WO2011120351A1

WO2011120351A1 - Process for preparing 2-bromo-6-fluoronaphthalene

Info

Publication number: WO2011120351A1
Application number: PCT/CN2011/070575
Authority: WO
Inventors: 刘加庚; 林峰
Original assignee: 大唐(杭州)医药化工有限公司
Priority date: 2010-04-01
Filing date: 2011-01-25
Publication date: 2011-10-06
Also published as: CN101870636B; KR101363583B1; KR20120036357A; JP2013503115A; CN101870636A; JP5335997B2

Abstract

Disclosed is a process for preparing 2-bromo-6-fluoronaphthalene, wherein the raw material is a Tobias acid, and the product is obtained by bromating-debrominating, diazotizating, and thermal decomposing. The product obtained by the present process has high purity and stable quality. Moreover, in the present process, the route is simple, the reaction condition is mild, and there is no need for high pressure. Therefore, the process is suitable for industrial production.

Description

Method for preparing 2-bromo-6-fluoronaphthalene

The invention belongs to the technical field of pharmacy and relates to a preparation method of 2-bromo-6-fluoronaphthalene.

Background technique

2-Bromo-6-fluoronaphthalene is an intermediate for the synthesis of a class of niacin receptor competition drugs. EP1809284 reports that these drugs can be used to treat lipid abnormalities in patients with kidney disease, and can effectively reduce plasma low-density lipoprotein LDL, VLDL, At the same time increase the level of high-density lipoprotein HDL. Bioorganic & Medicinal Chemistry (2000), 8(8), 1925-1930 and (2005), 13(9), 3117-3126, Tetrahedron: Asymmetry (2002), 13(10), 1073-1081 and (2004), 15(22), 3601-3608 reported a pyrrole analgesic synthesized from 2-bromo-6-fluoronaphthalene as a basic raw material, which has a significant effect on the treatment of chronic pain. JP 2001019649 and EP 952135 (A1) report a method for synthesizing a liquid crystal active component using 2-bromo-6-fluoronaphthalene, the liquid crystal added to the component is highly dispersible and easy to crystallize, and such a liquid crystal can be greatly reduced. Extreme voltage and high responsiveness. Since 2-bromo-6-fluoronaphthalene has a large birefringence factor and the polarity of the molecule is small, it can be used for source matrix driving display.

In the method reported in the literature, there are 5 steps in the synthesis of 2-bromo 6-fluoronaphthalene. There are two synthetic routes, and route 1 is

Among them, the aminolysis of 6-bromo-2-naphthol or 1,6-dibromo-2-naphthol needs to be carried out under high pressure and the yield is not high. The hexafluoride is used in the production of diazonium salt. Acid, so not only the process is complicated, the equipment requirements are high, but the synthesis cost is also very high.

Journal of the American Chemstry, 1967, 89, 386-390, J. Org. Chem., 1960, 25, 214-215 and Bioorg. Med. Chem., 2005, 8, 1925-1930 report 6-bromo- 2-naphthylamine is a method for synthesizing a starting material, 6-bromo-2-naphthylamine is subjected to diazotization reaction with sodium nitrite in a hydrochloric acid medium, and then hexafluorodibenzoic acid is added to form hexafluorodicarboxylic acid diazonium salt, After the nitrogen salt is thoroughly dried, it is thermally decomposed to obtain a product of 2-bromo-6-fluoronaphthalene in a yield of 55% to 65%.

The Chinese patent application CN101565352A discloses a preparation method of 2-fluoronaphthalene. The method comprises the following steps: (1) reacting 2-naphthol with p-toluenesulfonyl chloride (or p-toluenesulfonic acid) to form p-toluenesulfonic acid-2-naphthyl ester; (2) treating p-toluenesulfonic acid obtained in (1) 2-naphthyl ester and inorganic fluoride are prepared by reaction of a tertiary amine bidentate ligand with metallic copper in an aprotic high boiling solvent. However, the invention requires a reaction at a high temperature. Under the reaction conditions, the inorganic fluoride used is quite corrosive to the equipment, and therefore the requirements for the equipment are very demanding. In addition, the method employs a nucleophilic substitution reaction on an aromatic ring. When a more active bromine substituent is present at the 6-position, substitution is also likely to occur, and thus it is not suitable for the synthesis of 2-bromo-6-fluoronaphthalene. Summary of the invention

The object of the present invention is to provide a preparation method of 2-bromo-6-fluoronaphthalene, which is obtained from low-cost toluic acid as a starting material, and is obtained by three steps of bromination-debromination, diazotization and thermal cracking. The product 2-bromo-6-fluoronaphthalene has a short synthetic route, mild conditions and easy industrialization, and the product has high purity and stable quality.

The above technical problem of the present invention is implemented by the following technical solutions:

A method for preparing 2-bromo-6-fluoronaphthalene, the method comprising the steps of:

(1) bromination of toluic acid in an acidic medium to obtain 1,6-dibromo-2-naphthylamine, adding a reducing metal powder, and heating in an acidic medium to obtain 6-bromo-2-naphthylamine;

(2) reacting 6-bromo-2-naphthylamine obtained in step (1) with nitrous acid, nitrite or nitrite in an acidic medium to obtain a diazonium salt, adding fluoroboric acid or a salt thereof or fluorophilic acid or The salt is reacted to obtain 6-bromo-2-naphthylamine fluoroborate diazonium salt or fluorochemical acid diazonium salt;

(3) The fluoroboric acid diazonium salt or the fluorochemical acid diazonium salt obtained in the step (2) is thermally decomposed to obtain 2-bromo-6-fluoronaphthalene.

The synthetic route of the invention is as follows:

Toluic acid is an important intermediate widely used in the dye industry, and the raw materials are readily available and the price is very low. Toluic acid reacts with liquid bromine in an acetic acid medium, and a bromination reaction occurs at the 6-position while the 1-sulfenyl group of the naphthalene ring is substituted by bromine. This reaction has not seen any patents or academic papers published, is a new discovery. The 1,6-dibromo-2-naphthylamine formed by bromination is directly reacted with metallic tin powder without isolation to obtain 6-bromo-2-naphthylamine, which simplifies the operation and is very satisfactory in yield.

Fluoroboric acid is a basic chemical raw material widely produced and applied in China. Compared with hexafluorodicarboxylic acid, it has the advantage of being inexpensive and easy to obtain. Therefore, the present invention uses fluoroboric acid to prepare a diazonium salt. Although the diazonium salt prepared using fluoroboric acid has a lower yield in the subsequent cleavage reaction, the fluoroboric acid method still has a certain cost advantage because of the great price difference between fluoroboric acid and hexafluoro-pure acid.

Preferably, the acidic medium in the step (1) is a pity acid, sulfuric acid or a linear or branched saturated carboxylic acid having 6 or less carbon atoms, and the above various acids have a mass concentration ranging from 60% to 100%. %, preferably in the range of 80% to 100%. This concentration of acidic environment facilitates the reaction.

Preferably, the acidic medium in the step (2) is pity acid, sulfuric acid, hydrochloric acid or a linear or branched saturated carboxylic acid having 6 or less carbon atoms, and the acid and 6-bromo-2- The molar ratio of naphthylamine ranges from 2 to 6: 1, and the preferred range is from 2 to 3:1. The diazotization reaction must be carried out under acidic medium. The theoretical molar ratio of acid to 6-bromo-2-naphthylamine is 2:1, which should be excessive, but too much excess leads to an increase in cost.

Preferably, the reducing metal powder according to the step (1) is reduced iron powder, metallic nickel powder, reduced zinc powder, metallic copper powder or metallic tin powder. 5: 1。 The molar ratio of the amount of the above-mentioned metal powder and the amount of 6-bromo-2-naphthylamine is in the range of 0. 5-3: 1, preferably in the range of 1-1. 5: 1.

As a preferred embodiment, the temperature of the bromination reaction in the step (1) is 50-100 ° C, preferably in the range of 60-80 ° C; the temperature of the debromination reaction is 50-100 ° C, preferably in the range of 60-80 ° C. As a preferred embodiment, the temperature of the diazotization reaction in the step (2) is -10-10 ° C, preferably the temperature range is -2-5 ° C; the temperature of the salt formation reaction is 0-30 ° C, and the preferred range is 10-20 ° C.

5至倍范围之间的摩尔比的优选的范围内的范围内的范围内的范围内的范围内的范围内。 5倍倍。 The preferred range is 1. 5-2 times.

As a preferred embodiment, the thermal decomposition temperature of the diazonium salt in the step (3) is from 120 to 180 ° C, preferably from 130 to 150 ° C. The diazonium salt can be decomposed smoothly at temperatures above 130 °C. If the temperature is too high, the decomposition will be too fast and carbonization will occur easily. Therefore, the optimum temperature range is 130-150 °C.

As a preferred embodiment, the thermal decomposition of the diazonium salt in step (3) is carried out in an inert medium. More preferably, the inert medium is a linear or branched anthracene hydrocarbon having from 12 to 20 carbon atoms, or a silicone oil having a boiling point in the range of from 250 to 300 °C. Thermal decomposition can be carried out smoothly in an inert medium.

As a preferred embodiment, in the step (3), 2-bromo-6-fluoronaphthalene is dissolved in an organic solvent and filtered, and the obtained liquid is subjected to distillation under reduced pressure to obtain a pure product. Distillation under reduced pressure can lower the distillation temperature.

In summary, the method used in the present invention has only three steps in the synthesis process, the route is simple, and high pressure conditions are not required, and the production of the diazonium salt uses the fluoroboric acid which is inexpensive and easily available, and has the basis of industrial production.

DRAWINGS

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a 1H-NMR chart of 2-bromo-6-fluoronaphthalene prepared in Example 1 of the present invention.

Specific form

The following are specific embodiments of the invention; these examples may further complement and illustrate the invention, but the invention is not limited to the examples.

Example 1

(1) Synthesis of 6-bromo-2-naphthylamine: In a 2000 ml three-necked flask equipped with a dropping funnel, a thermometer, a stirring device and a reflux condenser, 1100 ml of glacial acetic acid and 57.47 g (0.25 mol) of toluic acid were added, stirring was started, and heating was carried out to 70 ° C to spit. The acid dissolves. 80 g (0.5 mol) of liquid bromine was added dropwise through a dropping funnel, and the temperature of the reactant was maintained at 70-72 ° C during the dropwise addition, and the addition was completed in about 1 hour. After the completion of the dropwise addition, the temperature was raised to reflux, and stirring was continued for 1.5 hours under reflux to complete the reaction. After the end of the reaction, the temperature of the reaction mixture was lowered to 65 ° C, 29.8 g (0. 251 mol) of metallic tin powder and 340 ml of hydrochloric acid having a concentration of 35% were added, and then the temperature of the reaction mixture was raised to reflux and refluxed. Stirring was continued for 2 hours. After the reaction was completed, glacial acetic acid was recovered by distillation under reduced pressure. To the residue was added 1250 ml of hot methanol and stirred until all solids dissolved. The reaction was cooled to room temperature (about 20 ° C) with stirring to precipitate white crystals. 5%。 The solid was washed with a small amount of methanol, and dried to give 38.3 g of white 6-bromo-2-naphthylamine solid, yield 67%, HPLC analysis purity 99.5%.

(2) Synthesis of 6-bromo-2-naphthylamine fluoroborate diazonium salt:

In a 2000 ml three-necked flask equipped with a dropping funnel, a thermometer, and a stirring device, 38. 3 g of 6-bromo-2-naphthylamine (0.172 mol) obtained in the step (1), 650 ml of water and 94 ml of concentrated hydrochloric acid ( 1. 03 mol), start stirring and heat to 6-bromo-2-naphthylamine hydrochloride to dissolve completely to form a clear and clear solution. It was then cooled to -5 ° C in an ice salt bath, at which time white 6-bromo-2-naphthylamine hydrochloride precipitated as fine crystals. A solution consisting of 14.78 g of sodium nitrite (0.241 mol) and 100 ml of water was added dropwise through a dropping funnel. During the dropwise addition, the temperature of the reactants was controlled to be below 0 ° C. During the dropwise addition, the crystals of 6-bromo-2-naphthylamine hydrochloride gradually dissolved, and finally a yellow transparent solution was formed. The end point of the reaction was detected with potassium iodide-starch test paper, and the test paper was blue and the color was not faded within 30 seconds. After the completion of the dropwise addition, stirring was continued for 30 minutes at 0 ° C, and then 57 ml of a 40% commercial fluoroboric acid solution was added dropwise through a dropping funnel under vigorous stirring, and a large amount of white solid was immediately produced during the dropwise addition. Continue to stir after the addition is completed 30 The crystals were completely taken up in vacuo, and suction filtered with Buchner funnel. The obtained solid was washed with 195 ml of ethanol, and filtered under reduced pressure. The filter cake was washed with 195 ml of diethyl ether, and then filtered under reduced pressure. The obtained solid was dried under vacuum for 24 hours. 40.6 g of 6-bromo-2-naphthylamine fluoroboric acid diazonium salt was obtained (yield 78%).

(3) Synthesis of 2-bromo 6-fluoronaphthalene

A 250 ml three-necked flask equipped with a reflux condenser and a tail gas absorption device at the top of the condenser was heated to 135 ° C with an oil bath, and 10 g of the diazonium salt obtained in the step (2) was added, and the diazonium salt was immediately melted and decomposed after the addition. A boron trifluoride gas was emitted and a pale yellow oily liquid appeared in the flask. When substantially no bubbles are emitted, the remaining diazonium salt is added in portions, and a total of 43.06 g of 6-bromo-2-naphthylamine fluoroborate diazonium salt is added in portions. Stirring was continued for 30 minutes after the last addition. The reaction was cooled to room temperature, and 136 ml of 60-90 ° C petroleum ether and 136 ml of toluene were added, stirred for 5 minutes, and filtered through a Buchner funnel containing a small amount of silica gel to give an almost colorless solution. The solution was recovered under reduced pressure of petroleum ether and toluene, and the residue was distilled under reduced pressure at a pressure of 5 mmHg to receive a fraction of 130-135 °C. After the distillate solidified, 17 g of white 2-bromo-6-fluoronaphthalene solid was obtained, and the yield was 56.4%. The purity of the product was 99.6%, and the 1H-NMR spectrum of the product 2-bromo-6-fluoronaphthalene was as shown in the figure. 1 is shown.

Example 2:

The product yield was 56.9. The product was obtained in the same manner as in Example 1, except that the thermal decomposition of the diazonium salt in the step (3) was carried out in a silicone oil having a boiling point of 250-300 ° C. The yield of the product was 56.9. %, HPLC detection purity 99. 5%.

Example 3:

4%。 The product was obtained in the same manner as in Example 1, except that the thermal decomposition of the diazonium salt in the step (3) was carried out in liquid paraffin (C16-C20 normal terpene hydrocarbon), the yield of the product was 58.4%. 7%。 HPLC, the purity of 99.7%. Example 4:

The same procedure as in Example 1 was carried out except that the thermal decomposition temperature of the diazonium salt in the step (3) was controlled within the range of 130-150 ° C, and the product yield was 49.8 by atmospheric distillation. %, HPLC detection purity 99.0%.

Example 5

The same procedure as in Example 1 was carried out except that 34.75 g of a fluoroboric acid having a mass concentration of 50% was added in the step (2) so that the molar ratio of fluoroboric acid to 6-bromo-2-naphthylamine was 1:1.5. The final yield of the product was 52.6%, and the purity of the HPLC was 99.5%.

Example 6:

The same procedure as in Example 1 was carried out except that in step (2), 69.5 g of a concentration of 50% by weight of fluoroboric acid was added so that the molar ratio of fluoroboric acid to 6-bromo-2-naphthylamine was 1:3. The yield of the final product was 55.4%, and the purity by HPLC was 99.0%.

Example 6:

The same procedure as in Example 1 was carried out except that in the step (2), the temperature of the diazotization reaction was controlled in the range of -2-5 ° C, and the temperature of the salt formation reaction was controlled at about 25 ° C. The final product yield was 52.7%, and the HPLC purity was 99.8%.

Example 7

The same procedure as in Example 1 was carried out except that the metal tin powder in the step (2) was changed to a reduced iron powder, and the molar ratio of the reduced iron powder to the 6-bromo-2-naphthylamine was 1:1. The yield of the final product was 56.8%, and the purity by HPLC was 99.8%. It is a copper powder, and the molar ratio of reduced iron powder to 6-bromo-2-naphthylamine is 1.5:1. The yield of the final product was 59.1%, and the purity by HPLC was 99.8%.

Example 9

The same procedure as in Example 1 was carried out except that the fluoroboric acid in the step (2) was changed to a fluorine pity acid, and the molar amount of the fluorine pity acid was twice that of 6-bromo-2-naphthylamine, and the fluorine pity was obtained. The diazonium salt was thermally decomposed by the step (3), and finally the product was obtained in a yield of 57.8%, and the purity of the HPLC was 98.9%.

Example 10

The same procedure as in Example 1 was carried out except that the fluoroboric acid in the step (2) was changed to sodium fluoroborate, and the molar amount of sodium fluoroborate was 3 times that of 6-bromo-2-naphthylamine. The yield of the final product was 51.8%, and the purity by HPLC was 99.1%.

Example 11

The same procedure as in Example 1 was carried out except that the glacial acetic acid in the step (1) was changed to a pity acid solution having a mass concentration of 60%, and the yield of the product was 53.1%, and the purity of the HPLC was 99.3%.

Example 12:

The same procedure as in Example 1 was carried out except that the glacial acetic acid in the step (1) was changed to 1100 ml of a propionic acid solution. The yield of the final product was 53.5%, and the purity by HPLC was 99.4%.

Example 13

The same procedure as in Example 1 was carried out except that the concentrated hydrochloric acid in the step (2) was changed to a commercially available concentrated sulfuric acid of 54% by mass concentration of 54.25 mlo, and the final product yield was 58.9%, and the purity of the HPLC was 99.6. %.

Example 14 5: 1。 The molar ratio of metal nickel powder to 6-bromo-2-naphthylamine is 0. 5: 1. 8%。 HPLC yield purity of 98. 8%.

Example 15:

The same procedure as in Example 1 was carried out except that the metal tin powder in the step (2) was changed to a reduced zinc powder, and the molar ratio of the reduced zinc powder to the 6-bromo-2-naphthylamine was 3:1. 9%。 The final product yield was 52.1%, HPLC detection purity 98.9%.

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 -3: 1, preferably in the range of 1-1. 5: 1.

The specific embodiments described in the present invention are merely illustrative of the spirit of the invention. A person skilled in the art can make various modifications or additions to the specific embodiments described, or in a similar manner, without departing from the spirit of the invention or the scope of the appended claims. The scope of the definition. While the invention has been described in detail and shown in the embodiments of the embodiments

Claims

Rights request

A method for producing 2-bromo-6-fluoronaphthalene, the method comprising the steps of:

(2) reacting 6-bromo-2-naphthylamine obtained in the step (1) with nitrous acid, nitrite or nitrite in an acidic medium to obtain a diazonium salt, adding fluoroboric acid or a salt thereof or fluorine pity or The salt is reacted to obtain 6-bromo-2-naphthylamine fluoroborate diazonium salt or fluorochemical acid diazonium salt;

The method according to claim 1, wherein the acidic medium of the step (1) is pity acid, sulfuric acid or a linear or branched saturated carboxylic acid having 6 or less carbon atoms.

The method according to claim 1, wherein the acidic medium in the step (2) is pity acid, sulfuric acid, hydrochloric acid or a linear or branched saturated carboxylic acid having 6 or less carbon atoms.

The method according to claim 1, wherein the reducing metal powder in the step (1) is reduced iron powder, metallic nickel powder, reduced zinc powder, metallic copper powder or metallic tin powder.

The method according to claim 1, wherein in the step (1), the temperature of the bromination reaction is 50 to 100 ° C, and the temperature of the debromination reaction is 50 to 100 ° C.

The method according to claim 1, characterized in that in step (2), the temperature of the diazotization reaction At -10-10 ° C, the temperature of the salt formation reaction is 0-30 ° C.

The method according to claim 1, wherein in the salt forming reaction of the step (2), the molar ratio of fluoroboric acid or a salt thereof or a fluorochemical acid or a salt thereof to 6-bromo-2-naphthylamine is 1 : 1. 5-3.

The method according to claim 1, wherein the thermal decomposition temperature of the diazonium salt in the step (3) is 120-180 ° C.

The method according to any one of claims 1-8, characterized in that the thermal decomposition of the diazonium salt in step (3) is carried out in an inert medium.

The method according to claim 9, wherein the inert medium is a linear or branched anthracene hydrocarbon having 12 to 20 carbon atoms or a silicone oil having a boiling point in the range of 250 to 300 °C.