CN108484495B - Synthetic method of 3-bromo-7-hydroxyquinoline - Google Patents
Synthetic method of 3-bromo-7-hydroxyquinoline Download PDFInfo
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- CN108484495B CN108484495B CN201810324855.8A CN201810324855A CN108484495B CN 108484495 B CN108484495 B CN 108484495B CN 201810324855 A CN201810324855 A CN 201810324855A CN 108484495 B CN108484495 B CN 108484495B
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- hydroxyquinoline
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- trifluoromethanesulfonate
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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
- C07D215/20—Oxygen atoms
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Abstract
The invention provides a synthetic method of 3-bromo-7-hydroxyquinoline. The synthesis method of the 3-bromo-7-hydroxyquinoline comprises the following steps: 1) dissolving 7-hydroxyquinoline in a solvent, adding trifluoromethanesulfonic anhydride, and reacting at a low temperature to obtain quinoline-7-trifluoromethanesulfonic acid ester, wherein the molar ratio of 7-hydroxyquinoline to trifluoromethanesulfonic anhydride is 1 (1-1.5); 2) dissolving quinoline-7-trifluoromethanesulfonate obtained in the step 1) with a solvent, adding N-bromosuccinimide, and reacting to obtain 3-bromoquinoline-7-trifluoromethanesulfonate; 3) hydrolyzing the 3-bromoquinoline-7-trifluoromethanesulfonate obtained in the step 2) under an alkaline condition to obtain 3-bromo-7-hydroxyquinoline. The synthetic method of the 3-bromo-7-hydroxyquinoline has the advantages of stable raw materials, no toxicity, simple synthetic process and high yield.
Description
Technical Field
The invention belongs to the technical field of synthesis of drug intermediates, and relates to a synthesis method of 3-bromo-7-hydroxyquinoline.
Background
3-bromo-7-hydroxyquinoline is a pharmaceutical intermediate with significant medicinal value, and researchers in Janssen pharmaceutical NV found that a series of compounds synthesized by using 3-bromo-7-hydroxyquinoline as an intermediate are highly effective inhibitors of PRMT5, and PRMT5 is one of the main methyltransferases responsible for monooxygenation and symmetric dimethylation of arginine, and participates in various cellular processes by epigenetically regulating expression of a target gene or post-translational modification of a signal molecule. Strikingly, although PRMT5 is considered a clinically relevant drug target, few selective PRMT5 inhibitors have been published (WO2017032840a 1).
Therefore, there is a strong demand for new PRMT5 inhibitors in the market, which opens up a new approach for the treatment or prevention of cancer. 3-bromo-7-hydroxyquinoline has attracted attention as a medical intermediate of a novel PRMT5 inhibitor, and the synthesis of specific compounds by taking the 3-bromo-7-hydroxyquinoline as the intermediate to obtain a high-efficiency drug candidate molecule has attracted wide attention in the pharmaceutical chemistry field, but the related synthesis reports are few.
At present, 7-nitro-1, 2, 3, 4-tetrahydroquinoline and dichlorodicyanoquinone are used as raw materials to react at room temperature to generate 7-nitroquinoline, then the 7-nitroquinoline reacts with NBS to obtain 3-bromo-7-nitroquinoline, then the 3-bromo-7-aminoquinoline is obtained through reduction reaction, and finally the 3-bromo-7-hydroxyquinoline is obtained through Sandmeyer reaction. However, the raw material dichlorodicyano benzoquinone (DDQ) in the process is very easy to decompose when meeting water, releases hydrogen cyanide and has strong toxicity; and the total yield of the 3-bromo-7-hydroxyquinoline in the process is low.
Therefore, it is necessary to develop a synthesis method of 3-bromo-7-hydroxyquinoline which has stable and nontoxic raw materials, simple synthesis process and high yield.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a synthetic method of 3-bromo-7-hydroxyquinoline, which has the advantages of stable raw materials, no toxicity, simple synthetic process and high yield.
In order to achieve the purpose, the invention adopts the following technical scheme:
a synthetic method of 3-bromo-7-hydroxyquinoline, comprising the following steps:
1) dissolving 7-hydroxyquinoline in a solvent, adding trifluoromethanesulfonic anhydride, and reacting at a low temperature to obtain quinoline-7-trifluoromethanesulfonic acid ester, wherein the molar ratio of 7-hydroxyquinoline to trifluoromethanesulfonic anhydride is 1 (1-1.5);
2) dissolving quinoline-7-trifluoromethanesulfonate obtained in the step 1) with a solvent, adding N-bromosuccinimide, and reacting to obtain 3-bromoquinoline-7-trifluoromethanesulfonate;
3) hydrolyzing the 3-bromoquinoline-7-trifluoromethanesulfonate obtained in the step 2) under an alkaline condition to obtain 3-bromo-7-hydroxyquinoline.
In the step 1), the solvent is dichloromethane.
In the step 1), the molar ratio of the 7-hydroxyquinoline to the trifluoromethanesulfonic anhydride is 1 (1-1.5), and for example, the molar ratio of the 7-hydroxyquinoline to the trifluoromethanesulfonic anhydride is 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1: 1.5.
Preferably, in the step 1), the temperature of the low-temperature reaction is-1 to 1 ℃, for example, the reaction temperature is-1 ℃, 0 ℃ and 1 ℃; the low-temperature reaction time is 1-3 h, for example, the reaction time is 1h, 1.5h, 2h, 2.5h and 3 h.
In the step 2), the solvent is glacial acetic acid.
In the step 2), the molar ratio of the quinoline-7-trifluoromethanesulfonate to the N-bromosuccinimide is 1 (1-3), and for example, the molar ratio of the quinoline-7-trifluoromethanesulfonate to the N-bromosuccinimide is 1:1, 1:1.5, 1:2, 1:2.5, or 1: 3.
In the step 2), the reaction temperature is 80-100 ℃, for example, the reaction temperature is 80 ℃, 85 ℃, 90 ℃, 95 ℃ and 100 ℃; the reaction time is 1-3 h, for example, the reaction time is 1h, 1.5h, 2h, 2.5h, 3 h.
In the step 3), the alkaline condition is an aqueous solution of sodium hydroxide, lithium hydroxide and potassium hydroxide.
In the step 3), the concentration of the aqueous solution of sodium hydroxide, lithium hydroxide and potassium hydroxide is 10-20%, for example, the concentration of the aqueous solution of sodium hydroxide, lithium hydroxide and potassium hydroxide is 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% and 20%.
In step 3), the reaction temperature is 20-30 ℃, for example, the reaction temperature is 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃ and 30 ℃; the reaction time is 1-3 h, for example, the reaction time is 1h, 1.5h, 2h, 2.5h, 3 h.
As a preferable scheme of the invention, the synthesis method of the 3-bromo-7-hydroxyquinoline comprises the following steps:
1) dissolving 7-hydroxyquinoline with dichloromethane, adding trifluoromethanesulfonic anhydride in batches, reacting for 1-3 h at the temperature of-1 ℃ to obtain quinoline-7-trifluoromethanesulfonic acid ester, wherein the molar ratio of 7-hydroxyquinoline to trifluoromethanesulfonic anhydride is 1 (1-1.5);
2) dissolving the quinoline-7-trifluoromethanesulfonate obtained in the step 1) with glacial acetic acid, adding N-bromosuccinimide, and reacting at the temperature of 80-100 ℃ for 1-3 h to obtain 3-bromoquinoline-7-trifluoromethanesulfonate, wherein the molar ratio of the quinoline-7-trifluoromethanesulfonate to the N-bromosuccinimide is 1 (1-3);
3) adding the 3-bromoquinoline-7-trifluoromethanesulfonate obtained in the step 2) into a 10% sodium hydroxide solution, stirring the mixture at the temperature of 20-30 ℃ and reacting the mixture for 1-3 hours to obtain the 3-bromo-7-hydroxyquinoline.
In the invention, the synthesis process of 3-bromo-7-hydroxyquinoline comprises the following steps of reacting 7-hydroxyquinoline as a raw material with trifluoromethanesulfonic anhydride to obtain quinoline-7-trifluoromethanesulfonate, reacting with N-bromosuccinimide (NBS) to obtain 3-bromoquinoline-7-trifluoromethanesulfonate, and finally hydrolyzing in an aqueous solution of sodium hydroxide to obtain 3-bromo-7-hydroxyquinoline, wherein the reaction formula of the synthesis method is as follows:
the second purpose of the invention is to provide 3-bromo-7-hydroxyquinoline prepared by the above synthesis method.
Compared with the prior art, the invention has the beneficial effects that:
the method for preparing the 3-bromo-7-hydroxyquinoline takes the 7-hydroxyquinoline as a raw material, has the advantages of concise synthetic route, reasonable process selection, low cost of the raw material, simplicity, easy obtainment, convenient operation and post-treatment, high total yield, no use of highly toxic reagents, and capability of solving the defects of high toxicity, low total yield and the like of the reagents used in the prior art by reasonably controlling the reaction raw materials, the proportion and the reaction conditions, being easy to amplify and being capable of synthesizing the 3-bromo-7-hydroxyquinoline produced in a large scale.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments.
Unless otherwise specified, various starting materials of the present invention are commercially available or prepared according to conventional methods in the art.
Examples
The first step is as follows: synthesis of quinoline-7-triflate
7-Hydroxyquinoline (100g, 0.69mol) was added to dichloromethane (800ml), pyridine (140g, 1, 77mol) was added at 0 ℃ and a solution of trifluoromethanesulfonic anhydride (230g, 0.83mol) in dichloromethane (200ml) was added dropwise at this temperature and reacted for 2h after the addition was complete. After completion of the reaction, the reaction mixture was poured into ice water (500ml), the pH was adjusted to 6-7 with HCl, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give quinoline-7-trifluoromethanesulfonate (150g, 78.6%).
The second step is that: synthesis of 3-bromoquinoline-7-trifluoromethanesulfonate
Quinoline-7-triflate (40g, 0.14mol) was added to glacial acetic acid (800ml) at 90 ℃ and N-bromosuccinimide (38g, 0.22mol) was added in portions and reacted for 2 h. After completion of the reaction, acetic acid was spin-dried, extracted with ethyl acetate (500 ml. times.2), the organic phase was neutralized with an aqueous sodium carbonate solution, and subjected to column chromatography to give 3-bromoquinoline-7-trifluoromethanesulfonate (42g, 82.3%).
The third step: synthesis of 3-bromo-7-hydroxyquinoline
3-Bromoquinoline-7-trifluoromethanesulfonate (20g, 0.056mol) was dissolved in ethanol (80ml), and 10% sodium hydroxide solution (80ml) was added thereto, followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction solution was spin-dried, and the residue was neutralized with hydrochloric acid (50ml), filtered to obtain a crude product, dried and then extracted with dichloromethane: after stirring a solution of 1:1 petroleum ether (50ml) for 30min, 3-bromo-7-hydroxyquinoline (12g, 95.7%) was obtained by filtration.
1HNMR(400MHz，DMSO-d6)：7.82(d，J＝8.8Hz，1H)，8.54(d，J＝2.2Hz， 1H)，8.78(d，J＝2.4Hz，1H)，10.35(s，1H)，7.24(dd，J＝9.4，5.5Hz，2H)。
Comparative example 1
This comparative example is compared with example 1 except that in step 1), the molar ratio of 7-hydroxyquinoline to trifluoromethanesulfonic anhydride was 1:5, the other conditions were the same as in example 1, and this comparative example gave a yield of 82% of 3-bromo-7-hydroxyquinoline.
Comparative example 2
This comparative example is compared with example 1 except that in step 1), the molar ratio of 7-hydroxyquinoline to trifluoromethanesulfonic anhydride was 1:0.5, the other conditions were the same as in example 1, and this comparative example gave 3-bromo-7-hydroxyquinoline in a yield of 75%.
Comparative example 3
This comparative example is compared with example 1 except that in step 2), the molar ratio of quinoline-7-trifluoromethanesulfonate to N-bromosuccinimide is 1:6, the other conditions are the same as in example 1, and the yield of 3-bromo-7-hydroxyquinoline obtained in this comparative example is 84%.
Comparative example 4
This comparative example is compared with example 1 except that in step 2), the molar ratio of quinoline-7-trifluoromethanesulfonate to N-bromosuccinimide is 1:0.1, the other conditions are the same as in example 1, and the yield of 3-bromo-7-hydroxyquinoline obtained in this comparative example is 59%.
Comparative example 5
This comparative example is compared with example 1 except that the reaction temperature in step 1) was 40 deg.C and the other conditions were the same as in example 1, and the yield of 3-bromo-7-hydroxyquinoline obtained in this comparative example was 57%.
Comparative example 6
This comparative example is compared with example 1 except that in step 2), the solvent is hydrochloric acid, the other conditions are the same as in example 1, and the yield of 3-bromo-7-hydroxyquinoline obtained in this comparative example is 78%.
Comparative example 7
This comparative example is compared with example 1 except that in step 3), the concentration of the sodium hydroxide solution was 50%, the other conditions were the same as in example 1, and the yield of 3-bromo-7-hydroxyquinoline obtained in this comparative example was 69%.
The method for preparing the 3-bromo-7-hydroxyquinoline takes the 7-hydroxyquinoline as a raw material, has the advantages of concise synthetic route, reasonable process selection, low cost of the raw material, simplicity, easy obtainment, convenient operation and post-treatment, high total yield, no use of highly toxic reagents, and capability of solving the defects of high toxicity, low total yield and the like of the reagents used in the prior art by reasonably controlling the reaction raw materials, the proportion and the reaction conditions, being easy to amplify and being capable of synthesizing the 3-bromo-7-hydroxyquinoline produced in a large scale.
The present invention is illustrated by the above-mentioned examples, but the present invention is not limited to the above-mentioned detailed process equipment and process flow, i.e. it is not meant to imply that the present invention must rely on the above-mentioned detailed process equipment and process flow to be practiced. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (9)
1. A synthetic method of 3-bromo-7-hydroxyquinoline is characterized by comprising the following steps:
1) dissolving 7-hydroxyquinoline in a solvent, adding trifluoromethanesulfonic anhydride, and reacting at a certain temperature to obtain quinoline-7-trifluoromethanesulfonic acid ester, wherein the molar ratio of 7-hydroxyquinoline to trifluoromethanesulfonic anhydride is 1 (1-1.5);
2) dissolving quinoline-7-trifluoromethanesulfonate obtained in the step 1) with a solvent, adding N-bromosuccinimide, and reacting to obtain 3-bromoquinoline-7-trifluoromethanesulfonate;
3) hydrolyzing the 3-bromoquinoline-7-trifluoromethanesulfonate obtained in the step 2) under an alkaline condition to obtain 3-bromo-7-hydroxyquinoline.
2. The synthesis method according to claim 1, wherein in step 1), the solvent is dichloromethane;
in the step 1), the reaction temperature is-1 ℃, and the reaction time is 1-3 h.
3. The method of claim 1 or 2, wherein in step 2), the solvent is glacial acetic acid.
4. The synthesis method of claim 3, wherein in the step 2), the molar ratio of the quinoline-7-trifluoromethanesulfonate to the N-bromosuccinimide is 1 (1-3).
5. The synthesis method according to claim 4, wherein in the step 2), the reaction temperature is 80-100 ℃, and the reaction time is 1-3 h.
6. The synthesis method according to claim 5, wherein in step 3), the alkaline condition is an aqueous solution of sodium hydroxide, lithium hydroxide or potassium hydroxide.
7. The synthesis method according to claim 6, wherein the concentration of the aqueous solution of sodium hydroxide, lithium hydroxide and potassium hydroxide is 10-20%.
8. The synthesis method according to claim 7, wherein in the step 3), the reaction temperature is 20-30 ℃, and the reaction time is 1-3 h.
9. The method of synthesis according to claim 8, comprising the steps of:
1) dissolving 7-hydroxyquinoline with dichloromethane, adding trifluoromethanesulfonic anhydride in batches, reacting for 1-3 h at the temperature of-1 ℃ to obtain quinoline-7-trifluoromethanesulfonic acid ester, wherein the molar ratio of 7-hydroxyquinoline to trifluoromethanesulfonic anhydride is 1 (1-1.5);
2) dissolving the quinoline-7-trifluoromethanesulfonate obtained in the step 1) with glacial acetic acid, adding N-bromosuccinimide, and reacting at the temperature of 80-100 ℃ for 1-3 h to obtain 3-bromoquinoline-7-trifluoromethanesulfonate, wherein the molar ratio of the quinoline-7-trifluoromethanesulfonate to the N-bromosuccinimide is 1 (1-3);
3) adding the 3-bromoquinoline-7-trifluoromethanesulfonate obtained in the step 2) into a 10% sodium hydroxide solution, stirring the mixture at the temperature of 20-30 ℃ and reacting the mixture for 1-3 hours to obtain the 3-bromo-7-hydroxyquinoline.
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| US9120774B2 (en) * | 2004-11-03 | 2015-09-01 | University Of Kansas | Novobiocin analogues having modified sugar moieties |
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| CN101035780A (en) * | 2003-11-10 | 2007-09-12 | 默沙东有限公司 | Substituted nitrogen-containing six-membered amino-heterocycles as vanilloid-1 receptor antagonists for treating pain |
| WO2006050501A2 (en) * | 2004-11-03 | 2006-05-11 | University Of Kansas | Novobiocin analogues as anticancer agents |
| WO2011004276A1 (en) * | 2009-07-06 | 2011-01-13 | Pfizer Limited | Hepatitis c virus inhibitors |
| CN107129514A (en) * | 2016-03-02 | 2017-09-05 | 中国医学科学院药物研究所 | Erythromycin A ketolide antibiotics derivative, its preparation method and application |
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