CN104163798A - Synthesis method of 3-amino-8-trifluoromethyl quinoline - Google Patents
Synthesis method of 3-amino-8-trifluoromethyl quinoline Download PDFInfo
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- CN104163798A CN104163798A CN201410363728.0A CN201410363728A CN104163798A CN 104163798 A CN104163798 A CN 104163798A CN 201410363728 A CN201410363728 A CN 201410363728A CN 104163798 A CN104163798 A CN 104163798A
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- trifluoromethylquinocarboxylic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
Abstract
The invention relates to a synthesis method of 3-amino-8-trifluoromethyl quinoline. The synthesis method comprises the steps: carrying out a reaction of 8-trifluoromethyl quinoline with N-bromosuccinimide to generate 3-bromo-8-trifluoromethyl quinoline, then carrying out a reaction with tert-butyl carbamate in the presence of palladium acetate, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and cesium carbonate to generate 3-tert-butoxycarbonyl amino-8-trifluoromethyl quinoline, and finally carrying out deamination protection on the compound in a mixed solvent of hydrochloric acid and methanol to obtain 3-amino-8-trifluoromethyl quinoline. The synthesis method has the advantages of high total yield (57.80%), convenient operation, simple post-treatment, no use of highly toxic reagents, and low requirements on equipment and environmental protection, and is suitable for mass production.
Description
Technical field
The invention belongs to pharmaceutical intermediate synthesis technical field, be specifically related to a kind of synthetic method of 3-amino-8-Trifluoromethylquinocarboxylic.
Background technology
3-amino-8-Trifluoromethylquinocarboxylic and intermediate thereof are important intermediates in organic synthesis and pharmaceutical chemistry.Set out with these compounds, can synthesize a series of molecule drug candidates with fine pharmaceutical activity.Up-to-date research shows, these candidate molecules are except the retina shedding isoreactivity that has angiogenesis inhibitor, anticoagulation, antitumor and anti metastasis and anti-diabetic and cause, can also be used for the disease (US20030144507 such as treatment of arthritis and the easy syndromes of intestines, US20040018192, WO2004069792).In recent years, thus seeking some active good screening of medicaments by 3-amino-8-Trifluoromethylquinocarboxylic and intermediate thereof are connected with some specific structures has become one of focus of pharmaceutical chemistry circle.
Synthesizing of 3-amino-8-Trifluoromethylquinocarboxylic, current main method is by o-trifluoromethyl aniline and ethoxy methylene diethyl condensation, product high temperature cyclisation in phenyl ether generates 4-oxo-8-Trifluoromethyl-1,4-dihydroquinoline-3-ethyl formate, then obtains intermediate 8-Trifluoromethylquinocarboxylic-3-ethyl formate with phosphorus oxychloride reaction and through catalytic hydrogenation dechlorination.The hydrolysis of 8-Trifluoromethylquinocarboxylic-3-ethyl formate obtains 8-Trifluoromethylquinocarboxylic-3-formic acid, and the latter reacts the 3-amino-8-Trifluoromethylquinocarboxylic that obtains Boc radical protection in DMF with DPPA.This compound is taken off protective material and is obtained 3-amino-8-Trifluoromethylquinocarboxylic under acidic conditions.There is following shortcoming in the method: (1) synthetic route is longer, and aftertreatment trouble, can not fairly largely produce; (2) in phenyl ether, condensation need to be carried out above at 250 DEG C, has very high danger; (3) use severe toxicity and to the disagreeableness phosphorus oxychloride of environment, and in catalytic hydrogenation dechlorination, produced the dihydroquindine derivates of a large amount of over reductions, caused yield on the low side, aftertreatment trouble; (4) in 8-Trifluoromethylquinocarboxylic-3-formic acid and DPPA rearrangement process, produce a large amount of gas, punching material easily occurs, reaction can only occur at small-scale.
Summary of the invention
The synthetic method that the object of the invention is to overcome the deficiencies in the prior art and provide a kind of 3-amino-8-Trifluoromethylquinocarboxylic, the method total recovery is high, easy to operate, aftertreatment is simple, do not use poisonous reagent, low to equipment and environmental requirement, be applicable to scale operation.
In order to realize foregoing invention object, the present invention by the following technical solutions:
The synthetic method of 3-amino-8-Trifluoromethylquinocarboxylic; react with N-bromosuccinimide in acetic acid by 8-Trifluoromethylquinocarboxylic and generate the bromo-8-Trifluoromethylquinocarboxylic of 3-; then with t-butyl carbamate in palladium, 4; two diphenylphosphine-9 of 5-; under the existence of 9-dimethyl oxa-anthracene and cesium carbonate, reaction generates the tertiary oxygen carbonyl amino-8-of 3-Trifluoromethylquinocarboxylic, and finally this compound deaminizating protection in the mixed solvent of hydrochloric acid and methyl alcohol obtains 3-amino-8-Trifluoromethylquinocarboxylic.
Reaction formula is as follows:
Concrete technology is as follows:
The first step is substitution reaction: reaction substrate is 8-Trifluoromethylquinocarboxylic (1), and replacement reagent is N-bromosuccinimide, and reaction solvent is acetic acid, and temperature of reaction is 110 DEG C, and the reaction times is 12h, obtains the bromo-8-Trifluoromethylquinocarboxylic of 3-; Wherein the mol ratio of 8-Trifluoromethylquinocarboxylic and N-bromosuccinimide is 1:1.2.
Second step is the bromo-8-Trifluoromethylquinocarboxylic of condensation reaction: 3-(2) with t-butyl carbamate in palladium, 4, two diphenylphosphine-9 of 5-, under the existence of 9-dimethyl oxa-anthracene and cesium carbonate, with 1,4-dioxane is reaction solvent, at 90 DEG C of reaction 4h, obtain the tertiary oxygen carbonyl amino-8-of 3-Trifluoromethylquinocarboxylic, wherein, the mol ratio of each substrate is the bromo-8-Trifluoromethylquinocarboxylic of 3-: t-butyl carbamate: cesium carbonate: 4, two diphenylphosphine-9 of 5-, 9-dimethyl oxa-anthracene: palladium=1:1.1:2:0.1:0.055.
The 3rd step is amino deprotection reaction: under normal temperature, 3-tertiary oxygen carbonyl amino-8-Trifluoromethylquinocarboxylic (3) is at the mixing solutions (V of methyl alcohol and hydrochloric acid
methyl alcohol: V
concentrated hydrochloric acid=1:1) in, reaction 2h obtains 3-amino-8-Trifluoromethylquinocarboxylic (4).
Synthetic method total recovery of the present invention high (57.80%), easy to operate, aftertreatment is simple, do not use poisonous reagent, low to equipment and environmental requirement, is applicable to scale operation.
Embodiment
Embodiment 1
The synthetic method of 3-amino-8-Trifluoromethylquinocarboxylic, technique is as follows:
Synthesizing of the bromo-8-Trifluoromethylquinocarboxylic of the first step: 3-
At 110 DEG C, in acetic acid (100mL) solution of 8-Trifluoromethylquinocarboxylic (10g, 0.05mol), add N-bromosuccinimide (10.7g, 0.06mol), mixture continues heated and stirred 12h at this temperature.After reacting completely, by acetic acid evaporate to dryness, and add ammoniacal liquor to pH=9 left and right.Mixed solution dichloromethane extraction, organic phase is washed with saturated sodium bicarbonate, after anhydrous sodium sulfate drying, is spin-dried for, and thick product is crossed post and is obtained the bromo-8-Trifluoromethylquinocarboxylic of 3-(10.9g, 78%).
1HNMR(400MHz，DMSO-d6):7.80-7.84(m，1H)，8.23-8.38(m，2H),8.91(d，J＝2.4Hz，1H)，9.13(d，J＝2.0Hz，1H)。
Synthesizing of the tertiary oxygen carbonyl amino-8-of second step: 3-Trifluoromethylquinocarboxylic
By bromo-3-8-Trifluoromethylquinocarboxylic (9g, 32.6 mmol), NH
2boc (4.2g, 36mmol), cesium carbonate (21.3g, 65mmol), palladium (0.5g, 1.8mmol) and Xantphots (2g, Isosorbide-5-Nitrae-dioxane (100mL) solution stirring reaction 4h at 90 DEG C 3.3mmol).After adding 200mL ethyl acetate, mixture is stirred to 10min, after mixture filters, organic phase is spin-dried for after drying.Thick product is crossed post and is obtained the tertiary oxygen carbonyl amino-8-of 3-Trifluoromethylquinocarboxylic (8g, 78%).
The 3rd step: 3-amino-8-trifluoromethyl synthetic
Add 50mL concentrated hydrochloric acid in methyl alcohol (50mL) solution of the tertiary oxygen carbonyl amino-8-Trifluoromethylquinocarboxylic of 3-(8g, 25.5mmol) after by mixture stirring at room temperature 2h.After reacting completely, by mixed solution evaporate to dryness, add 50mL water and 200mL ethyl acetate, and add ammoniacal liquor to pH=9 left and right.After aqueous phase separation, organic layer is spin-dried for, residue obtains 3-amino-8-Trifluoromethylquinocarboxylic (5.2g, 95%) by petroleum ether.
1HNMR(400MHz，DMSO-d6):5.88(s，2H),7.25(d，J＝2.8Hz，1H),7.49(t，J＝8Hz，16Hz，1H)，7.69(d，J＝7.2Hz，1H)，7.90(d，J＝8.4Hz，1H),8.57(d，J＝2.8Hz，1H)。
Claims (7)
- The synthetic method of 1.3-amino-8-Trifluoromethylquinocarboxylic, is characterized in that: comprise the following steps:Step 1,8-Trifluoromethylquinocarboxylic and N-bromosuccinimide are under heating condition, and reaction generates the bromo-8-Trifluoromethylquinocarboxylic of 3-;Step 2, the bromo-8-Trifluoromethylquinocarboxylic of step 1 gained 3-and t-butyl carbamate are in palladium, 4, and two diphenylphosphine-9 of 5-under the existence of 9-dimethyl oxa-anthracene and cesium carbonate, are reacted and are generated the tertiary oxygen carbonyl amino-8-of 3-Trifluoromethylquinocarboxylic under heating condition;Step 3, under room temperature, the tertiary oxygen carbonyl amino-8-of step 2 gained 3-Trifluoromethylquinocarboxylic is under acidic conditions, and deaminizating protection obtains 3-amino-8-Trifluoromethylquinocarboxylic.
- 2. the synthetic method of 3-amino-8-Trifluoromethylquinocarboxylic according to claim 1, is characterized in that: the solvent that step 1 adopts is acetic acid.
- 3. the synthetic method of 3-amino-8-Trifluoromethylquinocarboxylic according to claim 1, is characterized in that: the temperature of reaction of step 1 is 110 DEG C, the reaction times is 12h.
- 4. the synthetic method of 3-amino-8-Trifluoromethylquinocarboxylic according to claim 1, is characterized in that: in step 1, the mol ratio of 8-Trifluoromethylquinocarboxylic and N-bromosuccinimide is 1:1.2.
- 5. the synthetic method of 3-amino-8-Trifluoromethylquinocarboxylic according to claim 1, is characterized in that: it is reaction solvent that step 2 adopts Isosorbide-5-Nitrae-dioxane.
- 6. the synthetic method of 3-amino-8-Trifluoromethylquinocarboxylic according to claim 1, it is characterized in that: in step 2, the mol ratio of each substrate is the bromo-8-Trifluoromethylquinocarboxylic of 3-: t-butyl carbamate: cesium carbonate: 4, two diphenylphosphine-9 of 5-, 9-dimethyl oxa-anthracene: palladium=1:1.1:2:0.1:0.055.
- 7. the synthetic method of 3-amino-8-Trifluoromethylquinocarboxylic according to claim 1, is characterized in that: the temperature of reaction of step 2 is 90 DEG C, the reaction times is 4h.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112375037A (en) * | 2020-09-01 | 2021-02-19 | 苏州康润医药有限公司 | Synthetic method of 3-amino-5-bromoquinoline |
| CN114409515A (en) * | 2021-12-09 | 2022-04-29 | 南京工业大学 | Preparation method of gem-difluoroolefin compound |
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| CN1396833A (en) * | 2000-02-03 | 2003-02-12 | 卫材株式会社 | Integrin expression inhibitors |
| CN102448959A (en) * | 2009-05-26 | 2012-05-09 | 雅培制药有限公司 | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
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2014
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Patent Citations (2)
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| CN1396833A (en) * | 2000-02-03 | 2003-02-12 | 卫材株式会社 | Integrin expression inhibitors |
| CN102448959A (en) * | 2009-05-26 | 2012-05-09 | 雅培制药有限公司 | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
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| JINGJUN YIN: "Palladium-Catalyzed Intermolecular Coupling of Aryl Halides and Amides", 《ORGANIC LETTERS》, vol. 2, no. 8, 22 March 2000 (2000-03-22), pages 1101 - 1104, XP002413650, DOI: doi:10.1021/ol005654r * |
| MOHAMED ALI SOUSSI: "Discovery of azaisoerianin derivatives as potential antitumors agent", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》, vol. 78, 13 March 2014 (2014-03-13), pages 178 - 189, XP028847841, DOI: doi:10.1016/j.ejmech.2014.03.032 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112375037A (en) * | 2020-09-01 | 2021-02-19 | 苏州康润医药有限公司 | Synthetic method of 3-amino-5-bromoquinoline |
| CN112375037B (en) * | 2020-09-01 | 2022-04-12 | 苏州康润医药有限公司 | Synthetic method of 3-amino-5-bromoquinoline |
| CN114409515A (en) * | 2021-12-09 | 2022-04-29 | 南京工业大学 | Preparation method of gem-difluoroolefin compound |
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