KR101363583B1 - Process for preparing 2-bromo-6-fluoronaphthalene - Google Patents

Abstract

The present invention relates to a method for producing a kind of 2-bromo-6-fluornaphthalene, in which the raw material is tobias acid, and the product undergoes bromination-bromination, diazotization, pyrolysis, and fish in this manner. This method is suitable for industrial production, since the prepared product is of high purity and stable in quality, and also has a simple route, mild reaction conditions, and no high pressure.

Description

Process for preparing 2-bromo-6-fluornaphthalene {PROCESS FOR PREPARING 2-BROMO-6-FLUORONAPHTHALENE}

TECHNICAL FIELD The present invention relates to the field of pharmaceutical technology, and more particularly, to a process for preparing a kind of 2-bromo-6-fluornaphthalene.

2-bromo-6-fluornaphthalene is an intermediate of nicotinic acid receptor drugs, and as reported in EP1809284, these drugs can be used for lipid dysplasia in patients with nephropathy, and can lower plasma low density lipoprotein LDL, VLDL, while High density lipoprotein HDL can be increased. 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 type of pyrrole-type analgesic that synthesizes 2-bromo-6-fluornaphthalene as a base material, which has a significant effect on the treatment of chronic pain. JP 2001019649 and EP 952135 (Al) reported a method for synthesizing the active component of liquid crystal using 2-bromo-6-fluornaphthalene. The liquid crystal added with this component has high dispersibility and crystallinity. It is easy. Also, such liquid crystals can drastically lower the limit voltage. 2-Bromo-6-fluornaphthalene not only has a birefringence factor but also a small polarity of the molecule, so that it can be used for the source matrix drive display.

In the method reported in the literature, the synthesis of 2-bromo-6-fluornaphthalene has five stages and two kinds of synthetic roots. Route 1 is shown below.

Route 2 is shown below.

Among them, the ammonolysis of 6-bromo-2-naphthol or 1,6-dibromo-2-naphthol proceeds at high pressure, and the yield is not so high, and the production of diazonium salt is very expensive. Because of the use of hexafluorophosphoric acid, the process is complicated and the demands on the equipment are high, thus the synthesis cost is 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 'reported a synthesis method using 6-bromo-2-naphthylamine as a raw material. That is, 6-bromo-2-naphthylamine is subjected to a diazotization reaction with sodium nitrite in hydrochloric acid medium, and then hexafluorophosphoric acid is added to form hexafluorophosphate and hexaluorophosphote diazonium salts. After the diazonium salt is completely dried, pyrolysis is performed to produce 2-bromo-6-fluornaphthalene. Yield is 55% to 65%.

Chinese patent CN101565352A discloses a method for producing a kind of 2-fluornaphthalene. This method is as follows. (1) 2-naphthol reacts with P-toluene sulfonyl chloride (or P-toluene sulphonic acid) to produce phytoluene sulfonic acid-2-naphthyl ester. (2) proceeds the reaction of the phytoluene sulfonic acid-2-naphthyl ester produced in (1) together with an inorganic fluoride under a tertiary amine bidentate ligand and a metal copper catalyst in a solvent having a high aprotic boiling point. In the present invention, since the reaction proceeds at a high temperature, and the inorganic fluoride used in the reaction conditions has a very strong corrosion on the equipment, the demand for the equipment is very high. In addition, since the above method causes nucleophilic substitution of the aromatic ring and replacement is easy when the active bromo substituent is present at the 6-site, the synthesis of 2-bromo-6-fluornaphthalene is difficult to apply.

The present invention is to solve the above-mentioned problems, to provide a method for producing a kind of 2-bromo-6- fluornaphthalene, inexpensive tobias acid as a starting material, brominated-bromine number (Debromination), dia Its purpose is to produce 2-bromo-6-fluornaphthalene through three steps such as roughening and pyrolysis. The method of the present invention also has a short synthetic route, mild conditions and easy production of industrialization. The product is not only high purity but also stable in quality.

In order to achieve the above object, a method of preparing 2-bromo-6-fluornaphthalene of the present invention includes the following steps.

(1) Tobias acid is brominated in an acid medium to produce 1,6-dibromo-2-naphthylamine, and a reducing metal powder is added, followed by heating reaction in an acidic medium to 6-bromo 2-naphthylamine is produced.

(2) reacting the 6-bromo-2-naphthylamine of step (1) with nitrous acid, nitrite ester or nitrite in an acidic medium to form a diazonium salt, and then adding fluoroboric acid or fluoroborate or adding fluorophosphoric acid or Fluorophosphate is further reacted to produce a fluoroboric acid diazonium salt (diazonium tetrafluoroborate) or fluorophosphoric diazonium salt of 6-bromo-2-naphthylamine.

(3) Pyrolysis is performed on the fluoroboric acid diazonium salt or the fluorophosphoric diazonium salt produced in step (2) to produce 2-bromo-6-fluornaphthalene.

Synthetic root of the present invention is as follows.

Tobias acid is an important intermediate that is widely used in the dyeing industry, and raw materials are readily available and very inexpensive. Tobias acid reacts with liquid bromine in acetic acid medium, and the sulfo group is replaced by bromine at the naphthalene 1-site, and simultaneously bromination occurs at the 6-site. This reaction is a new discovery since it has never been published in a patent or academic paper. Brominated 1,6-dibromo-2-naphthylamine is not isolated and is reacted directly with the metal tin powder to produce 6-bromo-2-naphthylamine. This not only simplifies the task but also yields very satisfactory yields.

Fluoroboric acid is a chemical industry raw material widely produced and applied in China. Compared with hexafluorophosphoric acid, this has the advantage of being cheap and easy to obtain. The present invention therefore uses fluoroboric acid to produce diazonium salts. Although diazonium salts made with fluoroboric acid have relatively low yields in subsequent cracking reactions, fluoroboric acid is less expensive than hexafluorophosphoric acid, so the method using fluoroboric acid is still cost effective. Holds.

Preferably, the acidic medium of step (1) is phosphoric acid, sulfuric acid or straight chain or branched chain saturated organic acids containing up to 6 carbon atoms. The concentration range of the various acids is 60% to 100%, and the preferred range is 80% to 100%. This acidic environment is advantageous for the progress of the reaction.

Preferably, the acidic medium of step (2) is phosphoric acid, sulfuric acid, hydrochloric acid or a straight chain or branched chain saturated organic acid containing up to 6 carbon atoms. The molar ratio of the acid and 6-bromo-2-naphthylamine is 2-6: 1, preferably 2-3: 1. The diazotization reaction must proceed in an acidic medium, and the ratio of the molar ratio of acid to 6-bromo-2-naphthylamine and the theoretical molar ratio is 2: 1. In practice, the amount of theoretical molar ratio must be exceeded, but too much increases the cost.

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

Preferably, the temperature of the bromination reaction in step (1) is 50 to 100 ° C. The most preferable temperature is 60-80 degreeC. In addition, the bromine number reduction (Debromination) temperature is 50 to 100 ℃, the most preferred temperature is 60 to 80 ℃.

Preferably, the temperature of the diazotization reaction in step (2) is -10 to 10 ° C. The most preferable temperature is -2-5 degreeC. In addition, the reaction temperature at which the salt is produced is 0 to 30 ℃, the most preferred temperature is 10 to 20 ℃.

Preferably, in the reaction in which the salt of step (2) is produced, fluoroboric acid or fluoroborate or fluorophosphoric acid or fluorophosphate is 1.5 to 3 times (molar ratio) of 6-bromo-2-naphthylamine. The most preferred range is 1.5 to 2 times.

Preferably, the pyrolysis temperature of the diazonium salt in step (3) is 120 to 180 ° C. Most preferably, it is 130-150 degreeC. Diazonium salt can be decomposed smoothly only at a temperature of 130 ° C. or higher. If the temperature is too high, decomposition is too fast and carbonization is easily generated. The most suitable temperature is therefore 130 to 150 ° C.

Preferably, the pyrolysis of the diazonium salt of step (3) is carried out in inertia media. More preferably, the inert medium is a straight chain or branched chain alkane of 12 to 20 carbon atoms, or an organic silicone oil having a boiling point of 250 to 300 ° C. This can proceed pyrolysis very stably in an inert medium.

Preferably, 2-bromo-6-fluornaphthalene produced in step (3) is subjected to filtration with a solvent in an organic solvent, and then the resulting liquid is purely finished by vacuum distillation. Vacuum distillation can lower the distillation temperature.

As described above, the process of the present invention has three stages of synthesis, a simple route, no high pressure conditions, and inexpensive fluoroboric acid to produce diazonium salts. Suitable for

1 is a 1H-NMR spectrum diagram of 2-bromo-6-fluornaphthalene prepared in Example 1 of the present invention.

Hereinafter, the embodiments will be described in more detail with reference to the accompanying drawings. The invention is not limited to the following examples.

Example 1

(1) Synthesis of 6-bromo-2-naphthylamine

To a 2000 ml 3-neck boiling flask-3-neck equipped with a dropping pan, thermometer, agitator and countercurrent condensation tube, 1100 ml of ice acetic acid and 57.47 g (0.25 mol) of tobias acid were added and stirred, At the same time, heating to 70 ℃ to dissolve tobias acid. 80 g (0.5 mol) of liquid bromine is added drop by drop through the dropping filter, and the temperature of the reactant is maintained at 70-72 ° C. during the dropping process, and the dropwise addition is approximately 1 hour. After completion of the dropwise addition, the temperature was raised to reflux and further stirred for 1.5 hours in a countercurrent state to proceed with the complete reaction. After the reaction was completed, the temperature of the reaction mixture was lowered to 65 ° C., 29.8 g (0.251 mol) of metal tin powder and 340 ml of hydrochloric acid having a mass concentration of 35% were added, and then the temperature of the reaction mixture was raised to reflux. Stir for 2 hours at reflux. After the reaction is completed, ice acetic acid is recovered by distillation under reduced pressure. 1250 ml of hot methyl alcohol is added to the residue and stirred until all solids are dissolved. The reaction is cooled to room temperature (about 20 ° C.) under stirring to precipitate white crystals. Suction filtration, the solids are washed with a small amount of methyl alcohol and dried to yield 38.3 g of white 6-bromo-2-naphthylamine solid. The yield is 67% and the purity in HPLC analysis is 99.5%.

(2) Synthesis of 6-bromo-2-naphthylamine fluoroboric acid diazonium salt

38.3 g of 6-bromo-2-naphthylamine (0.172 mol) produced in step (1) was added to a 2000 ml 3-neck boiling flask-3-neck equipped with a dropping pan, a thermometer and a stirring device. , 650 ml of water and 94 ml of concentrated hydrochloric acid (1.03 mol) are added and heated until stirring to completely dissolve 6-bromo-2-naphthylamine hydrochloride to form a clear and clear solution. After cooling to -5 ° C in an ice salt bath, white 6-bromo-2-naphthylamine hydrochloride precipitates as fine crystals. Dropwise add dropwise a solution of 14.78 g of sodium nitrite (0.214 mol) and 100 ml of water. During the dropping process, the temperature of the reactant should be maintained at 0 ° C or below. In addition, the crystals of 6-bromo-2-naphthylamine hydrochloride are gradually dissolved, and finally a yellow transparent solution is formed. The reaction end point is detected by a potassium iodide-starch test paper, and the reaction end point can be said only when the test paper shows indigo blue and does not fade within 30 seconds. After completion of the dropwise addition, the mixture was stirred for 30 minutes at 0 ° C. or less, and thereafter, 57 ml of 40% of a commercial fluoroboric acid solution was added dropwise through vigorous stirring, and a large amount of white solid was produced during the dropwise addition. After completion of the dropping, stirring is continued for 30 minutes to allow the crystals to dissolve completely, and filtered under reduced pressure using a Buchner funnel. The resulting solid was washed with 195 ml of ethyl alcohol, again filtered under reduced pressure, and the filter cake was washed with 195 ml of ethyl ether. After filtration under reduced pressure, the resulting solid was dried under vacuum for 24 hours, yielding 43.06 g of 6-bromo-2-naphthylamine fluoroboric acid diazonium salt (yield 78%).

(3) Synthesis of 2-bromo-6-fluornaphthalene

A 250 ml 3-neck boiling flask-3-neck equipped with an exhaust gas absorber at the end of the counter-current condensation tube and the counter-current condensation tube was heated up to 135 ° C. in an oil bath. 10 g of diazonium salt produced at is added, and the diazonium salt after the addition decomposes immediately, simultaneously producing a gas of boron trifluoride, and a light yellow oil liquid appears in the heating flask. When no bubbles appear, the remaining diazonium salts are added dropwise, followed by 4 times, and a total of 43.06 g of 6-bromo-2-naphthylamine fluoroboric acid diazonium salt is added. Stirring is continued for 30 minutes after the last addition is complete. The reaction was cooled to room temperature, stirred for 5 minutes by the addition of 136 ml of 60-90 ° C. petroleum ether and 136 ml of methylbenzene, filtered using a Buchner funnel containing a small amount of silica gel and almost colorless. Generate a phosphorus solution. The solution recovers petroleum ether and methylbenzene under reduced pressure, and the residue is distilled under reduced pressure under a pressure of 5 mmHg, and receives a fraction of 130 to 135 ° C. The distillate cooled and produced 17 g of white 2-bromo-6-fluornaphthalene solid. The yield is 56.4%, the purity of the product is 99.6% by HPLC detection, Figure 1 is a 1H-NMR spectral diagram of 2-bromo-6- fluornaphthalene.

Example 2

Proceed in the same manner as in Example 1, the dissimilar part is thermal decomposition of the diazonium salt in step (3) is carried out in organic silicone oil having a boiling point of 250 to 300 ℃, the yield of the resulting product is 56.9%, HPLC detection The purity of is 99.5%.

Example 3

Proceed in the same manner as in Example 1, the dissimilar part is pyrolysis of the diazonium salt in step (3) is carried out in a fluidized paraffin (C16-C20 normal paraffin), the yield of the resulting product is 58.4%, HPLC detection The purity of is 99.7%.

Example 4

Proceed in the same manner as in Example 1, the part not equal to the pyrolysis of the diazonium salt in step (3) to control the temperature to 130 to 150 ℃, using the method of atmospheric distillation, the yield of the resulting product is 49.8% The purity of the HPLC detection was 99.0%.

Example 5

Proceed in the same manner as in Example 1, the unequal part is added in step (2) a fluoroboric acid having a mass concentration of 34.75 g of 50%, and the molar ratio of fluoroboric acid and 6-bromo-2-naphthylamine is 1: 1.5. The yield of the last product produced is 52.6%, the purity of HPLC detection is 99.5%.

Example 6

Proceed in the same manner as in Example 1, the unequal part was added in step (2) with a fluoroboric acid having a mass concentration of 50% of 69.5 g, and the molar ratio of fluoroboric acid and 6-bromo-2-naphthylamine was 1: 3. The yield of the last product produced is 55.4%, the purity of HPLC detection is 99.0%.

Example 7

Proceed in the same manner as in Example 1, the parts not the same control the temperature of the diazotization reaction to -2 to 5 ℃ in step (2), the temperature of the chemical reaction (chemical reaction) is controlled to about 25 ℃. The yield of the last product produced is 52.7%, the purity of HPLC detection is 99.8%.

Example 8

Proceed in the same manner as in Example 1, the parts not the same replace the metal tin powder of step (2) with reduced iron powder, the molar ratio of reduced iron powder and 6-bromo-2-naphthylamine is 1: 1. The yield of the last product produced is 56.8%, the purity of HPLC detection is 99.8%.

Example 9

Proceed in the same manner as in Example 1, where the unequal part replaces the metal tin powder of step (2) with metal copper powder, and the molar ratio of metal copper powder and 6-bromo-2-naphthylamine is 1.5: 1. . The yield of the last product produced is 59.1% and the purity of the HPLC test is 99.8%.

Example 10

Proceed in the same manner as in Example 1, wherein the unequal part replaces fluoroboric acid in step (2) with fluorophosphoric acid, and the molar amount of fluorophosphoric acid is twice that of 6-bromo-2-naphthylamine, and the resulting fluorine The diazonium phosphate salt is pyrolyzed in step (3) to produce a product. The yield is 57.8%, the purity of HPLC detection is 98.9%.

Example 11

Proceed in the same manner as in Example 1, the part not the same is replaced with sodium fluoroborate in step (2), the molar amount of sodium fluoride is 6-bromo-2-naphthylamine 3 times The yield of the last product produced is 51.8%, the purity of HPLC detection is 99.1%.

Example 12

Proceed in the same manner as in Example 1, and replace the ice acetic acid in step (1) with a phosphoric acid solution having a mass concentration of 60% of 1100 ml. Finally, the number of products produced was 53.1%, and the purity of HPLC detection was 99.3%.

Example 13

Proceed in the same manner as in Example 1, replace the ice acetic acid in step (1) with 1100 ml of propionic acid solution. The yield of the last product produced is 53.5%, the purity of HPLC detection is 99.4%.

Example 14

Proceed in the same manner as in Example 1, and replace the non-identical portion of concentrated hydrochloric acid in step (2) with commercial concentrated sulfuric acid having a mass concentration of 54.25 ml of 98%. The yield of the last product produced is 58.9%, the purity of HPLC detection is 99.6%.

Example 15

Proceed in the same manner as in Example 1, where the unequal part replaces the metal tin powder of step (2) with the metal nickel powder, and the molar ratio of the metal nickel powder and 6-bromo-2-naphthylamine is 0.5: 1. . The yield of the last product produced is 50.6%, the purity of HPLC detection is 98.8%.

Example 16

Proceed in the same manner as in Example 1, the parts not equal to the metal tin powder of step (2) is reduced to zinc powder, the molar ratio of the reduced zinc powder and 6-bromo-2-naphthylamine is 3: 1 . The yield of the last product produced is 52.1%, the purity of HPLC detection is 98.9%.

In addition, the metal tin powder of step (2) may be another kind of metal powder having reducibility, and the molar ratio of the amount of the metal powder to the amount of 6-bromo-2-naphthylamine is 0.5-3: 1. , Preferably 1-1.5: 1.

The present invention is not limited to the above-described embodiments, and various modifications and improvements related to the present invention are all within the scope of protection, unless the present invention is departed from the spirit and scope of the present invention.

Claims (10)

In the method for producing 2-bromo-6-fluornaphthalene,
(1) Tobias acid is brominated in an acid medium to produce 1,6-dibromo-2-naphthylamine, and a reducing metal powder is added, followed by heating reaction in the acid medium to 6-bromine. Generating mo-2-naphthylamine;
(2) reacting the 6-bromo-2-naphthylamine of step (1) with nitrous acid, nitrite ester or nitrite in the acidic medium to form a diazonium salt, and then adding fluoroboric acid or fluoroborate Fluorophosphoric acid or fluorophosphate is added to react to produce the fluoroboric acid diazonium salt (diazonium tetrafluoroborate) or fluorophosphoric diazonium salt of 6-bromo-2-naphthylamine. step;
(3) thermally decomposing the fluoroboric acid diazonium salt or the fluorophosphoric diazonium salt produced in step (2) to produce 2-bromo-6-fluoronaphthalene; The method for producing 2-bromo-6-fluornaphthalene.
The method of claim 1,
The acid medium of step (1) is a method for producing 2-bromo-6-fluornaphthalene, characterized in that the phosphoric acid, sulfuric acid or a straight chain or branched chain saturated organic acid containing up to 6 carbon atoms.
The method of claim 1,
Wherein said acidic medium of step (2) is phosphoric acid, sulfuric acid, hydrochloric acid or a straight chain or branched chain saturated organic acid containing up to 6 carbon atoms.
The method of claim 1,
The method of producing 2-bromo-6-fluornaphthalene, characterized in that the reducing metal powder of step (1) is reduced iron powder, metal nickel powder, reduced zinc powder, metal copper powder or metal tin powder.
The method of claim 1,
The temperature of the bromination reaction in the step (1) is 50 to 100 ℃, the temperature of the bromine number reduction (Debromination) is a method for producing 2-bromo-6- fluornaphthalene, characterized in that 50 to 100 ℃.
The method of claim 1,
In the step (2), the temperature of the diazotization reaction is -10 to 10 ℃, the reaction temperature for producing the salt is a method for producing 2-bromo-6- fluornaphthalene, characterized in that 0 to 30 ℃. .
The method of claim 1,
In the reaction in which the salt of step (2) is produced, the molar ratio of the fluoroboric acid or the fluoroborate or the fluorophosphoric acid or the fluorophosphate to the 6-bromo-2-naphthylamine is 1: 1.5-3 Method for producing 2-bromo-6-fluornaphthalene, characterized in that.
The method of claim 1,
The pyrolysis temperature of the diazonium salt in the step (3) is a method for producing 2-bromo-6- fluornaphthalene, characterized in that 120 to 180 ℃.
9. The method according to any one of claims 1 to 8,
The pyrolysis of the diazonium salt of step (3) is carried out in an inertia media (inertia media), characterized in that the production of 2-bromo-6- fluornaphthalene.
The method of claim 9,
The inert medium is a straight chain of 12 to 20 carbon atoms or branched chain alkanes, or a process for producing 2-bromo-6- fluornaphthalene, characterized in that the boiling point of 250 to 300 ℃ organic silicone oil.

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