JP2013503115A - Method for preparing 2-bromo-6-fluoronaphthalene - Google Patents

Abstract

The present invention belongs to the pharmaceutical technical field, and relates to a method for preparing 2-bromo-6-fluoronaphthalene, which uses inexpensive tobias acid as an initial raw material, and includes bromination-debromination, diazotization, and thermal decomposition. The step yields the desired product 2-bromo-6-fluoronaphthalene, the purity of the product obtained is high and the quality is stable. The method employed according to the present invention has only 3 steps in the synthesis process, the route is simple, the reaction conditions are mild, and there is no need for high-pressure conditions, and the production of diazonium salts is inexpensive and easy to obtain. Since fluoroboric acid is used, the cost is low and industrialization is easy to realize.
[Selection] Figure 1

Description

  The present invention belongs to the pharmaceutical technical field and relates to a process for the preparation of 2-bromo-6-fluoronaphthalene.

  2-Bromo-6-fluoronaphthalene is an intermediate that synthesizes one type of nicotinic acid receptor competitive drug, and Patent Document 1 discloses that this type of drug can be used for the treatment of lipid abnormalities in patients with kidney disease. It discloses that plasma low density lipoprotein LDL and VLDL can be effectively lowered and at the same time the level of high density lipoprotein HDL can be improved. Bioorganic & medicinal Chemistry (2000), 8 (8), 1925-1930 (Non-Patent Document 1), Bioorganic & medicinal Chemistry (2005), 13 (9), 3117-3126 (Non-Patent Document 2), Tetrahedron: Asymm 2002), 13 (10), 1073-1081 (Non-Patent Document 3) and Tetrahedron: Asymmetry (2004), 15 (22), 3601-3608 (Non-Patent Document 4) are based on 2-bromo-6-fluoronaphthalene. One kind of pyrrole analgesic synthesized as a raw material has been reported and shown to have a remarkable effect on the treatment of chronic pain. Patent Document 2 and Patent Document 3 disclose a method of synthesizing a liquid crystal active component using 2-bromo-6-fluoronaphthalene, and the liquid crystal to which the component is added has high dispersibility and is easily crystallized. This indicates that this type of liquid crystal can greatly reduce the limiting voltage and at the same time has a very high response capability. 2-Bromo-6-fluoronaphthalene has a very large birefringence factor and the molecular polarity is very small, so it can be used for active matrix driven display.

経路２は、

そのうち、６‐ブロモ‐２‐ナフトールまたは１，６−ジブロモ−２−ナフトールのアンモノリシス化は共に高圧下で行うことが必要であり且つ収率が高くなく、ジアゾニウム塩の生成において非常に高価なヘキサフルオロリン酸を使用しているため、プロセスが複雑であるだけでなく、設備要求も高くて、且つ合成のコストも非常に高い。 According to the methods reported in the literature, the synthesis of 2-bromo-6-fluoronaphthalene has a total of five steps, has two synthetic routes,
Path 1 is

Path 2 is

Among them, the ammonolysis 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, and it is very expensive in the formation of diazonium salt. Since fluorophosphoric acid is used, not only the process is complicated, but also the equipment requirements are high and the cost of synthesis is very high.

  Journal of the American Chemistry, 1967, 89, 386-390 (Non-patent Document 5), J. Am. Org. Chem. , 1960, 25, 214-215 (Non-Patent Document 6) and Bioorg. Med. Chem. , 2005, 8, 1925-1930 (Non-Patent Document 7) reported a synthesis method using 6-bromo-2-naphthylamine as an initial raw material, and 6-bromo-2-naphthylamine was diazotized with nitrite in a hydrochloric acid medium. The reaction is performed, and then hexafluorophosphoric acid is added to form a diazonium salt of hexafluorophosphoric acid. The diazonium salt is sufficiently dried and then thermally decomposed to obtain the product 2-bromo-6-fluoronaphthalene. The rate is shown to be 55% to 65%.

  On the other hand, Patent Document 4 discloses a method for preparing 2-fluoronaphthalene. The method comprises (1) reacting 2-naphthol with p-toluenesulfonyl chloride (or p-toluenesulfonic acid) to produce p-toluenesulfonic acid-2-naphthyl; (2) (1) And p-toluenesulfonic acid-2-naphthyl obtained by reacting with an inorganic fluoride, a tertiary amine bidentate ligand and metallic copper in an aprotic high boiling point solvent, ,including. However, the invention requires that the reaction be performed at a high temperature, and the inorganic fluoride used under the reaction conditions is very severely corroded on the equipment, so the demand on the equipment is very severe. Also, the method employs a nucleophilic substitution reaction in the aromatic ring, and even when an active bromo substituent is present at the 6-site, substitution is likely to occur, so 2-bromo-6-fluoronaphthalene It cannot be applied to the synthesis of

European Patent Application No. 1809284 JP 2001-019649 A European Patent Application No. 952135 Chinese Patent Application No. 101563522

Bioorganic & medicinal Chemistry (2000), 8 (8), 1925-1930 Bioorganic & medicinal Chemistry (2005), 13 (9), 3117-3126 Tetrahedron: Asymmetry (2002), 13 (10), 1073-1081 Tetrahedron: Asymmetry (2004), 15 (22), 3601-3608 Journal of the American Chemistry, 1967, 89, 386-390 J. et al. Org. Chem. , 1960, 25, 214-215 Bioorg. Med. Chem. 2005, 8, 1925-1930.

  The object of the present invention is to provide a process for the preparation of 2-bromo-6-fluoronaphthalene. In this method, cheap tobias acid is used as an initial raw material, and the desired product 2-bromo-6-fluoronaphthalene is obtained by three steps of bromination-debromination, diazotization, and thermal decomposition. It is calm and easy to industrialize, the purity of the obtained product is high and the quality is stable.

The technical problem of the present invention is implemented by the following means.
A process for preparing 2-bromo-6-fluoronaphthalene, the process comprising:
(1) bromination of tobias acid in an acidic medium to obtain 1,6-dibromo-2-naphthylamine, adding a reducing metal powder, and heating reaction in an acidic medium to obtain 6-bromo-2-naphthylamine; ,
(2) The 6-bromo-2-naphthylamine obtained in step (1) is reacted with nitrous acid, nitrite or nitrite in an acidic medium to obtain a diazonium salt, and fluoroboric acid or a salt thereof, or fluorophosphoric acid or Adding the salt and reacting to obtain a diazonium fluoroborate or diazonium fluorophosphate salt of 6-bromo-2-naphthylamine;
(3) a step of thermally decomposing the diazonium fluoroborate or diazonium fluorophosphate obtained in step (2) to obtain 2-bromo-6-fluoronaphthalene;
including.

The synthetic route of the present invention is as follows.

  Tobias acid is an important intermediate widely used in the dye industry, and its raw materials are easily available and its price is very low. Tobias acid interacts with liquid bromine in an acetic acid medium, and the bromination reaction occurs at the 6-site at the same time as the 1-site sulfo group of the naphthyl ring is replaced by bromine. This reaction has not been published in any patents or academic papers and is a new discovery. The 1,6-dibromo-2-naphthylamine produced by bromination is not separated and reacts directly with the metal tin powder to give 6-bromo-2-naphthylamine, simplifying the operation and very ideal yield It is.

  Fluoroboric acid is a basic chemical raw material that is widely produced and applied in the country, and has the advantages of being inexpensive and easily available compared to hexafluorophosphoric acid. Therefore, the present invention uses a diazonium salt using fluoroboric acid. To prepare. Although the diazonium salt prepared using fluoroboric acid has a low yield in the following fission decomposition reaction, the price difference between fluoroboric acid and hexafluorophosphoric acid is very large. Still has some cost advantage.

  Preferably, the acidic medium in step (1) is phosphoric acid, sulfuric acid or a linear or branched saturated carboxylic acid containing 6 or less carbon atoms, and the mass concentration range of the various acids is 60%. -100%, preferably 80-100%. This concentration of acidic environment is advantageous for the reaction to take place.

  Preferably, the acidic medium in step (2) is phosphoric acid, sulfuric acid, hydrochloric acid or a linear or branched saturated carboxylic acid containing 6 or less carbon atoms, and the acid and 6-bromo-2-naphthylamine The molar ratio is 2 to 6: 1, preferably 2 to 3: 1. The diazotization reaction must be carried out in an acidic medium, and the molar ratio of acid to 6-bromo-2-naphthylamine should be a theoretical molar ratio of 2: 1 and should be overdose, but if it is overdose, the cost Leading to a rise.

  Preferably, the reducing metal powder in step (1) is reduced iron powder, metallic nickel powder, reduced zinc powder, metallic copper powder or metallic tin powder. The molar ratio range between the amount of the metal powder used and the dose of 6-bromo-2-naphthylamine is 0.5-3: 1, preferably 1-1.5: 1.

  Preferably, in step (1), the bromination reaction temperature is 50 to 100 ° C., preferably 60 to 80 ° C., and the debromination reaction temperature is 50 to 100 ° C., preferably 60 to 80 ° C. .

  Preferably, in step (2), the diazotization reaction temperature is −10 to 10 ° C., the preferred temperature range is −2 to 5 ° C., and the salt formation reaction temperature is 0 to 30 ° C., preferably 10 to 10 ° C. 20 ° C.

  Preferably, in the salt-forming reaction of step (2), the dose of fluoroboric acid or a salt thereof, or fluoric acid or a salt thereof is in the range of 1.5 to 3 times the molar dose of 6-bromo-2-naphthylamine (molar ratio). ), Preferably 1.5 to 2 times.

  Preferably, the thermal decomposition temperature of the diazonium salt in step (3) is 120 to 180 ° C, preferably 130 to 150 ° C. When the temperature is 130 ° C. or higher, the diazonium salt can be decomposed smoothly, and when the temperature is too high, the decomposition is too quick and the carbonization is likely to occur, so that the optimum temperature range is 130 to 150 ° C.

  Preferably, the thermal decomposition of the diazonium salt in step (3) is performed in an inert medium. More preferably, the deactivation medium is a linear or branched alkane of 12 to 20 carbon atoms, or an organosilicone oil having a boiling point within the range of 250 to 300 ° C. Thermal decomposition can be carried out very calmly in an inert medium.

  Preferably, after the 2-bromo-6-fluoronaphthalene obtained in step (3) is dissolved in an organic solvent and filtered, the resulting liquid is obtained pure by the method of vacuum distillation. Vacuum distillation can lower the distillation temperature.

  In summary, the method employed by the present invention has a synthesis process with only three steps, a simple route, no need for high pressure conditions, and the production of diazonium salts is inexpensive and readily available. It uses boric acid and has the basis for industrial production.

1 is a ¹ H-NMR spectrogram of 2-bromo-6-fluoronaphthalene prepared according to Example 1 of the present invention.

  The following are specific examples of the present invention. These examples can further supplement and explain the present invention, but the present invention is not limited to these examples.

Example 1
(1) Synthesis of 6-bromo-2-naphthylamine Into one 2000 ml Erlenmeyer flask equipped with a dropping funnel, thermometer, stirrer and reflux condenser, 1100 ml glacial acetic acid and 57.47 g (0.25 mol) Tobias Add acid, start agitation and heat to 70 ° C. to dissolve tobias acid. 80 g (0.5 mol) of liquid bromine is added dropwise via a dropping funnel, and the temperature of the reaction product is maintained between 70-72 ° C. during the dropping process, and the dropping is completed in about 1 hour. After completion of the dropwise addition, the temperature is raised to reflux, and the reaction is completed by stirring for 1.5 hours under reflux. After completion of the reaction, the temperature of the reaction mixture is lowered to 65 ° C., 29.8 g (0.251 mol) metal tin powder and 340 ml of 35% strength hydrochloric acid are added, and then the temperature of the reaction mixture is raised to reflux and under reflux. Stir for 2 hours. After completion of the reaction, glacial acetic acid is recovered by distillation under reduced pressure. Add 1250 ml hot methanol to the residue and stir until all solids are dissolved. The reaction is cooled to room temperature (about 20 ° C.) with stirring to precipitate white crystals. Vacuum filtration was performed, and the solid was washed with a small amount of methanol and vacuum filtered to obtain 38.3 g of white 6-bromo-2-naphthylamine. The yield was 67% and the HPLC analysis purity was 99.5%. It is.

(2) Synthesis of 6-bromo-2-naphthylamine fluoroboric acid diazonium salt A 2000 ml Erlenmeyer flask equipped with a dropping funnel, a thermometer and a stirrer was charged with 38.3 g of 6- 6 obtained in step (1). Bromo-2-naphthylamine (0.172 mol), 650 ml water and 94 ml concentrated hydrochloric acid (1.03 mol) are added, stirring is started, and 6-bromo-2-naphthylamine hydrochloride is completely dissolved and clear solution Heat until. Thereafter, the mixture is cooled to −5 ° C. in an ice salt bath, and at this time, white 6-bromo-2-naphthylamine hydrochloride is precipitated in the form of fine crystals. A solution consisting of 14.78 g nitrite (0.214 mol) and 100 ml water was added dropwise through a dropping funnel, and the reaction was carried out while maintaining the temperature of the reaction product at 0 ° C. or lower. 2-Naphthylamine hydrochloride crystals are gradually dissolved and finally formed into a yellow clear solution. The reaction end point is detected using potassium iodide-starch test paper. When the test paper is blue and does not fade within 30 seconds, the reaction end point is reached. After the completion of the dropwise addition, the mixture was stirred for 30 minutes at 0 ° C. or less, and then 57 ml of a commercially available 40% fluoroboric acid solution was added dropwise through a dropping funnel with vigorous stirring. A large amount of white solid was immediately formed in the dropping process. The After completion of the dropwise addition, the mixture was stirred for 30 minutes to make the crystals sufficiently, filtered under reduced pressure using a Buchner funnel, the resulting solid was washed with 195 ml ethanol, filtered again under reduced pressure, and the filter cake was filtered with 195 ml ethanol. Washing is followed by vacuum filtration, and the resulting solid is dried under vacuum for 24 hours to give 43.06 g 6-bromo-2-naphthylamine fluoroboric acid diazonium salt (78% yield).

(3) Synthesis of 2-bromo-6-fluoronaphthalene One 250 ml Erlenmeyer flask with an off-gas absorption device attached to the reflux condenser tube and the top end of the condenser tube was heated to 135 ° C. in an oil bath. The diazonium salt obtained in 2) is added. After the addition, the diazonium salt immediately dissolves and decomposes, and boron trifluoride gas is started up to produce a pale yellow oily liquid in the flask. When the starting gas was almost exhausted, the remaining diazonium salt was added in several portions, and 43.06 g 6-bromo-2-naphthylamine fluoroboric acid diazonium salt was added in four portions in total. Stir for 30 minutes following the last single addition. Cool the reaction to room temperature, add 136 ml of 60-90 ° C. petroleum ether and 136 ml of toluene, stir for 5 minutes, and filter using a Buchner funnel filled with a small amount of silica gel to obtain a nearly colorless solution. . Petroleum ether and toluene are recovered from the solution under reduced pressure, and the residue is distilled under reduced pressure at 5 mmHg pressure, receiving a fraction at 130-135 ° C. After the distillate solidifies, 17 g of a white 2-bromo-6-fluoronaphthalene solid is obtained, the yield is 56.4% and the product purity is 99.6% as measured by HPLC. The ¹ H-NMR spectrogram of bromo-6-fluoronaphthalene is shown in FIG.

Example 2
This was performed based on the same method as in Example 1, and the difference was that the thermal decomposition of the diazonium salt in step (3) was performed on an organosilicone oil having a boiling point in the range of 250 to 300 ° C. The product yield was 56.9% and the HPLC purity was 99.5%.

Example 3
This was carried out based on the same method as in Example 1, and the difference was that the thermal decomposition of the diazonium salt in step (3) was carried out in liquid paraffin (C16-C20 n-alkane), and the resulting product The yield was 58.4% and the HPLC measurement purity was 99.7%.

Example 4
The same method as in Example 1 was performed. The difference was that the thermal decomposition of the diazonium salt in step (3) was performed while the temperature was controlled within the range of 130 to 150 ° C., and the atmospheric distillation method was used. The yield of the obtained product was 49.8%, and the HPLC measurement purity was 99.0%.

Example 5
The same procedure as in Example 1 was carried out except that in step (2) 34.75 g of fluoroboric acid having a mass concentration of 50% was added and the moles of fluoroboric acid and 6-bromo-2-naphthylamine were added. The ratio is 1: 1.5. The yield of the finally obtained product was 52.6%, and the HPLC measurement purity was 99.5%.

Example 6
The same procedure as in Example 1 was carried out except that in step (2), 69.5 g of fluoroboric acid having a mass concentration of 50% was added and the moles of fluoroboric acid and 6-bromo-2-naphthylamine were changed. The ratio is 1: 3. The yield of the finally obtained product was 55.4%, and the HPLC measurement purity was 99.0%.

Example 6
This is performed based on the same method as in Example 1, except that the temperature of the diazotization reaction is controlled in the range of −2 to 5 ° C. and the temperature of the salt formation reaction is controlled to about 25 ° C. in Step (2). This is the point. The yield of the finally obtained product was 52.7%, and the HPLC measurement purity was 99.8%.

Example 7
It is performed based on the same method as in Example 1, except that the metal tin powder in step (2) is changed to reduced iron powder, and the molar ratio of reduced iron powder and 6-bromo-2-naphthylamine is 1: 1. It is a point. The yield of the finally obtained product was 56.8%, and the HPLC measurement purity was 99.8%.

Example 8
It is performed based on the same method as in Example 1, except that the metal tin powder in step (2) is changed to metal copper powder, and the molar ratio of the metal copper powder to 6-bromo-2-naphthylamine is 1.5. : 1. The yield of the product finally obtained was 59.1%, and the HPLC measurement purity was 99.8%.

Example 9
The same procedure as in Example 1 was performed, except that the fluoroboric acid in step (2) was changed to fluorophosphoric acid, and the molar amount of fluorophosphoric acid was twice that of 6-bromo-2-naphthylamine. The obtained diazonium fluorophosphate salt was thermally decomposed in step (3) to obtain the final product. The yield was 57.8% and the HPLC measurement purity was 98.9%.

Example 10
The same procedure as in Example 1 was performed except that the fluoroboric acid in step (2) was changed to sodium fluoroborate, and the molar amount of sodium fluoroborate was three times that of 6-bromo-2-naphthylamine. It is. The yield of the finally obtained product was 51.8%, and the HPLC measurement purity was 99.1%.

Example 11
The difference was that the glacial acetic acid in step (1) was changed to 1100 ml of a 60% mass concentration phosphoric acid solution. The yield of the finally obtained product was 53.1%, and the HPLC measurement purity was 99.3%.

Example 12
The difference was that the glacial acetic acid in step (1) was changed to 1100 ml of propionic acid solution, based on the same method as in Example 1. The yield of the finally obtained product was 53.5%, and the HPLC measurement purity was 99.4%.

Example 13
The difference was that the concentrated hydrochloric acid in step (2) was changed to 54.25 ml of commercial concentrated sulfuric acid having a mass concentration of 98%. The yield of the product finally obtained was 58.9%, and the HPLC measurement purity was 99.6%.

Example 14
It is performed based on the same method as in Example 1, except that the metal tin powder in step (2) is changed to metal nickel powder, and the molar ratio of metal nickel powder and 6-bromo-2-naphthylamine is 0.5. : 1. The yield of the finally obtained product was 50.6%, and the HPLC measurement purity was 98.8%.

Example 15
It is performed based on the same method as in Example 1 except that the metal tin powder in step (2) is changed to reduced zinc powder, and the molar ratio of reduced zinc powder to 6-bromo-2-naphthylamine is 3: 1. It is a point. The yield of the finally obtained product was 52.1%, and the HPLC measurement purity was 98.9%.

  Further, the metal tin powder in step (2) may be any one other metal powder having reducibility, and the molar amount of the metal powder used and the amount of 6-bromo-2-naphthylamine used. The ratio range is 0.5-3: 1, preferably 1-1.5: 1.

  The specific embodiments described in the present invention are only described by way of example with respect to the gist of the present invention. Those skilled in the art of the present invention may make various modifications or supplements to the specific embodiments described or replace them by adopting similar methods, but are defined in the spirit of the invention or in the claims. Cannot be exceeded. Although the present invention has been described in detail and some specific examples have been given, it will be appreciated by those skilled in the art that various changes or modifications can be made without departing from the spirit and scope of the present invention. it is obvious.

Claims (10)

A process for preparing 2-bromo-6-fluoronaphthalene, the process comprising:
(1) bromination of tobias acid in an acidic medium to obtain 1,6-dibromo-2-naphthylamine, adding a reducing metal powder, and heating reaction in an acidic medium to obtain 6-bromo-2-naphthylamine; ,
(2) The 6-bromo-2-naphthylamine obtained in step (1) is reacted with nitrous acid, nitrite or nitrite in an acidic medium to obtain a diazonium salt, and fluoroboric acid or a salt thereof, or fluorophosphoric acid or Adding the salt and reacting to obtain a diazonium fluoroborate or diazonium fluorophosphate salt of 6-bromo-2-naphthylamine;
(3) a step of thermally decomposing the diazonium fluoroborate or diazonium fluorophosphate obtained in step (2) to obtain 2-bromo-6-fluoronaphthalene;
A process for preparing 2-bromo-6-fluoronaphthalene.   The process according to claim 1, characterized in that the acidic medium in step (1) is phosphoric acid, sulfuric acid or a linear or branched saturated carboxylic acid containing up to 6 carbon atoms.   The process according to claim 1, characterized in that the acidic medium in step (2) is phosphoric acid, sulfuric acid, hydrochloric acid or a linear or branched saturated carboxylic acid containing up to 6 carbon atoms.   The method according to claim 1, wherein the reducing metal powder in 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 step (1), the bromination reaction temperature is 50 to 100 ° C, and the debromination reaction temperature is 50 to 100 ° C.   The method according to claim 1, wherein in step (2), the temperature of the diazotization reaction is -10 to 10 ° C, and the temperature of the salt formation reaction is 0 to 30 ° C.   In the salt-forming reaction of step (2), the molar ratio of fluoroboric acid or a salt thereof, or fluorophosphoric acid or a salt thereof and 6-bromo-2-naphthylamine is 1: 1.5-3. The method of claim 1.   The method according to claim 1, wherein the thermal decomposition temperature of the diazonium salt in step (3) is 120 to 180 ° C.   The method according to any one of claims 1 to 8, characterized in that the thermal decomposition of the diazonium salt in step (3) is carried out in an inert medium.   10. The inactivation medium is a linear or branched alkane containing 12 to 20 carbon atoms, or an organosilicone oil having a boiling point in the range of 250 to 300 ° C. The method described.

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