.
3, whole reaction scheme mild condition need not silica gel column chromatography and separates, and has shortened production process, is suitable for suitability for industrialized production.
Embodiment
Embodiment 1: synthetic 5-((2,6-dichloropyridine-4-is amino) methylene radical)-2,2-dimethyl-1,3-dioxan-4,6-diketone (compound 3)
Michaelis acid (20g, 0.14 mole) and triethyl orthoformate (144g, 0.97 mole) are heated to 120 ℃, stir 3 hours.Be chilled to 70 ℃, add 2,6-dichloropyridine-4-amine (20g, 0.12 mole), stirred 4 hours.Underpressure distillation, the residue washed with isopropyl alcohol, vacuum-drying gets compound (3) 35g, productive rate: 90.4%.
Embodiment 2: synthetic 5,7-, two chloro-1,6-naphthyridines-4 (1H)-ketone (compound 4)
Compound 3 (35g, 0.11 mole) and biphenyl (100g) are suspended in phenyl ether (400 milliliters), are heated to 220 ℃, stir 2 hours.Cool to room temperature, suction filtration, the filter cake washed with dichloromethane gets gray solid compound (4) 18.5g, productive rate: 74.1%.
Embodiment 3: synthetic 1,6-naphthyridines-4 (1H)-ketone (compound 5)
Compound 4 (18.5g, 0.086 mole), 10% palladium carbon (5g) and triethylamine (50 milliliters) are dissolved in tetrahydrofuran (THF) (200 milliliters) and methyl alcohol (200 milliliters), under nitrogen atmosphere, and stirring at room 3 hours.Suction filtration concentrates to get white solid compound (5) 12.4g, productive rate: 98.7%.
Embodiment 4: synthetic 4-chloro-1,6-naphthyridines (compound 6)
Compound 5 (12.4g, 0.085 mole) and phosphorus oxychloride (50 milliliters) are heated to 100 ℃, stirred 4 hours, and then underpressure distillation, residue is neutralized to weakly alkaline with saturated sodium bicarbonate solution, ethyl acetate extraction.Organic phase is dry, concentrated, gets off-white color solid 4-chloro-1,6-naphthyridines 10g, productive rate: 71.4%.
Claims (5)
1. the present invention discloses a kind of 4-chloro-1, the new synthesis process of 6-naphthyridines, contain following steps: (1) Michaelis acid, 2,6-dichloropyridine-4-amine and triethyl orthoformate generation condensation reaction obtain intermediate 5-((2,6-dichloropyridine-4-is amino) methylene radical)-2,2-dimethyl-1,3-dioxan-4,6-diketone; (2) high temperature closes ring, obtains key intermediate 5,7-two chloro-1,6-naphthyridines-4 (1H)-ketone; (3) the catalytic hydrogenation dechlorination obtains 1,6-naphthyridines-4 (1H)-ketone; (4) chlorination obtains target compound 4-chloro-1,6-naphthyridines.
2. 4-chloro-1 as claimed in claim, the synthetic method the first step of 6-naphthyridines is characterized in that: the temperature of Michaelis acid and triethyl orthoformate generation condensation reaction is at 120 ℃; Then gained intermediate and 2,6-dichloropyridine-4-amine condensation, the temperature of reaction is at 70 to 75 ℃.
3. 4-chloro-1 as claimed in claim, the synthetic method second step of 6-naphthyridines is characterized in that: the first step gained intermediate high temperature closes ring, and reaction solvent can be phenyl ether, can be also the mixture of the biphenyl-biphenyl ether such as Dowtherm A; Temperature of reaction is at 220 ℃.
4. 4-chloro-1 as claimed in claim in the 3rd step of synthetic method of 6-naphthyridines, is characterized in that: the catalyzer that the catalytic hydrogenation dechlorination is used, including but not limited to 10% palladium carbon, 5% palladium carbon, 20% palladium hydroxide and 10% palladium hydroxide etc.; Alkali used is including but not limited to triethylamine, diisopropylethylamine, sodium carbonate, salt of wormwood, sodium-acetate, Potassium ethanoate, sodium hydroxide and potassium hydroxide etc.; Reaction solvent is tetrahydrofuran (THF)-methyl alcohol, also can be DMF, methyl alcohol, tetrahydrofuran (THF), tetrahydrofuran-ethyl alcohol and ethanol etc.; Temperature of reaction is in room temperature.
5. 4-chloro-1 as claimed in claim in the 4th step of synthetic method of 6-naphthyridines, is characterized in that: chlorination reagent used is including but not limited to the mixture of phosphorus oxychloride, phosphorus pentachloride, phosphorus oxychloride and phosphorus pentachloride etc.; Alkali used, including but not limited to triethylamine, diisopropylethylamine, DMA and N, N-Diethyl Aniline etc.; The temperature of reaction is at 100 to 105 ℃.
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| CN2013101258266A CN103145709A (en) | 2013-04-12 | 2013-04-12 | Synthesis process for 4-chloro-1,6-naphthyridine |
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| CN2013101258266A CN103145709A (en) | 2013-04-12 | 2013-04-12 | Synthesis process for 4-chloro-1,6-naphthyridine |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200406413A (en) * | 2002-06-26 | 2004-05-01 | Glaxo Group Ltd | Compounds |
| TW200538120A (en) * | 2004-02-20 | 2005-12-01 | Kirin Brewery | Compound having TGF-beta inhibitory activity and pharmaceutical composition containing same |
| WO2008124083A2 (en) * | 2007-04-05 | 2008-10-16 | Amgen Inc. | Aurora kinase modulators and method of use |
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2013
- 2013-04-12 CN CN2013101258266A patent/CN103145709A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200406413A (en) * | 2002-06-26 | 2004-05-01 | Glaxo Group Ltd | Compounds |
| TW200538120A (en) * | 2004-02-20 | 2005-12-01 | Kirin Brewery | Compound having TGF-beta inhibitory activity and pharmaceutical composition containing same |
| WO2008124083A2 (en) * | 2007-04-05 | 2008-10-16 | Amgen Inc. | Aurora kinase modulators and method of use |
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Application publication date: 20130612 |